C Afferent Axons/Fibers C and a Fibers Cachexia CACNA1A Calbindin

Home , Baths (musician), Neurolytic block

nated, polymodal C-fibers are activated by a variety C Afferent Axons/Fibers of high-intensity mechanical, chemical, hot and cold stimuli. In addition, low threshold fibers (Aβ) that nor- Synonyms mally only transfer innocuous sensations like touch, can CFibers contribute to neuropathic pain following nerve damage. Opioids in the Periphery and Analgesia Definition One kind of fiber in the peripheral nerve; unmyelinated thin fibers. These high-threshold sensory afferents conduct very slowly (less than 2 m/s), and are thought to be Cachexia responsible for the sensation of deep, burning pain that follows ’first pain’ after injury. Although C fibers ma- Definition β ture earlier than low-threshold A fibers, anatomically General ill health and malnutrition that presents as mus- and neurochemically, other aspects of their function are cle wasting, dehydration and reduced behavioral activ- delayed, for example, the phenomenon of neurogenic ities in untreated diabetic animals. edema, and the development of functional central con- NeuropathicPainModel,DiabeticNeuropathyModel nections within the spinal cord. AFibers(A-Fibers) Alpha(α) 2-Adrenergic Agonists in Pain Treatment Infant Pain Mechanisms CACNA1A Insular Cortex, Neurophysiology and Functional Imaging of Nociceptive Processing Magnetoencephalography in Assessment of Pain in Definition Humans α CACNA1A is a gene encoding the 1A subunit of a Morphology, IntraspinalOrganizationofVisceralAf- voltage sensitive calcium channel abundantly expressed ferents in neuronal tissue. It is activated by high voltage and Nociceptor, Categorization gives rise to P/Q-type calcium currents. Mutations in Nociceptors in the Orofacial Region (Temporo- the human gene are related to diseases like spinocere- mandibular Joint and Masseter Muscle) bellar ataxia type 6, familial hemiplegic migraine and Nociceptor(s) episodic ataxia type 2. In mice, mutations in the or- Opiates During Development thologous gene are responsible for the “leaner” and Spinothalamic Tract Neurons, in Deep Dorsal Horn “tottering” phenotypes. Thalamus, Dynamics of Nociception Calcitonin Gene-Related Peptide and Migraine Vagal Input and Descending Modulation Headaches

C and A Fibers Calbindin Definition Definition Nociceptive input is conveyed from the peripheral terminals to the spinal cord, predominantly by two Vitamin D-dependent calcium-binding protein that is classes of primary afferent fibers. Of these, the slowly- present in specific sensory neuronal cell types. conducting, thinly-myelinated Aδ-fibers mediate ther- Spinothalamic Terminations, Core and Matrix mal and mechanical nociception, whereas the unmyeli- Thalamus,ReceptiveFields,ProjectedFields,Human 188 Calbindin D–28k

proteins from the blood stream pass into the surround- Calbindin D–28k ing tissue. Release of CGRP from the central terminals of DRG neurons modulates spinal cord neurons, in part Deﬁnition by enhancing the actions of substance P. It also plays a A member of the EF-hand family calcium binding pro- role in pain processing. teins, which buffer intracellular calcium concentration Alternative Medicine in Neuropathic Pain and mediate a variety of cellular functions. Calbindin Calcitonin Gene-Related Peptide and Migraine D–28k has six EF-hand domains, but only four of them Headaches bind to calcium. Calbindin D–28k has been used as Clinical Migraine without Aura a marker of nerve cells in neuroanatomical studies, Immunocytochemistry of Nociceptors since it selectively distributes in subpopulations of Migraine, Pathophysiology central nervous system neurons in speciﬁc regions. Neuropeptide Release in the Skin In the monkey thalamus, calbindin D–28k antibodies Nociceptor, Categorization selectively label the matrix domain of the medial ven- Nociceptors in the Orofacial Region (Meningeal/ troposterior nucleus of the thalamus, which is related Cerebrovascular) to trigeminothalamic projection from the caudal spinal Opioids in the Periphery and Analgesia trigeminal nucleus subnucleus caudalis. Opioid Modulation of Nociceptive Afferents In Vivo Trigeminothalamic Tract Projections Spinal Cord Nociception, Neurotrophins Thalamus, Visceral Representation

Calbindin-Immunoreceptive Matrix Cells Calcitonin Gene-Related Peptide and Deﬁnition Migraine Headaches

Sensory neurons that stain positively for the presence of KIRSTEN ARNDT,STEFAN JUST,HENRI DOODS vitamin D-dependent calcium-binding protein. CNS Pharmacology, Pain Research, Boehringer Thalamic Nuclei Involved in Pain, Human and Mon- Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, key Germany [email protected]

Calcitonin Gene-Related Peptide Synonym CGRP Synonyms CGRP Definition Migraineisacomplex,multi-symptomdiseaseaffect- Definition ing 10–16% of the western population. It has a higher CGRP is a 37-amino acid peptide that is produced by prevalence in women than in men. Migraine character- tissue-specific processing of the calcitonin gene. It istics are its episodic appearance and symptoms such belongs to the Calcitonin/CGRP family which includes as unilateral headache, phono- and/or photo-phobia, other peptides like calcitonin, amylin, adrenomedullin facial mechanical allodynia and nausea and vomit- and intermedin. CGRP is comprised of at least two ing (Headache Classification Subcommittee of the forms: αCGRP and βCGRP. Whereas αCGRP is found International Headache Society 2004). Preceding the in DRG neurons of all sizes, βCGRP is localized to headache, 20–30% of the patients experience focal neu- small- and medium-sized neurons. CGRP functions rological symptoms termed aura. Based on the presence primarily as a neuromodulator and signals via a het- or absence of an aura, migraines are classified as either erodimeric receptor complex consisting of a G-protein “classical” migraine (migraine with aura), or “com- coupled receptor (calcitonin-like receptor) and a recep- mon” migraine (migraine without aura). Generally, a tor activity modifying protein (RAMP1) and stimulates migraine attack can be subdivided into different phases cAMP formation intracellularly. Release of CGRP from that include the premonitory phase, headache and the the peripheral terminals of DRG neurons contributes to postdrome. The prevalence of the different symptoms neurogenic inflammation. During this process, CGRP varies over the phases with e.g. being tired and weary is the most potent vasodilator in the microcirculation as approximately equally prominent in all phases and identified so far and acts by relaxing small arteries “stiff neck” being most prevalent in the headache and and arterioles. Furthermore, CGRP acts together with postdrome phases. Typically, a migraine attack lasts substance P to potentiate plasma extravasation where from 4 to 72 hours. Calcitonin Gene-Related Peptide and Migraine Headaches 189

Calcitonin gene-related peptide (CGRP) is a neu- tion is coming from observations employing transcra- ropeptide and important vasodilator. It is released niallaserDopplermeasurements,whichsuggestthatmi- during migraine attacks. Blockade of CGRP receptors graine attacks are associated with intracranial large ar- in humans alleviates migraine pain. terial dilatation on the headache side. Together the possible causes described above provide C Characteristics links to the observed migraine symptomatologyand potential underlying mechanisms. They deliver thebiolog- Underlying Causes of a Migraine Attack ical “hardware” which contributes to migraine patho- Despite many approaches to understand the initiation genesis. The focus is on the cranial vasculature and the of migraine attacks, “the migraine trigger” or the phys- trigeminal sensory system controlling the vasculature iological starting point has not yet been identified. To and transmitting information to brainstem and midbrain date it is also not possible to come up with a primary un- nuclei,whichinturnmonitorandadjusttheincomingin- derlying cause for migraines and probably there is more formation. During a migraine attack, adjustments made than one. Several genetic factors have been discussed by these systems might be reflected by certain symp- as rendering a person more susceptible to developing toms. As an example, the symptom unilateral throbbing migraines, as well as disturbances of central neuronal pain at the temples seems to be caused by mechanisms function or cranial changes in vasodynamics. Many of like sensitization of sensory afferents in the periphery. these hypotheses evolved from studies of one subtype In addition, facial mechanical allodynia might be initi- of migraine patients, the ones experiencing classical atedbyneuronalsensitizationprocessesadvancingfrom migraines. Potential genetic defects which might cause sensory to central neurons (Burstein et al. 2000). Under- classical migraines include e.g. missense mutations in standing migraine symptoms and the potential mecha- the CACNA1A gene encoding the α1 subunit of the nisms driving an attack is an important basis for under- voltage dependent P/Q type calcium channel, which standing the disease and getting a handle on the essential accounts for 50% of an autosomal disease called famil- molecular drivers that direct the biological systems to- ial hemiplegic migraine (FHM1). Missense mutations wards a migraine attack. in the ATP1A2 gene, which encodes the α2 isoform of the enzyme Na, K-ATPase, have been shown to be The Neuropeptide CGRP, an Important Molecular Player in Mi- responsible for additional cases of FHM. graine Attacks Besides the genetic factors, local disturbances of central Several molecules have been identified that trigger neuronal function, i.e. the cortical spreading depression headache responses fulfilling the criteria of migraine (CSD) of Leão or activity changes in brainstem/ mid- attacks. Among them are NO released from glyceryl brain neuronal systems have been hypothesized to be trinitrate (GTN), histamine, prostaglandin E1 and a main cause underlying migraine attacks. In the fore- CGRP. These molecules have in common that they in- brain, CSD is a wave of excitation that propagates across duce vasodilatation and affect sensory neuron function. the cortex, followed by a wave of suppression. Recent The 37 amino acid neuropeptide CGRP has been shown evidence suggests that CSD is the physiological phe- to be one of the most potent vasodilators in human and nomenon causing the aura phenomenon of classical mi- animal tissues and is widely distributed throughout the graines (Hadjikhani et al. 2001). Whether CSDs also oc- body. Two isoforms, α and β CGRP are known, which cur in common migraines is not yet known. Neuronal originate from different genes. The isoforms differ by dysfunctionofbrainstem/midbrainneuronalsystemsin- only 1 and 3 amino acids in rats and humans, respec- volved in pain inhibition/facilitation has also been sug- tively. The peptides are expressed by primary afferent gested (Knight and Goadsby 2001; May 2003). Human neurons, which mostly fire in the C- and Aδ fiber range, fMRI studies during migraine attacks indicate changed as well as by motor neurons, the autonomous nervous neuronal activity in certain brainstem and midbrain ar- system and central neurons. The CGRP receptor medi- eas (Weiller et al. 1995). The anatomical location sug- ating CGRP function consists of three components, a G gests that the function of these regions is associated with protein coupled seven transmembrane receptor element adjusting nociceptive information entering the brain by known as calcitonin-like receptor (CLR) a receptor either inhibiting or facilitating the responses of neurons associated membrane protein 1 (RAMP1) and a protein and sensory terminals in the brainstem trigeminal nu- termed receptor component protein (RCP) (Poyner cleus caudalis (TNC). Furthermore, extensive changes et al. 2002). While CLR and RAMP1 are membrane in vasodynamicshavelong been implicatedin thepatho- constituents, RCP is a cytoplasmic protein shown to genesis of migraines, e.g. alterations in intracranial ves- be crucial for the efficient intracellular coupling of the sel diameters followed by reactive changes in extracra- G protein and adenylate cyclase and thus for the pro- nial vessel diameters were already investigated in 1938 duction of cAMP. Constituents of the CGRP receptor by Graham and Wolff. Also, the first specific treatment have been shown to be expressed by peripheral and employed, the ergotamines, work as vasoconstrictors. central neurons as well as by smooth muscle cells in More recent support for the importance of vasodilata- the vascular system. 190 Calcitonin Gene-Related Peptide and Migraine Headaches

Ample evidence that CGRP could play an important pain intensity and high CGRP levels detected early in an role in migraine pathophysiology comes from various attack, as well as current and future treatment affecting studies investigating the transmitter content of external CGRP function, point to a significant contribution of the jugular vein blood during migraine attacks (Goadsby neuropeptide to the pathogenesis of migraines. CGRP and Edvinsson 1994, Sarchielli et al. 2000). These stud- mightbenotonlyamarkerbutalsoanimportantdriverof ies demonstrate that levels of CGRP normally found to processesunderlyingmigrainesymptomatology.Never- be in the lower pM range and below are approximately theless, to date its mechanism of action in the migraine 2-fold increased during acute migraine attacks. Also, setting is still not fully understood. increasing theplasmalevelsbyashortinfusionofCGRP triggers immediate headaches fellowed by a delayed severe headache in migraineurs. The symptoms of the Potential Function of CGRP in Migraine delayed headache are indistinguishable from that of a Some insights into the potential function of CGRP migraine. Furthermore, current gold standard migraine come from animal studies investigating the activity of treatment with sumatriptan, a 5HT1B/1D agonist, re- the highly selective and competitive CGRP antago- duces blood levels of CGRP in humans and in animal nist BIBN4096 in the vascular and neuronal system. experiments. A relationship between pain intensity and BIBN4096 has a high affinity for the human CGRP re- plasma CGRP levels has been suggested. Finally, more ceptor (14.4 pM) and potently reverses CGRP-induced direct evidence for the contribution of CGRP to mi- vasodilatation in various rat and guinea pig vascular graine pain was introduced by a recent phase II clinical tissues as well as human cerebral arteries (Doods 2001). trial. Olesen et al. (2004) investigated the effectiveness Furthermore, in an in vivo model where an increase in of the small molecule CGRP antagonist BIBN4096 facial blood flow is induced by unilateral electrical in reducing migraine pain. In this multicenter, double stimulation of the trigeminal ganglion, BIBN4096 dose blind, randomized clinical trial, a dose dependent relief dependently reduces the evoked blood flow with an from migraine pain was observed after BIBN4096 in- ID50 of 0.003 mg/kg in marmoset monkeys. Recent travenous administration. The 2.5 mg dose represented detailed investigations into the mechanism of action of the dose group with the highest patient number. It dis- the antagonist in humans showed that in healthy volun- played a response rate of approximately 66% over 27% teers BIBN4096 prevented CGRP-induced extracranial for placebo (Fig. 1). A general pain relieving effect was dilatation and concomitantly reduced CGRP-induced already observed 30 min after application of BIBN4096. headaches (Petersen et al. 2005). Together these data Significant efficacy over placebo was also observed in supportthesignificanceofCGRP-inducedvasodynamic other migraine specific secondary endpoints, including changes in migraine headaches. the pain-free rate, the 24 hr recurrence rate and typical CGRP and its receptor system are not only expressed by migraine associated symptoms like nausea and phono- the vasculature but also by trigeminal and second order and/or photo-phobia. The drug was well tolerated and neuronsin thebrainstem TNC. Itthereforemightwellbe no serious adverse events were observed. that during migraine attacks increased CGRP levels in- In summary, evidence like increased CGRP levels dur- fluence trigeminal neuronal information processing being an attack, the induction of migraine attacks by in- sides affecting vasodynamics. Unfortunately, the role of fusion of CGRP, CGRP levels showing a relationship to CGRP is not very well explored in the trigeminal system. This is especially true for the primary afferent. In the central portion, direct application of αCGRP into the TNC increased the firing rate of the neurons. In this setting, intravenousadministrationoftheCGRPantagonist BIBN4096 dose dependently inhibited increased activity of TNC neurons. Because the selective CGRP antagonist BIBN4096 is able to reduce central neuronal activity, the data suggestthatCGRPparticipatesin increasing the activity of and/or sensitizing second orderneuronsin the TNC under these experimental conditions. Whether CGRP sensitizes central second order neurons directly orincreasesthefiringrateoftrigeminalneuronsthatthen drive central sensitization or both has still to be demonstrated. In summary, these experimental animal studies suggest that CGRP can affect nociceptive processing in Calcitonin Gene-Related Peptide and Migraine Headaches, the trigeminal system. Increased CGRP levels being Figure 1 Two hr headache response after intravenous administration of present during migraine attacks could imply a role of several doses BIBN4096 in the phase II clinical trial. CGRPin sensitization of primary and/or centralneurons Calcium Channels in the Spinal Processing of Nociceptive Input 191

Calcitonin Gene-Related Peptide and Migraine Headaches, Figure 2 Possible points of action of CGRP in migraine pathogenesis. besides inducing vasodynamic changes in the cranial headache and extracerebral artery dilatation. J Clin Pharmacol vasculature (Fig. 2). Ther 77:202–213 11. Poyner DR, Sexton PM, Marshall I et al. (2002) International Although migraine pathogenesis still offers vagueness Union of Pharmacology. XXXII. The mammalian calcitonin with respect to the trigger(s) and numerous hypotheses gene-related peptides, adrenomedullin, amylin, and calcitonin on causes and the biological processes behind the symp- receptors. Pharmacol Rev 54:233–246 toms, the testing of new molecular principles like that of 12. Sarchielli P, Alberti A, Codini M et al. (2000) Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides theCGRPantagonistBIBN4096opensnewpathsforthe in internal jugular vein blood during spontaneous migraine understanding of underlying mechanisms and the iden- attacks. Cephalalgia 20:907–918 tiﬁcation of important contributors to this complex dis- 13. Weiller C, May A, Limmroth V et al. (1995) Brain stem activation ease. in spontaneous human migraine attacks. Nat Med 1:658–660

References 1. Burstein R, Yarnitsky D, Goor-Aryeh I et al. (2000) An asso- Calcium Channel Blockers ciation between migraine and cutaneous allodynia. Ann Neu- rol 47:614–624 2. Doods H (2001) Development of CGRP antagonists for the treat- Definition ment of migraine. Curr Opin Investig Drugs 9:1261–1268 3. Goadsby PJ, Edvinsson L (1994) Neuropeptides in migraine and A class of drugs with the capacity to prevent calcium cluster headache. Cephalalgia 14:320–327 ions from passing through biologic membranes. These 4. Graham JR, Wolff HG (1938) Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychia- agentsareusedtotreathypertension,anginapectorisand try 39:737–763 cardiac arrhythmias; examples include nifedipine, dilti- 5. Hadjikhani N, Sanchez Del Rio M, Wu O et al. (2001) Mech- azem, verapamil, amlodipene. anisms of migraine aura revealed by functional MRI in human Headache Attributed to a Substance or its Withdrawal visual cortex. Proc Natl Acad Sci USA 98:4687–4692 6. Headache Classification Subcommittee of the International Headache Society (2004) The international classification of Headache disorders. Cephalalgia 24:9–160 7. Knight YE, Goadsby PJ (2001) The periaqueductal grey matter Calcium Channels in the Spinal modulates trigeminovascular input: a role in migraine? Neuro- science 106:793–800 Processing of Nociceptive Input 8. May A (2003) Headache: lessons learned from functional imaging. Br Med Bull 65:223–234 HORACIO VANEGAS 9. Olesen J, Diener HC, Husstedt IW et al. (2004) BIBN 4096 BS Instituto Venezolano de Investigaciones Cientificas Clinical Proof of Concept Study Group. Calcitonin gene-related (IVIC), Caracas, Venezuela and Institute for peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110 Physiology, Friedrich Schiller University, Jena, 10. Petersen KA, Lassen LH, Birk S et al. (2005) BIBN4096BS an- Germany tagonizes human alpha-calcitonin gene related peptide-induced [email protected] 192 Calcium Channels in the Spinal Processing of Nociceptive Input

Synonyms VDCCs present in a neuron or a neuronal ensemble such Voltage-Dependent Calcium Channels; VDCCs; volt- as the spinal cord, but the effect of one antagonist may age-sensitive calcium channels; VSCCs, high-threshold be additive to the effect of antagonists to other channel calcium channels; High-Threshold VDCCs; High- types. Voltage Calcium Channels; HVCCs; Low-Threshold Animal Models for the Study of VDCCs in Nociception Calcium Channels; Low-Threshold VDCCs; Low- On the one hand there are the models for “acute” noci- Voltage Calcium Channels; LVCCs; hyperalgesia; ception, in which brief and intense stimuli are applied allodynia; spinal dorsal horn; spinal nociceptive trans- to normal tissues (see Vanegas and Schaible 2000). mission These stimuli include noxious heat or noxious pressure Definition as applied to skin or joints, application or injection of algogenic substances such as capsaicin, mustard Calcium channels that open upon depolarization oil, formalin or acetic acid, and noxious distension of (voltage-dependent calcium channels, VDCCs) en- hollow viscera. Upon stimulus application, withdrawal able calcium ions to enter neurons. VDCCs are thereby reflexes and other protective behaviors can be measured involvedinsynaptictransmission,changesinmembrane or the response of dorsal spinal nociceptive neurons can excitability, intracellular regulation of second and third be recorded prior to and during the action of specific messengers and expression of genes. Spinal VDCCs VDCC antagonists. Also spinal neuronal responses to thatare opened byrelativelylargedepolarizations(high- electrical stimulation of nociceptive primary afferent threshold VDCCs) or by small depolarizations (low- fibers may serve as a measure of nociception. threshold VDCCs) are involved in normal nociception On the other hand, animal models of persistent damage as well as in the hyperalgesia and allodynia that result include inflammation of skin or joints, surgical wounds, from inflammatory andmechanicallesionsofperipheral long-lasting hyperexcitability induced by application tissues or from lesions of primary afferents fibers. or injection of capsaicin, mustard oil or formalin, ligation of peripheral nerves, and diabetic neuropathy Characteristics (see Vanegas and Schaible 2000). These manipulations Voltage-Dependent Calcium Channels induce peripheral and central sensitization and the VDCCs are classified according to their electrophysi- experimental animals thus respond in an exaggerated ological properties and their sensitivity to specific an- manner to the “acute” stimuli mentioned above. This is tagonists (Miljanich and Ramachandran 1995). L-, N-, akin to hyperalgesia and allodynia, and the effect P/Q- and R-type are high-threshold whereas T-type are of specific VDCC antagonists on these exaggerated low-threshold VDCCs. Most of what is known regard- responses can be investigated. ing the role of spinal VDCCs in pain (see Vanegas and It is now possible to generate mice that lack one of the Schaible2000 for acomprehensivereview)derivesfrom molecular subunits of specific calcium channels and to studies based on the use of specific channel antagonists study their nociceptive responses both under normal and or blockers (Table 1). By definition, there are no specific under sensitized conditions. The VDCC defect in these blockers for R-type VDCCs; their role in pain mecha- animals, however, is not restricted to the spinal cord. nismsisthereforeunclear. Oneandthesameneuronmay Role of Spinal VDCCs in Nociception express several types of VDCC. An antagonist to only one channel type therefore blocks only a fraction of the Normal Nociception In awake and in anesthetized rats, L- and N-type antagonists may or may not depress responses to mechanical Calcium Channels in the Spinal Processing of Nociceptive Input, innocuous or noxious, thermal noxious and visceral Table 1 Some antagonists to voltage-dependent calcium channels noxious stimuli, or responses to electrical stimulation channel antagonist of nociceptive afferents (e.g. Malmberg and Yaksh type 1994; Neugebauer et al. 1996). Blockade of spinal L Benzothiazepines: diltiazem P/Q-type channels causes a slight increase in neu- Dihydropyridines: nicardipine, nifedipine, nimodipine, ronal responses, thus suggesting that they normally nitrendipine Phenylalkylamines: verapamil participate in predominantly inhibitory mechanisms (Matthews and Dickenson 2001a; Nebe et al. 1999). N ω -Conopeptides: Finally, blockade of spinal T-type channels causes an natural: ω-conotoxin-GVIA, ω-conotoxin-CIVD (AM336) synthetic: SNX-111 (equivalent to ω-conotoxin-MVIIA), inhibition of spinal neuronal responses to electrical SNX-124 (equivalent to ω-conotoxin-GVIA), SNX-159, stimulation of nociceptive afferents as well as to low- SNX-239 and high-intensity mechanical and thermal stimuli P/Q ω- Agapeptide: ω-agatoxin-IVA (Matthews and Dickenson 2001b). Mice with a genetically induced lack of N-type VD- T ethosuximide CCs may or may not show decreased responses to Calcium Channels in the Spinal Processing of Nociceptive Input 193

“acute” thermal and/or mechanical noxious stimuli pressure or electrical stimulation of nociceptive affer- (Hatakeyama et al. 2001; Kim et al. 2001; Murakami ents (Matthews and Dickenson 2001a; see Vanegas et al. 2002; Saegusa et al. 2001). Mice that lack the α1E and Schaible 2000). In contrast, spinal application of subunit (which may be part of the R- or the T-type chan- N-type channel antagonists has proven effective against nel) have normal responses to thermal and mechanical neuropathic nociceptive behavior in animals (see Vane- C noxious stimuli (Saegusa et al. 2000). gas and Schaible 2000) and against the increased spinal neuronal responses to noxious heat, pressure or elec- Sensitized Nociception trical stimulation of nociceptive afferents induced by In animal models that utilize nociceptive stimulation nerve damage (Matthews and Dickenson 2001a). Also, by means of capsaicin or mustard oil (see Vanegas mice with a genetically induced lack of N-type VDCCs and Schaible 2000), blockade of spinal N-type chan- fail to develop neuropathic behavioral responses after nels always prevents the subsequent exaggeration of peripheral nerve damage (Saegusa et al. 2001). Intrathe- responses (primary and secondary hyperalgesia and al- cal administration of one N-type antagonist alleviated lodynia) to “acute” test stimuli. Also, blockade of spinal neuropathic pain and allodynia in human patients, al- L- or P/Q-type channels generally prevents secondary though with considerable adverse effects (Brose et al. hyperalgesia and allodynia. 1997; Penn and Paice 2000). Finally, the inhibition by a Asregardsresponsesto teststimuliduring inflammation T-type VDCC antagonist of spinal neuronal responses or inflammation-like processessuch assurgicalwounds, to noxious heat, pressure or electrical stimulation of no- blockade of N-type channels in animals has never failed ciceptive afferents remains unaltered after development to prevent or attenuate primary hyperalgesia, secondary of neuropathy (Matthews and Dickenson 2001b). hyperalgesia and allodynia or the late, “inflammatory” response to formalin injection (see Vanegas and In Summary Schaible 2000). The most effective doses of N-type PharmacologicalorgeneticreductionofVDCCfunction antagonists, however, cause motor disturbances after may or may not have an effect upon normal nocicep- 30–60 min. In human patients, one intrathecally admin- tive mechanisms. In situations where inflammation or istered N-type channel blocker alleviated postsurgical inflammation-like processes have induced an enhance- pain but produced severe adverse effects (Atanassoff ment of spinal nociceptive phenomena (central sensiti- et al. 2000). On the other hand, blockade of spinal L- zation), the participation of VDCCs in the spinal pro- type channels has generally prevented the late phase of cessing of nociceptiveinput becomes more obvious and the formalin response and has attenuated primary and reductionofL-,P/Q-,T-and,particularly,N-typeVDCC secondary mechanical hyperalgesia and allodynia (but functionattenuatestheexaggerationofresponsestonox- not thermal hyperalgesia) due to knee inflammation. ious and innocuous stimulation. N-type VDCC antago- Finally, blockade of spinal P/Q-type channels before nists also attenuate the spontaneous pain, the hyperalge- and during induction of inflammation prevents the ex- sia and the allodynia that result from damage to primary aggeration of responses to stimulation of the inflamed afferents, yet with considerable adverse effects. knee or the uninflamed ankle. However, blockade of P/Q-type channels when central sensitization is already Potential Therapeutic Use of VDCC Antagonists established attenuates only responses to stimulation Any hope of using VDCC antagonists for alleviating hy- of the sensitized nociceptors in the knee (primary hyperalgesia and allodynia in a clinicalsetting mustreckon peralgesia and allodynia) but has no influence upon with several drawbacks. All studies with spinal VDCC responses to stimulation of normal nociceptors in the antagonists have used the intrathecal route of adminis- uninflamed ankle (Nebe et al. 1997). The effect of a tration, which is problematic, especially for compounds given compound on the prevention of a painful condi- of low water solubility. On the other hand, systemically tion may therefore be different from its effect on the administered VDCC antagonists may have undesirable alleviation of the already established condition. effects on a variety of organs. Sufficiently beneficial ef- Mice with a genetically induced lack of either N-type fects with VDCC antagonists are attained mostly with VDCCs or the α1E subunit of VDCCs show an at- doses that already cause unwanted effects. At the same tenuation of the late phase of the formalin response time, VDCC antagonists have some positive attributes. (Hatakeyama et al. 2001; Kim et al. 2001; Saegusa et They may block the synaptic release of several media- al. 2000; Saegusa et al. 2001). The writhing response tors involved in nociceptive transmission, hyperalgesia to intraperitoneal acetic acid, a model of visceral noci- and allodynia. This would be an advantage over the use ception, may (Kim et al. 2001) or may not (Saegusa et of individual antagonists to, e.g. glutamate, substance al. 2000; Saegusa et al. 2001) be attenuated. P, neurokinin A and CGRP. In contrast with opioids, In animals with peripheral nerve damage, spinal appli- which may also decrease synaptic release,VDCCantag- cation of antagonists to either L- or P/Q-type VDCCs onistsdonotseemtogiverisetotolerance.Insomecases, does not alter the hyperalgesia and allodynia, nor the normal somethesia and motricity have been spared by increased spinal neuronal responses to noxious heat, doses that are effective against hyperalgesia and allody- 194 Calcium Spike Bursts nia. Specific antagonists to various VDCC types can be combined in submaximal doses to achieve a summated Calculosis effect. Finally, VDCC antagonists may synergize with, e.g. opiates and local anesthetics. Visceral Pain Model, Kidney Stone Pain

References 1. Atanassoff PG, Hartmannsgruber MW, Thrasher J et al. (2000) CAMs Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med 25:274–278 Cellular Adhesion Molecules 2. Brose WG, Gutlove DP, Luther RR et al. (1997) Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. Clin J Pain 13:256–259 Cancer Pain 3. Hatakeyama S, Wakamori M, Ino M et al. (2001) Differential α nociceptive responses in mice lacking the 1B subunit of N-type ZBIGNIEW ZYLICZ,MAŁGORZATA KRAJNIK 2+ Ca channels. NeuroReport 12:2423–2427 St. Elizabeth Hospice, Ipswich, Suffolk, UK 4. Kim C, Jun K, Lee T et al. (2001) Altered nociceptive responses [email protected] in mice deficient in the α1B subunit of the voltage-dependent calcium channel. Mol Cell Neurosci 18:235–245 5. Malmberg AB, Yaksh TL (1994) Voltage-sensitive calcium chan- Synonyms nels in spinal nociceptive processing: blockade of N- and P- type channels inhibits formalin-induced nociception. J Neurosci Malignant pain; Pain Due to Cancer; oncological pain 14:4882–4890 6. Matthews EA, Dickenson AH (2001a) Effects of spinally de- Definition livered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of ’Cancer pain’ is a conglomerate name for all kinds of neuropathy. Pain 92:235–246 pain symptoms experienced in the course of a malignant 7. Matthews EA, Dickenson AH (2001b) Effects of ethosuximide, a disease. The common denominator of pain associated T-type Ca2+ channel blocker, on dorsal horn neuronal responses in rats. Eur J Pharmacol 415:141–149 with cancer is that the suffering experienced by the pa- 8. Miljanich GP, Ramachandran J (1995) Antagonists of neuronal tient is a combination of many different kinds of pain, calcium channels: structure, function, and therapeutic implica- for example, other symptoms of the disease as well as tions. Annu Rev Pharmacol Toxicol 35:707–734 9. Murakami M, Fleischmann B, De Felipe C et al. (2002) Pain psychological, spiritual and existential factors. perception in mice lacking the β3 subunit of voltage-activated calcium channels. J Biol Chem 277:40342–40351 Characteristics 10. Nebe J, Vanegas H, Neugebauer V et al. (1997) ω-Agatoxin IVA, a P-type calcium channel antagonist, reduces nociceptive pro- Pain is experienced by 20–50% of cancer patients at cessing in spinal cord neurons with input from the inflamed but the time of diagnosis. This prevalence increases up to not from the normal knee joint -An electrophysiological study 75% in the case of patients with advanced stages of in the rat in vivo. Eur J Neurosci 9:2193–2201 the disease. Within these statistics half of the patients 11. Nebe J, Ebersberger A, Vanegas H et al. (1999) Effect of ω- agatoxin IVA, a P-type calcium channel antagonist, on the de- normally experience moderate or severe pain, whereas velopment of spinal neuronal hyperexcitability caused by knee 20–30% experience very severe or excruciating pain inflammation in rats. J Neurophysiol 81:2620–2626 (Anonymous 1990). 12. Neugebauer V, Vanegas H, Nebe J et al. (1996) Effects of N- Usually, cancer patients experience pain of more than and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the one quality and in more than one location. Only 20% of normal and inflamed knee joint J Neurophysiol 76:3740–3749 patients experience one single location of pain. In one 13. Penn RD, Paice JA (2000) Adverse effects associated with the third of patients there are three of more pain locations intrathecal administration of ziconotide. Pain 85:291–296 (Twycross et al. 1996). 14. Saegusa H, Kurihara T, Zong S et al. (2000) Altered pain responses in mice lacking the α1E subunit of the voltage-dependent According to Grond et al. (1996) cancer pain may be Ca2+ channel. Proc Natl Acad Sci USA 97:6132–6137 related to: 15. Saegusa H, Kurihara T, Zong S et al. (2001) Suppression of inflammatory and neuropathic pain symptoms in mice lacking the • tumor growth: 85% N-type Ca2+ channel. EMBO J 20:2349–2356 • tumor treatment: 17% 16. Vanegas H, Schaible H-G (2000) Effects of antagonists to high- • progressive debility:9% threshold calcium channels upon spinal mechanisms of pain, hy- • concurrent disorder: 9% peralgesia and allodynia. Pain 85:9–18 Cancer pain may originate in many locations and have multiple, inter-twined mechanisms. The top 10 pains among 211 patients (Twycross 2003) with advanced Calcium Spike Bursts cancer were: • bone Burst Activity in Thalamus and Pain • visceral Cancer Pain 195

• neuropathic Cancer Pain, Table 1 The WHO analgesic ladder • soft tissue Step 1 Step 2 Step 3 • immobility • constipation Non-opioids weak opioids strong opioids • myofascial paracetamol, various Codeine, tramadol, morphine, fentanyl, C • cramp NSAIDs low dose oxycodone oxycodone, • esophagitis methadone • degeneration of the spine

It therefore follows that careful evaluation and examination is necessary to make a diagnosis of cancer pain. Knowledge of the so called referred pain syndromes Evaluation of pain is based primarily on probability and (Giamberardino and Vecchiet 1995) can be helpful in pattern recognition. Factors that may be helpful in the establishing diagnosis (e.g. unilateral facial or ear pain diagnosis of cancer pain are: may be associated with mediastinal involvement by The natural history of the disease (e.g. breast cancer bronchial carcinoma or reflux esophagitis. Right shoul- often causes bone metastases and bone pain,ovarian der pain may be due to an enlarged liver. Metastases in cancermayrarelycausebrainmetastasesandheadache). the lower lumbar region may result in pain localized in A time course of the pain symptoms may be important. the sacroiliacal joint. Brachial or lumbal plexopathy that resulted in pain Most types of cancer pain respond readily to analgesics. even before radiation therapy is probably caused by the Principles of cancer pain treatments were elaborated by growth of the tumor, but may be exacerbated by the ra- the WHO (1990). In specialist centers, 95–98% of pain diation therapy. Lack of pain two or three weeks after symptoms can be successfully treated. irradiation may be not related to the opioids adminis- Cancer pain is not usually the only symptom of the dis- tered, but to the radiation therapy. ease. It is frequently accompanied by other symptoms Plain radiographic imaging is helpful in discovering like: delirium, nausea and vomiting, weakness, fa- the origin of bone pain. Pain originating in soft tissues tigue, weight loss, dyspnea, dry mouth, constipation or and neural tissues needs more sophisticated techniques diarrhea, pruritus and probably many others. Treatment (MRI). Some types of pain (e.g. neuropathic pain) of pain alone may decrease its intensity but increase may be “invisible” to radiographic imaging. Neuro- intensity of other symptoms. So cancer pain should pathic pain may frequently be a component of another always be seen in the context of other symptoms and in pain (Portenoy et al. 1999), it may be a complication of the context of the whole person. therapy, but may also be a paraneoplastic symptom. An Cognitive failure progressing to delirium, but also some evaluation of neurological deficit may frequently lead other adverse effects that emerge in the course of treat- to better understanding and diagnosis of pain. Spinal ment, may compromise the patients quality of life more cord compression (SCC) occurs in 3% of all cancer seriously than pain. So the aim of the treatment is the patients. balanced control of all symptoms, not only pain control. Nervecompression or entrapmentusually givesaspe- Sometimes making pain and other symptoms bearable, cific syndrome (e.g. vertebral collapse may cause nerve but not alleviating them fully, is the only viable option. root compression). The principles of WHO are as follows: Response to analgesics mayoftengiveacluetothe • preferably give the medication by mouth type of pain (e.g. nociceptive pain responds readily to • give the next dose of analgesics before the effect of opioids, while neuropathic pain may be resistant to this the previous dose ceases treatment). Full history of the pharmacological and non- • give drugs according to the analgesic ladder pharmacological treatment of the pain should be taken. • use adjuvant drugs, either to alleviate the adverse Emotional,socialandspiritualfactorsmaymakethepre- effects of analgesics or to enhance them, anal- cisediagnosisof pain difficult, andshould berecognized gesia therapy should be individualized (Anony- and addressed specifically. mous 1990) A distinction should be made between pain whilst at rest and pain during movement. Pain may have a circadian Cancer pain is usually a dynamic and complex phe- distribution. Many types of cancer pains are constant, nomenon that should be assessed regularly. Prolonged but some may appear to have an exploding character use of analgesics may induce plastic changes in the ( breakthrough pain), even when the optimalanalgesia central nervous system which are similar to those in- is provided (Portenoy et al. 1999). duced by pain itself. Also, prolonged use of opioid Patients who describe their pain as throbbing, lancinat- drugs for pain may induce tolerance, while the adverse ing and burning, and exacerbated by light touch during effects may increase. To prevent this, more and more examination, may appear to have mechanical allody- combinations of the various drugs are used. With proper nia. choice of drugs, continuous assessment and adjustment 196 Cancer Pain, Animal Models

Cancer Pain, Table 2 Analgesic adjuvants indication drugs used

insufﬁcient analgesic effects ketamine

neuropathic pain amitryptyline, venlafaxine, gabapentin

nerve entrapment, compression dexamethasone, NSAIDs

reﬂux esophagitis proton pump inhibitors

abdominal cramp, bladder cramp butyl-scopolamine

muscle cramp benzodiazepine, baclofen

respiratory depression, breathlessness, sedation, tiredness methylphenidate

constipation lactulose and sennosides, or macrogol

nausea and vomiting metoclopramide, haloperidol, levomepromazine, cyclizine

dry mouth pilocarpine

pruritus paroxetine of medication, it is possible to control pain with opti- Definition mal preservation of alertness in most cancer patients. Cancer pain, distinguished from non-malignant pain, Controlling cancer pain is of importance for the dying arises from tumor cells which invade soft tissue and/or patient, as well as for the family of the dying who need bony structures, or occur as a result of therapies used to carry on normal living insofar as that is possible, and to treat cancer. to adapt to the loss of a loved one. Cancer Pain Management, Treatment of Neuropathic Characteristics Components Pain Treatment, Intracranial Ablative Procedures Although there is significant variability in the type, Psychiatric Aspects of the Management of Cancer severity and evolution of this pain, two major compo- Pain nents are generally recognized. The first component, known as ongoing pain, is most often the first to References present, described as a dull ache or throbbing in character and usually increases in severity with disease 1. Anonymous (1990) Cancer Pain Relief and Palliative Care. Re- port of a WHO Expert Committee. World Health Organ Tech progression. A second component of bone cancer pain Rep Ser 804:1–75 frequently emerges over time and is more acute in 2. Giamberardino MA, Vecchiet L (1995) Visceral Pain, Referred nature. This second pain is known as incident or Hyperalgesia and Outcome: New Concepts. Eur J Anaesthesiol breakthrough pain, as it frequently occurs either Suppl 10:61–66 3. Grond S, Zech D, Diefenbach C et al. (1996) Assessment of spontaneously, with intermittent exacerbations of pain Cancer Pain: A Prospective Evaluation in 2266 Cancer Patients or by movement of the cancerous bone (Mercadante Referred to a Pain Service. Pain 64:107–114 and Arcuri 1998). For many patients, pain is the first 4. Portenoy RK, Payne D, Jacobsen P (1999) Breakthrough Pain: Characteristics and Impact in Patients with Cancer Pain. sign of cancer and 30–50% of all cancer patients will Pain 81:129–134 experience moderate to severe pain. Cancer-associated 5. Twycross R (2003) Cancer Pain Syndromes. In: Sykes N, Fal- pain can be present at any time during the course of lon MT, Patt RB (eds) Clinical Pain Management. Cancer Pain. the disease, but the frequency and intensity of cancer London, Arnold, pp 3–19 6. Twycross R, Harcourt J, Bergl S (1996) A Survey of Pain pain tends to increase with advancing stages of can- in Patients with Advanced Cancer. J Pain Symptom Man- cer. 75–95% of patients with metastatic or advanced age 12:273–282 stage cancer will experience significant amounts of cancer-induced pain (Portenoy et al. 1999). The first animal model of bone cancer pain involved the injection of murine osteolytic sarcoma cells into the Cancer Pain, Animal Models intramedullary space of the murine femur (Fig. 1). A critical component of this model is that the tumor cells MARY ANN C. SABINO,PATRICK W. MANTYH are confined within the marrow space of the injected Department Prevential Science, University of femur, and the tumor cells do not invade adjacent soft Minnesota, Minneapolis, MN, USA tissues (Schwei et al. 1999). Following tumor injec- [email protected] tion, the fluorescent cancer cells proliferate, and both Cancer Pain and Pain in HIV / AIDS 197

factors, and race and ethnicity (Anderson et al. 2004; Cancer Pain and Pain in HIV / AIDS Green et al. 2003). Education of patients, families and RUSSELL K. PORTENOY professional staff, and system level strategies such as Department of Pain Medicine and Palliative Care, quality improvement activities are needed to address C Beth Israel Medical Center, New York, NY, USA the problem of undertreatment. [email protected] Models of Care Synonyms In populations with life-threatening illnesses, the man- Cancer-related pain; HIV / AIDS-related pain; Pain in agement of pain should be incorporated into a broader HIV / AIDS efforttoamelioratethephysical,psychosocialandspir- itual issues that undermine quality of life or worsen Definition suffering for the patient or family. The therapeutic ap- Theterms“cancerpain”and“paininHIV/AIDS”refer proachthataddressestheseissuesisknownaspalliative care. The relationship between cancer pain and pallia- to the assessment and management of acute or chronic pain syndromes that are either directly related to a ma- tive care (see Cancer Pain Management, Interface lignant neoplasm or to HIV infection respectively or to betweenCancerPainManagementandPalliativeCare) the treatments that are used to manage these diseases. must be understood to optimize the care of these patients, particularly those with advanced disease. Palliative care is a therapeutic approach to the care of Introduction patients with life-threatening illnesses and their fami- Chronic pain, a highly prevalent symptom in popula- lies.Itisfocusedonmaintainingqualityoflifethrough- tions with cancer or HIV / AIDS, may be associated out the course of the illness and addressing the chal- with loss of function, compromised quality of life and lenging needs of patients who are approaching the end profound suffering. Although there are important dif- of life. The goals of this model include control of pain ferencesbetweencancerandHIV/AIDS,andeachdis- and other symptoms; management of psychological order itself is extraordinarily diverse, there are broad distress, comorbid psychiatric disorders and spiritual commonalities in the approach to pain assessment and distress; support for effective communication and de- management. The specific issues encountered in the cision making; provision of practical help in the home; management of HIV / AIDS are addressed in the es- and ongoing support for the family and management say on Pain in HIV / AIDS. The remaining essays of the dying process in a manner that allows a comfort- in this section, which focus on cancer pain may be unable and dignified death and effective grieving on the derstood to apply to both the cancer and HIV / AIDS part of the family. populations. Palliative care is now considered an approach that should be implemented at a generalist level by every physician who cares for those with serious med- Epidemiology ical illness. It should also be available at a special- Studies of cancer pain epidemiology reveal that ap- ist level for those patients and families who warrant proximately 30–50% of patients undergoing antineo- this level of care. The need for specialist level pallia- plastic therapy and 75–90% of patients with advanced tive care, which typically occurs in the setting of ad- diseasehavechronicpainsevereenoughtowarrantopi- vanced illness is being met in the United States by oid therapy (Vainio and Auvinen 1996). Although the a growing number of institution-based palliative care prevalenceofpaininHIV/AIDShasprobablydeclined programs(www.nationalconsensusproject.org)andby with the advent of highly active anti-retroviral therapy, more than 3300 hospice programs providingpalliative recent surveys suggest that chronic pain affects about care at the end of life. All of these programs are un- half of this population (Dobalian et al. 2004). derutilized and poorly understood by patients, families It is widely accepted that a large majority of patients and professional staff. with cancer pain can attain satisfactory relief with available therapies. Unfortunately, surveys indicate a highrateofundertreatment(Andersonetal.2004).Un- Evaluation of Pain dertreatment is a complex phenomenon that may result The goals of pain assessment include characteriza- from a variety of patient-related barriers and clinician- tion of the pain complaint, evaluation of the etiology, related barriers or from distortions in the health care syndromeandputativemechanismssustainingthepain system that limit access to treatment. Recent studies and the assessment of the impact of the pain and rele- underscore the influence on these barriers of cultural vant comorbidities. 198 Cancer Pain and Pain in HIV / AIDS

Pain Characteristics helps to define the underlying etiology and prognosis A comprehensive evaluation should begin with an as- and also may suggest the need for additional testing or sessment of the pain characteristics. The temporal fea- specific therapies. tures comprise onset, duration, course and fluctuation. Although inferences about the type of pathophysiol- Most patients with chronic pain related to a progres- ogy sustaining the pain represent a simplification of sive illness experience pain that begins insidiously and very dynamic processes occurring in both the periph- fluctuates broadly, but gradually progresses. Periodic ery and in the central nervous system, these inferences short-lived flares of pain, or “ breakthrough pain” have been incorporated into clinical practice because (Caraceni et al. 2004), are very common and should they have utility when deciding on a treatment strate- be separately assessed. gies. The labels that are applied to the pathophysiolog- Topographic features include primary location and ra- ical categories include nociceptive, neuropathic, psy- diation. Pain may be referred from any structure, in- chogenic and mixed. cluding nerve, bone, muscle, soft tissue and viscera, Nociceptive pain refers to pain that is believed to be and knowledge of pain referral patterns is needed to sustained by ongoing activation of pain sensitive pri- guide the evaluation. For example, pain in the inguinal mary afferent neurons by injury to tissue. In the setting crease may require evaluation of numerous structures of cancer, nociceptive pain usually is due to direct in- to identify the underlying lesion, including the pelvic vasion by the neoplasm (Caraceni et al. 1999). When bones and hip joint, pelvic sidewall, paraspinal gutter somatic structures are involved, the pain is termed “so- at an upper lumbar spinal level and intraspinal region matic pain” and the pain is typically aching, throbbing, at the upper lumbar level. stabbing and familiar. Bone pain is the most common Measurement of pain intensity may be accomplished type. “Visceral pain” occurs when the nociceptive le- usinganumericscale(0–10),verbalratingscale,(none, sion involves visceral structures; it is usually gnawing mild, moderate, severe) or a visual analogue scale. Pic- or crampy when arising from obstruction of a hollow torialscalesareparticularlyusefulwhenassessingpain viscus and aching or stabbing when arising from dam- in the pediatric cancer (see Cancer Pain, Assessment age to organ capsules. in Children) population and pain in the cognitively im- Pain is labeled neuropathic if it is believed to be sus- paired (see Cancer Pain, Assessment in the Cogni- tained by abnormal somatosensory processing in the tively Impaired). The particular scale is less important peripheral or central nervous systems (CNS). Neuro- than itsconsistentuseto monitor and documentthesta- pathic mechanismsare involvedinapproximately 40% tus of a specific pain (e.g. “worst pain during the past of cancer pain syndromes and may be caused by dis- week”) over time. In assessing pain intensity, it also ease or by treatment (Caraceni et al. 1999). Dysesthe- is important to obtain information about factors that sia, or abnormal uncomfortable sensations that may be increase or decrease the pain. The quality of the pain described using wordssuch as“burning”, “shock-like” is assessed using verbal descriptors, such as aching, or “electrical” are suggestive of neuropathic mecha- sharp, throbbing, burning or stabbing. Combined with nisms, as is the presence of abnormal findings on the other information, these descriptors allow broad infer- sensory examination, such as allodynia (pain induced ences about the type of pathophysiology that sustains by non-painful stimuli) or hyperalgesia (increased per- the pain. ception of painful stimuli). The term “psychogenic pain” is a generic label referring to pain that is believed to be sustained pre- Inferred Pathophysiology, Etiology and Syndromes dominantly by psychological factors. Pain of this Characterization of the pain complaint must be com- type may be more precisely characterized through the plemented by a physical examination and appropriate widely accepted taxonomy of somatoform disorders laboratorytestsandimagingtoprovidetheinformation proposed by the American Psychiatric Association necessary to elucidate the likely etiology of the pain, (1994). These pains share an assessment that reveals the pain syndrome and the inferred type of pathophys- positive evidence for the psychopathology that is be- iology sustaining the pain. In populations with cancer lieved to causally related to thepain. Although psycho- or HIV / AIDS, the etiology often relates to an identi- logical influences are profoundlyimportant in the pre- fiable structural lesion, such as neoplastic invasion of sentation of the pain and the patient’s ability to adapt bone. Identification of the etiology often informs the and function, psychogenic pain itself appears to be dis- overall treatment of the patient by defining the extent tinctly uncommon in the cancer and HIV / AIDS pop- of disease. ulations. Numerous pain syndromes have been characterized in Occasionally, pain occurs that defies clinical charac- the cancer (Caraceni et al. 1999) and HIV / AIDS (He- terization according to a clear etiology or syndrome. witt et al. 1997) populations. Syndrome identification In the absence of positive evidence for any distinctive Cancer Pain and Pain in HIV / AIDS 199 type of pain, it is usually best to label the symptom as opioid analgesics and adjuvant analgesics. The term “idiopathic.” In the setting of progressive medical ill- “adjuvant analgesic” is applied to a diverse group of nesses, idiopathic pains require regular reassessment drugs, most of which have primary indications other in the hope that an explanatory process will become than pain, but can be effective analgesics in specific clear over time. disorders such as neuropathic pain. C Impact and Comorbidities There is a broad consensus in favor of an approach to cancer pain management that was developed by an ex- The pain evaluation also must include an assessment pert panel of the World Health Organization almost of impact and relevant comorbidities (see Cancer two decades ago and was termed the “analgesic lad- Pain, Evaluation of Relevant Comorbidities and Im- der” (1996). This approach has been highly influential, pact). The impact of the pain may be considered from reinforcing the consensus view that persistent mod- the perspective of varied physical, psychosocial and erate to severe cancer pain should be treated with an spiritual domains. As appropriate, these domains and opioid-based drug regimen. The details of the model specificmedicalandpsychiatriccomorbiditiesmustbe have evolved over time, but it remains a useful as a tool specifically assessed to fully understand the targets for for educating clinicians and policymakers. treatment. According to the analgesic ladder approach, mild to moderate cancer pain is first treated with a nonopioid Pain Management analgesic(see CancerPainManagement,Nonopioid The overall treatment strategy (see Cancer Pain Analgesic), such as acetaminophen or a nonsteroidal Management, Overall Strategy) should proceed from anti-inflammatory drug (NSAID). This drug is com- the broader therapeutic perspective of palliative care. bined with an adjuvant drug that can be selected either The multidimensional assessment guides treatment to provide additional analgesia (i.e. an adjuvant anal- that is often multimodal and best implemented through gesic) or to treat a side effect of the analgesic or a coex- the efforts of professionals in varied disciplines. The isting symptom. Patientswho presentwith moderateto immediate goal of pain relief should be pursued in tan- severe pain or who do not achieve adequate relief after dem with interventions that address other sources of a trial of a NSAID should be treated with an opioid, distress. often combined with a NSAID or adjuvant drugs. Analgesic approaches can be broadly divided into 1) primary therapies directed against the etiology of the pain and 2) symptomatic therapies. Primary treat- Nonsteroidal Anti-Inflammatory Drugs ments for the pain include antineoplastic therapies – NSAIDs appear to be especially useful in patients with radiotherapy, chemotherapy,immunotherapyand bone pain or pain related to grossly inflammatory le- surgery (see Palliative Surgery in Cancer Pain Man- sions and relatively less useful in patients with neu- agement) – and other interventions directed at struc- ropathic pain (Wallenstein and Portenoy 2002). These tural pathology. Orthopedic surgery interventions(see drugs may have an opioid sparing effect that can limit Cancer Pain Management, Orthopedic Surgery)to the potential for dose-related opioid side effects. The address bony metastases exemplify the potential for use of the NSAIDs may be limited by their toxicities primary therapy directed at specific structural pathol- and a maximal efficacy that is insufficient to address ogy. In the HIV / AIDS population, primary treatment most cancer pain. All NSAIDs have the potential for may include anti-retroviral therapy and other interven- nephrotoxicity, with effects that range from periph- tions. If it is feasible and clinically appropriate to pro- eral edema to acute or chronic renal failure. All these vide a primary therapy that can effectively treat the drugs increase the risk of gastrointestinal ulcers and source of the pain, the analgesic consequences can bleeding. The selective cyclo-oxygenase (COX)-2 in- be profound. Most patients have pain that cannot be hibitors have a relatively reduced risk of these out- addressed solely by a primary disease modifying ap- comes and many clinicians recommend these drugs proach. The most important symptomatic therapy is an as first line therapy for all patients at relatively high opioid-based analgesic drug regimen, which may be risk of ulcer, including the elderly, those concurrently complemented by a large number of other treatments. receiving a corticosteroid and those with a prior history of peptic ulcer disease or NSAID-induced gastro- Pharmacotherapy duodenopathy (Wallenstein and Portenoy 2002). The Prospective trials indicate that more than 70% of pa- risk is also reduced by co-administration of a proton tients can achieve adequate relief of cancer pain using pump inhibitor, the prostaglandin analogue misopros- a pharmacologic approach (Schug et al. 1990). Effec- tolandpossiblyhighdoseH2blockers.Recentdatathat tive pain management requires expertise in the use of have raised concerns about an increased risk of cardio- the nonsteroidal anti-inflammatory drugs (NSAIDs), vascular events among those treated with the selective 200 Cancer Pain and Pain in HIV / AIDS

COX-2 inhibitors (Solomon et al. 2004), but the rela- inally labeled some opioids as “weak” (for moderate tive risks and benefits compared to nonselective drugs pain) and some as “strong” (for severe pain) (1996). in medically ill populations have yet to be defined. This distinction is based on conventional practice and There are also no data in the medical ill from which to not pharmacology. In the U.S., drugs typically admin- judge the relative outcomes associated with adminis- istered to address moderate pain in the opioid naïve tration of selective COX-2 inhibitors alone versus non- patient include codeine, hydrocodone(combined with selective NSAIDs plus a gastroprotective agent. At the acetaminophen or ibuprofen), dihydrocodeine (com- present time, the approach is a matter of clinical judg- bined with aspirin), oxycodone (combined with as- ment. pirin,acetaminophenoribuprofen),propoxypheneand occasionally, meperidine. Tramadol, a unique cen- Adjuvant Analgesics trally acting analgesic with a mechanism that is partly The adjuvant analgesics comprise numerous drugs in opioid is also generally included in this group. These diverse classes (Lussier and Portenoy 2004). Treat- drugs are conventionally used for moderate pain either ment with one of these drugs is generally considered if becauseofdosedependenttoxicityorbecausethecom- an optimally administered opioid regimen fails to pro- bination products contain a nonopioid analgesic with vide a satisfactory balance between pain relief and side a maximum safe dose. effects. These drugs are particularly useful in the treat- Opioids conventionally selected for severe pain, par- ment of neuropathic pain, bone pain and pain related ticularly when patients have already been exposed to to bowel obstruction. the short acting drugs on the first rung of the analgesic Corticosteroids are multipurpose adjuvant analgesics ladder, include morphine, fentanyl, oxycodone (with- and also are used to improve anorexia, nausea and out acetaminophen or aspirin), hydromorphone, oxy- fatigue. In populations with cancer pain or pain due morphone, levorphanol and methadone. Historically, to HIV / AIDS, the first-line adjuvant analgesics for morphine was described as the preferred first line drug, neuropathic pain (see Adjuvant Analgesics in Man- but there is large variation in the response to differ- agement of Cancer-Related Neuropathic Pain)arethe ent opioids and it is best to select an initial trial based corticosteroids, anticonvulsants and antidepressants. on the available formulations, cost and prior experi- Use of the anticonvulsants and antidepressants is sup- ence. Although the role of methadone has expanded ported by numerous controlled trials in varied popula- in recent years because of its low cost, long half life tions(Lussier and Portenoy 2004).Otherdrugsconsid- and unexpectedlyhigh potency (presumably related to ered for neuropathic pain comprise the GABA agonist the D-isomer in the racemate, which is a N-methyl- baclofen, alpha-2 adrenergic agonists and various N- D-aspartate blocker), it poses challenges in dose se- methyl-D-aspartate inhibitors. Topical agents, such as lection, dose adjustment and monitoring that are not thelidocainepatch,representanotherstrategyforthese shared by the other pure mu agonist opioids. Experi- pain syndromes. ence is needed to use this drug safely. Themostcommonly used adjuvantanalgesicsfor bone Opioids may be delivered by any of numerous routes pain (see Adjuvant Analgesics in Management of of administration (see Opioid Therapy in Cancer Bone-Related Pain) are the bisphosphonates. These Pain Management, Route of Administration). Long- drugs also have been demonstrated to reduce skeletal term dosing is best accomplished by an oral or trans- morbidity, such as fractures. Other drugs used for bone dermal route. Numerous oral formulations are avail- pain include radiopharmaceuticals and calcitonin. Ad- able, including modified release forms of morphine, juvant analgesics for bowel obstruction (see Cancer oxycodone or hydromorphone. Other drugs, such as Pain Management, Adjuvant Analgesics in Manage- oxymorphonemay become available. The latter drugs ment of Pain Due to Bowel Obstruction) can often con- provide effective analgesia with a prolonged dosingin- trol pain and other symptoms and obviate the need for terval, increasing convenience and potentially adher- drainage procedures. Treatment usually involves the ence to therapy. The transdermal route is available for combination of anticholinergic drugs, octreotide and fentanyl and offers a 48–72 h dosing interval. Other corticosteroids (Lussier and Portenoy 2004). transdermal formulations are in development. The oral transmucosal form of fentanyl has been shown to be Opioid Analgesics safe and efficacious when used to treat breakthrough Opioid pharmacotherapy is the mainstay approach for pain in cancer patients(Christie etal. 1998).Rectalfor- the management of moderate to severe pain in popula- mulations of many opioids, such as oxymorphone,hy- tions with cancer or HIV / AIDS. Guidelines for opi- dromorphone and morphine are available, but are sel- oid selection (see Cancer Pain Management, Princi- dom used for long-term administration. ples of Opioid Therapy, Drug Selection)haveevolved Long-term parenteral dosing is possible for patients from the WHO analgesic ladder approach, which orig- who are poor candidates for oral or transdermal for- Cancer Pain and Pain in HIV / AIDS 201 mulations. Continuous subcutaneous infusion or con- non-pharmacologicalapproach that would potentially tinuous intravenous infusion (if the patient has an in- reduce the opioid requirement might be considered. dwellingcentralvenousport)canbeimplementedwith This might involve an invasive therapy, such as neu- any opioid available in an injectable formulation. Opi- ral blockade or any of a variety of other approaches. oids and other drugs may also be delivered into the Patients who are treated for a prolonged period with C epidural or intrathecal spaces. The strongest indica- opioids must be continually reassessed for side effects. tion for neuraxial infusion is the presence of intoler- In addition to common toxicities, opioids may pro- able somnolence or confusion during systemic opioid duceavarietyofuncommoneffects(see CancerPain therapy. Management, Opioid Side Effects, Uncommon Side The most important principle of opioid administration Effects)oroutcomesthatareyetpoorlyrecognized.For is individualization of the dose (Jacox et al. 1994). In example, endocrine changes (see Cancer Pain Man- all cases, the dose of an opioid should be gradually in- agement, Opioid Side Effects, Endocrine Changes and creased until acceptable analgesia is produced or un- Sexual Dysfunction) associated with opioid use, such manageable side effects supervene. The absolute dose as hypogonadism may be associated with fatigue, sex- of the opioid is immaterial as long as the balance be- ual dysfunction or osteoporosis and should be assessed tween analgesia and side effects remains acceptable to in some populations. the patient. Most patients achieve a favorable outcome Opioids are potentially abusable drugs and the clini- and remain on a stable dose until pain recurs as a result cians who prescribe them for chronic pain should be of disease progression. Recurrent pain following a pe- familiar with the principles of addiction medicine. Al- riod of dose stability usually requires re-evaluation of though abuse and addiction during opioid therapy for the patient and another period of dose titration. pain are very uncommon in the population of cancer Forpersistentorfrequentlyrecurringpain,thebestout- patients with no prior history of substance abuse, these come is achieved by a fixed, around the clock dosing outcomesshouldalwaysbeassessedandaresignificant schedule. Long acting opioids are often used because concerns in subpopulations with substance use disor- oftheconvenienceandthelikelihoodthattreatmentad- ders. Understanding the special considerations posed herence will be better than with frequent daily doses. by opioid use in patients with substance use dis- Breakthroughpaincommonlyismanagedbycoadmin- orders (see Opioid Therapy in Cancer Patiens with istration of short acting, as needed, “rescue doses.” Substance Abuse Disorders, Management) provides Dose titration usually yields a favorable balance be- essential information that must be applied in the treat- tween analgesia and side effects. In some cases, how- ment of all patients. ever, treatment-limiting side effects occur and render the treatment ineffective. This scenario is known Other Approaches in the Management of Chronic Pain as poor opioid responsiveness, a phenomenon that There are numerous alternative strategies that may be should be viewed as individual to the patient, the drug considered in the treatment of pain related to cancer and route and the moment in time. or HIV / AIDS. In almost every situation, the use of Patients with pain that is poorly responsive to the opi- these approaches has been extrapolated from experi- oid therapy must undergo a change in treatment. There ence in the populations with chronic non-cancer pain are no comparative trials to guide clinical practice. syndromes. Noninvasive analgesic strategies can be Four strategies should be considered and a specific broadly categorized into psychological interventions, approach selected based on the assessment and clin- rehabilitative treatments and complementary or alter- ical judgment. Given the individual variation in the re- native medicine approaches. Specific psychological sponse to different drugs, one strategy is to switch to approaches have been applied successfully in the man- analternativeopioid,anapproachcalled opioidrota- agement of pain and related symptoms (Breitbart et tion. A second strategy is to co-administer one or more al. 2004). Treatments include relaxation training, dis- treatments for the side effect that limits dose escala- traction, hypnosis and biofeedback. Although many of tion. Sophisticated approachesare nowavailable to ad- these techniques require experienced personnel to im- dress cognitive dysfunction and gastrointestinal ef- plement, several forms of relaxation training can be fects (see Cancer Pain Management, Gastrointesti- taught by the non-specialist. Behavioral interventions, nal Dysfunction as Opioid Side Effects), the two most like the use of an activities diary to improve physical common types of opioid-related toxicity. A third strat- functioninghaveachievedwideacceptanceintheman- egy involves the use of a pharmacological approach agement of non-cancer pain and are occasionally con- that would potentially allow reduction in the require- sidered for medically illpatients. Avariety of psychoe- ment for the systemic opioid. Coadministration of a ducational and psychotherapeutic approaches may be NSAID or adjuvant analgesic or a trial of neuraxial in- implemented in an effort to improve coping, adapta- fusion might be considered. Finally, a strategy using a tion, family integrity, functioning and quality of life. 202 Cancer Pain and Pain in HIV / AIDS

Rehabilitative therapies (see Cancer Pain Manage- to a subcutaneous portal. The latter techniques are usu- ment, Rehabilitative Therapies), such as therapeutic allypreferredforpatientswithlifeexpectanciesshorter exercise, use of orthotics, and modalities such as heat, than 3 months. cold and electrical stimulation, may be useful in se- Conclusion lected patients. Refractory, movement-induced pain, such as that related to bone metastases may be partially Pain is a common complication of cancer and relieved by bracing the painful part and a well fitting HIV / AIDS. Treatment of pain from a broader per- prosthesis may reduce stump pain. Therapeutic exer- spective of palliative care is likely to yield the best cise may lessen pain associated with immobility, trig- outcomes. Relatively simple therapeutic approaches ger points in muscle, and ankylosis. Although all the can provide effective pain relief in a large majority rehabilitativeapproachesremaininadequatelystudied, of patients. Pain relief must be considered an aspect clinical experience is favorable. of best clinical practice for all clinicians who treat Complementary and alternative medicine (CAM) ap- patients with these illnesses. proaches are commonly pursued by medically ill pa- References tients. Some of these interventions, such as meditation 1. American Psychiatric Association (1994) Somatoform disor- and other mind-body approaches, nutritional support, ders. In: Diagnostic and statistical manual of mental disorders acupuncture and massage, are widely used for pain and (DSM-IV), 4th edn. American Psychiatric Association, Wash- are generally considered mainstream strategies (Pan et ington, pp 445–471 al. 2000). Others, such ashomeopathyand naturopathy 2. Anderson KO, Mendoza TR, Payne R et al. (2004) Pain education for underserved minority cancer patients: a randomized have little scientific support. Clinicians should provide controlled trial. J Clin Oncol. 22:4918–4925 whatever data are available aboutthese approachesand 3. Breitbart W, Payne D, Passik S (2004) Psychological and psy- support informed decision-making. chiatric interventions in pain control. In: Doyle D, Hanks G, Cherny NI et al. (eds) Oxford Textbook of Palliative Medicine, Invasive strategies for pain include neurosurgical in- 3rd edn. Oxford University Press, Oxford, pp 424–438 terventions (see Cancer Pain Management, Neuro- 4. Caraceni A, Portenoy RK, and a Working Group of the IASP surgicalInterventions), suchascordotomy;avariety of Task Force on Cancer Pain (1999) An international survey of injection therapies, including neural blockade; and the cancer pain characteristics and syndromes. Pain 82:263–274 5. Caraceni A, Martini C, Zecca E et al. (2004) Breakthrough pain implantable therapies of neuraxial infusion and spinal characteristics and syndromes in patients with cancer pain. An cord stimulation. Although the injection therapies and international survey. Palliat Med 18:177–183 implants are sometimes described as anesthesiological 6. Christie JM, Simmonds M, Patt R et al. (1998) A dose-titration, therapies(see Cancer Pain Management, Anesthesi- multicenter study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients us- ologic Interventions, Neural Blockade), they are now ing transdermal fentanyl for persistent pain. J Clin Oncol performedbypainspecialistsinavarietyofdisciplines. 16:3238–3245 Neural Blockade includes a diverse group of pro- 7. Dobalian A, Tsao JC, Duncan RP (2004) Pain and the use of cedures that transiently or permanently block sympa- outpatient services among persons with HIV: results from a nationally representative survey. Med Care 42:129–138 thetic nerves, somatic nerves or both (Swarm et al. 8. Green CR, Anderson KO, Baker TA et al. (2003) The unequal 2004).Injectionsmaybediagnostic,prognosticorther- burden of pain: confronting racial and ethnic disparities in pain. apeutic. The solutions injected may be local anesthet- Pain Med 4:277–294 ics, in which case the effects typically are short-lived 9. Hewitt DJ, McDonald M, Portenoy RK et al. (1997) Pain syndromes and etiologies in ambulatory AIDS patients. Pain only or neurolytic substances. Neurolytic blockade 70:117–124 generally is seldom employed and considered in the 10. Jacox A, Carr DB, Payne R et al. (1994) Management of Can- context of advanced illness. One exception is the celiac cer Pain. AHCPR Publication No. 94-0592: Clinical Practice Guideline No. 9. Rockville, MD, U.S. Department of Health plexusblockade for pancreatic cancer, experience with and Human Services, Public Health Service which is sufficiently favorable to apply early in the 11. Lussier D, Portenoy RK (2004) Adjuvant analgesics. In: Doyle treatment of pain. D, Hanks G, Cherny NI et al. (eds) Oxford Textbook of Pal- In medically ill populations, neuraxial infusion and liative Medicine, 3rd edn. Oxford University Press, Oxford, pp 349–377 stimulation (see Cancer Pain Management, Anes- 12. Pan CX, Morrison RS, Ness J et al. (2000) Complementary and thesiologic Interventions, Spinal Cord Stimulation, alternative medicine in the management of pain, dyspnea, and and Neuraxial Infusion) are seldom considered. The nausea and vomiting near the end of life. A systematic review. role of neuraxial infusion may evolve as a result of a J Pain Symptom Manage 20:374–387 13. Schug SA, Zech 0, Dorr U (1990) Cancer pain management controlled trial that demonstrated benefits of an im- according to WHO analgesic guidelines. J Pain Symptom Man- planted pump for intrathecal drug delivery over con- age 5:27–32 ventional systemic opioid therapy in a population with 14. Smith TJ, Staats PS, Stearns LJ et al. (2002) Randomized clin- cancer(Smithetal.2002).Othertechniquesforneurax- ical trial of an implantable drug delivery system compared with comprehensive medical management for refractory can- ial infusion include a tunneled percutaneous epidural cer pain: impact on pain, drug-related toxicity, and survival. J catheter and an implanted epidural catheter connected Clin Oncol 19:4040–4049 Cancer Pain, Animal Models 203

15. Solomon DH, Schneeweiss S, Glynn RJ et al. (2004) Re- 17. Vainio A, Auvinen A (1996) Prevalence of symptoms among lationship between selective cyclooxygenase-2 inhibitors patients with advanced cancer: an international collaborative and acute myocardial infarction in older adults. Circulation study. J Pain Symptom Manage 12:3–10 109:2068–2073 18. Wallenstein DJ, Portenoy RK (2002) Nonopioid and adjuvant 16. Swarm, RA, Karanikolas M, Cousins MJ (2004) Anaesthetic analgesics. In: Berger AM, Portenoy RK, Weissman DE (eds) techniques for pain control In: Doyle D, Hanks G, Cherny NI Principles and Practice of Palliative Care and Supportive On- C et al. (eds) Oxford Textbook of Palliative Medicine, 3rd edn. cology. Lippincott-Raven, Philadelphia, pp 84–97 Oxford University Press, Oxford, pp 378–395 19. World Health Organization (1996) Cancer pain relief, 2nd edn. World Health Organization, Geneva 20. www.nationalconsensusproject.org

Cancer Pain, Animal Models, Figure 1 Bone cancer pain animal model. (a) Radiograph of lower half of adult mouse demonstrating the femur through which osteolytic fluorescent sarcoma cells were injected. Tumor cells are confined within the intramedullary space by placement of an amalgam plug (arrow). Two weeks later, femurs can be assessed at the whole bone level for extraosseous invasion (none noted in b), tumor burden (using excitation filters to visualize green fluorescent protein expressed by tumor cells, (c) and bone destruction (high power radiographic imaging, arrow denotes extensive bone destruction, d). ongoing and movement-evoked pain related behaviors Following the publication of the first animal model of increase in severity as the tumor develops. These pain cancer pain, several rodent models of soft tissue and behaviors correlate with the progressive tumor-induced bone cancer pain have been described. A rat model of bone destruction that ensues, which appears to mimic bone cancer pain was developed (Medhurst et al. 2002) the condition seen in patients with primary or metastatic whereby MRMT-1 mammary carcinoma cells were bone cancer. In this model, peripheral nerve destruc- injected into the tibiae of syngeneic rats. Morphine- tion as well as alterations in neurochemical markers reversible pain behaviors and osteolysis were evident implicated in pain transmission has been observed 2–3 weeks following inoculation. Mouse models of (Fig. 2). soft tissue sarcoma (Wacnik et al. 2001) and rat models

Cancer Pain, Animal Models, Figure 2 Neurochemical changes in the spinal cord and dorsal root ganglia (DRG) in bone cancer pain. (a) confocal imaging of glial fibrillary acidic protein (GFAP) expressed by astrocytes in a spinal cord of a tumor-bearing mouse. Note increased expression only on side ipsilateral to tumorous limb. (b) High power magnification of spinal cord showing hypertrophy of astrocytes (green) without changes in neuronal numbers (red, stained with neuronal marker, NeuN). (c) Confocal image of dorsal root ganglia labeling injured neurons labeled with activating transcription factor 3 (magenta, ATF-3). (d) Non-myelinating schwann cells (green, GFAP) and macrophage infiltration (yellow, CD68) can also be seen. 204 Cancer Pain, Animal Models of neuropathic cancer (Eliav et al. 2004) were also cate endothelin antagonists may be useful in inhibiting developed, and involved growth of tumor cells in soft cancer pain. tissues surrounding bones and alongside sciatic nerves, Osteoclasts, the body’s principal bone resorbing cell, respectively. Mechanical and thermal hyperalgesia, play an essential role in cancer-induced bone loss, and demyelination, progressive tumor infiltration and nerve contribute to the etiology of bone cancer pain (Honore destruction were seen in these models. et al. 2000; Luger et al. 2001; Sabino et al. 2002; Sev- Given the development of animal models of cancer pain, cik 2004). Osteoprotegerin (OPG) is a secreted soluble significant advances have been made in understanding receptor that prevents the activation and proliferation of the molecular and cellular mechanisms which drive osteoclasts. Bisphosphonates induced osteoclast apop- cancer pain (Fig. 3). Cancer cells and tumor associated tosishave been reported to reducepainin cancer patients macrophages have both been shown to express high lev- and in animalmodelsof bonecancerpain (Sevcik2004). elsofCOX–2,leadingtohighlevelsof prostaglandins. Both anti-resorptive compounds were highly potent in Prostaglandins have been shown to be involved in the reducing both cancer-induced bone destruction and the sensitization and/or direct excitation of nociceptors, development of pain-related behaviors, suggesting an by binding to several prostanoid receptors expressed by important role for osteoclasts in the development and nociceptors that sensitize or directly excite nociceptors maintenance of bone cancer pain. (Vasko 1995). Treatment of cancer animals with selec- Cancer pain in advanced cancer patients is typically tive COX–2 inhibitors resulted in significant attenuation recalcitrant to both non-steroidal anti-inflammatory of pain behaviors, as well as many of the neurochemical agentsandopioids,andtypicallyrequiresadjuvantssuch changes, suggestive of both peripheral sensitization as gabapentin for adequate management. Gabapentin is and central sensitization (Medhurst et al. 2002; Sabino also commonly used to treat neuropathic pain patients et al. 2003). who are unresponsive to opioids. In several cancer pain Endothelins have been found in cancer patients (Nel- models, peripheral nerve destruction within skin (Cain son et al. 1995) and in cancer-bearing mice (Wacnik et al. 2001) and bone (Peters et al. 2005) have been ob- 2001), and their levels have been correlated with the served.Likewise,sensitizationofunmyelinatedprimary severity of pain (Nelson et al. 1995). Endothelins could afferent fibers and damage to small and medium sized contribute to cancer pain by directly sensitizing or sensory neurons suggest that a neuropathic component exciting nociceptors, as a subset of small unmyeli- exists in cancer pain. nated primary afferent neurons express endothelin A Insights into the mechanisms that induce cancer pain receptors (Pomonis et al. 2001). Furthermore, direct are now coming from animal models. These models application of endothelin to peripheral nerves induces have begun to provide a glimpse into the mechanisms by activation of primary afferent fibers and an induction of which tumors cause pain and how this sensory informa- pain behaviors (Davar et al. 1998). These findings indi- tion is processed. Chemicals derived from tumor cells,

Cancer Pain, Animal Models, Figure 3 Sensory neurons and detection of noxious stimuli due to tumor cells. Nociceptors use a diversity of signal transduction mechanisms to detect noxious physiological stimuli, and many of these mechanisms may be involved in driving cancer pain. Thus, when nociceptors are exposed to products of tumor cells, tissue injury or inflammation, their excitability is altered and this nociceptive information is relayed to the spinal cord and then to higher centers of the brain. Some of the mechanisms that appear to be involved in generating and maintaining cancer pain include activation of nociceptors by factors such as extracellular protons (+), endothelin-1 (ET-1), interleukins (ILs), prostaglandins (PG), and tumor necrosis factor (TNF). Cancer Pain, Assessment in Children 205 inflammatory cells and cells derived from bone appear to be simultaneously involved in driving this frequently Cancer Pain, Assessment in Children difficult to control pain state. Understanding the mech- GARY A. WALCO anisms involved in the pathophysiology of cancer pain The David Center for Childrens Pain and Palliative will improve our ability to provide mechanism-based Care, University Medical Center Hackensack, NJ, C treatments and therapies, and improve the quality of USA life of cancer patients. Insights such as this promise [email protected] to fundamentally change the way cancer pain is controlled. Definition References Cancer pain in children is associated with three major 1. Cain DM, Wacnik PW, Turner M et al. (2001) Functional Inter- etiologies:(a) proceduraldistress,(b) iatrogenicef- actions between Tumor and Peripheral Nerve: Changes in Ex- fects of treatment, and (c) disease-related pain. Chronic citability and Morphology of Primary Afferent Fibers in a Murine pain among long-term cancer survivors (see cancer Model of Cancer Pain. J Neurosci 21:9367–9376 2. Davar G, Hans G, Fareed MU et al. (1998) Behavioral Signs survivorship) is increasingly recognized as surveillance of Acute Pain Produced by Application of Endothelin–1 to Rat ofthesepatientscontinues.Eachhasuniquecomponents Sciatic Nerve. Neuroreport 9:2279–2283 that dictate the nature of the assessments to be made and 3. Eliav E, Tal M, Benoliel R (2004) Experimental Malignancy in treatments that may ensue. the Rat Induces Early Hypersensitivity Indicative of Neuritis. Pain 110:727–737 4. Honore P, Luger, NM, Sabino MA et al. (2000) Osteoprotegerin Characteristics Blocks Bone Cancer-Induced Skeletal Destruction, Skeletal Pain Procedural Distress and Pain-Related Neurochemical Reorganization of the Spinal Cord. Nat Med 6:521–528 For many of the cancers most common in the pedi- 5. Luger NM, Honore P, Sabino MA et al. (2001) Osteoprote- atric population (e.g. leukemia, lymphoma), invasive gerin Diminishes Advanced Bone Cancer Pain. Cancer Res procedures are integral to the diagnostic and treatment 61:4038–4047 6. Medhurst SJ, Walker K, Bowes M et al. (2002) A Rat Model of process. Included here are bone marrow aspirations and Bone Cancer Pain. Pain 96:129–140 biopsies, for diagnostic purposes, and lumbar punc- 7. Mercadante S, Arcuri E (1998) Breakthrough Pain in Cancer tures, both for diagnostic purposes as well as to deliver Patients: Pathophysiology and Treatment. Cancer Treat Rev 24:425–432 intrathecal chemotherapy as prophylaxis against or 8. Nelson, JB, Hedican SP, George DJ et al. (1995) Identification treatment for central nervous system disease (Balis et of Endothelin–1 in the Pathophysiology of Metastatic Adeno- al. 2002). The latter occurs on a recurrent basis over the carcinoma of the Prostate. Nat Med 1:944–949 course of several months of treatment. Among survivors 9. Peters C M, Ghilardi JR, Keyser CP et al. (2005) Tumor-Induced Injury of Primary Afferent Sensory Nerve Fibers in Bone Cancer of pediatric cancer, the trauma of undertreated procedu- Pain. Exp Neurol 193:85–100 ral distress is often the most disturbing element of their 10. Pomonis JD, Rogers SD Peters CM et al. (2001) Expression entire cancer experience, sometimes severe enough to and Localization of Endothelin Receptors: Implication for the leave children and parents with posttraumatic stress Involvement of Peripheral Glia in Nociception. J Neurosci 21:999–1006 symptoms (Stuber et al. 1998). Interventions combining 11. Portenoy RK, Payne D, Jacobsen P (1999) Breakthrough Pain: sedating and analgesic agents along with preparatory Characteristics and Impact in Patients with Cancer Pain. Pain and cognitive-behavioral strategies (see Cognitive- 81:129–134 Behavioral Treatment of Pain) have greatly reduced the 12. Sabino MA, Ghilardi JR, Jongen JL et al. (2002) Simultaneous Reduction in Cancer Pain, Bone Destruction, and Tumor Growth pain and anxiety associated with invasive procedures by Selective Inhibition of Cyclooxygenase–2. Cancer Res 62: (Berde et al. 2002; Conte et al. 1999). Assessment 7343–7349 strategies involve three modalities: self-report of the 13. Sabino MA, Luger NM, Mach DB et al. (2003) Different Tu- mors in Bone Each Give Rise to a Distinct Pattern of Skeletal child, behavioral observations, and physiological in- Destruction, Bone Cancer-Related Pain Behaviors and Neuro- dicators of stress (Walco et al. 2005). As these do not chemical Changes in the Central Nervous System. Int J Cancer necessarily correlate with one another, it is imperative to 104:550–558 specify the target outcome(s) of the intervention (Walco 14. Schwei MJ, Honore P, Rogers SD et al. (1999) Neurochemical and Cellular Reorganization of the Spinal Cord in a Murine Model et al. 2005). Ultimately the goal would be to implement of Bone Cancer Pain. J Neurosci: 19:10886–10897 an algorithm optimizing the match between patient 15. Sevcik MA, Luger NM, Mach DB et al. (2004) Bone Cancer needs and available interventions, so that comfort may Pain: The Effects of the Bisphosphonate Alendronate on Pain, be assured while risk and cost are minimized. Skeletal Remodeling, Tumor Growth and Tumor Necrosis. Pain 111:169–180 Iatrogenic Effects 16. Vasko MR (1995) Prostaglandin-Induced Neuropeptide Release from Spinal Cord. Prog Brain Res 104:367–380 Treatments for cancer involve chemotherapy, radiation, 17. Wacnik PW, Eikmeier LJ, Ruggles TR et al. (2001) Func- surgery, and stem cell transplantation. Each poten- tional Interactions between Tumor and Peripheral Nerve: tially leads to iatrogenic pain problems (Collins and Morphology, Algogen Identification, and Behavioral Charac- terization of a New Murine Model of Cancer Pain. J Neurosci Weisman 2003). Symptoms resulting from chemother- 21:9355–9366 apeutic and radiation treatment most commonly include 206 Cancer Pain, Assessment in Children nausea and vomiting, fatigue, neutropenia and related child. Parental ratings of pain may also be helpful in vulnerability to infection, and pain. Common iatro- preverbal children. genic pain syndromes in pediatric cancer are related to For procedural distress, assessment strategies should in- mucositis, infectious process, and neuropathic pain cludetwomajorcomponents,anxietyandpain.Theterm (from peripheral neuropathy) associated with agents “distress” is used as a way to represent the combined such as vincristine. Pain secondary to radiation is also effect of these two factors, as they are separable only seen in some instances. Painful sequelae of surgical in concept, not in practice. Behavior rating instruments interventions occur, including phantom limb pain typically define specific behaviors, and frequency of oc- related to amputations. Acute abdominal pain, severe currence, duration, or intensity is scored during a spec- enough to require administration of opioids, has been ified period. Typically, this includes a segment prior to, noted among patients who have undergone allogeneic during, and after the procedure. Likewise, physiologi- bone marrow transplantation. Finally, as follow-up calindicators,includingheartrate,bloodpressure,vagal programs for long-term survivors of childhood cancer tone, and cortisol responses have been used as indicators provide data, it appears that chronic pain syndromes of acute distress. Self-report measures focus on the sub- may be of concern. For example, aseptic necrosis of the jective experience of the child and typically encompass bone is a known long-term effect of high dose steroid concernsaboutpain,anxiety,andperceivedself-efficacy usage, and does not manifest until well after the child in coping (Walco et al. 2005). has completed standard treatment protocols. For pain related to both disease and the iatrogenic effects oftreatment,selfreportmeasureshelpascertaintheloca- Disease-Related Pain tion of pain, intensity, sensory, affective, and evaluative Disease-related pain in pediatric cancer is not as com- components,aswellastheimpactofpainonfunctioning. mon as in neoplasms common in the adult population. Especiallywhenconfrontingpainthatismorechronicor Painmaybepresentatthetimeofdiagnosis,aspaininthe recurrent in nature, assessing the contextual factors as- long bonesisassociated with leukemia, severe headache sociated with the pain experience (developmentallevel, isasymptom of brain tumors, solid tumorsmay elicitso- temperament,characteristicpainresponsiveness,family matic pain in the focal area of tumor growth or infiltra- issues, impact of pain, etc.) becomes very important. tion, and abdominal tumors may generate visceral pain. In contrast to adult patients with such tumors, children References withcancerusuallyexperienceasignificantremissionof 1. American Academy of Pediatrics Committee on Psychosocial pain within two weeks of beginning treatment (Miser et Aspects of Child and Family Health, American Pain Society Task al. 1987). Unfortunately, the other circumstance where Force on Pain in Infants, Children, and Adolescents (2001) Policy Statement: The Assessment and Management of Acute Pain in In- pain is problematic is in advanced illness, often in the fants, Children and Adolescents (0793). Pediatrics 108:793–797 contextofend-of-lifecare. Thus,manyofthesametypes 2. Balis FM, Holcenberg JS, Blaney SM (2002) General Principles of syndromes seen at presentation, where pain is of high of Chemotherapy. In: Pizzo PA, Poplack DG (eds) Principles and intensityandoftenunrelenting,recurinadvancedillness Practice of Pediatric Oncology, 4th edn. Lippincott, Williams & Wilkins, Philadelphia, pp 237–308 and should be addressed in service of maximizing qual- 3. Berde CB, Billett AL, Collins JJ (2002) Symptom Management ity of life (Wolfe and Grier 2002). in Supportive Care. In: Pizzo PA, Poplack DG (eds) Principles and Practice of Pediatric Oncology, 4th edn. Lippincott, Williams Assessment Strategies & Wilkins, Philadelphia, pp 1301–1332 Specific pain assessment strategies depend on the age 4. Collins JJ, Weisman SJ (2003) Management of Pain in Childhood Cancer. In: Schechter NL, Berde CB, Yaster M (eds) Pain in or developmental level of the child and the nature Infants, Children, and Adolescents, 2nd edn. Lippincott, Williams of the pain in question (McGrath and Gillespie 2001). & Wilkins, Philadelphia, pp 517–538 Whenever possible, it is optimal to use patients’ verbal 5. Conte PM, Walco GA, Sterling CM et al. (1999) Procedural Pain Management in Pediatric Oncology: A Review of the Literature. reports to assess their pain experience, skills that emerge Cancer Investigation 17:448–459 in children between the ages of 3 and 7 years (Ameri- 6. Franck LS, Greenberg CS, Stevens B (2000) Pain Assessment can Academy of Pediatrics Committee on Psychosocial in Infants and Children. Pediatric Clinics of North America Aspects of Child and Family Health, American Pain 47:487–512 7. Lilley CM, Craig KD, Grunau RE (1997) The Expression of Society Task Force on Pain in Infants, Children, and Pain in Infants and Toddlers: Developmental Changes in Facial Adolescents 2001). In preverbal children, pain is as- Action. Pain 72:161–70 sessed through physiological indicators of distress 8. McGrath PJ (1998) Behavioral Measures of Pain. In: Finley GA, (Sweet and McGrath 1998), through specific behav- McGrath PJ (eds) Measurement of Pain in Infants and Children. Progress in Pain Research and Management, vol 10. IASP Press, ioral indicators (McGrath 1998; Lilley et al. 1997), or Seattle, Washington, pp 83–102 through some combination thereof (Franck et al. 2000). 9. McGrath PA, Gillespie J (2001) Pain Assessment in Children During the toddler and preschool years, as children be- and Adolescents. In: Turk DC, Melzack R (eds) Handbook of nd gin to use language meaningfully, increased emphasis Pain Assessment, 2 edn. Guilford, New York, pp 97–118 10. Miser A, Dothage J, Wesley R et al. (1987) The Prevalence of may be placed on verbal report, but one must take care Pain in a Pediatric and Young Adult Cancer Population. Pain to use language and terminology that is familiar to the 29:73–83 Cancer Pain, Assessment in the Cognitively Impaired 207

11. Stuber ML, Kazak AE, Meeske K et al. (1998) Is Posttraumatic and subsequent postherpetic neuralgia. One might Stress a Viable Model for Understanding Responses to Child- then reasonably expect that individuals suffering from hood Cancer? Child and Adolescent Psychiatric Clinics of North America 7:169–182 dementia and delirium would also be disproportion- 12. Sweet SD, McGrath PJ (1998) Physiological Measures of Pain. ately affected by these syndromes, resulting in a large In: Finley GA, McGrath PJ (eds) Measurement of Pain in Infants number of cognitively impaired elderly in desperate C and Children. Progress in Pain Research and Management, vol 10. need of aggressive and appropriate pain assessment and IASP Press, Seattle, Washington, pp 59–81 13. Walco GA, Conte PM, Labay LE et al. (2005) Procedural distress treatment. in children with cancer: self-report, behavioral observations, and In addition, older patients as a group are at high risk for physiological parameters. Clin J Pain 21:484–90 undertreatment of cancer pain. Cleeland et al. showed 14. Wolfe J, Grier HE (2002) Care of the Dying Child. In: Pizzo that those over the age of 70 were at higher risk of re- PA, Poplack DG (eds) Principles and Practice of Pediatric On- ceiving inadequate pain management (Cleeland 1998). cology, 4th edn. Lippincott, Williams & Wilkins, Philadelphia, pp 1477–1493 Bernabei et al. documented significant numbers of nursing home patients with cancer suffering from daily pain, and those over age 85 were at particular risk of having no analgesia at all (Bernabei et al. 1998). Cancer Pain, Assessment in the Cognitively Impaired Dementia versus Delirium Folstein and Folstein define dementia as “a syndrome WENDY M. STEIN characterized by a decline in multiple cognitive func- San Diego Hospice and Palliative Care, UCSD, San tions occurring in clear consciousness” (Folstein and Diego, CA, USA Folstein 1994b). Dementia has been estimated in [email protected] 10–15% of elderly surgical patients, one-third of elderly medical inpatients, and more than 50% of nursing home Synonyms residents (Folstein and Folstein 1994b). Delirium, on Cognitive Impairment; dementia; delirium the other hand, is noted for its acute or subacute presentation with waxing and waning levels of consciousness, Definition global cognitive impairment, and disorganized wake- sleep cycles. Delirium has been well described in the Cognitive impairment or altered mental state is a change medical literature in patients with cancer (Derogatis in the patient’s usual premorbid state of mind, which can et al. 1983); however, it also occurs commonly in the include delirium and dementia as well as altered emo- elderly, especially in those with underlying dementias. tions and behaviors (8). Rates of delirium have ranged as high as 50% in hospitalized patients with previously diagnosed dementia Characteristics (Ouslander et al. 1997); in reality the figures may be This section will focus on the challenging assess- even larger, as in the community dementia is often ment of cancer pain in the communicative and non- well hidden by well meaning family and friends who communicative cognitively impaired patient. Acute compensate for gradually increasing mental deficits and subacute changes in mental status have been well over time. documented in as many as 20–30% of medical inpatients and 50–90% of nursing home residents (Folstein Studies of Pain in the Communicative Cognitively Impaired and Folstein 1994b), and can substantially impair a The reader should keep in mind that most pain studies of patient’s ability to participate actively in both the initial assessment in the cognitively impaired have not focused pain assessment and subsequent evaluation of treatment specifically on cancer pain, but on all types of pain in efficacy. The initial step is to establish the patient’s pre- general.Parmaleeetal.(1996)studiedself-reportedpain morbid mental status, and the nature and association in 758 elders with mild to moderate levels of cognitive of any clinical changes that may have occurred. Vision impairment. This study showed that pain complaints de- and hearing impairments can further complicate both creased with increasing levels of cognitive impairment the assessment and treatment of pain in the cognitively over time, i.e. that patients became less good at report- impaired and need to be adequately compensated. ingtheirpain.However,whencognitivelyimpairedindi- Population-based studies of community dwelling el- viduals reported pain, their pain complaints were no less derly have shown a two-fold increase in pain problems valid. Ferrelletal. (1995)studiedpatientswithmoderate significant enough to impair daily function among those to severe degrees of cognitive impairment in 10 com- over age 60 (Crook et al. 1984). Older patients have munity nursing homes. The researchers presented five a higher prevalence of a number of specific pain syn- commonly used pain scales in enlarged format and with dromes including most types of cancer, peripheral vas- adequate amounts of light, and with hearing augmenta- cular disease, temporal arteritis and polymyalgia tion if required. Of those presented, the Present Pain rheumatica, peripheral neuropathies, herpes zoster Intensity Subscale (PPI) had the highest rate of comple- 208 Cancer Pain, Assessment in the Cognitively Impaired tion (65%). Although only 32% could complete all five General Recommendations scales presented, 83% of these patients with significant The clinician needs to create an optimal environment cognitive impairment could complete at least one of the in order to adequately assess pain in the communica- scalespresented.Thesefindingsvalidatetheutilityofof- tive cognitively impaired. Limited attention span may fering a variety of scales when using standardized mea- demand dividing up the initial assessment into several sures with the cognitively impaired, and then continuing shorter sessions. Additional time should be allowed for with what works best for that patient. the patient to assimilate questions to allow for receptive or expressive aphasia. Ensuring that large print cards, Pain in Non-Communicative Cognitively Impaired Patients adequate lighting, and hearing aids or pocket amplifi- Unfortunately, many early studies of pain assessment cation devices and refractive lenses are available is vi- in this population focused on the use of pediatric instru- tal. Qualitative descriptions of pain should bear equal ments, and specifically those developed for neonates, weight and be encouraged. If using standardized tools, without first establishing data in this population. These multiple tools should be presented upon initial assess- tools were developed to measure acute, and often exter- ment so as to discern which is easiest for that particular nally induced procedure related pain. In the cognitively patient,documentthisintheclinicalrecord,andcommu- impaired elderly, clinicians are most often evaluating nicate thiswith the care team (Stein 1996). Copiesofthis chronic, or acute on chronic pain, which is likely to tool can be made available (without identifying data on present differently. There have now been multiple stud- it) on the chartand atthe bedside, ensuringthateach sub- ies to validate the use of standardized tools specifically sequent assessment is performed exactly the same way adapted and/or developed for use in this population such regardless of the team member asking the questions. As as the Faces Pain Scale (Herr et al. 1998). However, the cognitively impaired elderly are often unable to re- global evaluations of a combination of nonverbal behav- port on previous pain, assessment should be conducted ior, vocalizations, changes in function, and caregiver more frequently than would be necessary with a cogni- reports are most often used as indicators of pain in the tively intact patient (Stein 2001). Family members and non-communicativecognitively impaired elderly (AGS caregivers can assist in this process by helping to jour- Panel on Chronic Pain in Older Persons 2002). Marzin- nal the patient’s pain when they visit, thus providing a ski (1991) studied 60 patients living in a dementia unit, comprehensive picture. of which 43% had potentially painful conditions based Deviation from what is considered baseline or ‘nor- on chart review. The most clinically interesting finding mal’ behavior for the non-communicative cogni- of this study was that the nursing staff could clearly tively impaired patient remains the clinical imperative identify what amounted to normative behavior for in- (Stein 2001). This should trigger a comprehensive bed- dividual patients, and once aberrations were identified, side physical examination coupled with laboratory and to act upon them. imaging studies, consistent with the benefits and bur- Several studies have sought to link assessment with dens likely to be incurred and the patient and/or family’s initiating pain interventions empirically in non-com- wishes. Physical examination should specifically focus municative cognitively impaired elders. The most on occult sources or atypical presentations of infection comprehensive project of this nature is that of Ko- such as pneumonia or urinary tract infection, as well vach et al. (1999). The research team worked with as fecal impaction. The clinical involvement of the 104 non-communicative demented elderly who had entire interdisciplinary team should be sought to elicit signs or symptoms of pain or discomfort at 32 nursing alterations in sleeping, eating or elimination as sources homes. The nursing staffs were instructed in the use of of change in behavior. Chart review should exclude the Assessment of Discomfort in Dementia (ADD) changes in medications, doses or dose intervals as po- Protocol if a patient displayed signs or symptoms of tential causes. After all of the above have been carefully distress. After excluding common physical causes for completed and reviewed with family members and staff, discomfort such as occult infection, or impaction by and informed consent obtained from involved family thorough physical assessment, and review of history members, there may be a role for a well-defined empiric including consultations with family and/or physicians, trial of short-acting pain medication with consistent and nonpharmacologic comfort interventions were un- continual reassessment (Stein 2001). dertaken. If unsuccessful, the nurses were educated to administer ‘as needed’ non-opioid analgesics, and References continue up the WHO ladder depending on response 1. AGS Panel on Chronic Pain in Older Persons (2002) The Man- and discussion with physicians. The sample population agement of Chronic Pain in Older Persons. JAGS 50:1–20 decreased behavioral symptoms associated discomfort 2. Bernabei R, Gambassi G, Lapane K et al. (1998) Management from an average of 32.85–23.47 symptoms on protocol, of Pain in Elderly Patients with Cancer. SAGE Study Group. which was a statistically significant change. Of note Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 279:1877–1882 was the fact that 88% of the staff felt that the protocol 3. Cleeland CS(1998) Undertreatment of Cancer Pain in the Elderly. was beneficial. JAMA 279:1914–1915 Cancer Pain, Assessment of Cultural Issues 209

4. Crook J, Rideout E, Browne G (1984) The Prevalence of Pain family, and practitioners are more or less influenced Complaints among a General Population. Pain 18:299–314 by the culture of the health care system, the disease 5. Derogatis LR, Morrow GR, Fetting J et al. (1983) The Preva- lence of Psychiatric Disorders among Cancer Patients. JAMA and the larger society. It is at this interface that under- 249:751–757 standing, collaboration and negotiation needs to occur 6. Ferrell BA, Ferrell BR, Rivera L (1995) Pain in Cognitively (Koenig and Gates-Williams 1995; Kagawa-Singer and C Impaired Nursing Home Patients. J Pain Symptom Manage Blackhall 2001; Kagawa-Singer 1996). 10:591–598 7. Folstein MF, Folstein SE (1994a) Neuropsychiatric Assessment Studies of the relationship of culture and pain date of Syndromes of Altered Mental State. In: Hazzard WB, Bierman back to 1950 and include both clinical and laboratory EL, Blass JP et al. (eds) Principles of Geriatric Medicine and research. Studies have focused on such varied aspects Gerontology. McGraw-Hill, pp 221–228 as pain threshold, pain perception and description, 8. Folstein MF, Folstein SE (1994b) Syndromes of Altered Men- tal State. In: Hazzard WB, Bierman EL, Blass JP et al. (eds) attitudes and behaviors, undertreatment in minority Principles of Geriatric Medicine and Gerontology. McGraw-Hill, patients, coping strategies, use of opioid medications, pp 1197–1204 beliefs, ascribed meaning and outcomes (Edwards et 9. Herr KA, Mobily PR, Kohout FJ et al. (1998) Evaluation of the al. 2001; Zatzick and Dimsdale 1990). As far back as Faces Pain Scale for Use with the Elderly. Clin J Pain 14:29–38 10. Kovach CR, Weissman DE, Griffi J et al. (1999) Assessment and 1952, Zborowski studied the influence of ethnicity on Treatment of Discomfort for People with Late-Stage Dementia. pain response patterns, attitudes, beliefs and meaning J Pain Symptom Management 18:412–419 (Zborowski 1952). In 1966, Zola studied interethnic dif- 11. Marzinski LR (1991) The Tragedy of Dementia: Clinically As- ferences in the response and attitudes toward symptoms sessingPainintheConfused, Nonverbal Elderly. JGerontological Nursing 17:25–28 such as pain (Zola 1966). 12. Ouslander JG, Osterweil D, Morley J (1997) Delirium and De- Cultural aspects of pain such as meaning, attribution, mentia. In: Medical Care in the Nursing Home. McGraw-Hill, description and health seeking behaviors become in- pp 147–162 13. Parmalee PA (1996) Pain in Cognitively Impaired Older Persons. creasingly relevant as research points to the importance In: Ferrell BA, Saunders WB (eds) Clinics In Geriatric Medicine, of these factors on outcomes. For example, a study of pp 473–485 chest pain in a population from the Southern United 14. Stein WM (1996) Cancer Pain in the Elderly. In: Ferrell BR, States revealed that cultural differences resulted in Ferrell BA (eds) Pain in the Elderly. IASP Press, Seattle, pp 69–80 15. Stein WM (2001) Assessment of Symptoms in the Cognitively atypical descriptions, which have the potential to mis- Impaired. In: Topics in Palliative Care. Oxford University Press lead clinicians who depend on the description of the 5:123–133 character of chest pain as they triage for ischemic heart disease (Summers et al. 1999). A study of indigenous and non-indigenouspeople with persistent chest pain in Cancer Pain, Assessment of Cultural the Northern Territory of Australia revealed that delays in presentation affected both rural and urban indige- Issues nous peoples, as well as rural non-indigenous people; TERRY ALTILIO these delays influence management options for acute Department of Pain Medicine and Palliative Care, Beth myocardial infarction (Ong and Weeramanthri 2000). Israel Medical Center, New York, NY, USA Such information assists clinicians and health educators [email protected] to know that signs and symptoms, and pain-related behaviors, may not be the same for all culturalgroups. Pain Definition related to a diagnosis of cancer becomes complicated by the values and beliefs surrounding the disease itself, Culture is defined as learned values, beliefs, behaviors which may vary among optimism, hopelessness, shame and systems of meaning which guide a worldview and or acceptance. These findings can provide direction to inform decisions. Culture is constantly redefined and culturally informed assessment, education and outreach negotiated and respectful, comprehensive care requires efforts. combining theoretical knowledge with a meaningful Within available research, there is considerable vari- exploration of the “patients unique history, family ation in study populations, theoretical formulations, constellation and socioeconomic status” (Koenig and study design and findings. There is much opportunity Gates-Williams 1995). for ongoing research in this rich and complex topic. Assessment and study challenges include cross-cultural Characteristics validity of behavioral cues to indicate pain level, cross- Although knowledgeof specific cultures can be instruc- cultural validity of assessment tools, and expanding tive, cultural identification alone is not predictive of spe- study designs to include variables such as intracultural cific behaviors, values or beliefs. Intracultural variation differences and influence of clinician culture on out- emanating from such factors as gender, age, geographic come. Assessment tools such as the Brief Pain Inventory location, ties to country of origin, assimilation and and McGill Pain Questionnaire have been validated and acculturation contribute to the dynamic nature of cul- translatedintolanguagesotherthanEnglish.Inaddition, ture. Culture infuses the experience of the patient and acceptance of unique cultures requires understanding 210 Cancer Pain, Assessment of Cultural Issues that linear assessment tools may have little relevance experience, such as a diagnosis of a life threatening in cultures where numbers have no relationship to pain illness. Culture influences how, if and to whom the rating, or where narrative or pictures are essential to subjective pain experience is expressed and whether it communication (Kagawa-Singer and Blackhall 2001, is described in direct, substitute or metaphoric terms. Hallenbeck and Goldstein 1999). In cultures where control is valued, endurance and Consideration of cultural issuesin the health care setting stoicism would be expected and outward expression of means that practitioners have to reconcile the possibil- pain viewed as a sign of weakness, possibly resulting in ity that their personal beliefs and values, and the values guilt or shame. Similar behaviors are not always based of the medical system, may not be shared by the patient in the same value system. For example, stoicism may and family (Hallenbeck 2002). Consequently, clinicians reflect a reluctance to impose or disrupt others rather need to develop an awareness of the culture and tradi- than a sign of endurance. This is especially important tions of the population they treat. This awareness be- with a diagnosis of cancer, where historically emphasis comes a hypothesis and serves only as background to has been on curing the disease and pain, and quality of guide inquiry and exploration. The subjective nature of life issues have been perceived as a distraction from that pain requires that each patient’s pain description, report primary goal. Expressions of pain, such as crying, curs- and behaviors be explored and understood in the context ing or moaning, can be the learned and expected way ofculturalvariationrelatedtopain.Cliniciansbringtheir to express distress and seek care, and are not always own personal and professional cultural perspectives into correlated with the degree of pain. These behaviors the medical setting and it is at this interface that the as- may relate to feared consequences rather than the pain sessment of pain, clinical judgement and related treat- itself (Mims 1989). In patients with cancer, emerging or ment interventions take place. As early as 1977, Davitz increasing pain may be interpreted as a sign of progress- et al. reported on the emergency room care of a 45-year- ing disease, and the symbolic significance of the pain old male whose pain behaviors were observed by three becomes a source of suffering and distress. Dramatic nurses of different ethnic group backgrounds (Davitz expressions of pain can serve an important purpose in et al. 1977). Each nurse had different reactions and judg- systems and situations where people have to compete ments of his expression of pain. A nurse from North- for care, or where healthcare professional have mini- ern Europe described the patient as very emotional and mized or challenged reports of pain. Cultures that value overreactive.A nurse from Puerto Rico felt the patient’s patience and choose not to disrupt others need outreach outbursts were understandable and an American nurse from health care staff to create an environment where expected that an adult male of his age and background patients feel their comfort to be an important focus of would be stronger and more stoic. A follow-up study care. Another variable that influences the expression of found thatnursesfrom variouscountriesdifferedin their pain and related content is time orientation. In societies judgments about the degree of patient suffering. These that are future-oriented, patients may project ahead, findingsareanalerttoalldisciplinesoftheimportanceof and rather than focus on the sensation of pain and relief, self awareness, asclinician beliefsand valuescan signif- will anticipate and worry about the future impacts of icantly impact on attitudes and practice (Bonham 2001). pain and disease (Mims 1989). Characteristics of pain assessment and management may be influenced by culture. While categorized as Meaning of Pain discrete aspects, these variables are integrated and over- The meaning of pain may have an importantrelationship lapping, and related to the larger historical/political, toresponse,behaviorsandcoping.Culturaltraditionsof- class and socioeconomic issues (Koenig and Gates- ten prepare individualstoanticipatepainincertainsitua- Williams 1995). For example, in some countries, the tions, which can increase feelings of control and lessen experience of marginalization and discrimination of anxiety and distress related to the unknown. Pain that minority patients creates an environment of mistrust has been experienced before has different meaning than and/or hopelessness, which requires clinicians to spend pain that is related to a life-threatening illness, or is un- additional time and ongoing effort to establish begin- expected, and all will be integrated in accordance with ning rapport and credibility. The undertreatment of personal and cultural beliefs and values. The narratives pain, including cancer pain, in minority populations and descriptions not only reflect pain but also attempt to has been identified in a variety of studies, and further make sense of it within a cultural context and within the work is needed to isolate the multidimensional factors context of a known diagnosis (Hallenbeck 2002; Davitz that influence these outcomes (Zborowsk 1969). etal.1977;Lipsonetal.2000).Healthmaybeconsidered a gift from God or a reflection of internal equilibrium. Expression and Language of Pain Cancer and pain may be interpreted as a sign of inter- Pain complaints can be conveyed using verbal, facial or nal imbalance, divine displeasure, a curse, witchcraft, body language. For many, how one expresses and re- or perhaps, the result of transgressions in prior life. If sponds to pain is learned through childhood experience pain is considered part of God’s plan, a test of faith or an and either reinforced in adulthood or modified by other opportunity for character building and redemption, then Cancer Pain, Assessment of Cultural Issues 211 acceptance and the manner of coping may be a demon- associated with addiction or death. When medications stration of courage and faith. Where pain is an extension are feared, patients may discontinue them quickly. In of God’s will, or when suffering is felt to be an expected high context cultures, treatment plans and options may part of life, there may be a feeling of fatalism that re- need to be discussed with family and community, which sults in a feeling of powerlessness with no expectation may include healers, elders or clergy (Hallenbeck and C or acceptance of treatment (Hallenbeck 2002; Davitz et Goldstein 1999). al. 1977; Lipson et al. 2000).

Expectations of Health Care Professionals Caregiver Responses The expectations of healthcare professionals are highly The responses of caregivers are multifaceted and often influenced by cultural variables. Respect for clinicians relate to how care is provided to a sick family or com- maybeexpressedbybehaviorssuchasnotmakingdirect munity member. The expected roles and responses of eye contact and not challenging or questioning practi- patients, parents, siblings, family and community may tioners. Many traditions support a hierarchical system, evolve from an acute illness model. For some, a cancer and patients do not expect a consultative model where diagnosismay yield helplessnessand passivity asthe ac- they are asked for feedback and given options. Expect- ceptedandexpectedresponsetoillnessandpain(Hallen- ing to be guided by experts, patients may interpret the beck and Goldstein 1999). Transition to a chronic dis- consultative approach as a reflection of incompetence. ease state can challenge traditional beliefs and behav- Health care relationships are a reflection of the larger iors, as the support must become long-term, and there is culture, which may be high or low-context. Low-context a need to accommodate to a person who receives ongo- culture, similar to Western biomedicine, places empha- ing treatments and may or may not be disabled (Lipson sis on individuality and a more linear verbal communi- et al. 2000). Traditional beliefs, which encourage rest cation, whereasa high-contextenvironmentemphasizes and dependence can be very responsive to situations of the relational aspects that are important to care, decision pain in life threatening illness and less helpful in chronic making and inclusion of family and community (Hal- settings, where goalsof care include recoveringfunction lenbeck 2002; Davitz et al. 1977). Consultation with a andencouragingparticipationbeyondtheroleofpatient. health care professional may follow the primary heal- The convergence of culture, pain and the diagnosis of ing efforts of family or healers. Acknowledging and in- cancer provides a rich and challenging opportunity for tegrating these traditional interventions can be signs of clinicians to individualize assessment and intervention, respect for patients and their support systems and may and maximize the support, comfort and continuity that enhance outcome. In situations where the language of comes from cultural beliefs and sustains patients and patient and clinician differ, perceptions of patient and families through medical and life transitions, crises and family aboutthe use of medicaltranslatorsneed to be ex- beyond. plored. Family members are untrained in the use of med- icalterminologyandwhenactingasinterpretersmayex- perience role conflict and confusion (Zhou et al. 1993). References Clinicians are in the unique position of being unaware of 1. Bonham VL (2001) Race, Ethnicity and Pain Treatment: Striving the actual content and accuracy of the communication to Understand the Causes and Solutions to the Disparities in Pain whenfamilyandfriendstranslatethroughtheirowncog- Treatment. J Law Med Ethics 29:52–68 2. Davitz LL, Davitz JR, Higuchi Y (1977) Cross-Cultural In- nitive and emotional filters. ferences of Physical Pain and Psychological Distress. Nursing Times 73:521–558 Response to and Acceptance of Treatments 3. Edwards CL, Fillingim RB, Keefe F (2001) Race, Ethnicity and Pain – Topical Review. Pain 94:133–137 Treatment response is based on a range of values and 4. Groce NE, Zola IK (1993) Multiculturalism, Chronic Illness and beliefs. In addition to the ongoing investigation of in- Disability. Pediatrics 91:1048–1055 terethnic differences in drug response, culture impacts 5. Hallenbeck JL (2002) Cross-Cultural Issues. 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10. Lipson JG, Dibble SL, Minarik PA (eds) (2000). Culture & which studies were conducted. In many instances, the Nursing Care: A Pocket Guide. California: UCSF Nursing issue of potential confounding factors has not been ad- Press, pp 3–4 11. Mims BC (1989) Sociologic and Cultural Aspects of Pain. In: Tol- equately addressed. There is also non-distinction on the lison CD (ed) Handbook of Chronic Pain Management. Williams various measures of disease occurrence and risk used and Wilkins, Baltimore, pp 17–25 in measuring the distribution, determinants, and natu- 12. Ong MA, Weeramanthri TS (2000) Delay Times and Man- ral history of pain. For example, prevalence measures agement of Acute Myocardial Infarction in Indigenous and Non-Indigenous People in the Northern Territory. Med J (which quantify the proportion of a population with Australia 173:173–174 a condition at a given point in time (point prevalence 13. Summers RL, Cooper GJ, Carlton FB et al. (1999) Prevalence rate), the proportion of persons affected by the condi- of Chest Pain Descriptions in a Population from the Southern tion during a defined period of time (period prevalence United States. Amer J Medical Science 318:142–145 14. Zatzick DF, Dimsdale JE (1990) Cultural Variation in Response rate), or the proportion of a population affected over to Painful Stimuli. Psychosom Med 52:544–557 their lifetime (lifetime prevalence rate)) are commonly 15. Zborowski M (1952) Cultural Components in Responses to Pain. confused with incidence measures (which quantify J Social Issues 8:16–30 the probability or rate of onset of a condition among 16. Zborowski M (1969) People in Pain. Jossey-Bass, San Francisco, pp 30–41 persons with no prior history). A recent report of the 17. Zhou HH, Sheller JR, Nu H et al. (1993) Ethnic Differences in National Cancer Institute (Patrick et al. 2004), while Response to Morphine. Clin Pharmacol Ther 54:507–513 emphasizing the need for better symptom epidemio- 18. Zola J (1966) Culture and Symptoms, an Analysis of Patients logic studies, elaborates the methodological issues and Presenting Complaints. Am Sociol Rev 31:615 challenges facing researchers who study the epidemiology of pain. In this essay, we report on studies of the prevalence of pain among cancer patients and the risk Cancer Pain, Epidemiology factors associated with pain and its undertreatment, and offer recommendations for future studies on the CIELITO C. REYES-GIBBY,CHARLES S. CLEELAND epidemiology of pain. The University of Texas M. D., Anderson Cancer Center, Houston, TX, USA Prevalence of Cancer Pain [email protected] Pain is prevalent for large numbers of patients with cancer (Cleeland et al. 1997; Cleeland et al. 1994; Definition Portenoy et al. 1994; Von Roenn et al. 1993). Approxi- mately 55% of outpatients with metastatic cancer have Epidemiology provides a framework for measuring the disease-related pain, and 36% have pain of sufficient prevalence, incidence, and risks associated with pain in severity to impair their functioning and quality of life. cancer patients. Epidemiology provides research meth- Significant pain is rarely a problem at diagnosis, but as ods that can be used to answer the following questions: disease becomes metastatic, a majority of patients will What is the occurrence of pain in people with cancer? At have pain (Daut and Cleeland 1982). Pain prevalence what stage of the disease does pain become a problem? and severity obviously varies with the adequacy of Are cancer patients at a higher risk for pain compared pain management. However, despite the existence of to patients with chronic conditions such as diabetes or national and internationalpain managementguidelines, cardiovascular disease? To what extent does the preva- many patients with pain are not prescribed an analgesic lence of cancer pain vary by age, gender, or race? What appropriate to the severity of their pain. Multicenter factors are associated with the prevalence or incidence studies indicate that approximately 40% of patients of pain? What proportion of patients receives adequate with cancer pain are not prescribed analgesics potent treatment for pain? enough to manage their pain, with additional patients receiving insufficient doses of the analgesic prescribed. Characteristics Studies of pain related to specific cancers show pain as Although many studies have attempted to answer these highly prevalent. For example, a study of breast cancer basic questions, consistent results have been difficult patients (stages II, III, and IV breast cancer) showed to obtain. Estimates of the number of cancer patients 47% had severe pain (Gaston-Johansson et al. 1999). experiencing pain vary widely, mainly because of a In a study of pancreatic cancer patients, at least 44% lack of uniformity (or standardization) in the defini- were found to have severe pain (Brescia et al. 1992). A tions and assessment measures used (i.e. there is no review of studies of lung cancer patients document that gold standard) and the heterogeneity of pain conditions as many as 85% experienced severe pain (Potter and (nociceptive vs. neuropathic). Other factors contribut- Higginson 2004). ing to the wide variability of results include, but are not Studies of pain following surgical treatment show pain limited to, the heterogeneity of cancer types (breast, as prevalent treatment sequelae. Despite the thousands lung, etc.), the stage of disease, and the type of treat- of cancer patients who are treated with curative surgery, ment settings (outpatient vs. inpatient or palliative) in very little is known about the prevalence, duration, Cancer Pain, Epidemiology 213 and functional impact of pain in this patient popula- et al. 1994). Patients treated at university centers and at tion. Patients not only suffer from the side effects of centers seeing primarily African Americans, Hispanics, the chemotherapy or radiotherapy before surgery for or both, were more likely to receive inadequate anal- their cancer, but may also develop serious post-surgical gesia than patients treated in non-minority community symptoms. treatment settings (77% vs. 52%, respectively). Minor- C Among breast cancer patients, 41% of those who had ity patients had the severity of their pain underestimated conservative breast surgery with radiotherapy reported by their physicians, reported that they needed stronger pain as a consequence of treatment. Pain generally pain medication, and felt that they needed to take more started within three months after the completion of analgesics than their doctors had prescribed. Assessing therapy, was localized in the axillary region, and was differences between minority groups, more Hispanic intermittent (Amichetti and Caffo 2003). The pain was patients reported lower levels of pain relief than did mainly described as aching (59%), tender (51%), and African Americans. cramping (43%). In comparison to the patients who did Although few disagree that painful conditions should not experience pain, those who suffered from pain had be treated regardless of age, studies document under- significantly worse scores in physical, psychological, treatment of cancer pain in older populations. In a study and other quality-of-life measures. of 4,003 elderly cancer patients (24%, 29%, and 38% Itislessrecognizedthatmanycancerpatientscontinueto of those aged 85 years or older, 75–84 years, and 65–74 experience pain well after treatment has ended. Chaplin years, respectively), Bernabei and colleagues (1998) and Morton (1999) assessed 93head andneckcancerpa- found that more than a quarter (26%) of patients experi- tients and found that 48% had head and neck pain when encing daily pain received no analgesic agent. Patients firstseen,andthat25%and26%hadpainthatpersistedat aged 85 years or older were less likely to receive mor- 12and24months,respectively.Theprevalenceofshoul- phine or other strong opiates than those aged 65–74 der and arm pain was greater after treatment, increasing years (13% vs. 38%, respectively), and were more from 14% at diagnosis to 37% at 12 months and 26% at likely to receive no analgesia at all. African American 24 months. Any pain (pain in either the head and neck or elderly patients were also at a higher risk for under- shoulder and arm or both)at24monthswasstronglypre- treatment, suggesting the disparity in pain treatment dicted by earlier post-treatment pain (at three months or is compounded for elderly minority patients. A study at 12 months). Shoulder and arm pain at 24 months was that looked at undertreatment of pain for ambulatory strongly correlated with surgical treatment of the neck, patients with metastatic cancer (Cleeland et al. 1994) although no difference in pain experience was noted be- also showed that older age (70 years or older) was a tween those who had radical neck dissections and those significant predictor of inadequate analgesia, according who had more conservative procedures. to the World Health Organization guidelines (World Studies have examined the prevalence of pain among Health Organization 1986) for treatment of patients cancer patients in advanced stage. As part of the SUP- with cancer pain. PORT studies, McCarthy et al. (2000) evaluated over 1,000 cancer patients during the three days before death, at one to three months before death, and three Factors Associated with Inadequate Treatment and Control of to six months before death. As expected, as patients Pain progressed toward death, their six-month prognosis Undertreatment of pain is a major factor in the preva- deteriorated significantly and the severity of their lence and severity of pain. A number of factors predict disease worsened. Cancer patients experienced signif- poor control or undertreatment of pain. Poor pain as- icantly more pain and confusion as death approached. sessmentremainsthe mostsalientbarrier. Cleeland etal. Severe pain was common; more than one quarter (1994) found the degree of discrepancy between physi- of patients with cancer experienced significant pain cian estimate and patient report of pain severity was a three to six months before death, and more than 40% major predictor of undertreatment. However, although were in significant pain during their last three days of quantitative pain assessment has demonstrated its feasi- life. bility and validated pain assessment tools are available, While it is recognized that pain is prevalent for the data from a community-based oncologysetting (Rhodes majority of cancer patients, evidence suggests that the et al. 2001) show a virtual absence of documentation of elderly and patients from minority groups may have an quantitative pain assessment (only 0–5% of medical and even greater risk for pain and poor pain management radiationoncologyphysicians’notescontainedanysuch (Cleeland et al. 1997; Anderson et al. 2000). Undertreat- documentation). Twenty-eight percent of patients with ment of pain was shown to be higher among minority significantpainhadnomentionofpaininthephysicians’ patients seen at clinics serving minority clients, with notes, and 48% had no documented analgesic treatment. minority patients three times more likely to be un- These findings point to the critical role of adequate as- dermedicated with analgesics than patients treated in sessmentandmonitoringforthecontrolofpainandother non-minority community treatment settings (Cleeland symptoms. 214 Cancer Pain, Epidemiology

Many cancer specialists recognize that pain control is intervention group (P = 0.05). The findings from this often suboptimal. Medical oncologists were surveyed study suggest that standardized pain assessment leads about their treatment of cancer pain in a study con- to improved cancer pain management. ducted by the Eastern Cooperative Oncology Group Beginning with the publication of the World Health (ECOG) (Von Roenn et al. 1993). Only half of the Organization’s Cancer Pain Management guidelines physicians surveyed indicated that cancer pain control in 1986 (World Health Organization 1986), several was “good” or “very good” in their practice setting. guidelines for the practice of cancer pain management Seventy-five percent of the physicians indicated that have been issued. There is, however, only one published the most important barrier to cancer pain management study that evaluates the effectiveness of adherence to a was inadequate pain assessment. Over 60% reported pain management guideline for cancer pain (Du Pen et that physicians’ reluctance to prescribe analgesics and al. 1999). In this study, 81 cancer patients were enrolled patient unwillingness to report pain or take opioids in a prospective, longitudinal, randomized controlled were barriers to adequate pain treatment. Inadequate study from 26 medical oncologist outpatient clinics knowledge about cancer pain management was rein western Washington. A multilevel treatment algo- ported by over 50% of the ECOG physicians surveyed. rithm based on the AHRQ Guidelines for Cancer Pain The survey documents that a substandard level of Management was compared with standard–practice education about cancer pain management and a re- (control) therapies for pain and symptom management luctance to address it in practice existed at all levels used by community oncologists. Patients randomized of professional health care. Cleeland and colleagues to the pain algorithm group achieved a statistically (2000) repeated the ECOG study format with physi- significant reduction in pain intensity when compared cian members of the Radiation Therapy Oncology with standard community practice. Group. Although there has been some improvement A recently completed Eastern Cooperative Oncology in the use of stronger analgesics, many barriers to Group study (Cleeland etal. 2005) foundthatthe institu- good pain control remain, and poor pain assessment tional use of a protocol for pain management improved is still seen as the major barrier to good pain manage- pain control in lung and prostate cancer patients, but ment. failed to improve the pain management of other patients (breast cancer and myeloma patients) in the same in- Improving Control of Cancer Pain stitutions who were not specifically treated by the pain In spite of the recent concerns over symptom manage- protocol. Forty-eight percent of patients with lung and ment, there is substantial evidence that symptoms that prostate cancer in the institutions that used a protocol could, in principle, be well managed are nonetheless un- for pain management reported a statistically significant dertreated. Pain could be more adequately controlled if reduction in moderate and severe pain (P < 0.02), com- we systematically applied the knowledge that we now pared with 15% of lung and prostate patients treated as have about its management. usual in the control institutions. There is at least preliminary evidence that improving More recently, a system improvement approach was pain assessment can improve pain management, and used to improve pain management in a national health- may improve the management of other symptoms as care system (Cleeland et al. 2003), with some reported well. Trowbridge et al. (1997) conducted a randomized success. The focus of the project, a collaborative ini- controlled trial of 320 patients and 13 oncologists. tiative of the Veterans Health Administration and the Patients were asked while in the clinic to complete Institute for Healthcare Improvement (VHA-IHI), was assessments of their pain, their pain treatment regi- to achieve rapid improvements in pain management in mens, and the degrees of relief received. Follow-up the clinical and operational areas in the national VHA was conducted four weeks later by mail-in survey. The system. An underlying premise was the spread of ex- intervention group’s clinical charts contained a sum- isting knowledge to multiple sites. A total of 70 teams mary of the completed pain scales, and the oncologists were formed and were asked to identify their goals who treated these patients were instructed to review the and to implement changes in their practice setting. summary sheet prior to an evaluation. This summary Importantly, faculty involved in the initiative developed was not available for the oncologists treating the pa- the attributes of an ideal pain management system. tients in the control group. Results showed a significant Changes that were implemented included the develop- difference (P = 0.016) in the physicians’ prescription ment of new assessment forms to increase the number patterns. In the control group, prescriptions for 86% of patients with documented assessment and follow-up of the patients did not change, without any increase for treatment plan; development of guidelines and/or in analgesic prescriptions. In the intervention group, protocols; formation of one-on-one, group-provider, or analgesic prescriptions changed for 25% of the patients, computer-based educational methods to improve both decreasing for 5% and increasing for 20%. A decrease assessment and follow-up, and/or ways to effectively in the incidence of pain described as “more than life’s link provider education with other system changes such usual aches and pains” was found at follow-up for the as drug ordering or assessment processes; and develop- Cancer Pain, Evaluation of Relevant Comorbidities and Impact 215 ment of innovativeways to link primary care physicians 8. Cleeland CS, Janjan NA, Scott CB et al. (2000) Cancer pain man- with pain specialists. agement by radiotherapists: a survey of radiation therapy oncology group physicians. Int J Radiat Oncol Biol Phys 47:203–208 The following outcomes were reported: moderate or 9. Cleeland CS, Portenoy RK, Rue M, et al. (2005) Does an oral severe pain on study units dropped from 24% to 17%; analgesic protocol improve pain control for patients with can- pain assessment increased from 75% to 85%; pain care cer? An intergroup study coordinated by the Eastern Cooperative C plans for patients with at least mild pain increased from Oncology group. Ann Oncol 16:972–980 10. Cleeland CS, Reyes-Gibby CC, Schall M et al. (2003) Rapid im- 58% to 78%; and the number of patients provided with provement in pain management: the Veterans Health Administra- pain educational materials increased from 35% to 62%. tion and the institute for healthcare improvement collaborative. The results of these studies, taken together, suggest Clin J Pain 19:298–305 that improved assessment should improve symptom 11. Daut RL, Cleeland CS (1982) The prevalence and severity of pain in cancer. Cancer 50:1913–1918 management for cancer patients. 12. Du Pen SL, Du Pen AR, Polissar N et al. (1999) Implementing guidelines for cancer pain management: results of a randomized Future Directions controlled clinical trial. J Clin Oncol 17:361–370 13. Gaston-Johansson F, Fall-Dickson JM, Bakos AB et al. (1999) Overall, studies of the incidence, prevalence, severity, Fatigue, pain, and depression in pre-autotransplant breast cancer and treatment of cancer-related pain have shortcomings patients. Cancer Pract 7:240–247 14. McCarthy EP, Phillips RS, Zhong Z et al. (2000) Dying with that need to be addressed and remedied. Pain is often cancer: patients’ function, symptoms, and care preferences as evaluated and reported without stratifying for hetero- death approaches. J Am Geriatr Soc 48:S110–S121 geneity with respect to pain type, disease type and stage, 15. Patrick DL, Ferketich SL, Frame PS et al. (2004) National In- disease treatment, and response to disease treatment. stitutes of Health State-of-the-Science Panel National Institutes of Health State-of-the-Science Conference Statement: Symptom Although pain may endure for days, months, or years, management in cancer: pain, depression, and fatigue, July 15–17, assessments are often performed cross-sectionally 2002. J Natl Cancer Inst Monogr 32:9–16 rather than longitudinally, thus failing to assess patterns 16. Portenoy RK, Thaler HT, Kornblith AB et al. (1994) Symptom and trajectories. prevalence, characteristics and distress in a cancer population. Qual Life Res 3:183–189 Moreover, we need to explore whether pain and other 17. Potter J, Higginson IJ (2004) Pain experienced by lung cancer symptoms experienced by cancer patients differ quanti- patients: a review of prevalence, causes and pathophysiology. tatively and qualitatively with those of non-cancer pop- Lung Cancer 43:247–257 18. Rhodes DJ, Koshy RC, Waterfield WC et al. (2001) Feasibility ulations. Cohort studies that will provide clinicians with of quantitative pain assessment in outpatient oncology practice. information regarding the incidence, severity, and dura- J Clin Oncol 19:501–508 tionofthesesymptomsafteradiagnosisofcancershould 19. Trowbridge R, Dugan W, Jay SJ et al. (1997) Determining the also be useful in determining the epidemiology of can- effectiveness of a clinical-practice intervention in improving the control of pain in outpatients with cancer. Acad Med 72:798–800 cer pain. Finally, we need to identify the current ade- 20. Von Roenn JH, Cleeland CS, Gonin R et al. (1993) Physician quacy of care for these symptoms, including identifying attitudes and practice in cancer pain management. A survey what factors (e.g. patient-related, clinician-related, and from the Eastern Cooperative Oncology Group. Ann Intern system-related) are predictive of poor symptom man- Med 119:121–126 21. World Health Organization (1986) Cancer pain relief. World agement. Health Organization, Geneva

References 1. Amichetti M, Caffo O (2003) Pain after quadrantectomy and radiotherapy for early-stage breast cancer: incidence, characteristics and influence on quality of life. Results from a retrospective Cancer Pain, Evaluation of Relevant study. Oncology 65:23–28 Comorbidities and Impact 2. Anderson KO, Mendoza TR, Valero V et al. (2000) Minority cancer patients and their providers: Pain management attitudes MYRA GLAJCHEN and practice. Cancer 88:1929–1938 Department of Pain Medicine and Palliative Care, Beth 3. Bernabei R, Gambassi G, Lapane K et al. (1998) Management of pain in older adult patients with cancer. SAGE Study Group. Israel Medical Center, New York, NY, USA Systematic Assessment of Geriatric Drug Use via Epidemiology. [email protected] JAMA 279:1877–1882 4. Brescia FJ, Portenoy RK, Ryan M et al. (1992) Pain, opioid use, and survival in hospitalized patients with advanced cancer. J Clin Oncol 10:149–155 Definition 5. Chaplin JM, Morton RP (1999) A prospective, longitudinal study The assessment of patients with cancer pain often re- of pain in head and neck cancer patients. Head Neck 21:531–537 6. Cleeland CS, Gonin R, Baez L et al. (1997) Pain and treatment of veals the existence of important physical or psychiatric pain in minority patients with cancer. The Eastern Cooperative comorbidities.Thesecomorbiditiesmayormaynotcon- Oncology Group Minority Outpatient Pain Study. Ann Intern tribute to the pain. They often influence the selection of Med 127:813–816 pain therapy, and may be independent problems in need 7. Cleeland CS, Gonin R, Hatfield AK et al. (1994) Pain and its treatment in outpatients with metastatic cancer. N Engl J Med of management in the broad strategy to improve quality 330:592–596 of life. 216 Cancer Pain, Evaluation of Relevant Comorbidities and Impact

Characteristics About 44% of cancer patients report anxiety during treatment, while 23% report high anxiety (Nordin and In some cases, a comorbid condition is both an inde- Glimelius 1999; Pereira et al. 1997). Anxiety that is pendent medical issue and a potential etiology of the unusually intense or persistent may suggest an adjust- pain. For example, major depression may be expressed, ment disorder or anxiety disorder in need of targeted in part, by persistent pain. Under these circumstances, treatment. Factors that increase the likelihood of de- treatment for the depression must be given priority veloping adjustment disorders include pain, a history and included among the analgesic strategies pursued. of anxiety disorders, functional limitations, advancing In other circumstances, a comorbid condition may be disease and absence of social support (Breitbar 1995; unrelated to the pain itself, but may impair function Schag and Heinrich 1989; Stark et al. 2002). Patients and negatively affect treatments intended to restore can become immobilized by anxiety, and be unable to functioning. This is commonly encountered in the comply with treatment. Therefore, prompt diagnosis cancer patient with persistent gastrointestinal distress and early intervention are optimal. following chemotherapy. Depression is a disabling condition affecting 15–25% A useful taxonomy for evaluating the impact of rele- of cancer patients (Breitbart et al. 2000; Nelson et vant comorbidities on cancer pain is listed below. The al. 2002). While some sadness is normal in reaction to coexisting symptom or condition should be evaluated cancer, it is important to distinguish normal sadness for its: direct contribution to the pain, predisposition from an adjustment disorder with depressed mood or to cause adverse treatment effects, compromise of re- a depressive disorder (Block 2000). Clinicians should habilitative efforts, ability to independently undermine assess mood carefully and have a low threshold for quality of life, and ability to increase risk of serious initiating therapies. Early intervention is indicated if adverse medical outcomes. symptoms persist or recur, or if patients present with a Fatigue is a common comorbidity, affecting 14-96% history of depression, poor social support, a poor prog- of people with cancer (Cella et al. 2002; Vogelzang nosis and higher levels of disability. A combination of et al. 1997). Generally, fatigue is characterized by a psychotherapy and antidepressant drugs represents the decrease in energy, distress and decreased functional most effective strategy for pain-related depression. An- status (Pickard-Holley 1991; Stone et al. 1998). Fatigue tidepressants with established analgesic effectiveness in cancer patients can result from the course of the dis- may be preferred (Breitbart 1995). ease, preexisting physical or psychological conditions, Delirium, agitation and cognitive impairment occur effects of medication, or lack of exercise. Fatigue may in 28-48% of patients with advanced cancer (Pereira also result from surgery, chemotherapy, and radiation et al. 1997; Lawlor et al. 2000). The causes of delir- therapy. As fatigue can severely undermine the sense of ium are multifactorial, and may include direct effects well being, activities of daily living, relationships with of the disease on the CNS, metabolic or electrolyte family and friends, and treatment compliance, prompt disturbances, treatment and medications (Lawlor et diagnosis and treatment are recommended. al. 2000; Morita et al. 2002). The presence of delirium Gastrointestinal complications (constipation, impac- poses a major barrier to doctor-patient communication, tion, bowel obstruction, nausea, vomiting and diarrhea) family distress and treatment adherence (Fainsinger et are common in oncology patients. The growth and al. 1993). Prompt diagnosis and treatment are therefore spread of cancer, as well as related treatment, contribute optimal. to these conditions. Despite advances in management, Nearly one-third of the population of the United States nausea and vomiting remain among the most distressing has used illicit drugs, and an estimated 6-27% have a side effects for patients and families (Wickham 1999). substanceabuseproblemofsometype(see aberrant In addition, gastrointestinal comorbidities undermine drug-related behaviors and pseudoaddiction)(Col- quality of life and interfere with treatment (Pisters and liver and Kopstein 1991). Although problematic drug Kris 1998). use is sometimes related to undertreatment (Weiss- Alterations in nutritional status begin at diagnosis, and man and Haddox 1989), primary abuse or addiction may proceed through treatment. Protein-calorie mal- may be encountered in the oncology setting. A his- nutrition (PCM) is common and can lead to progressive tory of substance abuse can increase the risk of mor- wasting, weakness, and debilitation. Anorexia, the loss bidity or mortality among those with progressive of appetite, is present in 15-25% of patients at diagnosis life-threatening disease, and undermine treatment and may also occur as a treatment side effect (Vigano et adherence. This can be mitigated by a therapeutic al. 1994). Depression, lossof hopeandanxiety areallas- strategy that addresses drug-taking behavior while sociatedwithanorexia(Ross1990).Anorexiacanhasten implementing other therapies. Knowledge about the the course of cachexia, a progressive wasting syndrome basic concepts of addiction medicine and collab- (Ross 1990) marked by weakness and progressive loss oration with addiction specialists is needed (Sub- of body weight, fat, and muscle. Pain treatment in the stance Abuse and Mental Health Services Administra- context of anorexia and cachexia is complex. tion 2002). Cancer Pain, Goals of a Comprehensive Assessment 217

Thegoalofacomprehensiveapproachtothepatientwith 22. Wickham R (1999) Nausea and Vomiting. In: Yarbo CH, Frogge cancer pain is to organize a therapeutic strategy, which MH, Goodman M (eds) Cancer Symptom Management, 2nd edn. can enhance comfort and function and ameliorate co- Jones and Bartlett Publishers, Sudbury, MA, pp 228–263 morbidities – all in an effort to reduce suffering and improve quality of life. C Cancer Pain, Goals of a Comprehensive References Assessment 1. Block SD (2000) Assessing and Managing Depression in the Terminally Ill Patient. ACP-ASIM End-of-Life Care Consensus PAULINE LESAGE Panel. American College of Physicians – American Society of Department of Pain Medicine and Palliative Care, Beth Internal Medicine. Ann Intern Med 132: 209–218 2. Breitbart W (1995) Identifying Patients at Risk for, and Treatment Israel Medical Center and Albert Einstein College of ofMajorPsychiatricComplicationsof Cancer. Support Care Can- Medicine, New York, NY, USA cer 3:45–60 [email protected] 3. Breitbart W, Rosenfeld B, Pessin H et al. (2000) Depression, Hopelessness, and Desire for Hastened Death in Terminally Ill Patients with Cancer. JAMA 284:2907–2911 Definition 4. Cella D, Lai JS, Chang CH et al. (2002) Fatigue in Cancer Patients Compared with Fatigue in the General United States Population. The assessment of cancer pain requires an understand- Cancer 94:528–538 ing of the disease and its extent, in addition to its di- 5. Colliver JD, Kopstein AN (1991) Trends in Cocaine Abuse Re- verse comorbidities, to clarify the nature of the pain and flected in Emergency Room Episodes Reported to DAWN. Public Health Rep 10:59–68 its physical, psychological, and social disturbances. The 6. Fainsinger RL, Tapper M, Breura E (1993) A Perspective on the list below describes a stepwise assessment of patients Management of Delirium in Terminally Ill Patients on a Palliative withcancerpain.Thisunderstandingwillguidethetreat- Care Unit. J Palliat Care 9:4–8 ment plan, focused on providing comfort and improving 7. Lawlor PG, Gagnon B, Mancini IL et al. (2000) Occurrence, Causes, and Outcome of Delirium in Patients with Advanced quality of life. Cancer: A Prospective Study. Arch Intern Med 160:786–294 8. Morita T, Tei Y, Tsunoda J et al. (2002) Underlying Pathologies Step 1: Data Collection and their Associations with Clinical Features in Terminal Delir- ium of Cancer Patients. J Pain Symptom Manage 23:107–113 • Pain-related history 9. Nelson CJ, Rosenfeld B, Breitbart W et al. (2002) Spirituality, Religion, and Depression in the Terminally Ill. Psychosomatics – Other relevant history 43:213–220 – Disease related 10. Nordin K, Glimelius B (1999) Predicting Delayed Anxiety and – Other symptoms Depression in Patients with Gastrointestinal Cancer. Br J Cancer 79:525–529 – Psychiatric history 11. Pereira J, Hanson J, Bruera E (1997) The Frequency and Clin- – Social resources ical Course of Cognitive Impairment in Patients with Terminal Cancer. Cancer 79:835–842 • 12. Pickard-Holley S (1991) Fatigue in Cancer Patients. A Descrip- Concurrent quality-of-life concerns tive Study. Cancer Nurs 14:13–19 – Other symptoms 13. Pisters KM, Kris MG (1998) Treatment-Related Nausea and Vomiting. In: Berger A, Portenoy RK, Weissman DE (eds) Prin- – Concerns in physical, psychological, social, and ciples and Practice of Supportive Oncology. Lippincott-Raven spiritual domains Publishers, Philadelphia, pp 165–178 – Other concerns (e.g. financial) 14. Ross BT (1990) Cancer’s Impact on the Nutrition Status of Pa- tients. In: Bloch AS (ed) Nutrition Management of the Cancer – Assessment of the family Patient. Aspen Publishers, Rockville, MD 15. Schag CA, Heinrich RL (1989) Anxiety in Medical Situations: • Available laboratory and imaging data Adult Cancer Patients. J Clin Psychol 45:20–27 16. Stark, D, Kiely M, Smith A et al. (2002) Anxiety Disorders – Radiographs and scans in Cancer Patients: Their Nature, Associations, and Relation to – Tumor markers Quality of Life. J Clin Oncol 20:3137–3148 17. Stone P, Richards M, Hardy J (1998) Fatigue in Patients with – Hematologic parameters Cancer. Eur J Cancer 34:1670–1676 – Biochemical parameters 18. Substance Abuse and Mental Health Services Administra- tion: Results From the 2001 National Household Survey on Drug Abuse: Volume I. Summary of National Findings (2002) Step 2: Interpret the Findings SAMHSA, Office of Applied Studies, DHHS, Rockville, MD • Pain-related constructs 19. Vigano A, Watanabe S, Bruera E (1994) Anorexia and Cachexia in Advanced Cancer Patients. Cancer Surv 21:99–115 – Etiology 20. Vogelzang NJ, Breitbart W, Cella D et al. (1997) Patient, Care- giver, and Oncologist Perceptions of Cancer-Related Fatigue: – Inferred pathophysiology Results of a Tripart Assessment Survey. The Fatigue Coalition. – Syndrome identification Semin Hematol 34:4–12 21. Weissman DE, Haddox JD (1989) Opioid Pseudoaddiction – An Iatrogenic Syndrome. Pain 36:363–366 • Extent of disease 218 Cancer Pain, Goals of a Comprehensive Assessment

• Goals of care moderate, severe), or a visual analogue scale. The particular scale used is less important than its regular use – Prolonging survival to record the status of the pain over time. – Optimizing function – Optimizing comfort Interpreting the Assessment Step 3: Formulating a Treatment Strategy Thepainhistory,combinedwiththeinformationgleaned from a physical examination and appropriate imaging • Further evaluation, if needed and laboratory studies, usually provides sufficient data • Multimodality approach to the pain to generate meaningful conclusions concerning the eti- • Treatment of the pain etiology, if possible ology of the pain, its pathophysiology, and its defining • Treatments for concurrent concerns syndrome. The latter constructs are very useful in clari- • Patient/family education fying the need for additional evaluation,prognosticating outcomes, and developing an efficient therapeutic strat- Characteristics egy.

The comprehensive assessment of pain characteris- Etiology tics should include information about: 1) temporal characteristics (onset and duration); 2) course (stable, The etiology of acute pain is usually clear-cut. Further improving, worsening, or widely fluctuating); 3) sever- evaluation to determine the underlying lesion is not in- ity (both average and worst); 4) location; 5) quality, and dicated unless the course varies from the expected. In 6) provocative and palliative factors. contrast, the etiology of chronic cancer-related pain may Acute pain usually has a well-defined onset and a read- be more difficult to characterize. In most cases, pain is ily identifiable cause (e.g. surgical incision). It may be due to direct invasion of pain-sensitive structures by the associated with anxiety, overt pain behaviors (moaning neoplasm (Cherny et al. 1994; Foley 1996). The struc- or grimacing), and signs of sympathetic hyperactivity tures most often involved are bone and neural tissue, but (including tachycardia, hypertension, and diaphoresis). pain can also occur when there is an obstruction of hol- In contrast, chronic pain is usually characterized by an lowviscus,distentionoforgancapsules,distortionoroc- ill-defined onset and association with persistent focus clusion of blood vessels, and infiltration of soft tissues. of pathology. The course of the pain may be linked to In about one-quarter of patients, the etiology relates to the disease, and may change with the response to pri- an antineoplastic treatment, and fewer than 10% have mary antineoplastic therapies. With chronic pain, overt painunrelatedtotheneoplasmoritstreatment(Chernyet pain behaviors and sympathetic hyperactivity are typi- al. 1994; Foley 1996). Many patients, particularly those cally absent, and vegetative signs, including lassitude, with advanced illness, have multiple etiologies and sev- sleep disturbance, and anorexia, may be present. A clin- eral sources of pain. ical depression evolves in some patients. Given the association between pain and the underlying Most patients with chronic cancer pain also experience neoplasm, clarification of the specific relationship be- periodicflaresofpain,orbreakthroughpain(PattandEl- tween the pain and the disease is an essential element of lison 1999). An importantsubtypeof breakthroughpain the assessment. A survey of patients referred to a pain is known as incident pain. Diagnosis of breakthrough service in a major cancer hospital noted, that previously pain may suggest specific interventions, such as the use unsuspected lesions were identified in 63% of patients of supplemental medication that specifically targets the (Gonzalez et al. 1991). This outcome altered the known cause. extent of disease in virtually all patients, changed the Pain may be focal, multifocal, referred or generalized. prognosis for some, and provided an opportunity for a Pain may be referred from a lesion involving any of a primary antineoplastic therapy in approximately 15%. large group of structures, including nerve, bone, muscle or other soft tissue, and viscera (Ness and Gebhart 1990; Pathophysiology Torebjork et al. 1984). Various subtypes of referred Although inferences about the predominating mecha- pain can be distinguished. Pain may be referred any- nismsunderlyingpainarecertainlygrosssimplifications where along the course of an injured peripheral nerve of very complex and dynamic processes, and can never (such as pain in the thigh or knee from a lumbar plexus be proved in the clinical setting, this classification has lesion) or nerve root (known as radicular pain). Pain utility in treatment planning. Pain syndromes may be la- may also be referred to a site remote from a nociceptive beled nociceptive, neuropathic, psychogenic and mixed lesion and outside the dermatome affected by the lesion (Merskey and Bogduk 1994). (e.g. shoulder pain from diaphragmatic irritation). The quality of somatic nociceptive pain is typically Measurement of pain intensity is an essential element in described as aching, stabbing, throbbing, or pressure- the pain assessment. Intensity may be monitored using like. The quality of visceral nociceptive pain is usually a numeric scale (0–10), verbal rating scale (none, mild, gnawing or crampy when related to obstruction of hol- Cancer Pain, Goals of a Comprehensive Assessment 219 low viscus, and aching or stabbing when associated with injury to other visceral structures. Neuropathic mechanisms are involved in approximately 40% of cancer pain syndromes and can be disease-related (e.g. tumor invasion of nerve plexus) C or treatment-related (e.g. postmastectomy syndrome or chemotherapy-induced painful polyneuropathy) (Caraceni and Portenoy RK, and a working group of the IASP Task Force on Cancer Pain 1999). Among Cancer Pain, Goals of a Comprehensive Assessment, those with metastatic disease, neuropathic pain usu- Figure 1 Distinctions and interactions between nociception, pain, ally results from neoplastic injury to peripheral nerves and suffering. (Reproduced with permission from Portenoy RK (1992) (peripheral neuropathic pain). Other, less common, Cancer pain: pathophysiology and syndromes. Lancet 339:1026). subtypes include: 1) those sustained by CNS processes (sometimes generically termed deafferentation pain); and 2) those in which the pain is believed to be main- loss of role functioning, familial disruption, or tension tained by efferent activity in the sympathetic nervous in the relationship with a significant other; or to spiritual system (so-called sympathetically-maintained pain) concerns such as loss of faith. Other factors, such as fi- (Galer 1995). nancial concerns, may be prominent. Psychosocial and Neuropathic pain is diagnosed on the basis of the pa- spiritualstrengthsandweaknessesthatlongpredatedthe tient’s verbal description of the pain, the findings on cancer may be important. examination, and evidence of nerve injury. If patients Comprehensive pain assessment must address issues re- describe pain in dysesthetic terms, such as “burning,” latedtosuffering.Anunderstandingofthephysical,psy- “shock-like,” or “electrical,” this is suggestive of neu- chological, social and spiritual issues important to the ropathic mechanisms (Grond et al. 1999). Likewise, the patient is fundamental to this process. A therapeutic ap- existence of neuropathic pain may be inferred by the proach focused only on pain may not meaningfully ben- findings of abnormal sensations on physical examina- efit a patient whose suffering is caused by other distur- tion, most notably allodynia and hyperalgesia. bances. Pain may be labeled psychogenic if there is positive evidence from the assessment that psychological factors Pain and Quality of Life predominate in sustaining the symptom. Psychogenic Quality of life is related to the construct of suffering but pain may be more formally characterized according to hasbeenmoreformallycharacterizedforaresearchcon- the widely-accepted taxonomy of the American Psychi- text. Numerous instruments have been created to mea- atric Association (one of the Somatoform Disorders de- sure quality of life, and these have been developed from scribed in the Diagnostic and Statistical Manual, 4th Re- theperspectiveoftwomajorcharacteristics:subjectivity vision). Although psychological factors commonly in- and multidimensionality (Skeel 2002). fluence the expression and severity of pain in the cancer The inherent subjectivity of quality of life has impli- population, it is rare to identify a pain as psychogenic. cations for assessment. Although clinicians commonly If a credible pathophysiologic diagnosis is not apparent, make inferences about patients’ well-being, or rely on and there is no strong evidence of a predominating psy- proxy evaluation by family or others, the likelihood chological cause, it is best to label the pain idiopathic. of inaccuracy in such appraisals must be appreciated (Grossman et al. 2001). For the evaluation of quality Assessment of Related Constructs of life, and each of its contributing concerns, including Chronic cancer-related pain is best addressed with con- pain, the “gold standard” of assessment is self-report. sideration of a set of broader constructs, including suf- Like pain itself, quality of life is multidimensional. fering, quality of life, symptom distress, and the goals of Although a single question can screen for overall well- care.Theseunderstandingscontinuallyinformdecision- being, a fuller understanding of the factors that must be making about interventions to manage pain. addressed to improve quality of life requires probing of issues related to physical, psychological, social, and Pain and Suffering spiritual functioning. Suffering, a global constructintricately related to the experience of pain (Fig. 1), has been described as a per- Pain and Symptom Distress ceived threat to the integrity of the person, as a type of Most patients with chronic cancer pain experience other “total pain,” or as overall impairment in quality of life symptoms concurrently. Studies have demonstrated that (Cassell 1982). Suffering may be primarily related to pain, fatigue, and psychological distress are most preva- symptoms such as pain or physical losses; to psychiatric lent across populations with advanced cancer. Global disorders such as depression or psychological processes symptom distress is a useful construct that characterizes such as disturbed body image; to social issues such as overall symptom burden (Portenoy et al. 1994). 220 Cancer Pain, Palliative Care in Children

Goals of Care Synonyms In developing a therapeutic approachtoaddresspainand Pain Control in Children with Cancer; Palliative Care in other quality-of-life concerns in patients with cancer, it Children; End of Life Care; Dying Child is essential to clarify the goals of care. At any point in time,treatmentmaybeguidedbyoneormoreoverriding Definition goals: 1) to cure or prolong life; 2) to maintain function; Pain control is an integral component of caring for and 3) to provide comfort. These goals are strongly in- all children with cancer. Children with cancer may fluenced by many factors, including the status of the dis- experience many different types of pain from invasive ease, the availability and burdens of therapy, psychoso- procedures, the cumulative effects of toxic therapies, cialcomorbidity,andthedegreeofspiritualorexistential progressive disease or from psychological factors. distress. Goals are very dynamic, and often evolve over While the goal in cancer care is to minimize morbidity time with the vagaries of the disease, the availability of on the road to cure, at times even with the best of care, treatment and optimal palliative care. Current goalscon- we fail to achieve this goal and thus we also address the tinually influence therapeutic decision-making. issue of palliative pain management. Palliative care References is the management of patients with active, progressive, far-advanced disease, for whom prognosis is limited 1. Caraceni A, Portenoy RK, and a working group of the IASP Task Force on Cancer Pain (1999) An international survey of cancer and the focus of care is the quality of life. pain characteristics and syndromes. Pain 82:263–274 2. Cassell EJ (1982) The nature of suffering and the goals of Characteristics medicine. N Engl J Med 306:639–645 3. Cherny NI, Coyle N, Foley KM (1994) Suffering in the advanced Pediatric cancer pain encompasses four broad etiologic cancer patient: a definition and taxonomy. J Palliat Care 10:57–70 categories – procedural pain, the cumulative effects 4. Foley KM (1996) Pain syndromes in patients with cancer. In: of toxic therapies, progressive disease and psycholog- Portenoy RK, Kranner RM (eds) Pain management: Theory and practice. FA Davis, Philadelphia, pp 191 ical factors. Children’s cancer pain is often complex 5. Galer BS (1995) Neuropathic pain of peripheral origin: advances with multiple sources, comprised of nociceptive and in pharmacologic treatment. Neurology 45:S17–25 neuropathic components (Collins and Weisman 2003; 6. Gonzalez GR, Elliott KJ, Portenoy RK, Foley KM (1991) The McGrath and Brown 2004; Miaskowski et al. 2005; impact of a comprehensive evaluation in the management of cancer pain. Pain 47:141–144 World Health Organization 1998). In addition, several 7. Grond S, Radbruch L, Meuser T et al. (1999) Assessment and situational factors usually contribute to children’s treatment of neuropathic cancer pain following WHO guidelines. pain, distress and disability. Thus, to treat pain in these Pain 79:15–20 children adequately, we must evaluate the primary pain 8. Grossman SA, Sheidler VR, Sweden K et al. (2001) Correlation of patient and caregiver ratings of cancer pain. J Pain Symptom sources and also ascertain which situational factors are Manage 6:53–57 relevant for which children and families. Treatment 9. Merskey H, Bogduk N (1994) Classification of chronic pain: emphasis should shift accordingly from an exclusive descriptions of chronic pain syndromes and definitions of pain disease-centered framework to a more child-centered terms, 2nd edn. IASP Press, Seattle 10. Ness TJ, Gebhart GF (1990) Visceral pain: a review of experi- focus. mental studies. Pain 41:167–234 In 1993 the World Health Organization (WHO) and the 11. Patt RB, Ellison N (1999) Breakthrough pain. In: Aronoff GM International Association for the Study of Pain (IASP) (ed) Evaluation and treatment of chronic pain, 3rd edn. Williams invited experts in the fields of oncology, palliative care, & Wilkins, Baltimore, pp 377 anesthesiology, neurology, pediatrics, nursing, pal- 12. Portenoy RK, Thaler HT, Kornblith AB et al. (1994) Patients with cancer: The Memorial Symptom Assessment Scale: an instru- liative care, psychiatry, psychology and pastoral care ment for the evaluation of symptom prevalence, characteristics to write guidelines for the management of pediatric and distress. Eur J Cancer 30A:1326–1336 cancer pain and palliative care, resulting in the 1998 13. Skeel RT (2002) Measurement of outcomes in supportive care: Quality of life. In: Berger AM, Portenoy RK, Weissman DE (eds) publication “Cancer pain relief and palliative care in Principles and practice of palliative care and supportive oncology. children”. Lippincott Williams & Wilkins, Philadelphia, pp 1107–1122 A child-centered framework is required for understand- 14. Torebjork HE, Ochoa JL, Schady W (1984) Referred pain from ing and controlling pain for these children. Pain control intraneural stimulation of muscle fascicles in the median nerve. Pain 18:145–156 should include regular pain assessments, appropriate analgesics administered at regular dosing intervals, adjunctive drug therapy for symptom and side effects Cancer Pain, Palliative Care in Children control and non-drug interventions to modify the situational factors that can exacerbate pain and suffering. STEPHEN C. BROWN Parents concerned about medication centered on their Department of Anesthesia, Divisional Centre of Pain children’s comfort are calling for improved commu- Management and Pain Research, The Hospital for Sick nication, standardization of nursing procedures and Children, Toronto, ON, Canada techniques and a guide for a clear understanding of [email protected] what to expect and from whom (Sobo et al. 2002). Cancer Pain, Palliative Care in Children 221

Basic information on pathophysiology, pharmacology, Certain child factors are stable such as gender, tem- analgesic guidelines for children and management of perament and cultural background, while other factors procedural pain is presented in other essays in this change progressively such as age, cognitive level, pre- Encyclopedic Reference of Pain. This essay provides a vious pain experience and family learning. These child complementary focus by describing the unique nature characteristics shape how children generally interpret C of children’s cancer pain including the primary factors and experience the various sensations caused by tis- that affect their pain and quality of life, providing ref- sue damage. In contrast, various cognitive, behavioral erences to guidelines for selecting and administering and emotional factors are not stable. They represent a drug therapy in accordance with the nociceptive and unique interaction between the child and the situation neuropathic components and recommending practical in which the pain is experienced. These situational non-drug therapies for integration within a hospital, factors can vary dynamically throughoutthe course of a home or hospice setting. child’s illness, depending on the specific circumstances in which children experience pain. For example, a child The Nature of a Child’s Cancer Pain receiving treatment for cancer will have repeated injec- Throughout the last decade, we have gained an increas- tions, central port access and lumbar punctures – all of ing appreciation of the plasticity and complexity of a which may cause some pain (depending on the anal- child’s pain. As with adults, a child’s pain is often ini- gesics, anesthetics or sedatives used). Even though the tiated by tissue damage caused by noxious stimulation, tissue damage from these procedures is the same each but the consequent pain is neither simply nor directly re- time, the particular set of situational factors for each lated to the amount of tissue damage. Perhaps even more treatment is unique for a child – depending on a child’s than in adults, differing pain responses to the same tis- (and parent’s) expectations, a child’s (and parent’s sue damage are noted. The eventual pain evoked by a and staff’s) behaviors and on a child’s (and family’s) relatively constant noxious stimulus can be different de- emotional state. Although the causal relationship be- pending on children’s expectations, perceived control or tween an injury and a consequent pain seems direct and the significance that they attach to the pain. Children do obvious, what children understand, what they do and not sustain tissue damage in an isolated manner, devoid how they feel all affect their pain. Certain factors can of a particular context, but actively interpret the strength intensify pain, exacerbate suffering or affect adversely and quality of any pain sensations, determine the rele- a child’s quality of life. While parents and health care vance of any hurting and learn how to interpret the pain providers may be unable to change the more stable child by observing the generalenvironment,especiallythebe- characteristics, they can modify situational factors and havior of other people. Children’s perceptions of pain dramatically improve children’s pain and lives. are defined by their age and cognitive level, their previous pain experiences against which they evaluate each The Impact of Situational Factors on a Child’s Pain new pain, the relevance of the pain or disease causing Cognitive factors include children’s understanding pain, their expectations for obtaining eventual recovery about the pain source, their ability to control what and pain relief and their ability to control the pain them- will happen, their expectations regarding the quality selves. While plasticity and complexity are critical fea- and strength of pain sensations that they will experi- tures for all pain perception, plasticity seems an even ence, their primary focus of attention (that is distracted more important feature for controlling children’s pain. away from or focused primarily on the pain) and their Much research has been conducted to identify the knowledge of pain control strategies. In general, chil- critical factors responsible for the plasticity of pain dren’s pain can be lessened by providing accurate perception. Recent PET and functional MRI studies age-appropriate information about pain, for example have demonstrated that painful stimulation activates emphasizing the specific sensations that children will different cortical regions – depending on an individual’s experience (such as the stinging quality of an injection, expectations and attention (Price and Bushnell 2004). rather than the general hurting aspects), by increasing Human studies evaluating the impact of environmental their control and choices, by explaining the rationale for and psychological factors on the perception of experi- what can be done to reduce pain and by teaching them mentally induced pain have been conducted primarily in some independent pain reducing strategies (Brown adults. However, results from the few laboratory studies and McGrath 2005). Behavioral factors refer to the conducted with children are consistent with those from specific behaviors of children, parents and staff when adult studies (see Experimental Pain in Children). In children experience pain and also encompass parents’ addition, much compelling evidence about the powerful and children’s wider behaviors in response to a course of mediating role of psychological factors in children’s repeated painful treatments, chronic pain or progressive pain derives from clinical studies of acute, recurrent illness. Common behavioral factors include children’s and chronic pain. These studies highlight the need to distress or coping reactions (e.g. crying, using a pain recognize and evaluate the mediating impact of these control strategy, withdrawing from life) and parents’ factors in order to optimally control children’s pain. and health staff’s subsequent reactions to them (e.g. dis- 222 Cancer Pain, Palliative Care in Children playing frustration, calmly providing encouragement • Passive approach to pain control for children to use pain control strategies, engaging • Secondary gains: stress reduction them in conversation and activities). Emotional factors – emotional denial include parents’ and children’s feelings in response to – parent or staff attention pain and to the daily effects of the underlying illness or condition. Children’s emotions affect their ability to understand what is happening, their ability to cope • Inappropriate drug management: choice or mode of positively, their behaviors and ultimately their pain. drug administration Therearedynamicinteractionsamongcognitive,behav- • Failure to treat opioid-related side-effects aggres- ioralandemotionalfactors.Healthstaffcansignificantly sively lessen children’s pain, not only by administering potent • Failure to evaluate pain sources and document pain analgesics but also by increasing children’s understand- level ing and control, by decreasing their emotional distress • Failure to use effective non-drug therapies and by teaching children some simple physical, behavioral and cognitive methods to complement analgesic Emotional medications and further reduce their pain. • Anxiety about: dying and death If the disease progresses and treatment emphasis shifts from curative to palliative, cognitive and emotional fac- – suffering tors become the most salient situational factors that af- – meaning of life fect pain for children. Children probably have endured a prolonged period of intermittent pain, physical disabil- • Fear of: separation ity and multiple aversive treatments. Children receiving curative therapies are more focused on the future – inadequate pain control consequencesoftheirdisease.Theirthoughts,behaviors – increasing adverse symptoms and feelings change if their care becomes palliative. If – impact on family this should happen, the type of support, information and guidance children require changes. While the impact of • Anger palliation is profound for all children and families, each • Sadness or depression child and family is unique with respect to their specific • Distancing by staff and friends psychological, medical, social and spiritual needs. All families experience anguish and grief, but they may also A shift in care from curative to palliative therapies may experience denial, anxiety, anger, guilt, frustration and signify to some children and families that health profes- depression. It is essential that health professionals listen sionals are giving up on the child. Children and fami- attentively and observe carefully, not only to ensure that lies must understand that stopping ineffective therapies allthe needsof both the childandfamily are met, butalso is not giving up, but represents a rational decision based to resolve the myriad factors that can exacerbate chil- on children’s best interests. Pain control is an essential dren’s pain and suffering. The primary situational fac- component of cancer care and of palliative care (Chaf- tors in pediatric palliative care are listed (see below). fee 2001; Galloway and Yaster 2000; Goldman 1998; Goldman et al. 2003). Children and parents should not Situational Factors in Pediatric Palliative Care fear that health professionals have given up on control- Cognitive Factors ling pain and aversive symptoms. Pain and allsymptoms • Meaning of death mustbetreatedaggressivelyfromthedualperspectiveof • Inaccurate understanding: impact of situational fac- targeting the primary source of tissue damage and modi- tors on pain and quality of life fying thesecondary contributing factors. Althoughmost • Course of disease childrenreceiveaccurateinformationabouttheirdisease • Palliative versus curative therapy and required treatments, few children or their parents • Little independent control over pain receive concrete information about their pain, the fac- • Limited choices tors that can attenuate or exacerbate it, a rationale for • Expectation for continuing pain and suffering the interventions they receive and training in effective • Misunderstanding of drug therapy: opioids non-pharmacologicalpaincontroltechniques.Thelatter may be particularly important for children in palliative – dosing and administration care, who have diminishing control in their lives. Chil- – criteria for evaluating effectiveness dren and their parents do not know that prescribed pain controltreatmentsmay vary in efficacy atdifferenttimes Behavioural Factors throughout their treatment due to variations in disease • Social withdrawal activity or situational factors. Without this knowledge, • Physical inactivity their confidence in certain therapies can decrease, even Cancer Pain, Palliative Care in Children 223 thoughthesetherapieswouldeffectivelyalleviatepainat young children can easily learn to use a variety of practi- another time. The fear of inadequate pain control places cal pain control methods to lessen their anxiety, distress an enormous emotional burden on an already distressed and pain. The specific methods depend on the age of the child and family and can create a situation in which their child, the type of pain experienced and the resources pain and disability intensifies. available. Deep breathing, alternately tightening and C Children seem to know intuitively, even when dying has relaxing their fists, squeezing their mother’s hand, lis- not been discussed directly with them. They fear separa- tening to stories or music and imagining that they are tion and abandonment;some children mayfear thattheir in a pleasant setting can be very effective for reducing illness is a punishment. Dying children may feel fright- procedural-related pain, when used with appropriate ened, isolated and guilty unless they are able to openly analgesics. Families should understand that what they expressandresolvetheirconcerns.Manyobservershave think, how they behave and how they feel affects their noted that children who are dying have a level of matu- children’s pain. Then they can begin to work inde- rity far beyond their years. It is essential to acknowledge pendently and with staff to create additional non-drug and resolve their fears. Children should receive accurate pain control methods based on the child’s interest, the information, consistent with their religious beliefs, pre- cultural setting and the availability of resources. sented in a calm reassuring manner. They may need concrete reassurance that they will not suffer when they die, Summary that they will not be alone and that their families will Optimal pain control for children with cancer and for remember them. Unresolved emotions add anguish and children receiving palliative care requires an integrated may intensify their pain. treatment plan with both drug and non-drug therapies (Frager 1997; Hooke et al. 2002; McGrath and Brown Treating a Child’s Pain 2004). Comprehensive care includes curative therapies A treatment algorithm illustrating a practical approach when available, pain and symptom management and for treating a child’s pain is illustrated in Fig. 1. Pain compassionate support for children and their families. It assessment is an integral component of diagnosis and isessentialto focusnotonly onthemedicalmanagement treatment. The differential diagnosis of a child’s pain is of children’s disease but also on the psychosocial and a dynamic process that guides clinical management. We spiritual factors that affect children’s pain and suffering. should select specific therapies to target the responsible Specific interventions must be selected after determi- central and peripheral mechanisms and to mitigate the nation of the primary and secondary sources of noxious pain-exacerbating impact of situational factors, recog- stimulation and after a thorough assessment of the nizing that the multiple causes and contributing factors unique situational, behavioral, emotional and familial will vary over time. Drug therapies – analgesics, adju- factors that affect a child’s pain. All analgesics should vant analgesics and anesthetics - are essential for pain be selected ‘by the ladder’ and administered ‘by the control, butnon-drug therapies– cognitive, physicaland clock’, ‘by the child’ and by an effective and painless behavioral - are also essential. As we monitor the child’s route. Dosing intervals should be frequent enough to improvement in response to the therapies initiated, we control pain adequately, so that children do not expe- refineourpaindiagnosisandtreatmentplanaccordingly. rience an alternating cycle of pain, drowsy analgesia, DrugtherapiesarecoveredintheessayAnalgesicGuide- pain, etc. Special problems in palliative pain control lines for Children; anesthetic blocks are covered in the may arise when children die at home, unless parents and essay Post-operative Pain Control in Children and acute medical and nursing teams communicate openly about procedural pain is covered in the essay by Liossi. the availability of potent analgesics and the flexibility The optimal relief of pain in pediatric palliative care of dosing routes and regimens. The choice for pain begins with the recognition that you are assessing and control is not merely ‘drug versus non-drug therapy’, treating an individual child with pain, not managing but rather a therapy that mitigates both the causative and pain as a symptom apart from the child. A thorough contributing factors for pain. We have the knowledge medical history, physical examination and assessment and thus the obligation to ensure that children receive of pain characteristics and contributing factors are nec- adequate pain control from the time that they are diag- essary to establish a correct clinical diagnosis. Specific nosed with cancer throughout their treatment protocol, interventions should be selected and administered to including those cases that proceed to palliative care. children as part of a comprehensive pain programme, in the same manner as the most appropriate analgesics are References selected and administered in adequate doses, at regular 1. Brown SC, McGrath PA (2005) Pain In Children. In: Pappagallo dosing intervals, through the most efficient routes. M (ed) The Neurological Basis of Pain. McGraw-Hill, New York Children seem to possess an enhanced ability to absorb 2. Chaffee S (2001) Pediatric palliative care. Prim Care 28:365–390 themselves completely in a task, game or imagined 3. Collin, JJ, Weisman SJ (2003) Management of pain in childhood cancer. In: Schechter NL, Berde CB, Yaster M (eds) Pain in In- event and thus might be more able than adults to trigger fants, Children, and Adolescents. Lippincott Williams & Wilkins, endogenous pain-inhibitory mechanisms. Even very Philadelphia, pp 517–538 224 Cancer Pain Management

Cancer Pain, Palliative Care in Children, Figure 1 Treatment algorithm for pain management.

4. Doyle D, Hanks GWC, Cherny NI et al. (eds) (2004) Oxford Text- ical Practice Guidelines Series, No. 3. American Pain Society, book of Palliative Medicine 3rd edn. Oxford University Press, Glenview, Illinois Oxford, pp 775–789 12. Price DD, Bushnell MC (2004) Psychological Modulation of 5. Frager G (1997) Palliative care and terminal care of children. Pain: Integrating Basic Science and Clinical Perspectives. IASP Child Adoles Clinic North Am 6:889–909 Press, Seattle 6. Galloway KS, Yaster M (2000) Pain and symptom control in 13. Sobo EJ, Billman G, Lim L et al. (2002) A rapid interview pro- terminally ill children. Pediatr Clinic North Am 47:711–747 tocol supporting patient-centered quality improvement: hearing 7. Goldman A (1998) ABC of palliative care. Special problems of the parent’s voice in a pediatric cancer unit. Jt Comm J Qual children. BMJ 316: 49–52 Improv 28:498–509 8. Goldman A, Frager G, Pomietto M (2003) Pain and Palliative 14. World Health Organization (1998) Cancer pain relief and pal- Care. In: Schechter NL, Berde CB, Yaster M (eds) Pain in In- liative care in children. World Health Organization, Geneva fants, Children, and Adolescents. Lippincott Williams & Wilkins, Philadelphia, pp 539–562 9. Hooke C, Hellsten MB, Stutzer C et al. (2002) Pain management for the child with cancer in end-of-life care: APON position paper. J Pediatr Oncol Nurs 19:43–47 Cancer Pain Management 10. McGrath PA, Brown SC (2004) Paediatric palliative medicine – Pain control. In: Doyle D, Hanks G, Cherny N et al (eds) Ox- ford Textbook of Palliative Medicine, 3rd edn. Oxford University Definition Press, Oxford, pp 775–789 11. Miaskowski C, Cleary J, Burney J et al (2005) Guideline for the Adisciplinedapproachtoassessment,pharmacological, Management of Cancer Pain in Adults and Children, APS Clin- and nonpharmacological treatment aimed at reducing or Cancer Pain Management, Adjuvant Analgesics in Management of Pain Due To Bowel Obstruction 225 eliminating pain in patients who have a diagnosis of can- Three types of medication are commonly used: 1) an- cer. ticholinergics; 2) corticosteroids; and 3) the synthetic Cancer Pain Management, Adjuvant Analgesics in somatostatin analogue octreotide. Management of Pain Due To Bowel Obstruction Cancer Pain Management, Anesthesiologic Interven- Characteristics C tions, Neural Blockade The pharmacological management of pain associated Cancer Pain Management, Anesthesiologic Interven- with malignant bowel obstruction addresses three tions, Spinal Cord Stimulation, and Neuraxial Infu- critical pathophysiological mechanisms: 1) intestinal sion distention and resultant bowel ischemia; 2) paroxysmal Cancer Pain Management, Cancer-Related Break- intestinal hypermotility; and 3) increased intestinal through Pain, Therapy secretions that perpetuate a vicious cycle of distention- Cancer Pain Management, Chemotherapy intestinal secretion-peristalsis (Basson et al. 1989; Cancer Pain Management, Gastrointestinal Dysfunc- Rousseau 1998). tion as Opioid Side Effects Opioids are the mainstay of pain management in ma- Cancer Pain Management, Interface between Cancer lignant bowel obstruction, and frequently assuage the Pain Management and Palliative Care pain associated with intestinal distention and bowel Cancer Pain Management, Neurosurgical Interven- ischemia. The pain that occurs secondary to intesti- tions nal hypermotility is often referred to as colic, and is Cancer Pain Management, Nonopioid Analgesics precipitated by paroxysms of increased peristalsis that Cancer Pain Management, Opioid Side Effects, Cog- thrust against the mechanical resistance of a malignant nitive Dysfunction obstruction (Baines 1998). Colicky pain often requires Cancer Pain Management, Opioid Side Effects, En- the use of anticholinergic medications in addition to docrine Changes and Sexual Dysfunction opioids to mitigate the excruciating discomfort of in- Cancer Pain Management, Opioid Side Effects, Un- testinal hypermotility (Rousseau 1998; Baines 1998; common Side Effects Krouse et al. 2002; Lublin and Schwartzentruber 2002; Cancer Pain Management, Orthopedic Surgery Ripamonti et al. 2000; Ripamonti et al. 2001). Cancer Pain Management, Overall Strategy Anticholinergic medications decrease peristalsis of the Cancer Pain Management, Palliation of Upper GI gastrointestinal tract through a competitive inhibition Cancer of the muscarinic receptors of intestinal smooth muscle, Cancer Pain Management, Patient-Related Barriers and an impairment of ganglionic neural transmission Cancer Pain Management, Principles of Opioid Ther- in the bowel wall (Mercadante 1997; Baines 1994). Al- apy, Dosing Guidelines though there are few well-controlled studies evaluating Cancer Pain Management, Principles of Opioid Ther- their efficacy in reducing abdominal colic in malignant apy, Drug Selection bowel obstruction, anecdotal experience supports their Cancer Pain Management, Radiotherapy ability to relieve malignant colic, and they are com- Cancer Pain Management, Rehabilitative Therapies monly used in the management of bowel obstruction. Cancer Pain Management, Treatment of Neuropathic Recommended medications include glycopyrrolate, Components hyoscine butylbromide, scopolamine, hyoscyamine Cancer Pain Management, Undertreatment and sulfate, and atropine. Glycopyrrolate, a quaternary am- Clinician-Related Barriers monium anticholinergic, and hyoscine butylbromide Pain Management, Cancer-Related Breakthrough (not available in the United States) both exhibit limited Pain Therapy lipid solubility (Rousseau 1998; Krouse et al. 2002; Davis and Furste 1999). They penetrate the blood-brain barrier less than other anticholinergics, and as a result, reduce central nervous system side effects such as agi- Cancer Pain Management, Adjuvant tation and hallucinations (Rousseau 1998; Baines 1998; Analgesics in Management of Pain Due To Mercadante 1997). Aside from agitation and hallucinations, anticholinergic drugs can cause dry mouth Bowel Obstruction and eyes, drowsiness, tachycardia, hypotension, and PAUL C. ROUSSEAU urinary retention; dry mouth can be reduced by sucking VA Medical Center, Phoenix, AZ, USA ice cubes and drinking small sips of water, while dry [email protected] eyes can be alleviated with physiologic eye drops. Corticosteroidshavebeenusedempiricallyinmalignant bowel obstruction to reduce peritumor and perineural Definition inflammatory edema (Rousseau 1998; Baines 1998; Non-opioid analgesics utilized in the management Krouse et al. 2002; Mercadante 1997), and thereby of pain and colic in malignant bowel obstruction. improve gastrointestinal transport and colicky pain 226 Cancer Pain Management, Adjuvant Analgesics in Management of Pain Due To Bowel Obstruction

(Ripamont 1994). They act both as antiemetics and Cancer Pain Management, Adjuvant Analgesics in Management of analgesics, the latter ostensibly due to prostaglandin Pain Due To Bowel Obstruction, Table 1 Adjuvant Analgesics in Ma- inhibition, suppression of migration of polymorphonu- lignant Bowel Obstruction* clear leukocytes, and reversal of increased capillary Drug Dose permeability. In an inclusive meta-analysis of pub- glycopyrrolate** 1–2 mg tid-qid OR lished articles and studies on the use of corticosteroids in malignant bowel obstruction, secondary to advanced 0.1–0.2 mg tid-qid SC/IV gynecological and gastrointestinal cancers, Feur and hyoscine butylbromide 40–120 mg daily SC/IV Broadley noted a trend for improvement in bowel obstruction for patients treated with corticosteroids, but Scopolamine 400–800 mcg OR every 4–6 h thistrend did notreach statisticalsignificance. Although 1–2 TDP every 48–72 h corticosteroids did appear to improve the symptoms 0.8–2 mg via CSI every 24 h of bowel obstruction, Feur and Broadley did not explicitly mention their ability to relieve pain (Feur and Atropine 1–2 drops ophthalmic solution SL Broadley 1999). In another study on the benefits of every 4 h corticosteroids in malignant bowel obstruction, 68% 0.4mgORevery4h of patients without a nasogastric tube prescribed corticosteroids, versus 33% without a nasogastric tube pre- 0.4mgSCevery4h scribed a placebo, achieved symptom relief (p = 0.047); Dexamethasone 4–8 mg daily OR however, in patients who already had a nasogastric tube in place, the results were less significant (60% versus 2–8mgevery6h SC/IV 33%, p = 0.080). Unfortunately, the sample size of this 2–12 mg via CSI every 24 h study was small, and while the authors mentioned colic Prednisone 5–20 mg every 4–6 h as a symptom in 62% of study participants, they did not specify if colic was relieved with corticosteroids (Laval Octreotide 150 mcg tid SC et al. 2000). Side effects of corticosteroids are minimal 0.2–0.9 mg via CSI every 24 h when used in malignant bowel obstruction, with oral candidiasis the most commonly reported adverse event *List is not inclusive, dosages are suggested initial doses that may be (Mercadante 1997). prescribed as scheduled and/or prn doses, may need to be titrated to effect dependent upon patient’s clinical condition and expected life expectancy Octreotide, a synthetic analogue of somatostatin, re- *Reduce dose in renal insufficiency duces the gastrointestinal secretion of gastrin, vasoac- OR, oral; SC, subcutaneous; IV, intravenous; TDP, transdermal patch; SL, tive intestinal peptide (VIP), insulin, pepsin, glucagon, sublingual; CSI, continuous subcutaneous infusion; prn, as needed and pancreatic bicarbonate and enzymes; reduces mesenteric blood flow (Mercadante 1997, Pandha and Waxman 1996); exhibits a proabsorptive effect on water and ions (Rousseau 1998); and inhibits intesti- References nal motility (Rousseau 1998; Baines 1998; Krouse 1. Baines M (1994) Intestinal Obstruction. In: Hanks GW (ed) Pal- et al. 2002; Pandha and Waxman 1996). By reduc- liative Medicine: Problem Areas in Pain and Symptom Man- ing intestinal secretions and inhibiting gastrointestinal agement. Cold Spring Harbor Laboratory Press, Plainview, New York, pp 147–156 motility, octreotide positively modulates gastrointesti- 2. Baines MJ (1998) The Pathophysiology and Management of Ma- nal function and controls emesis in 70–100% of patients lignant Intestinal Obstruction. In: Doyle D, Hanks GWC, Mac- (Baines 1998; Krouse et al. 2002). Abdominal disten- Donald N (eds) Oxford Textbook of Palliative Medicine, 2nd edn. tion and colic are similarly controlled in a significant Oxford University Press, Oxford, pp 526–534 3. Basson MD et al. (1989) Does Vasoactive Intestinal Polypeptide number of patients (Baines 1998). These statistics are Mediate the Pathophysiology of Bowel Obstruction? Am J Surg supported by a prospective randomized controlled trial 157:109–115 comparing the antisecretory effects of octreotide and 4. Davis MP, Furste A (1999) Glycopyrrolate: A Useful Drug in hyoscine butylbromide in patients with inoperable ma- the Palliation of Mechanical Bowel Obstruction. J Pain Symptom Manage 18:153–154 lignant bowel obstruction who have nasogastric tubes. 5. Feur DJ, Broadley KE (1999) Systematic Review and Met- In this study, octreotide was very effective in reducing Analysis of Corticosteroids for the Resolution of Malignant the amount of gastrointestinal secretions in patients Bowel Obstruction in Advanced Gynaecological and Gastroin- with nasogastric tubes, and as an implicit consequence, testinal Cancers. Ann Oncol 10:1035–1041 6. Krouse RS et al. (2002) When the Sun can Set on an Unoperated though not specifically stated, reducing colicky pain Bowel Obstruction: Management of Malignant Bowel Obstruc- (Ripamonti et al. 2000). The toxicity and side effect tion. J Am Coll Surg 195:117–128 profile of octreotide is excellent (aside from discom- 7. Laval G et al. (2000) The Use of Steroids in the Management of fort at the site of injection), with no major side effects Inoperable Intestinal Obstruction in Terminal Cancer Patients: Do They Remove the Obstruction? Palliat Med 14:3–10 reported, even at a dose of 1.2 mg daily (Riley and 8. Lublin M, Schwartzentruber DJ (2002) Bowel Obstruction. Fallon 1994). In: Berger A, Portenoy RK, Weissman DE (eds) Principles & Cancer Pain Management, Anesthesiologic Interventions 227

Practice of Palliative Care & Supportive Oncology. Lippincott The use of local anesthetics and spinal opioids to modu- Williams & Wilkins, Philadelphia, pp 250–263 late pain transmission has gained popularity in the past 9. Mercadante S (1997) Assessment and Management of Mechan- ical Bowel Obstruction. In: Portenoy RK, Bruera E (eds) Topics decade, because of the low risk involved and the ability in Palliative Care, vol 1. Oxford University Press, New York, to reverse the treatment course at any time. pp 113–130 The use of local anesthetics to provide long-term pain C 10. Pandha HS, Waxman J (1996) Octreotide in Malignant Intestinal relief for cancer patients has principally involved in- Obstruction. Anti-Cancer drugs 7:5–10 11. Riley J, Fallon MT (1994) Octreotide in Terminal Malignant Ob- filtration around peripheral nerves, and epidural or struction of the Gastrointestinal Tract. Eur J Palliat Care 1:23–25 intrathecal administration. Local anesthetics injected 12. Ripamonti C (1994) Management of Bowel Obstruction in Ad- close to a peripheral nerve or the spinal cord will block vanced Cancer Patients. J Pain Symptom Manage 9:193–200 nerve impulses and provide degrees of nociceptive, 13. Ripamonti C et al. (2000) Role of Octreotide, Scopolamine Butyl- bromide, and Hydration in Symptom Control of Patients with In- sensory, or motor nerve blockade. Anesthesiologists operable Bowel Obstruction and Nasogastric Tubes: A Prospec- have searched for the correct combination of local anes- tive Randomized Trial. J Pain Symptom Manage 19:23–34 thetic concentration, infusion site, and rate of infusion 14. Ripamonti C et al. (2001) Clinical-Practice Recommendations to achieve analgesia without the significant side effects for the Management of Bowel Obstruction in Patients with End- Stage Cancer. Support Care Cancer 9:223–233 of motor or sensory blockade. Two common sites of 15. Rousseau PC (1998) Management of Malignant Bowel Obstruc- peripheral nerve block with local anesthetic infusion tion in Advanced Cancer: A Brief Review. J Palliat Med 1:65–72 are the brachial plexus (Fig. 1) and lumbar plexus. Tumors originating in lung, head and neck, or other sites may invade the brachial plexus, resulting in se- Cancer Pain Management, vere neuropathic pain, and pelvic tumors may similarly Anesthesiologic Interventions invade the lumbar plexus. The percutaneous insertion of catheters for the infusion of local anesthetics has PAUL A. SLOAN provided excellent and long-term pain relief among Department of Anesthesiology, University of such cancer patients (Vranken et al. 2001; Douglas and Kentucky, Lexington, KY, USA Bush 1999). A basal infusion may be physician pre- [email protected] scribed, and augmented by the use of patient-controlled boluses for breakthroughpain. Portable infusion pumps Synonyms (small enough to be worn on the body) allow the patient to return home for as long as possible. Typical local Nerve block; anesthetic block anesthetics used are bupivacaine (1–5 mg/ml), lido- Definition caine (5–10 mg/ml) or ropivacaine (1–5 mg/ml), with infusion rates of 3–8 ml/h. Information about noxious events is transmitted to the The spinal cord is bathed by cerebrospinal fluid (CSF) brain via neurons of the peripheral and central nervous that is contained in a strong protective membrane, the system. Blockade of thisnerve conduction using applied dura mater. Local anesthetics applied outside the dura localanestheticstotemporarilyblockpaintransmission, mater (epidural) or within the CSF (intrathecal) have spinal medications (e.g. opioids) to modulate pain trans- been used to control cancer pain (Fig. 2). A catheter mission, or neurolytic substances to destroy the pain- is usually placed percutaneously into the epidural transmitting nerves is the domain of anesthesiologic interventions for cancer pain management.

Characteristics Most patients with cancer pain can have their pain well managedusingstandardopioidsandotheranalgesicsvia the oral or parenteral routes. However, approximately 15% of cancer patients with pain will experience severe pain resistant to traditional analgesic therapies (Sloan andMelzack1999).Fortheseunfortunatepatients,anesthesiologic techniques often provide welcome pain relief.Theuseofalcoholtodestroynervetissueinthetreat- ment of painful conditions is almost 75 years old, and, along with phenol, became popular in the 1950’s and 1960’s for the treatment of cancer pain (Maher 1955). With more recent acceptance and use of chronic opioid therapy for cancer pain, the current role of neuroablative techniques has chieﬂy been for patients with terminal Cancer Pain Management, Anesthesiologic Interventions, disease and pain unresponsive to traditional analgesics. Figure 1 Interscalene approach to brachial plexus block. 228 Cancer Pain Management, Anesthesiologic Interventions

Cancer Pain Management, Anesthesiologic Interventions, Figure 2 Cross-section through a lumbar vertebrae. or intrathecal space for the chronic infusion of local achieve successful analgesia, with morphine remaining anesthetics. The catheter may be tunneled under the the most common. A single injection of spinal morphine skin and exit to an external portable pump, or remain will provide 12–24 h of pain relief. However, a continu- buried and attached to an implanted pump. These pro- ous infusion of opioid is often used and can be managed cedures are usually performed using local anesthesia safely at home (Samuelsson et al. 1995). The effective and intravenous sedatives. The pumps allow for the dose is titrated to analgesia or intolerable side effects. constant infusion of local anesthetics such as bupiva- A useful starting dose for epidural morphine is 20% of caine (Dahm et al. 2000). Cancer patients with lower the current daily oral morphine dose, and the final daily extremity or truncal pain to the waist are best suited epiduraldosesreportedintheliteraturehaverangedfrom to these approaches. Possible complications include 2 to over 1000 mg. local anesthetic toxicity (uncommon), hypotension, The combination of opioids and local anesthetics ap- tachyphylaxis, infection, and motor weakness. De- plied to the spinal cord in animals has resulted in a spite the side effect potential, most patients tolerate synergistic effect (Akerman et al. 1988), and led to chronic infusion of anesthetics without difficulty and the clinical practice of combining spinal analgesics to can be monitored at home. In addition to spinal ad- achieve powerful analgesia with the fewest possible ministration, anesthetics have been infused chronically side effects. The co-administration of these drugs has into the pleural space via a percutaneous catheter for gained widespread acceptance and has been shown the relief of refractory lung cancer pain (Aguilar et to limit morphine dose progression during long-term al. 1992). spinal infusion (Dongen et al. 1999). Other spinal Spinal administration of opioids for pain relief was first drugs that have provided some analgesia include alpha- applied to patients in 1979 (Behar et al. 1979), and has adrenergic agonists (clonidine, dexmedetomidine) and been advocated for the relief of intractable cancer pain. NMDA receptor antagonists (ketamine). Spinal opioids can be given by both the epidural and Complications (10% of all patients) associated with intrathecal routes of administration, with the epidural spinal analgesics include local infection, CSF leak, dose being approximately 10 times the intrathecal dose. pain on injection, mechanical problems with catheter It is believed that spinally applied opioids modulate pain function, headache, meningitis and epidural hematoma transmission by direct action on specific opioid recep- (Basta and Sloan 1999) or abscess (Fig. 3). Local in- tors in the dorsal horn of the spinal cord (Bedder 1997). fection can usually be managed with antibiotics and In this way, there may be fewer and/or less intense sys- catheters can remain in place for months. The typical temic opioid side effects and a better quality of analge- side effects of opioids may be seen, including nausea sia may be obtained. Many opioids have been used to and vomiting, sedation, urinary retention, and pruritus. Cancer Pain Management, Anesthesiologic Interventions 229

Cancer Pain Management, Anesthesiologic Interventions, Figure 3 MRI of low thoracic epidural abscess in a patient treated with chronic epidural analgesics.

Patient accommodation to these side effects of opioids for head or neck pain. Noninvasive gamma knife typically occurs. destruction of the pituitary has also been tried for The historic “nerve block” using neurolytic agents to intractable bilateral cancer pain (Sloan et al. 1996). physically modify nerve tissue to produce analgesia has Other innovations may prove valuable in the future. Zi- now become the least prevalent anesthesiologic proce- conotide, a neuronal-specific calcium channel blocker, dure for the management of cancer pain. Nonetheless, will be available for intrathecal use and has been shown among terminally ill patients with pain not well con- to be an effective analgesic in controlled trials. The per- trolled by other measures, certain neurolytic injections cutaneous injection of adrenal medullary allografts, ob- can provide excellent pain relief with a minimum of tained from organ donors, into the lumbar CSF presents complications. The destruction of the celiac plexus an exciting possibility for interventional management of in the upper abdomen is the most common neurolytic cancer pain. These cells produce met-enkephalin, and block performed. Upper abdominalpainassociatedwith bothstudiesinanimalsandsmallsurveysinhumans(La- cancer of the pancreas, distal esophagus, stomach or zorthes et al. 2000) have yielded positive findings. liver may be treated using a simple percutaneous tech- Anesthetic interventions for pain are well established nique. Imaging studies (x-ray, CT scan, ultrasound) and new therapies are evolving. The appropriate use of guide accurate needle placement, and the injection anesthesiologic interventions to help manage acute and of 25–50 ml of alcohol or phenol results in destruc- chronic pain among cancer patients will ensure pain re- tion of nociceptive neurons passing through the celiac lief and improved quality of life. plexus, thus producing pain relief in the majority of References patients that may last for many months (Rykowski and Hilgier 2000). While significant complications (para- 1. Aguilar JL, Montes A, Samper D et al. (1992) Interpleural Anal- gesia through a DuPen Catheter for Lung Cancer Pain. Cancer plegia, pneumothorax) are infrequent and have been 70:2621–2623 reduced by radiographic needle placement, they have 2. Akerman B, Arwestrom E, Post C (1988) Local Anesthetics not been entirely eliminated. Common complications Potentiate Spinal Morphine Antinociception. Anesth Analg include postural hypotension and diarrhea. 67:943–948 3. Basta M, Sloan PA (1999) Epidural Hematoma following Epidu- Additional neurolytic blocks occasionally used to treat ral Catheter Placement in a Patient with Chronic Renal Failure. cancer pain include lumbar sympathetic block for uro- Can J Anesth 46:271–274 logic pain, superior hypogastric block for pelvic pain, 4. Bedder MD (1997) Neuraxial Analgesic Blockade: Physiology, Pharmacology, and Complications. In: Parris WCV, Foster HW, subarachnoid block for chest wall pain, subarachnoid Melzack R (eds) Cancer Pain Management: Principles and Prac- saddle block for perineal pain, and cranial nerve block tice. Butterworth-Heinemann, Newton, MA, pp 171–180 230 Cancer Pain Management, Anesthesiologic Interventions, Neural Blockade

5. Behar M, Magora F, Olshwang D et al. (1979) Epidural Morphine may become numb and partly paralyzed. Interruptions in Treatment of Pain. Lancet 1:527–529 of pain impulses conducted through visceral nerves, e.g. 6. Dahm P,Lundborg C, Janson M et al. (2000) Comparison of 0.5% Intrathecal Bupivacaine with 0.5% Intrathecal Ropivacaine in the the celiac plexus of the upper abdomen; do not cause Treatment of Refractory Cancer and Noncancer Pain Conditions: numbness or skeletal muscle weakness. Severe forms of Results from a Prospective, Crossover, Double-Blind, Random- cancer pain can be relieved effectively by skillfully ap- ized Study. Reg Anesth Pain Med 25:480–487 plied anesthesiologic interventions (Breivik 2000). The 7. Dongen RT van, Crul BJ, Egmond J van (1999) Intrathecal Coad- ministration of Bupivacaine Diminishes Morphine Dose Progres- risk of adverse effects exists and must be understood sion during Long-Term Intrathecal Infusion in Cancer Patients. when considering these approaches. Clin J Pain 15:166–172 8. Douglas I, Bush D (1999) The Use of Patient-Controlled Bo- Reversible Blockade of Pain Impulses by Local Anesthetic luses of Local Anaesthetic Via a Psoas Sheath Catheter in the Drugs Management of Malignant Pain. Pain 82:105–107 9. Lazorthes Y, Sagen J, Sallerin B et al. (2000) Human Chromaffin Infiltration of a painful primary or metastatic tumor, or Cell Graft into the CSF for Cancer Pain Management: A Prospec- the peripheral nerves innervating a painful cancerous tive Phase II Clinical Study. Pain 87:19–32 growth, with a local anesthetic drug results in local or 10. Maher RM (1955) Relief of Pain in Incurable Cancer. Lancet 1:18 regional anesthesia and pain relief lasting from 1–12 h. 11. Rykowski JJ, Hilgier M (2000) Efficacy of Neurolytic Celiac The duration can be prolonged with repeated injections Plexus Block in Varying Locations of Pancreatic Cancer: Influ- or infusion into perineural catheters. Local anes- ence on Pain Relief. Anesth 92:347–354 thetic infiltrations and simple nerve blocks should 12. Samuelsson H, Malmberg F, Eriksson M et al. (1995) Outcomes of Epidural Morphine Treatment in Cancer Pain: Nine Years of be used liberally (Twycross 1994). Relief of acute, Clinical Experience. J Pain Symptom Manage 10:105–112 overwhelmingly intense breakthrough pain from a 13. Sloan PA, Hodes J, John W (1996) Radiosurgical Pituitary Ab- pathological fracture or an acute tumor infarct can be lation for Cancer Pain. J Palliat Care 12:51–53 relieved effectively with a regional anesthetic block. 14. Sloan PA, Melzack R (1999) Long-Term Patterns of Morphine Dosage and Pain Intensity among Cancer Patients. Hospice J Local anesthetic nerve blocks should not be used to 14:35–47 predict the effect of neurolytic blocks or other neurode- 15. Vranken JH, Vegt MH van der, Zuurmond WW et al. (2001) structive treatment, such as thermocoagulation or Continuous Brachial Plexus Block at the Cervical Level using a Posterior Approach in the Management of Neuropathic Cancer surgical denervation (Hogan and Abrams 1997). Pain. Reg Anesth Pain Med 26:572–575 Spinal Cord Analgesia by Epidural or Subarachnoid Catheter Infusion of Drugs Cancer Pain Management, Epidural Analgesia Anesthesiologic Interventions, Neural Potent pain relief can occur when low concentrations of a local anesthetic drug, an opioid, and an adrenergic Blockade drug are administered epidurally (Breivik 2002a). With HARALD BREIVIK an epidural catheter at the appropriate spinal cord seg- Department of Anesthesiology, Rikshospitalet mental level (cervical to the upper lumbar), a reliable in- University Hospital, University of Oslo, Oslo, Norway fusion pump and trained nurses, analgesia can be main- [email protected] tained for prolonged periodsathome, ina hospice or palliative care institution. Stable and sterile drug mixtures Synonyms are needed (Breivik 2002a). Details of epidural catheter placement and maintenance, monitoring and prevention Anesthesiological Interventions; Neural Blockade and management of complications are described in text- Definition books (Breivik 2002a). Anesthesiologic interventions are transient or long last- ProlongedInfusionintotheSpinalSubarachnoidSpace ing interruptions of pain impulse conduction in periph- Insertion of a catheter into the subarachnoid space al- eral nerves, nerve roots, or the spinal cord. This will hin- lows infusion of a local anesthetic solution containing der the conscious perception of pain and lessen the suf- an opioid and donidine or adrenaline directly into the fering associated with cancer and its destruction of nor- cerebrospinal fluid. This may give satisfactory anal- mal tissues. gesia when most other methods have failed (Nitescu et al. 2002). Prolonged, effective, and safe pain relief is Characteristics possible,evenwhenthepatientislivingathome(Nitescu Anesthesiologic interventions may be performed with et al. 2002). local anesthetic drugs, which stop pain impulse conduction along nerves for up to several hours, or with Inflammatory Pain Treated with Injections of Local neurolytic drugs, which block transmission for up to Anesthetic and Corticosteroid Drugs several months. These interventions will remove pain Corticosteroids have analgesic effects when adminis- from the locally anesthetized part of the body, which tered epidurally, perineurally or intralesionally. These Cancer Pain Management, Anesthesiologic Interventions, Neural Blockade 231 are in part systemic effects, in part local effects on no- upperabdomenareindicationsaswell.Whenabdominal ciceptive nerve endings, and in part effects on inflam- wall involvement occurs, pain impulses will also travel matory or neurogenic pain mechanisms (Breivik 2000, through somatic afferent nociceptor fibers of the inter- Twycross 1994). costal nerves. Neurolytic block of the visceral afferent Segmental epidural applications of local anesthetic nociceptor fibers passing through the celiac plexus will C drugs combined with methylprednisolone, dexametha- not relieve this pain. soneortriamcinolonemayrelieve radicularnerveroot pain (Breivik 2000), including that caused by a tumor Techniques of Celiac Plexus and Splanchnic Nerve impinging on spinal nerve roots (Twycross 1994). Per- Blockade ineural injections of a mixture of a local anesthetic and The celiac plexus is the prevertebral sympathetic plexus a corticosteroid may cause immediate and prolonged that supplies the upper abdominal viscera with sympa- pain relief in nerves made hyperexcitable from local thetic innervations. It is located in the retroperitoneal trauma, infiltration of tumor or inflammatory reactions tissue space, anterior to the body of the first lumbar (Twycross 1994). and twelfth thoracic vertebrae. The aorta lies behind, Intralesional injection of local anesthetics and depot and the inferior vena cava and right renal vessels lie in corticosteroids similarly may cause immediate, and in front of the celiac plexus. The greater, the lesser, and some patients, prolonged pain relief, e.g. in multiple the least splanchnic nerves connect the celiac plexus myeloma lesions or metastases from breast cancer in via the spinal nerve roots to the thoracic spinal cord. ribs (Twycross 1994). These nerves can be interrupted by radiofrequency denervation in the thoracic region, an approach favored Neurolytic Nerve Blocks with Ethanol or Phenol by some (Medicis and Leon-Casasola 2002). The advantage of neurolytic blocks is apparent when The celiac plexus can be injected intraoperatively when a single intervention can replace or reduce the need the surgeon has determined that the tumor is unre- for daily administration of multiple drugs. However, sectable (Lillemo et al. 1993). However, the block has a misplaced injection or injection of an inappropri- most often been performed with needles through the ate dose may cause severe complications. Duration skin from the back, or with an anterior approach with of analgesia after a neurolytic block is limited. How- needle-guidance from computerized tomography scan- ever, some blocks can be repeated with success. Due to ning (CT) (Medicis and Leon-Casasola 2002). In the the possibility of severe post-denervation neuropathic traditional technique (Breivik 2000, Breivik 2002b) pain, neurolytic blocks of peripheral nerves should be (Fig. 1), the patient is prone and a needle is inserted on reserved for patients with life expectancy of less than each side under the midpoint of the 12th rib. With local about one year. Visceral sympathetic blocks may be anesthetic infiltration, the needle is advanced towards considered in patients with longer life expectancy. the anterolateral corner of the body of the first lumbar vertebra. When this bone is contacted, the depth marker Celiac Plexus Block is moved 1.5–2 cm from the skin level towards the hub Celiac plexus block relieves pain from cancer in the of the needle. The needle is now withdrawn to the sub- upper part of the abdomen (Breivik 2000). One double- cutaneous tissue, redirected, and advanced 1.5–2 cm blind, randomized, placebo-controlled study of intraop- beyond the anterolateral corner of the vertebral body. If erative celiac plexus neurolysis demonstrated improved the aorta is punctured on the left side, or the vena cava pain control, reduction in opioid analgesic consump- on the right side, the needle is withdrawn until blood tion, and significantly prolonged survival (Lillemo stops coming on aspiration. At this point, 5 ml of lido- et al. 1993). The block can be repeated with success caine 20 mg/ml is injected in each needle. The patient if pain recurs after weeks to months. Pneumothorax is soon able to tell whether his pain has disappeared. and shoulder pain from ethanol irritation of the di- He will also be able to inform the anesthesiologist of aphragmatic peritoneum are short-lived side effects. any signs of intraspinal or intravascular injection. This The sympatholysis that results may cause orthostatic is sufficient information to be able to go ahead with an hypotension and diarrhea for a few days. However, injection of 50 ml of 50% ethanol (96% ethanol diluted paraplegia and intestinal infarction may result if the with bupivacaine 2.5 mg/ml) in each of the two needles. neurolytic solution is injected into arteries. Severely It should be noted that radiographic imaging of the nee- misplaced epidural, paravertebral, and subarachnoid dle position is no guarantee that the injected neurolytic injections have been reported, with tragic consequences agent will not cause somatic neurological deficit. Two (Breivik 2000). reported cases of paraplegia following celiac plexus block in spite of radiographic needle control under- Indications for Celiac Plexus Block score this important point (Breivik 2000). If this block Cancer of the pancreas is the classic indication. How- is performed with the patient under general anesthesia, ever, cancer of the stomach, duodenum, liver, gallblad- the indications of correct needle positioning from a test der, and choledocalductcausing visceraltype painin the dose of a small, concentrated dose of local anesthetic 232 Cancer Pain Management, Anesthesiologic Interventions, Neural Blockade are lost. Some of the reports of poor or short lasting Subdural and Epidural Neurolytic Blockade with Phe- pain relief from celiac plexus block may be due to an nol insufficient injected volume orconcentration of ethanol, These techniques have been used for cancer pain in the which should not be less than 50 ml of 50%. cervical and upper thoracic region where subarachnoid block is less effective (Breivik 2000). Side Effects of Celiac Plexus Block with Ethanol Neurolytic Blocks of Selected Peripheral and Paravertebral An immediate side effect of celiac plexus block is a Nerves (Hill 2002) drop in blood pressure and also orthostatic hypotension for some time following the block. If this occurs, it Trigeminal nerve block may be indicated for pain may be treated with ephedrine and intravenous colloid- from head and neck cancer with trigeminal nerve in- containing fluids. Due to the sympathetic denervation volvement. Less than 0.5 ml ethanol 96% is needed to of the major part of the gastrointestinal tract, diarrhea anesthetize an appropriate branch (Swerdlow 1983). may also result, often a desirable effect in patients who Glossopharyngeal nerve block may give good pain have been on oral opioids for some time. The patient relief when pharmacological therapy fails in painful should be warned that transient shoulder pain may be conditions of the mouth and throat. Ethanol is injected a result of the ethanol reaching the diaphragm. Too at the jugular foramen and may easily also block the rapid a discontinuation of morphine may cause with- vagus, accessory and hypoglossal nerves, causing dys- drawal symptoms. Some patients may need a reduced phagia if bilateral block is required (Montgomery and dose of oral morphine for residual pain, or for pain Cousins 1972). stemming from tumor invasion of the abdominal wall Intercostal nerve block with 1.0 ml of ethanol 96% or (Breivik 2000). phenol 5–6% often gives excellent pain relief, lasting up to a few weeks. Superior Hypogastric Plexus Block and Bilateral Lum- Paravertebral Spinal Nerve Blocks bar Sympathetic Block For well-localized somatic pain, a paravertebral spinal Phenol blocks of the superior hypogastric plexus or bi- nerve block can be performed, with needle insertion lateral lumbar sympathetic block may relieve patients 2–3 cm lateral to the spinous process (of the same ver- with visceral pain from pelvic organs and sigmoid colon tebra in the lumbar region, but of the vertebra above the (Breivik2000,MedicisandLeon-Casasola2002).Local segmental nerve to be blocked in the thoracic region). pelvic infiltration of cervical or prostatic carcinoma can After contact with the transverse process, the needle is cause somatic nociceptive pains that limit the effective- redirected below the transverse process, and 3–5 ml of ness of sympathetic blocks. The same is true for perineal the solution is injected. Pain relief may be good, but pain, when mainly of somatic origin and pain impulses the duration is unpredictable. The block can be consid- travel via sacral and pudendal nerves. ered in debilitated and bedridden patients with severe pain not responding well to pharmacological treatment. Subarachnoid Spinal Nerve Root Neurolytic Block Unintended subarachnoid injection, or injection into Segmental, one-sided denervation of sacral nerve roots a radicular artery to the spinal cord, may cause severe can be obtained by spinal puncture close to the af- neurological complications (Breivik 2000). fected nerve roots, followed by subarachnoid injection Sacral Nerve Blocks (Posterior Transsacral Blocks) of 0.3–0.6 ml of hypobaric ethanol (96%) with the When pelvic metastases cause nerve compression pain patient’s painful side up, or hyperbaric phenol (5% in which is not well controlled by pharmacological means, glycerol) with the painful side down. This technique sacral nerve blocks may be useful. The second sacral is used less nowadays due to the dissatisfaction with foramenlies1cmbelowandmedialtotheposteriorsupe- the degree and duration of relief, and because of risks rioriliacspine.Thefifthsacralforamenlies1cminferior of severe side effects (Breivik 2000, Twycross 1994). and lateral to the sacral cornua. The 3rd and 4th foram- Continuous catheter infusion of local anesthetics with ina lie on the line between the 1st and the 5th (Hill 2002). opioids is an alternative that is more effective and has The needle is advanced 0.5–1.5 cm beyond the opening less risk of severe complications (Nitescu et al. 2002). of the foramina and about 3 ml of the solution is injected However, under circumstances with very limited re- at each site. sources, where other pain relief is unavailable, the simple methods of subarachnoid ethanol or phenol References block may still have a place. It can be performed at the 1. Breivik H (2000) Nerve Blocks – Simple Injections, Epidurals, bedside with a spinal needle and a syringe (Stovner and Spinals and More Complex Blocks. In: Simpson KH, Budd K Endresen 1972). It is superior to no pain relief at all (eds) Cancer Pain Management. A Comprehensive Approach. in a terminally ill cancer patient who is suffering from Oxford University Press, Oxford, pp 84–98 2. Breivik H (2002a) Epidural Analgesia. In: Breivik H, Campbell excruciating pain (Swerdlow 1983, Kuzucu et al. 1966, W, Eccleston C (eds) Clinical Pain Management. Practical Ap- Drechsel 1984). plications and Procedures. Arnold, London, pp 409–416 Cancer Pain Management, Anesthesiologic Interventions, Spinal Cord Stimulation, and Neuraxial Infusion 233

3. Breivik H (2002b) Sympathetic Blocks. In: Breivik H, Camp- Humane treatment demands aggressive treatment of bell W, Eccleston C (eds) Clinical Pain Management. Practical cancer pain. To this end, the World Health Organization Applications and Procedures. Arnold, London, pp 233–246 4. Drechsel U (1984) Treatment of Cancer Pain with Neurolytic (World Health Organization 1990), and the Agency for Agents. Recent Results of Cancer Research 89:137–147 Health Care Policy and Research (Jacox et al. 1994) 5. Hill D (2002) Peripheral Nerve Blocks. In: Breivik H, Camp- havepublishedguidelinesonthemanagementofcancer- C bell W, Eccleston C (eds) Clinical Pain Management. Practical related pain. These guidelines, however, either fail to Applications and Procedures. Arnold, London, pp 197–232 6. Hogan QH, Abrams SE (1997) Neural Blockade for Diagnosis mention or minimize the importance of the role of in- and Prognosis: A Review. Anesthesiology 86:216–241 terventional therapy. Although opioids continue to be a 7. Kuzucu EY, Derrick WS, Wilber SA (1966) Control of In- mainstay of cancer pain treatment, patients frequently tractable Pain with Subarachnoid Alcohol Block. J American experience side effects, such as sedation and consti- Med Ass 195:541–544 8. Lillemo KD, Cameron JL, Kaufman HS et al. (1993) Chemi- pation. Many experience only imperfect cancer pain cal Splanchnicectomy in Patients with Unresectable Pancreatic relief. Cancer. Annals of Surgery 217:447–457 9. Medicis E de, Leon-Casasola de O (2002) Neurolytic Blocks. In: Breivik H, Campbell W, Eccleston C (eds) Clinical Pain Manage- The Role of Interventional Therapies ment. Practical Applications and Procedures. Arnold, London, Interventionaltherapies include neural blockade, spinal pp 247–254 10. Montgomery W, Cousins MJ (1972) Aspects of Management of drug delivery, and spinal cord stimulation (Staats 1998). Chronic Pain Illustrated by Ninth Nerve Block. British Journal Clinicians should consider using these therapies in can- of Anaesthesia 44: 383–385 cer patients who suffer intractable opioid side effects, 11. Nitescu PV,Apelgren L, Curelaru IA (2002) Long-Term Intrathe- or in whom opioids provide inadequate relief. Altering cal and Intracisternal Treatment of Malignant and Nonmalignant Pain Using External Pumps. In: Breivik H, Campbell W, Eccle- pain conduction with neural blockade techniques or ston C (eds) Clinical Pain Management. Practical Applications delivering lower doses of agents directly to the spinal and Procedures. Arnold, London, pp 285–306 cord can often improve the balance between analgesia 12. Stovner J, Endresen R (1972) Intrathecal Phenol for Cancer Pain. and side effects. Interventional therapies may also be Acta Anaesthesiol Scand 16:17–21 13. Swerdlow M (1983) Relief of Intractable Pain, 3rd edn. Excerpta cost-effective (Erdine and Talu 1998); for example, Medica, Amsterdam long-term (more than three months) administration 14. Twycross R (1994) Pain Relief in Advanced Cancer. Churchill of high-dose opioids delivered at home via patient- Livingstone, Edinburgh controlled-analgesia, is much more expensive on a strictly medical cost basis than implantable drug delivery. In appropriate patients, interventional therapies Cancer Pain Management, can make it possible to achieve the goal of decreasing pain and the side effects associated with higher doses Anesthesiologic Interventions, Spinal of systemic therapy while also reducing health care and Cord Stimulation, and Neuraxial Infusion associated costs. MUTHUKUMAR VAIDYARAMAN,PETER S. STAATS Division of Pain Medicine, The Johns Hopkins Neural Blockade University, Baltimore, MD, USA The effect of a nerve block can be short-term (using lo- [email protected], [email protected] cal anesthetics) or long-term (with chemical, thermal, or surgical applications). Nerve blocks can be periph- Synonyms eral, visceral, or intraspinal. Intraspinal blocks are now rarely performed because advances in spinal analgesia Anesthesiological Interventions; spinal cord stimula- offer alternatives, and increased life expectancy in can- tion; neuraxial infusion cer patients makes the risk of its associated complica- Definitions tions unacceptable. Short-acting local anesthetic blocks carry a very low Anesthesiologic interventions, spinal cord stimula- risk and are usually diagnostic, guiding clinical de- tion and neuraxial infusion are types of interventional cisions about the use of longer-acting methods. For therapies that may be used in the treatment of cancer example, the physician may anesthetize the painful pain. areas prior to a neurodestructive technique. This offers the patient the opportunity to experience the feeling of Characteristics a permanent procedure. If anesthesia is not associated Cancer is the second-most frequent cause of death in the with pain relief, it also helps the physician prognosticate United States. Cancer patients fear pain more than other the permanent neurolytic procedure. In some cases, a symptoms,andatleastathirdsufferpainatthetimeofdi- series of blocks with local anesthetic (e.g. sympathetic agnosis (Jacox et al. 1994). Pain is heterogeneous(Bon- blockade) can achieve lasting relief of neuropathic pain. ica 1990), and the prevalence and complexity of pain in- Althoughclinicianscommonlyrefertoneurodestructive creases in populations with advanced disease. blocks as permanent, the nerve may regenerate, leading 234 Cancer Pain Management, Anesthesiologic Interventions, Spinal Cord Stimulation, and Neuraxial Infusion to a return of pain. Neurolysis typically provides three intrathecal delivery of half of the oral opioid dose con- to six months of relief. verted to its intrathecal equivalent. The remaining oral dose should be replaced with an equivalent intrathecal Anatomic Location of Nerve Blocks dose titrated over the next few days (Krames 1993). Among the many possible peripheral nerve blocks, If the pain decreases by half with no intolerable side clinicians most frequently block intercostal (Bolotin et effects, the patient receives an external pump with a al. 2000) and trigeminal nerves to treat somatic pain. percutaneous catheter (for treatment duration of ≤ A visceral nerve block can be performed to address three months) or an implanted constant flow-rate or visceral pain. The most common is the celiac plexus programmable pump block (Polati et al. 1998). The superior hypogastric plexus block is indicated for the visceral pain that Pain Treatment and Survival in Cancer Patients may be prominent in patients with various pelvic or- Investigators are beginning to report findings of in- gan cancers, even in advanced stages (Leon-Casasola creased survival rates in cancer patients whose pain et al. 1993; Plancarte et al. 1997), and ganglion impar is controlled in a manner that reduces side effects and (Walther’s) blockade mitigates the burning visceral pain improves quality of life. In one study, patients with in the perineal area and can have a beneficial impact on unresectable pancreatic cancer who received an alcohol urgency (Plancarte et al. 1990). celiac block survived longer than those who received a Neuromodulation placebo block (Staats et al. 2001). Another study that compared optimal medical management alone with Spinal Cord Stimulation (SCS) optimal medical management plus intrathecal drug SCSmay be efficaciousin patientswhose painhasaneu- delivery, in a randomized trial involving 200 patients ropathic component (Grabow et al. 2003) and may ben- with refractory cancer pain, intrathecal therapy reduced efit certain cancer patients, for example, those with post- the incidence of drug-related toxicity and reliance on thoracotomy pain, postherpetic neuralgia, and/or radic- systemic analgesics while improving pain scores, qual- ular lower extremity pain. With this approach, an elec- ity of life for patients and caregivers, and survival rates trical current is applied to the dorsal aspect of the spinal (Smith et al. 2002). The possibility that controlling pain cord through an implanted wire. The current is created will lengthen the life of terminally-ill patients is intrigu- eitherbyanimplantedgeneratororanexternalgenerator ing, and should add to our urgency in promoting the that transmits to an implanted antenna. There have been consideration of pain as a disease that must be treated no controlled trials of SCS in cancer patients, but anec- as aggressively as possible. dotalexperience hasbeen favorable in carefully selected patients. References Neuraxial Infusion 1. Bolotin G, Lazarovici H, Uretzky G et al. (2000) The Efficacy Epidural delivery of morphine with an external pump is of Intraoperative Internal Intercostal Nerve Block during Video- Assisted Thoracic Surgery on Postoperative Pain. Ann Thorac widely used to treat cancer pain, especially in the post- Surg 70:1872–1875 operative setting. The timing of doses of epidural anal- 2. Bonica JJ (1990) Cancer Pain. In: Bonica JJ (ed) The Manage- gesia can be patient-controlled, and patients may con- ment of Pain, vol 1, 2nd edn. Lea and Febiger, Philadelphia, tinue to use this method of pain control after they are pp 200–460 discharged from the hospital. 3. Erdine S, Talu GK (1998). Cost Effectiveness of Implantable Devices versus Tunneled Catheters. Current Review of Pain Compared with epidural delivery,intrathecaldelivery of 2:157–162 opioids has the advantages of providing analgesia with 4. Grabow TS, Tella PK, Raja SN (2003) Spinal Cord Stimula- a much smaller dose of the drug, and a reduced chance tion for Complex Regional Pain Syndrome: An Evidence-Based Medicine Review of the Literature. Clin J Pain 19:371–383 of infection with implanted systems. Intrathecal drug 5. Jacox A, Carr DB, Payne R (1994) New Clinical Practice delivery should be considered in those patients with Guidelines for the Management of Cancer Pain. N Engl J Med chronic pain inadequately relieved by maximum medi- 330:169–173 calmanagement,orrelievedattheexpenseofintolerable 6. Krames ES (1993). Intrathecal Infusion Therapies for Intractable Pain: Patient Management Guidelines. J Pain Symptom Manage side effects (Paice et al. 1996). Only preservative-free 8:36 morphine is approved to treat pain intrathecally. Ad- 7. Leon-Casasola de OA, Kent E, Lema MJ (1993) Neurolytic Su- ditional widely-used agents include hydromorphone, perior Hypogastric Plexus Block for Chronic Pelvic Pain Asso- fentanyl, clonidine, and bupivacaine. Ziconotide, a ciated with Cancer. Pain 54:145–151 8. Olson K (1992) An Approach to Psychological Assessment of novel n-type calcium channel blocker, is under inves- Chronic Pain Patients. NCS Assessments, Minneapolis tigation and has been demonstrated to be efficacious 9. Paice JA, Penn RD, Shott S (1996) Intraspinal Morphine for in a controlled trial (Staats et al. 2004). Screening for Chronic Pain: A Retrospective Multicenter Study. J Pain Symp- intrathecal treatment includes assessment and treatment tom Manage 11:71 10. Plancarte R, Amescua C, Patt RB (1990) Presacral Blockade of co-morbid psychological conditions (Olson 1992) of the Ganglion of Walther (Ganglion Impar). Anesthesiology and a trial with a single bolus dose, epidural delivery, or 73:A751 Cancer Pain Management, Cancer-Related Breakthrough Pain, Therapy 235

11. Plancarte R, de Leon-Casasola OA, El-Helaly M et al. (1997) or pain clinics, and in hospice inpatients or outpatients. Neurolytic Superior Hypogastric Plexus Block for Chronic Pelvic These studies have varied in their sampling procedures, Pain Associated with Cancer. Reg Anesth 22:562–568 12. Polati E, Finco G, Gottin L et al. (1998) Prospective Randomized and in inclusion and exclusion criteria. Breakthrough Double-Blind Trial of Neurolytic Celiac Plexus Block in Patients pain is usually characterized according to its loca- with Pancreatic Cancer. Br J Surg 85:199–201 tion, severity, temporal characteristics, relationship to C 13. Smith TJ, Staats PS, Pool G et al. (2002) Randomized Clini- regular analgesia, precipitating factors, predictabil- cal Trial of an Implantable Drug Delivery System Compared to Comprehensive Medical Management for Refractory Cancer ity, pathophysiology, etiology and palliative factors Pain: Impact on Pain, Drug-Related Toxicity, and Survival. J Clin (Portenoy 1997). The reported prevalence of break- Oncol 20:4040–4049 through pain has varied from 20 to 95% (Zeppetella 14. Staats PS (1998) Cancer Pain: Beyond the Ladder. J Back Mus- and Ribeiro 2003). Pain is typically of fast onset, short culoskeletal Rehabilitation 10:69–80 15. Staats PS, Hekmat H, Sauter P, Lillemoe K (2001) The Effects of duration and feels similar to background pain, except Alcohol Celiac Plexus Block, Pain, and Mood on Longevity in that it may be more severe. Like background pain, the Patients with Unresectable Pancreatic Cancer: A Double-Blind, pathophysiology of breakthrough pain may be visceral, Randomized, Placebo-Controlled Study. Pain Med 2:28–34 somatic or neuropathic, and the etiology may be related 16. Staats PS, Yearwood T, Charapata S et al. (2004) Intrathecal Ziconotide in the Treatment of Refractory Malignant Pain: A directly to cancer or cancer treatment, or unrelated to Controlled Clinical Trial. JAMA 291:63–70 the cancer. 17. World Health Organization (1990) Cancer Pain Relief. World Breakthrough pain is a heterogeneous phenomenon that Health Organization, Geneva maybedifferentforeachpatient;patientsmayhavemore than one pain type. Two types of breakthrough pain have been described; incident pain, which is precipitated by Cancer Pain Management, volitional factors such as movement or non-volitional Cancer-Related Breakthrough Pain, such as bladder spasm; and spontaneous pain, which oc- cursin the absence of a specific trigger. End-of-dose fail- Therapy ure is sometimes included as a breakthrough pain sub- GIOVAMBATTISTA ZEPPETELLA type. It occurs either because the analgesic is described St. Clare Hospice, Hastingwood, UK ataninadequatedoseortheintervalbetweenadministra- [email protected] tions is too long. As background pain is not controlled, end-of dose pain is not breakthrough pain. Definition Despite the self-limiting nature of breakthrough pain, it can have a profound impact on both patients’ and Breakthrough pain is a transient increase in pain in- carers’ quality of life. Patients with breakthrough pain tensity over background pain. It occurs commonly in are often less satisfied with their analgesic therapy, have cancer patients and is a heterogeneous phenomenon decreased functioning because of their pain and have an that may be incapacitating or debilitating, or signifi- increased level of anxiety and depression (Portenoy et cantly impact quality of life. Breakthrough pain is a al. 1999). Unrelieved breakthrough pain also increases distinct component of cancer pain and requires specific economic burden placed on the healthcare system (Fort- management. ner et al. 2002). Effective management is, therefore, essential and can only be achieved through meticu- Characteristics lous assessment, good communication, and patient People with cancer-related pain often report that their and caregiver participation. Failure to take these factors pain varies during the course of the day. Two patterns into account can lead to ineffective analgesia, unwanted of pain can be identified: continuous background pain, adverse effects and poor adherence to therapy. which may respond well to around-the-clock (ATC) Management of breakthrough pain should be part of analgesics (Fig. 1), and transitory exacerbations of a holistic framework and appropriate to the stage of pain, which break through the ATC analgesics (Fig. 2). the patent’s disease. A combination of pharmacologi- Transient increases in pain in a cancer patient who has cal and non-pharmacological treatment strategies may stable persistent pain treated with opioids may be de- be required. Three principles of management have fined as breakthrough pain (Portenoy and Hagen 1990). been proposed (Portenoy 1997). First, implementation The definition of breakthrough pain has been the subject of primary therapies can lead to improvement in both of much discussion, with some investigators classifying background and breakthrough pain. These interventions episodic pains as breakthrough pain irrespective of the include those that modify the pathological process (e.g. analgesic regimen, and others classifying episodic pains radiotherapy, chemotherapy, and surgery), and those in this way irrespective of whether background pain is that manage reversible problems (e.g. antitussives for controlled. Even the term ‘breakthrough’is not one that cough, laxatives for constipation and antispasmodics is universally accepted (Mercadante et al. 2002). for bladder spasm). Second, optimizingof thescheduled Anumberofstudieshaveevaluatedthecharacteristicsof analgesic regimen using the World Health Organization breakthrough pain in patients attending cancer centers analgesic ladder as a basis for therapy (World Health 236 Cancer Pain Management, Cancer-Related Breakthrough Pain, Therapy

Cancer Pain Management, Cancer- Related Breakthrough Pain, Therapy, Figure 1 Background pain. Successful management of background pain with regular analgesia and without serious adverse effects.

Cancer Pain Management, Cancer- Related Breakthrough Pain, Therapy, Figure 2 Breakthrough pain. A transient increase over background pain that breaks through the regular analgesia; pain may vary in frequency, intensity and duration.

Organization 1996). Patients may require a combina- spontaneous breakthrough pains can lead to adverse tion of opioid and non-opioid analgesics and, in some effects. cases, adjuvant analgesics such as antidepressants, Successful use of rescue medication requires adequate anticonvulsants, bisphosphonates and corticosteroids. analgesia to be obtained without excessive adverse ef- Third, use of speciﬁc non-pharmacological or phar- fects. When using rescue medication, a number of is- macological interventions for breakthrough pain. Non- suesshouldbeconsidered(Whatdowegive?Howmuch, pharmacological interventions include physiotherapy, when in relation to the pain? By what route and how fre- cognitive techniques and orthopedic procedures. Phar- quently?). Rescue medication is best administered be- macological management is usually in the form of fore or soon after the onset of breakthrough pain. As supplemental analgesia also known as rescue medica- breakthrough pain is typically of fast onset and short du- tion. End-of dose failure responds best to increasing ration, rescue medication should ideally be potent, ab- ATC medication, whereas other breakthrough pain sub- sorbed and excreted rapidly, easy to administer and pro- types are usually managed with rescue medication, as duce minimal adverse effects (Fig. 3). Opioids are most increasing the ATC medication to cover all incident and commonly used, and the current approach involves giv- Cancer Pain Management, Cancer-Related Breakthrough Pain, Therapy 237

Cancer Pain Management, Cancer-Related Breakthrough Pain, Therapy, Figure 3 Ideal rescue medication. The plasma level of medication follows the profile of breakthrough pain without excessive adverse effects. inganadditionaldosebasedonthepatient’sATCanalge- onset of action than the oral route and avoids hepatic sia. Opioids may be administered by several routes, in- firstpassmetabolism. Oraltransmucosalfentanylcitrate cluding oral, oraltransmucosal, rectal, intravenous, sub- (OTFC) is a fentanyl-impregnated lozenge, specifically cutaneousandintraspinal(intrathecalandepidural).The developed for the management of breakthrough pain. route of administration is important, as this can influ- OTFC is rapidly absorbed through the oral mucosa and ence the onset of analgesia and duration of effect. Oral in controlled studies has been shown to be safe and medication is generally used as it is convenient and of- effective (Coluzzi et al. 2001; Farrar et al. 1998). OTFC ten the most acceptable (Walker et al. 2003). When us- should be individually titrated to a successful dose that ingmorphineasrescuemedication,the’normal-release’ is not predicted from the ATC opioid dose. formulation (which hasafour-hourly duration ofaction) is used; the current recommendation by the European References Association for Palliative Care is to use the same as the 1. Coluzzi PH, Schwartzberg L, Conroy JD et al. (2001) Break- four-hourly dose of normal-release morphine (approx- through Cancer Pain: A Randomized Trial Comparing Oral imately 16% of the daily dose) when necessary (Hanks Transmucosal Fentanyl Citrate (OTFC) and Morphine Sulphate et al. 2001). However, as breakthrough pain can vary in Immediate Release (MSIR) Pain 91:123–130 2. Coyle N, Adelhardt J, Foley KM et al. (1990) Character of Ter- etiology, intensity and duration, the dose of rescue med- minal Illness in the Advanced Cancer Patient: Pain and Other ication may also vary (Fig. 3). Symptoms during the Last Four Weeks of Life. J Pain Symptom Patients with advanced disease may require more than Manage 5:83–93 one route of drug administration due to difficulty in 3. Farrar JT, Cleary J, Rauch R et al. (1998) Oral Transmucosal Fen- tanyl Citrate: Randomized, Double-Blind, Placebo-Controlled swallowing, nausea or other gastrointestinal problems Trial for the Treatment of Breakthrough Pain in Cancer Patients. (Coyle et al. 1990). Furthermore, the onset of effect J Natl Cancer Inst 90:611–616 with most currently available opioids does not match 4. Fortner BV, Okon TA, Portenoy RK (2002) A Survey of Pain- Related Hospitalizations, Emergency Department Visits, and the rapid onset of a typical breakthrough pain episode. Physician Office Visits Reported by Cancer Patients With and Parenteral opioids (subcutaneous, intravenous or intra- Without History of Breakthrough Pain. J Pain 3:38–44 muscular) achieve a peak effect more rapidly than oral 5. Hanks GW, De Conno F, Cherny N et al. (2001) Morphine and opioids but are invasive, inconvenient, costly, and can be Alternative Opioids in Cancer Pain: The EAPC Recommenda- tions. Br J Cancer 84:587–93 uncomfortable; the same is true of intraspinal opioids. 6. Mercadante S, Radbruch L, Caraceni A et al. (2002) Episodic Sublingualadministrationallowsrapidabsorptionandis (Breakthrough) Pain: Consensus Conference of an Expert Work- convenient, accessible, and generally well accepted, but ing Group of the European Association for Palliative Care. Can- absorption can be poor or irregular. Rectal administra- cer 94:832–839 7. Portenoy RK (1993) A combination of pharmacological and non- tion, although generally safe, effective and inexpensive, pharmacological treatment strategies may be required and three may be inconvenient and unacceptable to some patients, principles of management have been proposed and absorption can be unreliable. Oral transmucosal 8. Portenoy RK (1997) Treatment of Temporal Variations in administration provides a simple and convenient route, Chronic Cancer Pain. Semin Oncol 24:S16-7–S16-12 9. Portenoy RK, Hagen NA (1990) Breakthrough Pain: Definition, which offers the potential for more rapid absorption and Prevalence and Characteristics. Pain 41:273–281 238 Cancer Pain Management, Chemotherapy

10. Portenoy RK, Payne D, Jacobsen P (1999) Breakthrough Inclinicalsituationswherecureistheexpectedoutcome, Pain: Characteristics and Impact in Patients with Cancer Pain. survival is conventionally used as the therapeutic end- Pain 81:129–134 11. Walker G, Wilcock A, Manderson C et al. (2003) The Accept- point. In clinical situations where cure is a less likely ability of Different Routes of Administration of Analgesia for outcome, then clinical endpoints such as progression- Breakthrough Pain. Palliat Med 17:219–221 free survival, symptom-free interval, or overall survival 12. World Health Organization (1996) Cancer Pain Relief. WHO, are commonly used. The RECIST criteria have been Geneva 13. Zeppetella G, Ribeiro MDC (2003) The Pharmacotherapy of established as an objective reproducible measurement Episodic Pain. Expert Opin Pharmacother 4:493–502 of reduction in tumor; these criteria generally correlate with improvements in quality of life and survival. When the therapeutic intent is predominantly palliative, then other therapeutic endpoints are used. Com- Cancer Pain Management, Chemotherapy monly used palliative clinical trials endpoints include a > 50% decrease in pain score (measured using validated RONALD H. BLUM methodologies), > 50% decrease in opioid usage, and Beth Israel Medical Center, New York, NY, USA improvement in performance scale, all lasting more [email protected] than four weeks. Cancer chemotherapy with established benefits is un- Synonyms fortunately associated with what can be significant Chemotherapy toxicities. With the increasing availability of interventions to manage symptoms, chemotherapy can be Definition better tolerated. Fatigue is one of the most commonly encountered chemotherapy-associated toxicities. Al- Chemotherapy, the use of chemicals as therapy, is, along though often multifactorial, fatigue associated with with surgery and radiation, one of the most common chemotherapy is often caused by anemia. There is a treatments for cancer. Chemotherapy is generally ad- strong body of evidence demonstrating the value of the ministered intravenously, but oral agents are becoming erythropoietinsto increase the hemoglobin inpatients increasingly available. receiving chemotherapy. This erythropoietin-induced increase in hemoglobin is correlated with improvement Characteristics in quality of life and reversal of fatigue associated with Over the last generation, chemotherapy has evolved the cancer and cancer treatment. based on the principles of cytotoxicity in cellular sys- Granulocytopenia is also a common chemother- tems, empiric observation in preclinical models, and apy toxicity. With the availability of recombinant incremental improvements achieved with clinical tri- hematopoietic growth factors, the associated morbidi- als. Chemotherapeutic agents can be classified by their ties of fever, sepsis, and antibiotic use, which may presumed mechanism of action, e.g. alkylator of DNA, require hospitalization, are significantly reduced. antimetabolite, mitotic inhibitor, and repair enzyme Chemotherapy-induced nausea and vomiting, formerly inhibitor. Chemotherapy indications are based on clin- a dose-limiting toxicity, is almost always preventable ical trials data, with the optimum therapeutic ratio or at least greatly reduced by treatment. An array of determined by establishing the dose based on maxi- effective antiemetic agents is now available, including mum therapeutic benefit with acceptable toxicity. Many Serotonin Blockers, benzodiazepines, steroids, and chemotherapeutic agents are schedule-dependent, both the recently available NKδ1 blockers. for efficacy and toxicity. Combination therapy usually In addition to these chemotherapy-associated toxici- hasatherapeuticadvantageoversingleagenttreatments. ties, consideration needs to be given to the effects of Optimum benefit for cancer treatment is achieved with chemotherapy-associated organ damage. Examples a basic understanding of the tumor site- specific clin- are the cumulative myocardial damage associated with ical characteristics, including prognostic factors and anthracycline chemotherapy, the pulmonary toxicity as- patterns of spread, coupled with knowledge of the role sociated with bleomycin, the nephrotoxicity associated and sequencing of the treatment modalities. Depending with the platinols, and the peripheral neuropathy asso- on the tumor type and the presentation of the disease ciated with the vinca alkaloids. Other considerations in an individual patient, multidisciplinary planning for patients receiving chemotherapy revolve around the results in treatment that might involve a single modal- establishment of safe and easy venous access for the ity, such as surgery; the concurrent use of radiation administration of chemotherapy and the maintenance and/or chemotherapy; or sequential treatments, such of nutrition. as surgery followed by the addition of radiation and/or chemotherapy. Clinical Decision-Making Prospectiveclinicaltrials,oftenrandomized,haveestab- Given the reality that chemotherapy is often of limited lishedstandardsofpractice.Therapeuticendpointsvary. benefitandassociatedwithsignificanttoxicities,clinical Cancer Pain Management, Chemotherapy 239 decision-making is critically important. The decision endpoints of the study were pain intensity and related whether or not to use chemotherapy for palliative intent analgesic consumption, Karnofsky performance status, mustconsider a number ofimportantperspectives.From and weight. In order to meet the criteria of objective the provider prospective, medical decisions are usually benefit, the required improvement in these symptoms based on both evidence and the “expert” opinion of the had to be sustained for at least four weeks, without C provider. The provider preferences are influenced by worsening of any symptom during the observation many factors, including what could be globally defined period. The symptom improvement was correlated as self-serving interests, practical issues, and issues to objective tumor response, time to tumor progres- surrounding reimbursement. From the patient prospec- sion, and survival. There was evident clinical benefit tive, preferences are influenced by the understanding in 24% of patients who received gemcitabine and 5% and expectation of outcomes, by psychosocial issues treated with 5-fluorouracil (P = 0.0022); median sur- including developmentalstage and beliefs, and by prac- vival durations were 6 vs. 4 months (P = 0.0025), and tical and financial issues. Financial issues include not the 12-month survival rate was 18% vs. 2% (Burris et only reimbursement for medical expenses, but what can al. 1997). be burdensome, out-of-pocket expenses for such things as transportation and parking, and the loss of income Colon Cancer because of the patient or care partner not being able Patients with progressive metastatic colon cancer were to work. Clinical decision-making should be a shared randomized to test supportive care with or without medical decision-making process, which assumes that the chemotherapeutic agent irinotecan. The primary both provider and patient develop an understanding endpoint of survival demonstrated an improvement of the relative balance between the autonomy of the from 14% at one year to 36% (P = 0.001). Palliative physician and the preferences of the patient. benefit was evident with demonstration in the sec- A recent study (Koedoot et al. 2002) used clinical vi- ondary endpoints, with a longer duration of pain-free gnettes to identify variables that influence provider survival, longer duration to any significant decrease in preference for “watchful waiting,” that is, deferring performance status, and time to more than 5% weight the introduction of palliative chemotherapy. Based on loss. Corroborating data was evident in the results of information gathered from questionnaires administered quality-of-life assessments (Cunningham et al. 1998). to more then 1000 oncologists, age was the strongest predictor, followed by the patient’s wish to be treated, Breast Cancer and the expected survival gain. One of the conclusions The hypothesis that there is a relationship between of this study is that oncologists’ recommendations are tumor shrinkage and improvement in disease-related consistent and based on objective criteria (Koedoot et symptoms was evaluated in a prospective randomized al. 2002). trial of 300 women with metastatic breast cancer, dur- Probably the most important determinant of provider ing which symptoms were assessed for change over preference is the available evidence of palliative ben- time associated with the cancer chemotherapy (Geels efit of chemotherapy for a specific cancer diagnosis. et al. 2000). Utilizing established quality-of-life ques- Although high level evidence from clinical trials is tionnaires and what are now known as the Common limited, these trials form the basis for the general as- Toxicity Criteria, the authors were able to demonstrate sumption that chemotherapy can be a standard of care a clear correlation between patients’ symptoms and for palliation of symptoms associated with most ma- objective tumor response. lignancies. The risk/benefit determination of treatment versus no treatment must be highly individualized and Lung Cancer Chemotherapy based on the tumor type, the symptoms associated with For non-small cell lung cancer, the benefits of palliative the tumor, overall clinical status and, of course, coupled chemotherapy are evident from a meta-analysis of 52 with patient preference. randomized clinical trials of chemotherapy. Compar- ing best supportive care to chemotherapy in a group Pancreatic Cancer of patients who had not had prior chemotherapy for Perhaps the strongest argument for an evidence ba- metastatic disease, there was a 10% absolute improve- sis for the palliative benefit of chemotherapy is for ment and survival at one year with chemotherapy; pancreatic cancer. In a landmark prospective study expressed as a hazard ratio, this was equal to 0.73 that led to the licensing of gemcitabine, 126 symp- (Thongprasert et al. 1999). In a specific chemotherapy tomatic pancreas cancer patients were enrolled in a trial of docetaxel versus best supportive care in a group study that began with a lead-in period during which of 103 patients who had had previous treatment with patients were stabilized with analgesics. Patients were platinum-based chemotherapy, there was a significant then randomized to receive what was at that point the difference between the two groups in their require- experimental agent gemcitabine, or what was at that ment for opioid analgesics and other medications for time a standard of care, 5-fluorouracil. The primary symptom management (Shepherd et al. 2000). 240 Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side Effects

Prostate Synonyms For prostate cancer, the best evidence is from a prospec- Opioid-Induced Bowel Dysfunction; opioid-related tive randomized trial of prednisone with or without the bowel dysfunction; Narcotic Bowel Syndrome chemotherapeutic agent, mitoxantrone, in 161 men with metastatic prostate cancer. The primary endpoints were Definition improvement in health-related quality of life assessed A constellation of symptoms resulting from the ef- by questionnaire. Both groups demonstrated improve- fects of opioid analgesics on intestinal function. The ment in quality of life, but the important parameters of most common and enduring of these symptoms is con- physical functioning and pain were significantly better stipation. The other principal symptoms referable to in the mitoxantrone group, with longer duration of re- opioid-induced gastrointestinal dysfunction are nausea sponse compared to the prednisone alone group (Tan- and vomiting. nock et al. 1996). Ovary Cancer Characteristics For ovarian cancer, the data are not as well established, Gastrointestinal dysfunction due to opioids is important but implied from objective response data. Among 27 because of the impact upon patients’ quality of life, an women, only seven achieved an objective response, impact that issometimesrated higher than that of pain it- and there were improvements in symptom endpoints self. Nausea affects up to 70% of patients with advanced (Doyle et al. 2001). cancer, and vomiting 10 to 30%. In advanced disease, opioids are probably the single most important identifi- References able cause of constipation, but many other factors such 1. Burris HA III, Moore MJ, Anderson J et al. (1997) Improvements as impaired mobility and reductions or changes in di- in Survival and Clinical Benefit with Gemcitabine as First Line etary intake are involved. Thus 63% of cancer patients’ Therapy for Patients with Advanced Pancreas Cancer: A Ran- domized Trial. J Clin Oncol 15:2403–2413 not taking opioids need laxatives, but with opioids this 2. Cunningham D, Pyrohonen S, James RD et al. (1998) Ran- rises to 87% (Sykes 1998). domised Trial of Irinotecan plus Supportive Care versus Supportive Care alone after Fluorouracil Failure for Patients Nausea and Vomiting with Metastatic Colorectal Cancer. Lancet 352:1413–1418 3. Doyle C, Crump M, Pintilie M et al. (2001) Does Palliative Opioids act in at least three ways to cause nausea and Chemotherapy Palliate? Evaluation of Expectations, Outcomes, vomiting (Fig. 1): and Costs in Women Receiving Chemotherapy for Advanced Ovarian Cancer. J Clin Oncol 19:1266–1274 • Detection by the chemoreceptor trigger area in the re- 4. Geels P, Eisenhauer E, Bezjak A et al. (2000) Palliative Effect of gion of the area postrema and nucleus tractus solitar- Chemotherapy: Objective Tumor Response is Associated with ius. Symptom Improvement in Patients with Metastatic Breast Can- • cer. J Clin Oncol 18:2395–2405 Slowing of gastrointestinal transit and, in particular, 5. Koedoot CG, Haes JC de, Heisterkamp SH et al. (2002) Palliative gastric emptying Chemotherapy or Watchful Waiting? A Vignettes Study among • Increase of vestibular sensitivity. Oncologists. J Clin Oncol 20:3658–3664 6. Shepherd F, Dancey J, Ramlau R et al. (2000) Prospective Ran- A first step in management is to ensure that the patient domized Trial of Docetaxel versus Best Supportive Care in Pa- is actually vomiting rather than regurgitating, as the tients with Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy. J Clin Oncol 18:2095–2103 latter will not be helped by antiemetics. Undigested 7. Tannock IF, Osoba D, Stockler MR et al. (1996) Chemother- food eaten in a current or immediately past meal, re- apy with Mitoxantrone plus Prednisone or Prednisone Alone turned in small volumes with little or no prodromal for Symptomatic Hormone-Resistant Prostate Cancer: A Cana- nausea, suggests regurgitation. In any confirmed case dian Randomized Trial with Palliative End Points. J Clin Oncol 14:1756–1764 of nausea or vomiting, the existence of exacerbating 8. Thongprasert S, Sanguanmitra P, Juthapan W et al. (1999) Re- factors such as strong smells, anxiety and, of course, lationship between Quality of Life and Clinical Outcomes in constipation, must be considered and addressed. At Advanced Non-Small Cell Lung Cancer: Best Supportive Care least 30% of cancer patients receiving morphine do (BSC) versus BSC plus Chemotherapy. Lung Cancer 24:17–24 not need an antiemetic, but around 10% will need a combination of two or more antiemetics (Twycross and Lack 1986). The logical choice of antiemetic depends Cancer Pain Management, on which of the three mechanisms of opioid-induced Gastrointestinal Dysfunction as Opioid emesis appears to be acting most strongly (Table 1). In Side Effects practice, vestibular stimulation can be ignored unless the patient has to take a journey, as movement per se is NIGEL P. S YKES not usually the sole stimulus to nausea and vomiting in St. Christopher’s Hospice and King’s College, this patient group. University of London, London, UK Delayed gastric emptying is suggested by large volume [email protected] vomits, containing little or no bile, occurring suddenly Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side Effects 241

showntoovercomeopioid-relateduppergutslowingand associated vomiting (Stewart et al. 1976). The chemoreceptor areas involved in emetogenesis are rich in D2 dopamine receptors. In the absence of evidence of gastric hold-up, it is appropriate to use a drug C withantidopaminergicactivityforopioid-relatednausea or vomiting. The most potent and specific antidopamin- ergics are droperidol and haloperidol. Droperidol is short-acting, but haloperidol has a half-life of about 18 hours, rendering it suitable initially to be given once a day, usually in the evening because of its somewhat sedative effect. A systematic review of the use of haloperidol as an antiemetic in palliative care found evidence of effectiveness in nausea and vomiting due to a variety of causes, including morphine (Critchley et al. 2001). Extrapyramidal or Parkinsonian effects of haloperidol can be dose-limiting. Levomepromazine (methotrimeprazine) is a popular antiemetic for use in advanced disease in Britain, because its broad spectrum of receptor actions can cover the mixed etiology of vomiting characteristic of this patient group. It is effective at much lower doses than previously assumed (from 6.25 mg/day orally, or 2.5 mg/day subcutaneously), allowing the avoidance of sedation. Extrapyramidal effects are less than with haloperidol, but not absent. Cyclizine is an H1 antihistamine offering receptor Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side activity complementary to that of haloperidol. It has Effects, Figure 1 Receptor Activity of Commonly-Used Antiemetics been shown to have efficacy comparable with that of droperidol in nausea and vomiting associated with patient-controlled opioid analgesia (Walder and Aitken- head 1995). Its receptor activity suggests a role at vagal with little or no preceding nausea. There may be com- level, which would be relevantwhere nausea wasassoci- plaints of hiccups and heartburn, and there is often undi- ated with gut distension. The efficacy of any antiemetic gested food in the vomit from meals taken more than six in a vomiting patient is likely to be better if administered hourspreviously.Inthissituation,metoclopramideisthe by continuous subcutaneous infusion, and all the drugs rational first choice of antiemetic because of its proki- mentioned can be administered in this way, alone or in netic action on the upper gut. Metoclopramide has been combination with morphine.

Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side Effects, Table 1 Receptor Activity of Commonly-Used Antiemetics

D 2 ACh m H 1 5HT 3 5HT 4 Hyoscine - +++ - - -

Cyclizine - + +++ - -

Haloperidol +++ - - - -

Chlorpromazine ++ + ++ - -

Metoclopramide ++ - - + ++

Domperidone ++ - - - -

Ondansetron - - - +++ +

Levomepromazine ++ + + + -

Droperidol +++ - - - -

+++ indicates strong antagonism; - indicates little or no activity 242 Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side Effects

Among newer drugs, the place of 5HT3 antagonists in • Awareness of which drugs are likely to cause con- opioid-induced vomiting remains unclear. Moreover, stipation, e.g. vinca alkaloids and 5HT3 antagonist clinical trials of NK1 receptor antagonists indicate poor antiemetics,aswellasopioidanalgesics.Ifavoidance effectiveness in this indication (Loewen 2002). is impracticable, a laxative should beprescribed from Public interest in non-drug approaches to anti-emesis, the outset, withoutwaiting untilconstipation isestab- notably acupuncture and acupressure, is strong. There lished. is controlled trial evidence that acupuncture or acupres- • In institutions, ensure privacy for defecation. sure at the P6 point (just above the wrist) is effective for Despite prophylaxis, most patients taking opioids will nausea and vomiting due to opioid premedication. require a laxative. The basic division of laxatives is be- Constipation tween stimulant sand softener s (Fig. 2). This di- Constipating effects of opioids on the bowel include: vision seems useful in clinical practice, although in fact any drug that stimulates peristalsis will accelerate tran- • Reduction of peristalsis sit, allow less time for water absorption and so produce • Increase in sphincter tone a softer stool. Similarly, softening the stool involves in- • Increased water absorption creasing its bulk, which will result in increased disten- • Impairment of rectal sensation sion of the intestinal wall, and a consequent stimulation These actions are predominantlymediated through mu2 of reflex enteric muscle contraction. Most trials of laxa- receptors in the gut itself. Mu2 actions, such as delay- tive drugshave been carriedoutin gastroenterologyorin ing of intestinal transit, show less tolerance than mu1 geriatrics. The results do not allow a clear recommenda- mediatedanalgesia(Lingetal.1989).Incontrasttonau- tionofoneagentoveranotherbecauseofthesmallsizeof sea and vomiting caused by opioids, which usually sub- the studies, the number of different preparations, and the sides within 7 to 10 days, opioid-induced constipation various endpoints and conditions involved. However: is often persistent. • Systematic review evidence suggests that any In general, opioids differ little in their ability to con- kind of laxative can increase stool frequency by stipate. Oxycodone has not shown constipating effects about 1.4 bowel actions per week compared with significantly different from those of morphine and nei- placebo (Pettigrew et al. 1997). ther has hydromorphone. Reduction in laxative use • A volunteer trial using loperamide as a source of has been reported after changing from morphine to opioid-induced constipation, concluded that the op- methadone, but only on a case history basis (Daeninck timal combination of effectiveness with minimum and Bruera 1999). However, there is now good evidence adverse effects and medication burden was achieved that transdermal fentanyl is significantly less constipat- by using a combination of stimulant and softening ing than morphine (Radbruch et al. 2000), presumably laxatives, rather than either alone (Sykes 1997). because the gut is also exposed to relatively lower levels • Laxative preparations vary significantly in price and of the drug. physical characteristics. Given the lack of major dif- Functional definitions of constipation exist, but are un- ferences in efficacy, cost and individual patient ac- helpfulinpatientswhoseconstipationisrelatedtoopioid ceptability should both be strong influences in pre- use, where the condition’s importance is as a symptom scribing choice (NHS Center for Reviews and Dis- not a disease entity. Normal bowel habit is highly vari- semination 2001). able, and it is crucial to obtain a history of how bowel function has altered for the individual who is complain- Most patients prefer oral laxatives to rectal, so the use of ing of constipation. The most important differential di- suppositories and enemas should be minimized by opti- agnosis is intestinal obstruction by tumor or adhesions. The distinction is important, as attempts to clear ’constipation’ which is actually obstruction by use of stimulant laxatives can cause severe pain. It is better to prevent constipation rather than to treat it after ithasoccurred. Potentialprophylactic measuresin- clude: • Good general symptom control, without which no other measures are possible. • Encouragement and facilitation of physical activity. • An adequate fluid intake. • Increased dietary fiber. However, fiber alone will not correct severe constipation, and the priority remains Cancer Pain Management, Gastrointestinal Dysfunction as Opioid Side that food should be as attractive as possible to the per- Effects, Figure 2 Cancer Pain Management, opioid side effects, gastroin- son who is expected to eat it. testinal dysfunction . Cancer Pain Management, Interface between Cancer Pain Management and Palliative Care 243 mizinglaxativetreatmentbymouth.Thereis,however,a Definition particular role for enemas and suppositories in the relief The recently revised World Health Organization def- of fecal impaction and in bowel managementin patients inition of palliative care reads: “Palliative care is an whose neurological dysfunction is resulting in fecal in- approach that improves the quality of life of patients continence. Evidence to guide their use is even scantier and their families facing the problems associated with C than that for oral laxatives. Anything introduced into the life-threatening illness, through the prevention and rectum can stimulate defecation via the anocolonic re- relief of suffering by means of early identification flex, but among rectal laxatives, only bisacodyl supposi- and impeccable assessment and treatment of pain and tories have a pharmacological stimulant action. Glycer- other problems, physical, psychosocial and spiritual” ine suppositories, and arachis or olive oil enemas, soften (http://www.who.int/cancer/palliative/en/). and lubricate the stool, as do proprietary mini-enemas which contain mixtures of surfactants. Characteristics References Cancer Pain and Palliative Care: A Global Perspective and In- 1. Critchley P, Plach N, Grantham M, Marshall D, Taniguchi A, troductory Outline Latimer E (2001). Efficacy of Haloperidol in the Treatment of Nausea and Vomiting in the Palliative Patient: A Systematic Re- Cancer is one of those life-threatening illnesses review. J Pain Symptom Manage 22:631–634 ferred to in the WHO definition of palliative care. 2. Daeninck PJ, Bruera E (1999) Reduction in Constipation and Approximately one-third of the population in devel- Laxative Requirements following Opioid Rotation to Methadone. oped countries will be diagnosed with cancer. The J Pain Symptom Manage 18:303–309 3. Ling GS, Paul D, Simontov R, Pasternak GW (1989) Differential estimated worldwide number of new cases each year Development of Acute Tolerance. Life Sciences 45:1627–1636 is expected to rise from 10 million in the year 2000 to 4. Loewen PS (2002) Anti-Emetics in Development. Expert Opin- 15 million in 2020. The number of annual worldwide ion on Investigational Drugs 11:801–805 cancer related deaths is expected to rise from 6 to 10 mil- 5. NHS Center for Reviews and Dissemination (2001) Effectiveness of Laxatives in Adults. Effective Health Care 7:1–12 lion over the same period (World Health Organization 6. Petticrew M, Watt I, Sheldon T (1997) Systematic Review of and International Union against Cancer 2003). Much the Effectiveness of Laxatives in the Elderly. Health Technology of the projected increase in cancer mortality relates Assessment 1:1–52 to an increase in the elderly population, whose age is 7. Radbruch L, Sabatowski R, Loick G, Kulbe C, Kasper M, Grond S, Lehmann KA (2000) Constipation and the Use of Laxatives: A associated with an increased risk of developing cancer, Comparison between Transdermal Fentanyl and Oral Morphine. and who are likely to have multiple comorbidities and Palliative Medicine 14:111–119 increasing general care needs. Despite a survival rate 8. Stewart JJ, Weisbrodt NW, Burko TF (1976) Intestinal Reverse Peristalsis Associated with Morphine-Induced Vomiting. In: of approximately 50% in developed countries for all Kosterlitz HW (ed) Opiates and Endogenous Opioid Peptides. cancers combined, about 70% of all cancer patients Elsevier, Amsterdam, pp 46–58 are estimated to need palliative care. In developing 9. Sykes NP (1997) A Volunteer Model for the Comparison of Lax- countries, this proportion rises to around 80% (World atives in Opioid-Induced Constipation. J Pain Symptom Man- age 11:363–369 Health Organization 2002). Hence, for the majority 10. Sykes NP (1998) The Relationship between Opioid Use and of cancer patients, treatment with a curative outcome Laxative Use in Terminally Ill Cancer Patients. Palliative proves to be either ultimately elusive or an unrealistic Medicine 12:375–382 goal from the time of diagnosis. 11. Twycross RG, Lack SA. Control of Alimentary Symptoms in Far Advanced Cancer. Churchill Livingstone, Edinburgh, pp 153 Pain is present in 20–50% of cancer patients at diagno- 12. Walder AD, Aitkenhead AR (1995) A Comparison of Droperi- sis and in at least 75% of those patients with advanced dol and Cyclizine in the Prevention of Postoperative Nausea and disease, often in association with other distressing Vomiting Associated with Patient-Controlled Analgesia. Anaes- symptoms such as fatigue and anorexia (Donnelly and thesia 50:654–656 Walsh 1995; World Health Organization 1997). A survey of cancer patients suggested that pain was directly Cancer Pain Management, Interface related to the cancer in 85%, anti-cancer treatments such as surgery, chemotherapy and radiotherapy in 17%, and between Cancer Pain Management and other comorbidities in 9% (Grond et al. 1996). Palliative Care A consensus exists among pain management specialists regarding the multidimensional nature of cancer pain, PETER G. LAWLOR and scientific evidence supports the concept (World Our Lady’s Hospice, Medical Department, Dublin, Health Organization 1997; Lawlor 2003; Ahles et Ireland al. 1983; Portenoy and Lesage 1999). The ultimate [email protected] expression of pain intensity represents not only the perception of the basic physiological input from peripheral Synonyms nociceptor activation but varying levels of multiple Hospice care; supportive care; Palliative Care and Can- other inputs, which may relate to psychological state, cer Pain Management cognitive status (the presence of delirium or dementia), 244 Cancer Pain Management, Interface between Cancer Pain Management and Palliative Care the meaning of pain (for example, fears of disease progression), cultural norms, and distress of an existential and spiritual nature. The multidisciplinary palliative care model with its broad holistic principles recognizes these dimensions, and embodies a multidimensional assessment approach as an integral part of cancer pain management (Lawlor 2003). To enable the reader to appreciate the special role of palliative care, and to assist in understanding interactive roles in the interfaces of palliative care and cancer pain management, four broad aspects are described: firstly, the historical background of the palliative care model and its interfaces; secondly, the fundamental practice principles and service delivery levels of modern palliative care; thirdly, issues in palliative care delivery in the interface with other specialties and health care personnel at the various locations and stages of cancer care; and fourthly, bridging strategies at the aforementioned interfaces.

Palliative Care Interfaces: Historical Background Palliative care originated from the hospice model of care (MacDonald 1993). Although the term “hospice” has medieval origins referring to a place of shelter or rest, its 19th century use referred mainly to a site of care, but in addition many of these sites also included “hospice for the dying” as part of their name. Historically, “hos- Cancer Pain Management, Interface between Cancer Pain Manage- pice”thereforehasastrongassociationwiththeterminal ment and Palliative Care, Figure 1 Cancer pain and the multidisciplinary palliative care approach (Adapted from reference 7). phase of illness, and the terms hospice care and terminal care have been used interchangeably. Up to the 20th century, most medical care interventions were not curative but provided symptom relief, and as such were sion of the disease process affects functioning in the essentially palliative. Medical advances in the first half physical, psychological, spiritual, and social domains, of the 20th century resulted in a shift to obtaining a cure thereby reducing overall quality of life (QOL). Exam- and waging a “war” against cancer. The biomedical as- ples of problems in the QOL domains include: reduced pects of care largely became the focus of care, often at mobility; loss of independence; depression; anger; fear; the cost of ignoring the total illness experience from the anxiety; guilt; anticipatory grieving; financial hardship; patient and family perspective, an experience that in- family stress and exhaustion. The palliative care ap- variablygeneratessubstantialpsychosocialandspiritual proach recognizes the distress generated in the main needs.Themoremodernhospicemovement,incorporat- QOL domains, and aims to support patients and fami- ing the bulk of today’spalliative care principles, andtyp- lies in coping with the burden of advancing disease, in ified by StChristopher’sHospicein London, wasbornin striving to achieve optimal QOL, and in adjusting over the late 1960’s mainly to address these needs (MacDon- time to their inevitable demise. This recognition and ald 1993). In the US, hospice care eligibility is restricted intervention is especially important in the case of suf- byrequirementsforanestimated6-monthprognosisand fering (Cassell 1982) or total pain (Kearney 1996), willingness to forego life prolonging treatment. Gener- where the expression of pain is attributable only in ally, palliative care is broader in its scope than either part to nociceptor activation, but perhaps in greater hospice or supportive care, and is advocated earlier proportion to psychosocial and spiritual distress. in the disease trajectory. Palliative medicine now has TheWHOdefinitionofpalliativecarestatesthatitis“ap- medical specialty status in the UK, Australia, and Ire- plicableearlyinthecourseofillness,inconjunctionwith land. other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those Practice Principles and Service Delivery Levels of Modern Pal- investigations needed to better understand and manage liative Care distressing clinical complications” (World Health Orga- The complex web of palliative care with its broad holis- nization 2002). This distinguishes the modern palliative tic purview is summarized through a schematic matrix care approach as being active and not necessarily pas- in Fig. 1. For many patients with cancer pain, progressive. Nonetheless, the stigma of passivity often persists Cancer Pain Management, Interface between Cancer Pain Management and Palliative Care 245 and probably reflects the more traditional origins of palliative care, especially hospice care. In developed countries, especially those where palliative medicine is recognized as a specialty, palliative care services are often tiered from level one to three on the C basis of the specialization level and expertise of the professionals delivering palliative care (National Advisory Committee on Palliative Care 2001). Level one refers to the practice of the basic “palliative care approach”. This embodies a set of principles with which all health care professionals should be familiar and be capable of adopting in their practice. Level two or generalist palliative care refersto thatdelivered by professionalswho are not practicing full-time in palliative care, but who have some additional training in palliative care. Level three refers to specialist palliative care. Patients with more complex and demanding care needs, for example those patients with neuropathic pain, substance abuse histories, and features of “total pain” are referred to specialist palliative care services (Bruera et al. 1995). Conse- quently, these services are more resource intensive, and are akin to secondary or tertiary healthcare services. For the healthcare professional, ease of access to specialist palliative care advice as needed is essential. Healthcare delivery models should ensure that patients have access to the level of palliative care expertise most appropriate to their needs in a seamless and integrated fashion (Mac- Donald 1993; National Advisory Committee on Pallia- Cancer Pain Management, Interface between Cancer Pain Manage- tive Care 2001). ment and Palliative Care, Figure 2 Interface of palliative care and specific sites and levels of medical care during the cancer disease trajectory. Palliative Care and Cancer Pain Management: Clinical and Other Interface Issues The interface between cancer pain managementand pal- liativecarereferstotheboundarieseitherrealornotional between palliative care and the many locations of care delivery, and the temporal changes in the degree of involvement of palliative care duringthecourse of thecan- cer disease trajectory. The location or institutional interfaces are represented in an ideal, generic, developed world model in Fig. 2, which shows each level of health care from primary to tertiary, and each with a direct link to specialist palliative care services. In this model, some international or geographic differences may occur regarding the level of interaction between and within various levels, and also regarding the degree of provision of specialist palliative care. Cancer Pain Management, Interface between Cancer Pain Manage- The temporal interface of palliative care and disease ment and Palliative Care, Figure 3 Palliative care and its temporal in- modifying therapies, and their respective levels of use volvement compared to other therapies in the cancer disease trajectory. in the progressive disease trajectory (from diagnosis to death) of a hypothetical cancer patient is represented in schematic form in Fig. 3. Disease modifying therapies of palliative disease modifying interventions such as such as surgery, chemotherapy, and radiation can be radiation therapy. This phase ends rather abruptly prior offered depending on the relative burden/benefit associ- to a short terminal or hospice phase of care. The role ated with the treatment. This is done with either curative of palliative or supportive care progressively increases or palliative intent depending on the stage of disease. in association with disease progression, and finally en- The curative intent phase for this patient is relatively velopes the hospice contribution to the terminal phase brief, is followed by a phase where there is modest use of care. 246 Cancer Pain Management, Interface between Cancer Pain Management and Palliative Care

Although the high level of need for palliative care out all levels of health service delivery is of great is generally well recognized in advanced cancer, its assistance in communication regarding cancer pain delivery to patients and their families is often inade- management (MacDonald 1993; Chang et al. 2000). quate. This shortfall may be associated with various Other ways to facilitate communication include person health service delivery factors of a political and/or to person corridor conversations, joint rounds or joint financial nature, especially in the case of develop- clinics, and user friendly technology. For the purpose ing countries, where palliative care services are often of maintaining continuity of care, both the mutual ap- only rudimentary or sometimes non-existent (World preciation and enhanced communication paradigms Health Organization 2002). In developed countries, should ensure that the patient’s general practitioner or the shortfall in palliative care delivery may relate to family physician, and palliative home nurse are not professional factors such as lack of knowledge of pain disenfranchised, especially in the case of patients who management; multiple boundary issues such as the are discharged to the community. fear of losing or separating from the patient, or fear Other valuable bridging strategies include mutually that exposure to palliative care in itself will hasten shared research agendas; mutually shared educational a patient’s demise, or concern that the patient could rounds, ideally with some multidisciplinary input; inte- feel abandoned if palliative care are consulted; and grated treatment sites; integrated administrative input, a state of relative denial of disease progression. This for example, shared participation in regional council denial is often reflected by the relentless pursuit of bodies that might advise on care delivery and its de- burdensome treatments, whose outcomes often have a velopment; and shared use of resources. The benefits deleterious effect on quality of life, and are perceived for the patient with cancer pain as a result of smooth as being unnecessarily aggressive by the palliative care negotiation across the palliative care interfaces include professional. In addition, patient and caregiver denial ease of access to services, for example, fast-tracking may result in varying degrees of reticence to accept of radiation oncology referrals; integration and conti- the palliative care approach. Cultural norms may re- nuity of care, which diminishes the risk of a sense of sult in a “conspiracy of silence” (denial reflected by abandonment, a perception held by some patients when non discussion of disease status), or a “conspiracy of curative therapy is no longer possible. words” (denial reflected by limited discussion and use of euphemistic terms, for example, “spot” or “shadow” Summary and Conclusions to evasively describe the presence of cancer). This In conclusion, a multidimensional assessment of can- must be sensitively recognized as a potential challenge cer pain is paramount and constitutes an integral com- to both the delivery and acceptance of palliative care ponent of the palliative care approach. Optimal cancer in its most idealistic format (World Health Organiza- pain management must recognize unique individual pation 1997). tient and family care needs, whatever the location and Palliative Care and Cancer Pain Management: Interface Bridg- wherever this may occur in the cancer disease trajectory. ing Strategies Although the need for specialist palliative care services varies in relation to the temporal trajectory and location A number of strategies can allow a functionally smooth of cancer care, the basic palliative care approach is a and readily traversable interface between palliative care fundamental requisite that essentially spans all stages and other specialties in the management of cancer pain and sites of care. Although various political, cultural, and associated symptoms (MacDonald 1993). geographical, administrative and financial factors will Firstly, the need for mutual appreciation of each others clearly influence the degree of development and support roles is of pivotal importance, for example, the pallia- of the palliative care model in different areas, healthcare tive care physician needs to appreciate the potential pal- planning must aim to achieve a seamless integration of liative benefit associated with chemotherapy, radiation the different aspects of palliative care service delivery or surgery, and the oncologist or surgeon needs to ap- and other areas of cancer care, and to offer flexibility for preciate the benefit of early palliative care involvement patients to access the different levels of care (each level for symptom control advice, support for adjustment to with a link to specialist palliative care services) as de- disease progression, and assistance with the planning of termined by their individual and specific needs. care, such as instituting palliative home care support or discussing hospice placement. Such a premise willoften allow a shared care model, and thereby the shared goal References of achieving optimal QOL for patients and their fami- 1. Ahles TA, Blanchard EB, Ruckdeschel JC (1983) The Multidi- lies rightly takes precedence over “patient ownership” mensional Nature of Cancer-Related Pain. Pain 17:277–288 or territorial concerns. 2. Bruera E, Schoeller T, Wenk R et al. (1995) A Prospective Multi- Secondly, consistently good communication is essen- center Assessment of the Edmonton Staging System for Cancer Pain. J Pain Symptom Manage10:348–355 tial. The shared, systematic use of validated, low burden 3. Cassell EJ (1982) The Nature of Suffering and the Goals of assessment tools for pain and other symptoms through- Medicine. N Engl J Med 306:639–645 Cancer Pain Management, Neurosurgical Interventions 247

4. Chang VT, Hwang SS, Feuerman M (2000) Validation of the incontinence, mood changes, sedation, diarrhea, confu- Edmonton Symptom Assessment Scale. Cancer 88:2164–2171 sion, etc.) (McNicol et al. 2003). It might seem reason- 5. Donnelly S, Walsh D (1995) The Symptoms of Advanced Cancer. Semin Oncol 22:67–72 able to wait until medical management fails before pur- 6. Grond S, Zech D, Diefenbach C et al. (1996) Assessment of suing neurosurgical intervention, but in certain cases, Cancer Pain: A Prospective Evaluation in 2266 Cancer Patients for example when a patient foreseeably will need an im- C Referred to a Pain Service. Pain 64:107–114 planted device, neurosurgeons should intervene before 7. http://www.who.int/cancer/palliative/en/ Accessed November the patient’s condition deteriorates too far to support the 4th 2003 8. Kearney M (1996) Mortally Wounded. Stories of Soul Pain, intervention. Death, and Healing. Scribner, New York When neurosurgicaltechniquesresultinpainrelief, they 9. Lawlor PG (2003) Multidimensional Assessment: Pain and Pal- canenhanceapatient’squalityoflifebyincreasingfunc- liative Care. In: Bruera E, Portenoy RK (eds) Cancer Pain. Cam- tional capacity and offering freedom from troublesome bridge University Press, New York, pp 67–88 10. MacDonald N (1993) The Interface between Oncology and Pal- side effects. Compared with medical management, neu- liative Medicine In: Doyle D, Hanks GWC, MacDonald N (eds) rosurgical techniques can improve continuity of relief, Oxford Textbook of Palliative Medicine. Oxford University reduce the patient’s and physician’s time spent adjusting Press, Oxford, pp 11–17 dosages, and minimize the development of tolerance or 11. National Advisory Committee on Palliative Care (2001) Pallia- tive Care – An Overview. In: Report of the National Advisory adverse effects from opioids. It is possible that, in some Committee on Palliative Care. Department of Health and Chil- patients, neurosurgical intervention for pain relief will dren, Dublin prolong survival (Smith et al. 2002). 12. Portenoy RK, Lesage P (1999) Management of Cancer Pain. Lancet 353:1695–1700 13. World Health Organization and International Union against Patient Selection Cancer (2003) Global Action against Cancer. WHO and UICC, Geneva, pp 1–24 Patient selection for neurosurgical intervention is based 14. World Health Organization (1997) Looking Forward to Cancer on a consideration of the nature of the disease, the im- Pain Relief for All. International Consensus on the Management pact of the disease on the patient’s life, and the nature of Cancer Pain. WHO, Oxford, pp 1–70 of the pain. One major factor in assessing disease im- 15. World Health Organization (2002) Pain Relief and Palliative Care. WHO, Geneva, pp 83–91 pact and therapeutic options is the patient’s prognosis, which involves quantitative and qualitative factors, such as age, life expectancy, type of cancer, the intervention’s cost effectiveness, risk/benefit ratio, duration of Cancer Pain Management, Neurosurgical effect and the patient’s functional capacity, personal Interventions values/wishes, and living/family conditions. A multi- 1 2 modal assessment will reveal if a patient has a good RICHARD B. NORTH ,SAMUEL J. HASSENBUSCH (expected to survival at least a year and to be active 1The Johns Hopkins University, Baltimore, ML, USA 2 for most of that time) or a poor prognosis (expected to The University of Texas M. D. Anderson Cancer survive less than six months and to be inactive). Pain Center, Houston, TX, USA type and severity are also important indicators of the [email protected], [email protected] appropriate intervention. Relative contraindications for interventional pain therapy include the presence of an Definition untreated comorbid psychological disorder or current Cancer pain arises from the presence, progression, or drug abuse (North 2002; Levy 2002). treatment of cancer or from an unidentifiable source in patients with cancer. Cancer pain may be nociceptive, Treatment Options neuropathic, or a mixture of both. Interventional treatment options range from simple A neurosurgical intervention uses an ablative, augmen- injections of short-acting local anesthetics (and, oc- tative, or anatomic surgical technique, or a combination casionally, of an adjuvant steroid or lytic agent) to of these techniques, to relieve pain. complex anatomic, ablative, and augmentative neurosurgical techniques Characteristics Anatomic procedures address structural problems caus- Inhumans,cancerassumesmanyguises,canaffectevery ing pain – for example, tumor removal or debulking. physiologic system and tissue, and strikes with various Spinal reconstructive surgery (decompression, stabi- degreesofvirulence.Canceranditstreatmentcausepain lization) for metastatic disease isa common example. To in most patients, with the severity and impact of this pain the extent that this addresses the cause of pain directly, dictated by a host of influences (Patt 2002). it has obvious appeal; but the cause of pain may not be Medical management, which is often sufficient to treat completely clear, and there may be alternatives (such as cancerpain,sometimesfailstoprovideadequatereliefor radiation therapy alone). Patients with advanced disease results in side effects that substantially reduce the qual- and limited life expectancy may not be candidates for ity of the patient’s life (nausea, constipation, vomiting, reconstructive surgery. 248 Cancer Pain Management, Nonopioid Analgesics

Ablativeproceduresdestroyportionsoftheperipheralor Augmentative procedures modulate activity in the intact central nervous system to block pain transmission. This nervous system by electrical stimulation or continuous may be achieved through chemical (the direct applica- drug infusion to change pain perception. They have the tion of alcohol or phenol), thermal ( cryoablation or advantagesofreversibility,titrationofdose,andofatrial radiofrequency, see radiofrequency ablation), surgi- or testphasewhich emulatesthedefinitiveprocedureex- cal (cutting) or radiosurgical means. actly. This is not the case for anatomic or ablative pro- Peripheral ablative procedures are applicable to pain cedures. Due to the high initial expense, physicians re- generators in the distribution of specific peripheral serve implanted devices for patients expected to survive nerves, if they may be sacrificed without incurring at least three months. an unacceptable deficit. For example, a peripheral The usual indication for somatosensory stimulation neurectomy might relieve the pain in the distri- is neuropathic pain restricted to a specific area, and bution of the supra- or infraorbital nerve. Percuta- this stimulation can target the spinal cord, a peripheral neous radiofrequency or open dorsal rhizotomy has nerve, or the thalamus (to treat continuous neuropathic a role in cases where a tumor involves the chest wall. pain, such as post-radiation plexopathy). The goal of Sympathetic ganglionectomy involving several adja- such electrical stimulation is to induce a paresthesia cent levels will denervate somatic and/or visceral tissue that covers the painful area, effectively replacing the in the trunk or abdomen or in a limb. All of these may pain with a tolerable, non-noxious sensation. Noci- be emulated by reversible local anesthetic injections, ceptive pain may also be treated by periaqueductal or to predict the results of a permanent procedure and periventricular grey stimulation. thereby aid in patient selection. The best-established indication for continuous drug in- Intraspinal ablative techniques interrupt input or rostral fusion, in particular morphine, is diffuse midline or bi- transmission of nociceptive signals in patients with lateralnociceptivecancerpain.Theinfusioncatheteren- severe pain and a poor prognosis. These techniques ters the epidural, intrathecal, or intraventricular space, include open or percutaneous anterolateral cordo- and the drug delivery system includes an implanted or tomy for intermittent and/or evoked neuropathic pain an external pump (Staats and Luthardt 2004). affecting one, or sometimes, two limbs (Tasker 1995), and midline commissural myelotomy for diffuse References lower body pain. Cordotomy is associated with sig- 1. Hassenbusch SI (1996) Intracranial Ablative Procedures for Pain. nificant risks, especially with bilateral application for In: Youmans JR (ed) Neurological Surgery, 4th edn. WB Saun- midline or axial pain. Cordotomy is often ruled out ders, Philadelphia, pp 3541–3551 when pain is above C5 or the patient suffers from 2. Levy RM (2002) Intrathecal Opioids: Patient Selection. In: Burchiel K (ed) Surgical Management of Pain. Thieme, New pulmonary dysfunction. Myelotomy addresses bilat- York, pp 469–484 eral and midline pain in a single procedure and is 3. McNicol E, Horowicz-Mehler N, Fisk RA et al. American Pain best reserved for cancer patients with bladder, bowel, Society (2003) Management of Opioid Side Effects in Cancer- and sexual dysfunction. Most patients achieve nearly Related and Chronic Noncancer Pain: A Systematic Review. J Pain 4:231–256 complete pain relief after cordotomy and myelo- 4. North RB (2002) Spinal Cord Stimulation: Patient Selection. In: tomy, but some experience recurrent pain months Burchiel K (ed) Surgical Management of Pain. Thieme, New later. York, pp 469–484 Intracranial ablative therapies interrupt or change the 5. Patt RB (2002) Cancer Pain. In: Burchiel K (ed) Surgical Man- agement of Pain. Thieme, New York, pp 469–484 perception of pain transmission. Stereotactic cingu- 6. Smith TJ, Staats PS, Pool G et al. (2002) Randomized Clini- lotomy is appropriate for severe pain in diffuse areas cal Trial of an Implantable Drug Delivery System Compared of the body and provides at least three months relief to Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival. J Clin for most cancer patients (Hassenbusch 1996). The Oncol 20:4040–4049 less-frequently used stereotactic medial thalamo- 7. Staats PS, Luthardt F (2004) Intrathecal Therapy for Cancer Pain. tomy relieves pain for as many as 50%of patients with Just the Facts Pain Medicine. McGraw Hill, New York a good or poor prognosis and severe, otherwise in- 8. Tasker RR (1995) Percutaneous Cordotomy. In: Schmidek HH, Sweet WH (eds) Operative Neurosurgical Techniques: tractable, nociceptive pain that is widespread, midline, Indications, Methods and Results. WB Saunders, Philadelphia, bilateral, or located in the head or neck; it also may pp 1595–1611 help approximately 30% with neuropathic pain (intermittent and evoked neuropathic pain responds more readily than continuous pain). Hypophysectomy is an appropriate treatment for diffuse pain associated Cancer Pain Management, Nonopioid with widespread cancer, and provides relief through an Analgesics unknown mechanism of action in 45–95%of patients. These procedures may be performed not only by stereo- ALISON MURRAY,JOSE PEREIRA tactic probe placement but also by radiosurgery (see Foothills Medical Center, Calgary, AB, Canada stereotactic radiosurgery). [email protected], [email protected] Cancer Pain Management, Nonopioid Analgesics 249

Definition include: nephrotoxicity, blood dyscrasias, pancreatitis Nonopioid analgesics comprise of all those medications and angioedema. Caution should be used in patients prescribed for pain relief that do not fall into the opioid with impaired liver function/chronic alcohol use, or class. These include paracetamol (acetaminophen), impaired renal function (Flower et al. 1980). Most clin- aspirin (acetylsalicylic acid), and the nonsteroidal icians will consider paracetamol safe to use in patients C anti-inflammatory drugs (NSAIDS). Paracetamol is with liver metastases on the condition that overt hepatic an analgesic-antipyretic with weak anti-inflammatory failure is not present. There are no studies to support or activity. Aspirin is a derivative of salicylic acid and has refute this practice. analgesic, antipyretic and anti-inflammatory activity. Nonsteroidal anti-inflammatory drugs are a hetero- Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) geneous group of compounds. They share the same Mode of Action therapeutic action and side-effect profile as aspirin. NSAIDs inhibit peripheral prostaglandin synthesis Nonopioid analgesics are recommended for use in the through the inhibition of cyclo-oxygenase enzymes, case of mild cancer pain, as described in Step I of COX-1 (found in normal cells) and COX-2 (induced the World Health Organization Analgesic Ladder for during the inflammatory process). Inhibition of COX-2 the treatment of cancer pain (World Health Organiza- produces anti-inflammatory effects: decreased release tion 1986). Nonopioids were used on 11% of treatment of inflammatory mediators (such as substance P and days in a large prospective study involving 2118 cancer cytokines), which leads to decreased stimulation of patients, while the so-called “weak opioids” (WHO peripheral nociceptors (Jenkins and Bruera 1999). Step II) were used on 31% of days and the so-called COX-1 inhibition can lead to many of the known side “strong” opioids (Step III) on 49% of treatment days effects of NSAIDs, in particular gastrointestinal ul- (Zech et al. 1995). In another study, 52% of cancer ceration and inhibition of platelet aggregation. It has patients started on a nonopioid analgesic needed to be also been suggested that NSAIDs may have a central switched to a weak or strong opioid because of escalat- effect on pain perception by reducing NMDA-mediated ing pain (Ventafridda et al. 1987). Nonopioid analgesics hyperalgesia (Jenkins and Bruera 1999). are also used as adjuvant medications to opioids for the The older generation of NSAIDs (including aspirin) has management of moderate to severe pain (Step II and III variable effects on both COX-1 and COX-2. A new gen- of the WHO Analgesic Ladder). eration of NSAIDs (etodolac, meloxicam, nabumetone, Characteristics celecoxib, valdecoxib, and rofecoxib) show COX-2 selective inhibition (Jenkins and Bruera 1999), and those Paracetamol (Acetaminophen) created most recently (the coxibs celecoxib, valdecoxib, Mode of Action rofecoxib,andothersindevelopment)arehighlyCOX-2 Paracetamol has analgesic and antipyretic effects but selective. only weak anti-inflammatory effects. Its mechanism of action is unknown, although it is thought to act Pharmacokinetics centrally rather than peripherally (Flower et al. 1980). NSAIDS are given by the oral or the rectal route, with Paracetamol may be given orally or rectally. the exception of ketorolac, which is also available in a parenteral preparation. NSAIDs are metabolized by Pharmacokinetics the liver and excreted in the urine and faeces (Flower It is metabolized by the liver. et al. 1980). Efficacy Efficacy Paracetamol is considered to be a weak analgesic without anti-inflammatory effects. There is little evidence In multiple dose trials, NSAIDs have been found to be as supporting the use of paracetamol alone in cancer pain, effective as weak opioids or weak opioid/paracetamol although there are some studies which support its use preparations(Goudasetal.2001).NoindividualNSAID when combined with an opioid (codeine or oxycodone) or class of NSAID has been shown to be more effec- (Carlson et al. 1990). Paracetamol 600 mg plus codeine tive in the control of pain (Goudas et al. 2001; Mer- 60 mg has been found to be equivalent to ketorolac cadante 2001). NSAIDs appear to have a dose-response 10 mg, and superior to placebo in reducing cancer pain relationship with respect to analgesic efficacy (Eisen- in a double-blind randomized controlled study. berg et al. 1994), and they also demonstrate a ceiling effect (supramaximal doses do not demonstrate superi- Adverse Effects ority over recommended doses) (Eisenberg et al. 1994). Side effects include rash, urticaria and nausea. Parac- The efficacy of NSAIDs does not vary with the route of etamol may induce hepatotoxicity after acute ingestion administration (Tramer et al 1998). It has been common of large doses (> 10 g) or chronic ingestion of daily practice to prescribe NSAIDs for certain cancer pain doses exceeding 4 g. Other serious but rare side effects syndromes (in particular, metastatic bone pain), but the 250 Cancer Pain Management, Nonopioid Analgesics evidence to support this is largely lacking (Goudas et There are no trials comparing the side effects of COX- al. 2001; Mercadante 2001; Eisenberg et al. 1994). 2 inhibitors compared to nonselective NSAIDs in can- There are no current trials available involving the use cer populations (Goudas et al. 2001). The use of COX- of COX-2 selective inhibitors in cancer pain. Data from 2 inhibitors is associated with fewer endoscopic ulcers the non-malignant pain literature (largely osteoarthritis and fewer gastrointestinal events compared to nonselec- and rheumatoid arthritis populations) demonstrate that tive NSAIDs in the general population (Laine 2003), but coxibs are as effective as nonselective NSAIDs in terms they have a similar rate of nephrotoxic events. Coxibs of pain relief (Kuritzky and Weaver 2003). do not inhibit platelet function as nonselective NSAIDs When NSAIDs are coadministered with opioids as do. There is controversy about whether coxibs are as- adjuvant analgesics, they produce an opioid sparing sociated with an increased risk of cardiovascular events effect, but there is no consistent reduction in side ef- (DeMaria and Weir 2003). fects (Jenkins and Bruera 1999; Goudas et al. 2001; Mercadante 2001). It is difficult to evaluate the opioid Dipyrone sparing effects of NSAIDs, given that they have an Dipyrone has anti-inflammatory, anti-pyretic and anal- equally significant side effect profile of their own. gesic effects. Its mechanism of action is unknown. It is used in Europe, but it is not available in North Amer- Side Effects ica due to concerns about agranulocytosis (Flower et TheincidenceofsideeffectswithNSAIDsdemonstrates al. 1980). a dose-response relationship and rises significantly after multiple dosing over 7–10 days (Eisenberg et al. 1994). References One of the major side effects of nonselective NSAIDs 1. Carlson RW, Borrison RA, Sher HB et al. (1990) A Multi- is gastrointestinal ulceration (resulting in clinically sig- Institutional Evaluation of the Analgesic Efficacy and Safety nificant gastrointestinal bleeding) (Mercadante 2001). of Ketorolac Tromethamine, Acetaminophen plus Codeine, and The majority of studies have been performed in non Placebo in Cancer Pain. Pharmacotherapy 10:211–216 2. De Broe ME, Elseviers MM (1998) Analgesic Nephropathy. N cancer populations. NSAID users have three times Engl J Med 338:446–452 the risk of gastrointestinal ulceration compared to 3. DeMaria AN, Weir MR (2003) Coxibs – Beyond the GI tract: Re- non-users (Jenkins and Bruera 1999). Advanced age, nalandCardiovascular Issues. JPain Symptom Manage 25:41–49 history of peptic ulcer disease, and concurrent cor- 4. Eisenberg E, Berkey CS, Carr D et al. (1994) Efficacy and Safety of Nonsteroidal Anti-Inflammatory Drugs for Cancer Pain: A ticosteroid or anticoagulant therapy are known risk Meta-Analysis. J Clin Oncol 12:2756–2765 factors for NSAID-induced gastrointestinal bleeding 5. Flower RJ MS, Vane JR, Moncada S (1980) Analgesic- and perforation (Hernandez-Diaz and Rodriguez 2000). Antipyretics and Anti-Inflammatory Agents; Drugs Employed Omeprazolehasbeenshowntodecreasetheincidenceof in the Treatment of Gout. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 6th edn. MacMillan NSAID induced gastrointestinal ulceration. Eradication publishing Company Inc., New York of helicobacter pylori prior to NSAID administration 6. Goudas L, Carr DB, Bloch R et al. (2001) Management of Cancer may reduce the risk in the general population (Jenkins Pain. Evid Rep Technol Assess 35:1–5 and Bruera 1999). In uncontrolled studies of cancer 7. Hernandez-Diaz S, Rodriguez LA (2000) Association between Nonsteroidal Anti-Inflammatory Drugs and Upper Gastrointesti- populations, dyspepsia has been reported by 7–13% nal Tract Bleeding/Perforation: An Overview of Epidemiologic of users, and 5–20% of users discontinued NSAIDs Studies Published in the 1990’s. Arch Intern Med 160:2093–2099 due to an adverse event (Goudas et al. 2001). In cancer 8. Jenkins CA, Bruera E (1999) Nonsteroidal Anti-Inflammatory patients, advanced disease and the presence of liver Drugs as Adjuvant Analgesics in Cancer Patients. Palliat Med 13:183–196 disease (primary cancer or metastases) have been as- 9. Kuritzky L, Weaver A (2003) Advances in Rheumatology: Cox- sociated with a higher rate of gastrointestinal bleeding ibs and Beyond. J Pain Symptom Manage 25:6–20 events (Mercadante et al. 2000). 10. Laine L (2003) Gastrointestinal Effects of NSAIDs and Coxibs. J Pain Symptom Manage 25:32–40 Asecondsideeffectisimpairedrenalfunction.Acutere- 11. Mercadante S (2001) The Use of Anti-Inflammatory Drugs in nal dysfunction is usually reversible and improves after Cancer Pain. Cancer Treat Rev 27:51–61 discontinuation of the NSAID. It is caused by a decrease 12. MercadanteS, BarresiL, CassucioA et al. (2000)Gastrointestinal inprostaglandindependentrenalplasmaflow.Olderage, Bleeding in Advanced Cancer Patients. J Pain Symptom Manage 19:160–162 hypertension, concomitant use of diuretics, pre-existing 13. Tramer MR, Williams JE, Carroll D et al. (1998) Comparing renal failure, diabetes and dehydration are risk factors Analgesic Efficacy of Non-Steroidal Anti-Inflammatory Drugs for acute NSAID-induced renal failure (De Broe and El- Given by Different Routes in Acute and Chronic Pain: A Qual- seviers 1998). Chronic and permanent renal failure sec- itative Systematic Review. Acta Anaesthesiol Scand 42:71–79 14. Ventafridda V, Tamburini M, Caraceni A et al. (1987) A Valida- ondary to NSAIDs is much rarer, and is probably due to tion Study of the WHO Method for Cancer Pain Relief. Cancer acute tubular necrosis (Mercadante 2001). 59:850–856 Other known side effects of NSAIDs include platelet in- 15. World Health Organization (1986) Cancer Pain Relief. World hibition,blooddyscrasias,hepaticdamageandCNStox- Health Organization, Geneva 16. Zech DF, Grond S, Lynch J et al. (1995). Validation of World icity (tinnitus, visual disturbances, dizziness etc.) (Mer- Health Organization Guidelines for Cancer Pain Relief: A 10- cadante 2001). Year Prospective Trial. Pain 63:65–76 Cancer Pain Management, Opioid Side Effects, Cognitive Dysfunction 251

(Pereira et al. 1997; Manfredi et al. 2003; Farrell et Cancer Pain Management, Opioid al. 1996). Cognitive impairment may result from any Responsiveness of numerous disorders, including drug toxicity. Opioid therapy may cause cognitive disturbances that under- Opioid Responsiveness in Cancer Pain Management mine the positive effects of the drug, or render assess- C ment of the pain more difficult. Since a patient’s expression of distress requires cognition, a self-report by the patient should not be requested if the degree of cognitive Cancer Pain Management, Opioid Side impairmentissufficienttocompromisecommunication. Effects, Cognitive Dysfunction Management of Cancer Pain S. YENNURAJALINGAM,EDUARDO BRUERA Opioid-based pharmacotherapy is the mainstay in Department of Palliative Care and Rehabilitation cancer pain management and should be consid- Medicine, The University of Texas M. D. Anderson ered for all cancer patients with moderate or severe Cancer Center, Houston, TX, USA pain. Other approaches can be used in addition to the [email protected] opioid-based pharmacotherapy, based on the goals of care. Pure opioid agonists used as a single agent are Definition preferred for treating pain in cancer patients. Partial agonists and mixed agonists-antagonists have limited Cognitive dysfunction refers to changes in conscious- use in the management of cancer pain due to mixed ness, higher cortical functions, mood, or perception that receptor activity, side effects, and dose-related ceiling may be induced by any of numerous neurological or sys- effects. Once an opioid and route of delivery is selected, temic diseases, or by ingestion of substances, including effective therapy depends on adjustment of the dose. drugs, that have the potential for central nervous system There is no maximum recommended dose of opioids in toxicity. cancer pain management. The dose should be gradually escalated until effects are favorable or side effects im- Characteristics pose a maximum tolerated dose. Management of opioid Painincancerpatientsisnotyettreatedeffectively.Many side effects is an essential aspect of opioid therapy, studies have described undertreatment in this popula- which can allow opioid dose titration to effective levels tion. For example, a 1995 study of outpatients who had and directly improve the comfort of the patient. metastatic cancer found that pain occurred in 67% of the Opioid-Induced Cognitive Dysfunction patients, yet42%had notbeenprescribed adequateanal- gesic therapy (Cleeland et al. 1994). Similarly, a 2000 Sedation study found that 65% of minority patients with cancer Opioid-induced sedation usually occurs when opioid reported severe pain despite having received analgesics dosing is initiated or when the dose is increased. Ap- (Anderson et al. 2000). proximately 7–10% of patients receiving strong opioids Pain is multidimensional and can be described in terms for cancer pain have persistent sedation related to opi- of location, radiation, character, intensity, frequency, oid medication (Bruera et al. 1995). In some cases, this and syndromal presentation. Pain can also be described sedation is multifactorial; the opioid may contribute but in terms of its relationship to other symptoms. Preva- may not be the primary cause. Some patients, however, lence rates of the many symptoms reported by palliative appear to have a very narrow or non-existing therapeu- care patients vary: pain 41–76%, depression 33–40%, tic window, and the persistent sedation can be ascribed anxiety 57–68%, nausea24–68%,constipation65%, se- directly to the drug. dation/confusion 46–60%, dyspnea 12–58%, anorexia Persistent opioid-induced sedation can sometimes be 85% and asthenia 90% (Cleeland et al. 1994; Anderson managed by adding an opioid-sparing analgesic, ei- et al. 2000; Bruera 1998; Chang et al. 2000; Hopwood ther an NSAID or an adjuvant analgesic, such as a and Stephens 2000). corticosteroid. Alternatively, psychostimulants, such Due to the multidimensional nature of pain, health care as dextroamphetamine, methyphenidate or modafinil professionals assessing a patient’s level of pain should may help to counteract the effect. Patients who are not keep in mind the “production-perception-expression”- candidates for psychostimulant therapy may be tried model of symptoms (Bruera 1998). This cascade model on an anticholinesterase inhibitor, such as donepezil addresses the different levels of symptom development (Slatkin et al. 2001). In patients with persistent sedation, resultinginanindividualratingofthepatient’ssuffering. a change of opioid may also be helpful. This model applies well to the symptoms of sedation, mental clouding, confusion or related phenomena. Opioid-Induced Neurotoxicity These cognitive disturbances characterize diverse types Opioid-induced neurotoxicity may take the form of a of encephalopathy, including delirium and dementia syndrome that may include, in addition to severe seda- 252 Cancer Pain Management, Opioid Side Effects, Endocrine Changes and Sexual Dysfunction tion, cognitive impairment, hallucinosis, delirium, my- 15. Slatkin NE, Rhiner M, Maluso Bolton T (2001) Donepezil in the oclonus, and even seizures. Generalized hyperalgesia Treatment of Opioid-Induced Sedation: Report of Six Cases. J and allodynia may also occur. This syndrome, which Pain Symptom Manage 21:425–438 may occur in milder and partial forms, appears to be dose-related and also potentially associated with preexisting cognitive impairment or delirium, or metabolic disturbances such as dehydration or renal failure. When Cancer Pain Management, Opioid Side these changes occur in morphine-treated patients, Effects, Endocrine Changes and Sexual accumulation of morphine metabolites, specifically Dysfunction morphine-3-glucuronide (M3G), may be causative. The management of severe neurotoxicity related to opi- JUDITH A. PAICE oids incorporates the same strategies considered when Division of Hematology-Oncology, Northwestern the side effects are less severe. This begins with a de- University; Feinberg School of Medicine, Chicago, IL, tailed assessment to identify treatable causes. USA Therapeutic approaches include hydration, opioid [email protected] switching ( opioid rotation), opioid dose reduction, and discontinuation of contributing drugs like hyp- Definition notics. Symptomatic treatment with haloperidol or another neuroleptic may be needed. Endocrine changes associated with opioid use include altered concentrations of sex hormones (e.g. testosterone, prolactin). These changes alter ovulation and menstruation patterns in women and cause References hypogonadism in men. The resultant sexual dysfunction 1. American Psychiatric Association (1994) Delirium, Dementia, encompasses reduction in libido (see also sexual and Amnestic and Other Cognitive Disorders. In: American Psy- response) in both men and women, limited engorgement chiatric Association, Diagnostic and Statistical Manual of Mental and subsequent excitation and orgasm in women, and Disorders, 4th edn. (DSM-IV) American Psychiatric Association, Washington DC, pp 123–133 inability to obtain and maintain erection and ejaculation 2. Anderson KO, Mendoza TR, Valero V et al. (2000) Minority in males. Cancer Patients and their Providers: Pain Management Attitudes and Practice. Cancer 88:1929–1938 Characteristics 3. Bruera E (1998) Research into Symptoms other than Pain. In: Doyle D, Hanks GW, MacDonald N (eds) Oxford Textbook of Opioids alter libido and sexual performance in ani- nd Palliative Medicine, 2 edn. Oxford University Press, New York: mal models, individuals with addictive disease using pp 179–185 4. Bruera E, Watanabe S, Faisinger RL et al. (1995) Custom-Made heroin, and persons in methadone maintenance pro- Capsules and Suppositories of Methadone for Patients on High grams (Cicero et al. 1975; Wiesenfeld-Hallin and Dose Opioids for Cancer Pain. Pain 62:141–146 Sdersten 1984). Opioids have also been shown to pro- 5. Chang VT, Hwang SS, Feuerman M (2000) Validation of the duce galactorrhea, inhibit ovulation, and trigger Edmonton Symptom Assessment Scale. Cancer 88:2164–2171 6. Cleeland CS, Gonin R, Hatfield AK et al. (1994) Pain and its amenorrhea in animal models and in women attend- Treatment in Outpatients with Metastatic Cancer. N Engl J Med ing methadone clinics (Johnson and Rosecrans 1980; 330:592–596 Packman and Rothchild 1976; Pelosi et al. 1974). Little 7. Farrell KR, Ganzini L (1995) Misdiagnosing Delirium as De- attention has been given to these effects in persons pression in Medically Ill Elderly Patients. Arch Intern Med 155:2459–2464 prescribed opioids for the treatment of chronic pain. 8. Farrell MJ, Katz B, Helme RD (1996) The Impact of Dementia However, recent case reports document these reactions on the Pain Experience. Pain 67:7–15 (i.e. diminished libido, sexual dysfunction, and amen- 9. HopwoodP,StephensRJ(2000)Depression in Patientswith Lung Cancer: Prevalence and Risk Factors Derived from Quality-of- orrhea) in persons being treated with spinal or systemic Life Data. J Clin Oncol 18:893–903 opioids for chronic pain (Abs et al. 2000; Daniell 2002; 10. Lawlor PG, Bruera ED (2002) Delirium in Patients with Ad- Finch et al. 2000; Paice et al. 1994). vanced Cancer. Hematol Oncol Clin N Am 16:701–714 Evidence that the sexual dysfunction is due to opi- 11. Manfredi PL, Breuer B, Meier DE et al. (2003) Pain Assessment in Elderly Patients with Severe Dementia. J Pain Symptom Man- oids, rather than psychological mechanisms common age 25:48–52 in chronic pain, is provided by the reversibility of this 12. Mercadante S, Casuccio A, Fulfaro F et al. (2001) Switching phenomenon when the antagonist naloxone is adminis- from Morphine to Methadone to Improve Analgesia and Toler- tered or when the opioid is discontinued (Packman and ability in Cancer Patients: A Prospective Study. J Clin Oncol 19:2898–2904 Rothchild 1976). The underlying endocrine changes 13. Pereira J, Hanson J, Bruera E (1997) The Frequency and Clin- leading to sexual dysfunction appear to be multifacto- ical Course of Cognitive Impairment in Patients with Terminal rial. Opioids significantly suppress plasma testosterone Cancer. Cancer 79:835–842 levels in persons using heroin, methadone, or other 14. Ripamonti C, Bruera E (1991) Rectal, Buccal, and Sublingual Narcotics for the Management of Cancer Pain. J Palliat Care opioids (Finch et al. 2000; Paice et al. 1994; Mendel- 7:30–35 son et al. 1975). These suppressed testosterone levels Cancer Pain Management, Opioid Side Effects, Uncommon Side Effects 253 return to normal after stopping opioid therapy (Finch with alternative positions that are less likely to elevate et al. 2000). Although pain may contribute to altered pain levels, as well as education to facilitate sexual plea- testosterone levels, Abs and colleagues compared these sure. levels with case-matched chronic pain patients not re- Additional research is needed to determine the preva- ceiving opioids and found that individuals treated with lence of opioid-induced sexual dysfunction, as well C intraspinal opioids have lower testosterone levels (Abs as the long-term effects of testosterone suppression. et al. 2000). These data provide additional support for Suppression of testosterone may lead to chronic fatigue opioids being the causative agent in sexual dysfunction, and osteoporosis, of particular concern to cancer sur- rather than chronic pain alone leading to changes in vivors and individuals with non-cancer pain who might testosterone and performance. be treated with opioids for extended periods. Finally, Reduced testosterone levels are likely to be a result of studies to confirm the safety and efficacy of androgen increased prolactin levels. Prolactin levels are increased replacement and other therapies designed to relieve in heroin use (Ellingboe et al. 1980), in normal subjects sexual dysfunction due to opioids are indicated. given intravenous injections of morphine (Delitala et al. 1983; Zis et al. 1984), and in cancer patients given References intraventricular injections of morphine (Su et al. 1987). 1. Abs R, Verhelst J, Maeyaert J et al. (2000) Endocrine Conse- Normally, the hypothalamus releases dopamine to quences of Long-Term Intrathecal Administration of Opioids. J Clin Endocrinol Metab 85:2215–2222 tonically suppress prolactin release from the anterior 2. Cicero TH, Bell RD, Wiest WG et al. (1975) Function of the pituitary. Opioids disinhibit this suppression, leading Male Sex Organs in Heroin and Methadone Users. N Engl J Med to elevations in prolactin. Prolactin reduces levels of 292:882–887 luteinizing hormone (LH) and follicle stimulating hor- 3. Daniell HW (2002) Hypogonadism in Men Consuming Sustained-Action Oral Opioids. J Pain 3:377–384 mone (FSH), which subsequently depress testosterone. 4. Delitala G, Grossman A, Besser GM (1983) The Participation In females, prolactin stimulates lactation, and reduces of Hypothalamic Dopamine in Morphine-Induced Prolactin Re- LH and FSH levels, leading to depressed libido and lease in Man. Clin Endocrinol 19:437–444 cessation of menses. 5. Ellingboe J, Mendelson JH, Kuehnle JC (1980) Effects of Heroin and Naltrexone on Plasma Prolactin Levels in Man. Pharmacol Clinical experience suggests that testosterone replace- Biochem Behav 12:163–165 ment, either by injection, gel, or patch, may improve 6. Finch PM, Roberts LJ, Price L et al. (2000) Hypogonadism in Pa- sexual function in persons treated with opioids who tients Treated with Intrathecal Morphine. Clin J Pain 16:251–254 have depressed serum testosterone (Abs et al. 2000). In 7. Fleming MP, Paice JA (2001) Sexuality and Chronic Pain. J Sex Educ Ther 26:204–214 women with postmenopausal changes in libido, an oral 8. Johnson JH, Rosecrans JA (1980) Blockade of Ovulation by combination of estrogen and testosterone (Estratest) is Methadone in the Rat: A Central Nervous System-Mediated being used “off label” to relieve sexual dysfunction, as Acute Event. J Pharmacol Exp Ther 213:110–113 is methyltestosterone gel applied to the vulva (Fleming 9. Mendelson JH, Meyer RE, Ellingboe J et al. (1975) Effects of Heroin and Methadone on Plasma Cortisol and Testosterone. J and Paice 2001). Neither of these therapies has been Pharmacol Exp Ther 195:296–302 systematically evaluated in the relief of opioid-induced 10. Packman PM, Rothchild JA (1976) Morphine Inhibition of Ovu- sexual dysfunction. lation: Reversal by Naloxone. Endocrinology 99:7–10 11. Paice JA, Penn RD, Ryan W (1994) Altered Sexual Function and When decreased testosterone is also associated with Decreased Testosterone in Patients Receiving Intraspinal Opi- increased prolactin levels, testosterone replacement oids. J Pain Symptom Manage 9:126–131 alone may not be sufficient to restore sexual function, 12. Pelosi MA, Sama JC, Caterini H et al. (1974) Galactorrhea- as elevated prolactin levels prevent the body from Amenorrhea Syndrome Associated with Heroin Addiction. Am J Obstet Gynecol 118:966–970 responding normally to testosterone. Treatment for 13. Su CF, Liu MY, Lin MT (1987) Intraventricular Morphine Pro- hyperprolactinemiawith bromocriptine (Parlodel), per- duces Pain Relief, Hypothermia, Hyperglycaemia and Increased golide (Permax) or cabergoline (Dostinex) normalizes Prolactin and Growth Hormone Levels in Patients with Cancer serum prolactin levelsto restore normal sensitivityto the Pain. J Neurol 235:105–108 14. Wiesenfeld-Hallin Z, Sdersten P (1984) Spinal Opiates Affect sexual effects of testosterone (Fleming and Paice 2001). Sexual Behavior in Rats. Nature 309:257–258 However, the safety and efficacy of these drugs have 15. Zis AP, Haskett RF, Albala AA et al. (1984) Morphine Inhibits not been studied in persons with sexual dysfunction due Cortisol and Stimulates Prolactin Secretion in Man. Psychoneu- to opioids administered for pain and further research is roimmunology 9:423–427 needed. Sildenafil (Viagra) has been anecdotally described as being effective in relieving opioid-induced sexual dys- Cancer Pain Management, Opioid Side function in both men and women, although controlled Effects, Uncommon Side Effects trialsarewarrantedtoestablishefficacyandsafetyinthis population. Non-pharmacologic approaches, including CHRISTOPHER J. WATLING cognitive-behavioral techniques, may be useful to dis- The University of Western Ontario, London, Ontario, tract attention from pain, theoretically allowing reduc- Canada tions in opioid dose. Sex therapy may provide couples [email protected] 254 Cancer Pain Management, Opioid Side Effects, Uncommon Side Effects

Definition Pruritus Opioid analgesics are the mainstay of cancer pain Pruritus, when it occurs as an opioid side effect, is oftreatment. Opioid analgesia is mediated by interaction ten only a minor nuisance and may only be elicited by with specific receptors in the brain and spinal cord. direct questioning. For occasional patients, however, it In addition to the desired clinical effect of pain relief, is so severe that opioid therapy must be modified. Itch opioids may also produce a variety of unwanted ad- is considered an uncommon side effect of systemically- verse effects that may compromise their usefulness. administeredopioids,thoughmayaffectupto17%ofpa- Common side effects, including constipation, nausea, tients(Friedman etal. 2001). In contrast, itch iscommon vomiting, and sedation are well-recognized and pre- after neuraxial opioid administration, with a reportedin- dictable. Other adverse effects, including respiratory cidence of 30–100% (Szarvas et al. 2003). Even with depression, pruritus, sweating, urinary retention, and neuraxial opioid administration, however, severe pruri- headache, are less common, but may occasionally have tusisrare, probably affecting lessthan 1%of individuals important clinical implications in the cancer patient (Chaney 1995). Itch isnotgenerallyassociatedwith skin with pain. rash, which is distinctly uncommon with opioid administration. Pruritus after systemic opioid administration isgeneralized, while that after neuraxialopioidadminis- Characteristics trationisoftenlocalizedtotheface,neck,orupperthorax (Chaney 1995). Respiratory Depression The pathophysiology of opioid-induced pruritus is un- All opioids in clinical use, given in sufficient doses, may certain. Although opioids may induce histamine release decrease respiratory rate, tidal volume, or both, as a re- from mast cells in the periphery, it is not clear that this sult of their direct depressant effects on brainstem res- mechanism is important to the generation of pruritus. piratory centers (Duthie and Nimmo 1987). Although Rather, it is likely that a central mechanism is involved, perhaps the most feared of opioid side effects, clinically a hypothesis supported by the reversibility of neuraxial significant respiratory depression is very rarely encoun- opioid-induced pruritus with naloxone (Friedman and tered in practice, particularly in opioid-tolerant patients. Dello Buono 2001). Pain stimulates respiration, acting as a physiologic an- In spite of the lack of evidence for histamine release tagonisttotherespiratorydepressanteffectsofopioidsin being an important etiologic factor in opioid-induced an intensity-dependent fashion (Borgbjerg et al. 1996). pruritus, antihistamines may sometimes be an effective Two situations may arise in cancer pain management treatment, perhaps as a result of their sedative proper- where the risk of respiratory depression is higher and ties. Infusions of the opioid antagonists naloxone and merits special caution. First, the neuraxial administra- nalbuphine may prevent or reduce itch with neuraxial tion of opioids (see Neuraxial Infusion and Spinal opioids (Kendrick et al. 1996), while the oral opioid (Neuraxial) Opioid Analgesia), either epidural or in- antagonist methylnaltrexone has been shown to reduce trathecal, may be complicated by respiratory depression pruritus when co-administered with morphine (Yuan due to supraspinal migration of the drug. Although reset al. 1998). The long-term use of opioid antagonists piratory depression may occur within minutes of spinal for chronic opioid-induced pruritus has not been eval- opioidadministration,itsappearancemaybedelayedfor uated. Other potential treatments for opioid-induced hours (Chaney 1995). Risk factors for clinically signif- pruritus include NSAIDs, Survey (NSAIDs), the icant respiratory depression after spinally administered 5-HT3 receptor antagonist ondansetron (Szarvas et opioids include advanced age, coexisting medical or al. 2003), and the opioid agonist-antagonist butor- respiratory problems, lack of opioid tolerance,and phanol (Dunteman et al. 1996). Opioid rotation is also a concurrentadministration of parenteral opioids. Rarely, simple and potentially effective strategy for managing however, patients with no identifiable risk factors will opioid-induced pruritus (Katcher and Walsh 1999). develop life-threatening respiratory depression (Etches et al. 1989). Careful monitoring of respiration and level Sweating of consciousness is therefore necessary when initiating Sweating may be a significant problem in some cancer therapy with spinal opioids. patients treated with opioids. Though the prevalence of Second, patients on long-term opioid treatment may sweating has been reported to range from 14–28% in experience respiratory depression following complete this population, numerous non-opioid factors may also relief of pain by other methods. Opioid-treated cancer be causative, including effectsof the neoplasm itself, co- patients undergoing neural blockade or cordotomy, existing infection, and other drugs (Mercadante 1998). for example, are at risk of developing respiratory de- As such, the incidence of true opioid-induced sweat- pression following the pain-relieving procedure (Wells ing is difficult to estimate. Clearly, however, there are et al. 1984). This effect, and the need to rapidly ad- uncommon instances where intense sweating an occur just opioid dosing post-procedure, must be antici- secondary to opioid therapy, and has a significantly pated. adverse effect on quality of life. Numerous agents have Cancer Pain Management, Orthopedic Surgery 255 been used to control sweating, including NSAIDs, cor- 7. Katcher J, Walsh D (1999) Opioid-Induced Itching: Morphine ticosteroids, benzodiazepines, H2-receptor blockers, Sulfate and Hydromorphone Hydrochloride. J Pain Symptom Manage 17:70–72 thioridazine, and anticholinergic drugs such as hyoscine 8. Kendrick WD, Woods AM, Daly MY et al. (1996) Naloxone ver- hydrobromide or butylbromide, with varying degrees sus Nalbuphine Infusion for Prophylaxis of Epidural Morphine- of success (Mercadante 1998). Like many unwanted Induced Pruritus. Anesth Analg 82:641–647 C opioid side effects, the problem may also respond to 9. Mercadante S (1998) Hyoscine in Opioid-Induced Sweating. J Pain Symptom Manage 15:214–215 opioid rotation. 10. Rawal N, Möllefors K, Axelsson K et al. (1983) An Experimen- Urinary Retention tal Study of Urodynamic Effects of Epidural Morphine and of Naloxone Reversal. Anesth Analg 62:641–647 Urinary retention is a frequent effect of spinally admin- 11. Silberstein SD, Lipton RB, Goadsby PJ (1998) Headache in Clin- istered opioids, but less commonly may be observed af- ical Practice. Isis Medical Media Ltd, Oxford, pp 106–107 12. Szarvas S, Harmon D, Murphy D (2003) Neuraxial Opioid- ter oral, parenteral, or transdermal opioid administra- Induced Pruritus: A Review. J Clin Anesth 15:234–239 tion. This effect is likely to be mediated by interaction 13. Wells CJ, Lipton S, Lahuerta J (1984) Respiratory Depression with opioid receptors in the lower spinal cord (Rawal after Percutaneous Cervical Anterolateral Cordotomy in Patients et al. 1983). Caution should be exercised, however, in on Slow-Release Oral Morphine. Lancet 1:739 14. Yuan CS, Foss JF, O’Connor M et al. (1998) Efficacy of Orally attributing urinary retention in a cancer patient to opi- AdministeredMethylnaltrexone in Decreasing Subjective Effects oid therapy, particularly when the symptom appears in a after Intravenous Morphine. Drug Alcohol Depend 52:161–165 patient on chronic, stable doses of opioid, as neoplastic involvement of the spinal cord or cauda equina may also compromise bladder emptying. Cancer Pain Management, Orthopedic Headache Surgery Occasionally cancer patients report that opioids cause headaches, even as the pain for which the opioids are JOHN H. HEALEY prescribed resolves. The etiology of this seemingly Memorial Sloan Kettering Cancer Center and Weill paradoxical phenomenon is uncertain. Headache spe- Medical College of Cornell University, New York, NY, cialists have long recognized drug-induced or analgesic USA rebound headaches, often resulting from the frequent [email protected] useofshort-actingopioids.Onecouldspeculatethatsus- ceptible patients prescribed opioids for cancer pain may Definition develop such rebound headaches. The frequent use of Orthopedic cancer pain includes biologic or mechan- analgesics may transform previously episodic headache ical pain that affects the musculoskeletal system, and syndromes into chronic daily headaches (Silberstein et compromises the function and independence of canal. 1998), but it is possible that some individuals with- cer patients. Bone pain has a different neurochemical out a prior headache history may also develop rebound basis than either inflammatory or neuropathic pain. It headaches when exposed to frequent doses of opioid is often multifactorial in origin and requires treatment analgesics. Whether the use of long-acting opioids is of all contributing factors. Pain treatment includes the associated with a lower risk of rebound headaches than surgical stabilization of fractured bones and often of short-acting opioids is not known. Headaches in the impending fractures. cancer setting may have many causes, of course, including brain or meningeal metastases, and should not be Characteristics attributed to opioid therapy without diligent evaluation of other possibilities. Bone pain can be multifactorial and requires a multi- pronged approach for accurate diagnosis and effective References treatment. Afferent signals come from stimuli that are 1. Borgbjerg FM, Nielsen K, Franks J (1996) Experimental Pain inherently mechanical or biologic. Exclusion of remote Stimulates Respiration and Attenuates Morphine-Induced Res- causes, such as referred and radicular pain, and other piratory Depression: A Controlled Study in Human Volunteers. distant causes, must be done in each case to optimize Pain 64:123–128 2. Chaney MA (1995) Side Effects of Intrathecal and Epidural Opi- treatmentandavoidmissingconcomitantdiseasesuchas oids. Can J Anaesth 42:891–903 spinal cord compression. Comprehensive management 3. Dunteman E, Karanikolas M, Filos KS (1996) Transnasal Butor- of bone pain requires specific treatment to address each phanol for the Treatment of Opioid-Induced Pruritus Unrespon- cause. sive to Antihistamines. J Pain Symptom Manage 12:255–260 4. Duthie DJR, Nimmo WS (1987) Adverse Effects of Opioid Anal- One type of referred pain comes from an insult af- gesic Drugs. Br J Anaesth 59:61–77 fecting the same dermatome. Typically, this comes 5. Etches RC, Sandler AN, Daley MD (1989) Respiratory Depres- from a lesion affecting the same bone proximal to sion and Spinal Opioids. Can J Anaesth 36:165–185 the symptomatic site. The most common example is 6. Friedman JD, Dello Buono FA (2001) Opioid Antagonists in the Treatment of Opioid-Induced Constipation and Pruritus. Ann distal femur and knee pain due to a proximal femur Pharmacother 35:85–91 or hip lesion. A careful physical examination is the 256 Cancer Pain Management, Orthopedic Surgery best way to make the diagnosis clinically. The limp Boneisweakestandmostlikelytofracturewhenstrained that is due to a knee problem differs significantly from in torque (twisting on a firmly planted foot, for exam- that of a hip problem, and should alert the clinician ple.) It is relatively stronger when the stress is axial and to problems “upstream” from the reported site of the the forces are in compression or distraction (tension). pain. Certain provocative tests have compelling diag- Metastases and erosions weaken the bone to well de- nostic value. For example, passive abduction or fined degrees. A 50% cortical defect in the femur causes active adduction of the hip isolates the adductor 60–90% reduction in bone strength. The fracture risk musculature and its pubic origin as the source of pain. posed by a bone lesion can be characterized in differ- This can point away from intrinsic hip pathology and ent ways. Bone mineral density alone explains 80–90% can avoid an unnecessary hip replacement operation. of the fracture risk in cadaveric models of lytic bone le- Another common problem is an avulsion fracture of sions of the femur (Michaeli et al. 1999). Usually, but the anterior inferior iliac spine. Since this is the origin not always, these lesions are associated with pain. Con- for the rectus femoris, activities that stress it, such as versely, bone pain is usually associated with such a bony straight leg raising from a supine position, provoke defect. The presence of either a critical bone lesion or pain, whereas hip flexion from the seated position does mechanical pain constitutes an impending fracture. Me- not. Once again, identification of the pathologic pain chanical treatment is mandatory for such a lesion. This generator focuses treatment and prevents ill-advised can comprise of external support (crutches) or internal surgical or medical treatment. reinforcementof the bone (implant). A common error is Radicular pain is common from cervical tumors and to treat the mechanical pain with antineoplastic agents causes periscapular or arm pain that is often improperly or radiation and analgesics, without addressing the me- ascribed to other sources. Similarly, lumbar tumors chanical component. cause buttock or lower limb pain that may or may not Plain radiographs remain the most efficient way to as- be associated with neurologic symptoms of a sensory sess the global integrity of bone and determine whether or motor nature. surgery is a consideration to treat the mechanical pain Alternative sources of pain must also be excluded. (Hipp et al. 1995). Three-dimensional imaging such as For example, degenerative arthritis of the hip, knee, CT scans or MRI scans are occasionally needed to diag- spine, or shoulder is common in older cancer patients. noseoccultlesionsorplansurgeries,sincetheycaniden- Avascular necrosis, particularly of the hip or shoulder, tify bony defects that must be bypassed. The mere pres- may develop from steroids, chemotherapy, or radiation ence of a bone lesion or metastasis does not mean that is therapy used to treat the underlying cancer. Simple ra- the source of pain nor that it requires explicit treatment. diographs are the best way to look for these traditional, Most bone lesions are asymptomatic. Rapidly growing non-oncologic causes of bone pain in the cancer patient. lesions may evade diagnosis. Plain radiographs appear Occasionally, paraneoplastic syndromes may cause normal until 30% of the mineral is lost, and bone scintig- bone or joint pain and elude usual diagnostic tests. This raphy primarily identifies areas of bone reaction. If the problem can occur from any cancer, but seems to be host bone has not had sufficient time to respond, these most common in patients with small cell lung cancer studies may yield false negative results, so a high index and with HIV-related malignancies. In the midst of of suspicion is needed. chemotherapy, granulocyte colony stimulating factor Biologically rapidly growing tumors raise intraosseous (GCSF) is commonly used and will produce localized pressure by blocking venous blood return, expanding and diffuse bone pain. The cause is poorly defined, but it within a closed space, and releasing pain-mediating seems to be due to acute pressure developing in the bone substances. Many neural transmitters and nerve fibers marrow from marrow expansion, and possibly from the have been identified within bone. They are involved in evolution of nociceptors and cytokines in response to normal development and pathologic conditions (Sisask the GCSF. Finally, infection must be excluded, partic- et al. 1995, Bergstrom et al. 2003). Substance P, ularly in patients who have hematologic malignancies calcitonin gene-related product (CGRP), vasoin- or treatment-related neutropenia. testinal peptide, and other compounds that stimulate Mechanical pain characterizes orthopedic cancer pain. nociceptors, augment local perfusion, and have direct Excess force or weight bearing bends the mechanically metabolic effects on the bone contribute to the pain insufficient bone (strain). This stretches the periosteum, generating milieu. Nerve fibers that stain for CGRP stimulates pain receptors, and produces pain. Before are widely distributed in bone, periosteum and marrow. fracture occurs, normal stimuli such as walking can They directly regulate local bone remodeling during trigger lower extremity pain, and lifting or forceful growth, and repair by elevating the CGRP concentra- activity cause upper extremity pain. In the extreme con- tion in the microenvironment around bone cells (Irie et dition, these forces result in fractures that are associated al. 2002). The connection between brain function and with periosteal tears, hemorrhage and tissue trauma. bone metabolism has recently been postulated to occur Local cytokines are released and further stimulate the due to leptin and mediated by noradrenaline acting on β2 nociceptors. adrenergic receptors on osteoblasts (Takeda et al. 2002). Cancer Pain Management, Overall Strategy 257

Bone pain has a different profile of neurotransmitters hemiarthroplasty replacement is needed. This surgery than either inflammatory or neuropathic pain (Clohisy is very successful in alleviating mechanical cancer pain and Mantyh 2003; Schwei et al. 1999). For exam- acutely. It works well long-term if antitumor therapies ple, substance P and calcitonin gene-related peptide prevent local bone destruction and destabilization of are both up-regulated in inflammatory pain, down- the implant. C regulated in neuropathic pain, and unchanged in models Treatment consists of reinforcing the bone, stopping the of bone metastasis (Honore et al. 2000a). On the other cancer progression, and preventing new sites of symp- hand, GFAP (glial fibrillary acidic protein) is mas- tomatic disease involvement. sively up-regulated in the spinal cord in bone cancer pain, but not in inflammatory or neuropathic pain. Sev- References eral other changes occur in the spinal cord. There is 1. Bergstrom J, Ahmed M, Kreicbergs A et al. (2003) Purifica- up-regulation of c-FOS, reflecting increased neuronal tion and Quantification of Opioid Peptides in Bone and Joint activity, dynorphin, and the development of astrocyto- Tissues – A Methodological Study in the Rat. J Orthop Res 21:465–469 sis. These chemical and morphologic changes indicate 2. Clohisy D, Mantyh PW (2003) Bone Cancer Pain. Cancer a central reorganization of the neural system in cases 97:866–873 of orthopedic oncologic pain. 3. HealeyJH, BrownHK(2000)ComplicationsofBoneMetastases: Cancersencouragetherecruitmentofosteoclaststhatre- Surgical Management. Cancer 88:2940–2951 4. HippJA, SpringfieldDS, HayesWC(1995) PredictingPathologic absorb bone. This bone resorption contributes to pain Fracture Risk in the Management of Metastatic Bone Defects. due to biologic and mechanical reasons. Blocking the Clin Orthop 312:120–135 osteoclastic action with agents such as osteoprotogenin 5. Honore P, Rogers SD, Schwei MG et al. (2000a) Murine Models prevents pain in animal models of bone cancer (Honore of Inflammatory, Neuropathic and Cancer Pain Each Generate a Unique Set of Neurochemical Changes in the Spinal Cord and et al. 2000b). Once the cortex is breached, the advanc- Sensory Neurons. Neuroscience 98:585–598 ingcancermechanicallyandbiologicallyirritatesthepe- 6. Honore P, Luger NM, Sabino MA et al. (2000b) Osteoprotogenin riosteum. Weak bone incurs greater strain, and pain en- Blocks Bone Cancer-Induced Skeletal Destruction, Skeletal Pain, sues. and Pain Related to the Structural Reorganization of the Spinal Cord. Nat Med 6:521–528 Prevention of bone resorption prevents bone pain 7. Irie K, Hara-Irie F, Ozawa H et al. (2002) Calcitonin Gene- and improves patient quality of life. Clinical stud- Related Peptide (CGRP)-Containing Nerve Fibers in Bone ies have proven that aminobisphosphonates reduce Tissue and their Involvement in Bone Remodeling. Microsc Res Tech 58:85–90 bone resorption, pain, and the need for radiation ther- 8. Michaeli DA, Inoue K, Hayes WC et al. (1999) Density Predicts apy. Meta-analysis of 95 randomized studies with the Activity-Dependent Failure Load of Proximal Femora with more than six months follow up has shown that these Defects. Skeletal Radiol 28:90–95 agents significantly reduced the odds ratio for fractures 9. Ross JR, Saunders Y, Edmonds PM et al. (2003) Systematic Review of Role of Bisphosphonates on Skeletal Morbidity in (vertebral 0.69, 95% confidence interval 0.57–0.84, Metastatic Cancer. BMJ 327:469 P < 0.0001; non-vertebral 0.65, 0.54–0.79, P < 0.0001; 10. Schwei MG, Honore P, Rogers SD et al. (1999) Neurochemical combined 0.65, 0.55–0.78, P < 0.0001), radiother- and Cellular Reorganization of the Spinal Cord in a Murine Model apy (0.67, 0.57–0.79, P < 0.0001), and hypercalcemia of Bone Cancer Pain. J Neurosci 19:10886–10897 11. Sisask G, Bjurholm A, Ahmed M et al. (1995) Ontogeny of Sen- (0.54, 0.36–0.81, P = 0.003) but not for orthopedic sory Nerves in the Developing Skeleton. Anat Rec 243:234–240 surgery (0.70, 0.46–1.05, P = 0.086) or spinal cord 12. Takeda S, Elefteriou F, Levasseur R et al. (2002) Leptin Regu- compression (0.71, 0.47–1.08, P = 0.113). The reduc- lates Bone Formation Via the Sympathetic Nervous System. Cell tion in orthopedic surgery was significant in studies that 111:305–317 lasted over a year 0.59, 0.39–0.88, P = 0.009) (Ross et al. 2003). Despite the clear benefits of optimal medical manage- Cancer Pain Management, Overall ment, many patients will still have bone pain and sustain fractures. Mechanical pain responds to the relieving of Strategy loads on the bone, externally or internally (Healey and GILBERT J. FANCIULLO Brown 2000). External support and protection comes Pain Management Center, Dartmouth-Hitchcock from protected weight bearing with a walking aid (e.g. Medical Center, Lebanon, NH, USA a cane, crutches, or walker) or brace (e.g. a lumbar sup- [email protected] port or functional cast brace for the humerus). Internal fixation reinforces the bone with metal, bypassing the bony defect and sharing the stress with the intact bone. Definition Fixation of an orthopedic implant in normal bone is Painisanexperienceuniquetoeachindividualandbased needed proximal and distal to the deficiency. When the on perception, mood, and current and past experiences. defect is close to the end of the bone and it is impossible Cancer pain, even more so than chronic or acute pain, is to meet the goal of rigid fixation through the metaph- multidimensional, and has emotional, social, and spiri- ysis or epiphysis, the joint must be sacrificed and a tual vectors that must be assessed and addressed. Given 258 Cancer Pain Management, Overall Strategy the multidimensional nature of cancer pain, a team or are non-English speaking, have no support network, or multidisciplinary approach geared towards assessment who are in denial. and treatment is required to ensure the best care. Good cancer pain treatment is labor intensive, requires highly Characterization of Pain specialized knowledge and skill, can change the lives of Cancerpaincanbecausedbydirecteffectsoftumor,side cancer patients and their loved ones, and can be the most effects of treatment, paraneoplasticsyndrome s, or be fulfilling part of a pain clinicians practice. related to a preexisting or concomitant condition. Pain can be characterized as neuropathic, somatic or visceral, Characteristics or can be mixed. Diagnosis is based on history and physical examination, and pharmacological treatment deci- Epidemiology and Impact sions will vary based on the characteristics and etiology About half a million people in the United States and of the pain. about 6.6 million people worldwide die of cancer each Cancer pain related to direct effects of tumor can year (American Cancer Society 2003; World Health manifest as somatic, visceral or neuropathic pain Organization 1996). Lifetime probability of developing syndromes. Boney, particularly vertebral body and cancer is approximately 1 in 2 for men and 1 in 3 for rib metastases are common and often cause localized women (American Cancer Society 2003). The survival somatic pain but can cause neuropathic symptoms rate for adults is approximately 62% and for children is particularly with spinal cord, cauda equina, or nerve 97% (American Cancer Society 2003). Roughly 40% of root involvement or Visceral Nociception and Pain newly diagnosed cancer patients and 75% of advanced syndromes such as pleuritic pain with rib metastases. cancer patients suffer from pain (Sykes et al. 2003). Spinal cord compression occurs in approximately The prevalence of pain varies with the type of cancer. 3% of all cancer patients (Kramer 1992). Thoracic Pain in patients with head and neck cancer, genitouri- radiculopathic pain patterns are common and may be nary, prostate, and esophageal cancer is far more com- easily misdiagnosed. Brachial and lumbar plexopathy, mon than in patients with leukemia (Portenoy 1989; meningeal carcinomatosis ( meningeal carcinoma- Sykes et al. 2003). Patients with metastatic disease tous) and base of skull metastasis are frequent direct have more frequent pain complaints than those with tumor effect causes of neuropathic pain. Pleuritic pain, nonmetastatic cancer (Sykes et al. 2003). One-third of hepatic capsular stretch pain, and bowel obstruction patients with advanced cancer have two sites of pain and pain are examples of visceral pain syndromes requiring two-thirds have three or more sites of pain (Grond et special attention and skill to treat well. al. 1996). Seventeen percentof pain in patients with can- Mucositis is an extremely prevalent, difficult to treat, cer is treatment related and 9% is due to a concomitant and severe and debilitating pain syndrome caused by disease (Grond et al. 1996). cancer treatment. Peripheral neuropathy pain can occur The influence of uncontrolled cancer pain is dramatic. as a paraneoplastic syndrome in up to 5% of patients The severity and impact of pain caused by cancer is with lung cancer, or can occur as often as 82% in believed to be greater than pain in patients without patients being treated with chemotherapy (Smith et cancer. Beliefs about the meaning of pain in cancer pain al. 2002). Postthoracotomy pain syndrome can occur in patients have been shown to increase the severity of pain greater than 50% of patients undergoing thoracotomy as well as levels of depression, anxiety, somatization, (Perkins and Kehlet 2000). Fifty percent of woman and hostility (Ahles et al. 1983). Severe, uncontrolled undergoing breast surgery for cancer have pain one pain in patients with cancer is a major risk factor in year after surgery, and 30–80% of patients undergoing cancer related suicide (Chochinov and Breitbart 2000). amputation continue to suffer chronic pain (Perkins and Pain, depression, delirium and lack of social support Kehlet 2000). Radiation plexopathy or myelopathy have all been associated with an increased desire for a are not uncommon pain syndromes in cancer survivors, hastened death in cancer patients (Chochinov and Bre- nor is avascular necrosis secondary to corticosteroid itbart 2000). Many of these symptoms can be treated treatment. and pain can almost always be well controlled, often with simple and noninvasive remedies. Psychological Assessment distress is often lessened and psychiatric symptoms can A pain history should incorporate questioning about resolve with good pain treatment and relief (Chochinov multiple sites of pain since this information is often and Breitbart 2000). not volunteered by the patient. Cancer patients are Special patient populations can be especially challeng- frequently reluctant to report increasing pain, perhaps ingandincludechildrenandinfants,elderlypatients,pa- fearing progressive disease. The character, location, in- tients with concomitant preexisting personality or other tensity, frequency and relationship of pain to activities psychiatric disorders, patients with preexisting chronic should all be investigated. Pain syndromes that existed pain, patients who suffer from addiction, poverty, who prior to cancer diagnosis should be identified. Patients live in rural locations, are poorly educated or illiterate, with a long history of chronic pain, such as low back Cancer Pain Management, Overall Strategy 259 pain or fibromyalgia, which has never been adequately useful model upon which to guide therapy, but it must controlled even with long-term opioid treatment, may be remembered that cancer patients with severe pain be at risk of poorly-controlled pain as more aggressive should not be forced to fail treatment with NSAIDs be- treatments for cancer pain are administered. At the fore having an opioid added to their regimen (Sykes et same time, it is not unusual for chronic pain syndromes al. 2003). Patients with severe pain due to cancer should C to resolve or assume diminished importance within the almost always have therapy initiated with a single entity, context of a life threatening illness. pure mu agonist opioid at the time they are first seen. A pain history should include an understanding of the Routes of administration, such as intravenous, subcu- characteristics of the cancer type, including diagnosis, taneous, oral, rectal, buccal, and intranasal or inhaled, histology, extent of disease, and prognosis. History of should be considered in special circumstances. Drugs antineoplastic treatment is important in order to assess such as ketamine or local anesthetics can be infused peripheral neuropathy pain that might be secondary to intravenously for refractory pain syndromes. a paraneoplastic syndrome, chemotherapy or radiation The potential effectiveness of neural blockade in care- treatment. Prognosis and treatment may vary based on fully selected patients is exemplified by the neurolytic etiology. Knowledge of specific cancer pain syndromes celiac plexus block. This injection is still the most can help in diagnosis and in selecting treatments. For ex- useful of injection therapies for cancer pain, and can ample, radiation therapy may be more effective in treat- provide good to excellent analgesia in 85% of patients ing intermittent pain due to bone metastasis than anal- with localized pain secondary to pancreatic carcinoma. gesics. A history of remote or concurrent alcoholism or It should be an early option for patients with pain from drug addiction can be important in prioritizing therapy. this disease or other intraabdominal cancer (Patt and For example, an analgesic intrathecal infusion system Cousins 1998). Epidural, intrathecal, and regional nerve may be selected for treatment earlier in the paradigm, blocks can be done using neurolytic agents such as al- rather than oral opioids. A social and emotional history cohol or phenol and can be individualized in special is an essential part of the cancer pain history. An assess- circumstances. Analgesia from neurolytic blocks will ment of cognitive ability, educational level, dementia or typically last for 6 months. delirium should all be part of the history. Patients with severe pain refractory to noninvasive Athorough physicalexaminationcombinedwith acom- treatments should also be considered for treatment with plete history will almost always provide sufficient infor- intrathecal analgesics. Drugs routinely infused into the mation to formulate a good therapeutic plan. Review of intrathecal space include morphine, hydromorphone, upcoming procedures is also important, because painful bupivacaine, and clonidine. Intrathecal infusions can procedures in adults are too commonly overlooked as a be successfully employed and should be considered in treatablecomponentofcancerpain.Manycancercenters patients with severe neuropathic pain, incident pain, have “pain free” systems in place to ensure that infants or opioid tolerance or refractoriness. Patients with an and children can undergo bone marrow biopsy, MRI ex- estimated life expectancy of 3 months or less can have ams, and line and tube placement comfortably, but these a percutaneous system connected to a mobile infusion same options are not typically available for adults. Clin- pump. If life expectancy is greater than 6 months, a icians should offer analgesic guidance for procedures programmable, implanted pump can be used and will to ensure that they are not painful and anticipated with typically need to be refilled only every 90 days. Anal- dread and fear. gesic infusion systems can be a useful option, and there Theabilitytoreviewandinterpretlaboratorytests,radio- is now extensive experience supporting efficacy and graphs, MRI and CT scans, and to understand oncologic safety; these systems are labor intensive, however, and nomenclature, are important and useful skills when ad- may require frequent medication or rate adjustments. dressing the problem of cancer pain. Neurosurgicalproceduressuchasanterolateral cordotomy,medial myelotomy, dorsal root entry zone le- Treatment sioning, and other neurodestructive procedures are op- Cancer pain treatment can be divided into five strate- tions for carefully selected patients and can provide ex- gies: drugs, interventional approaches (surgery and cellent relief of pain in otherwise refractory situations. injections), behavioral medicine approaches, phys- They, too, should be considered in cancer pain patients ical medicine approaches, and complementary and whose pain does not respond to nondestructive remedies alternative approaches. (Burchiel 2002). Acetaminophen and nonsteroidal anti-inflammatory Behavioral interventions, such as coping skill training drugs; opioids; and adjuvant analgesics, such as anti- and pacing, learning about the differences between convulsants, antidepressants, topical agents (e.g. lido- hurt and harm, reduction of catastophizing, relaxation caine patch), and bisphosphonates are the backbone of techniques, self-hypnosis, biofeedback and other psy- therapy and will be effective for the large majority of chological interventions are an essential component of patients with cancer pain. The World Health Organi- any cancer pain reduction plan. Patients should be as- zation ladder approach to treatment selection can be a sessed for denial, anger, and depression. When severe, 260 Cancer Pain Management, Palliation of Upper GI Cancer these problems should be managed by a behavioral than providing a paradigm for the administration of medicine specialist. Astute pain medicine specialists medications and procedures. should possess enough skill and knowledge in this area Treatment of patients with cancer pain can be challeng- to enable them to provide this care to the majority of ing,requiresspecialskillsandknowledge,isbestaccom- cancer pain patients. Preexisting or concomitant psy- plished in a multidisciplinary setting and can be extraor- chiatric illness may make treating cancer pain more dinarily rewarding. Attention to other symptoms and to challenging, but can also increase the rewards of suc- the social, emotional, and spiritual needs of cancer pa- cessful therapy to the patient, his or her family, and all tients should be a routine part of cancer pain manage- providers involved. ment and can be addressed by pain specialists with in- Physical medicine interventions should be considered terests and skill in those areas, or may require the special in all patients with cancer, but especially those with talents of palliative medicine providers working in con- pain. Pain from immobility can be relieved with a pre- junction with pain providers. scribed regimen of physical activity, even if a patient is bed-bound or has advanced disease. Maintaining the References highest functional capacity possible will ensure the 1. Ahles TA, Blanchard EB, Ruckdeschel JC (1983) The Multidi- best quality of life for the majority of patients with mensional Nature of Cancer-Related Pain. Pain 17:277–288 2. American Cancer Society (2003) http://www.cancer.org/docroot/ cancer pain. Modalities used for acute pain, such as stt/stt\_0.asp fluidotherapy, heat, and massage, can be very useful in 3. Berger AM, Portenoy RK, Weissman, eds (2002) Principles and patients suffering from cancer pain. Physical medicine Practice of Palliative Care and Supportive Oncology. Lippincott specialists with special skill in cancer rehabilitation Williams & Wilkins, Philadelphia 4. Burchiel K (2002) Surgical Management of Pain. Thieme, New should be called upon early to help care for cancer York patients. 5. Chochinov HM, Breitbart W (2000) Handbook of Psychiatry in Complementary and alternative pain management Palliative Medicine. Oxford University Press, Oxford, pp 57–58 strategies should be employed whenever they might 6. Ernst E, Cassileth B (1998) The Prevalence of Complimen- tary/Alternative Medicine in Cancer. Cancer 83:777–782 be useful. Thirty percent of cancer patients world- 7. Grond S, Zech D, Diefenbach et al. (1996) Assessment of Cancer wide use complementary medicine approaches to help Pain: A Prospective Evaluation in 2266 Cancer Patients Referred manage their cancer and complications (Ernst and to a Pain Service. Pain 64:107–114 8. Kramer JA (1992) Spinal Cord Compression in Malignancy. Pal- Cassileth 1998). A patient who specifically asks about liative Med 6:202–211 acupuncture may be likely to find acupuncture a useful 9. Smith EL, Whedon MB, Bookbinder M (2002) Quality Improve- adjunct, whether there is a true therapeutic effect or ment of Painful Peripheral Neuropathy. Seminars in Oncology placebo effect alone. Patient’s belief in efficacy of com- Nursing 18:36–43 10. Patt RB, Cousins MJ (1998) Techniques for Neurolytic Neural plementary and alternative treatments and their high Blockade. In: Neural Blockade in Clinical Anesthesia and Man- therapeutic index should not be overlooked. agement of Pain (Cousins MJ, Bridenbaugh PO, Eds). Lippincott- Attention to spirituality and cultural beliefs is extremely Raven, Philadelphia. pp 1036–1037 important in managing patients with cancer pain. Spiri- 11. Perkins FM, Kehlet H (2000) Chronic Pain as an Outcome of Surgery. A Review of Predictive Factors. Anesthesiology tual beliefs may influence the patients understanding of 93:1123–1133 their illness and suffering, and may affect treatment de- 12. Portenoy RK (1989) Cancer Pain: Epidemiology and Syndromes. cision making. Spiritual beliefs may assist coping skills. Cancer 63:2298–2307 Providers should respect the beliefs of their patients and 13. Sykes N, Fallon MT, Patt RB (2003) Cancer Pain. Arnold Pub- lishers, London, p 22 appreciate the often profound importance of these be- 14. World Health Organization (1996) Cancer Pain Relief and Pal- liefs. This appreciation itself can be therapeutic, and en- liative Care, 2nd edn. World Health Organization, Geneva able the provider to help his or her patient take full ad- vantageof thepower ofthesebeliefs(Bergeretal.2002).

Summary Cancer Pain Management, Palliation of Pain in patients with cancer cannot be treated in a vac- Upper GI Cancer uum, as a hard-wired nociceptive sensation. It is best treated in context, taking advantage of the special skills Palliative Surgery in Cancer Pain Management and knowledge of other professionals. Pain physicians’ superior knowledge of the treatment of refractory cancer pain can be enhanced by the palliative physicians’ Cancer Pain Management, superior knowledge of communication skills; manage- Patient-Related Barriers ment of symptoms other than pain; ability to address social, spiritual, and emotional conditions; and impor- CIELITO REYES-GIBBY tantly, ability to organize and prioritize the efforts of The University of Texas MD Anderson Cancer Center, oncologists, surgeons, primary providers, nurses and Houston, TX, USA pain physicians. Good cancer pain medicine is more [email protected] Cancer Pain Management, Patient-Related Barriers 261

Definition fects of analgesics when their disease progresses (Clee- Patient-related barriers refer to patients’ limited knowl- land et al. 1997; Cleeland 1987). Due to this fear of drug edge of, beliefs about, and attitudes towards pain and tolerance, many withhold or “save” their medication un- pain treatment that detract from optimal pain manage- til they can no longer tolerate their pain. ment. Concern about side effects from pain medicines is C another commonly reported barrier to adequate pain management. Many believe that side effects from anal- Characteristics gesics are even more bothersome than the pain itself. In Patients, as consumers of health care, play an important a study of underserved cancer patients, Anderson and role in the successful managementof pain. Critical com- colleagues (Anderson et al. 2002) found that a majority ponents for the successful clinical management of pain (75%) reported problems with side effects from pain include the patients’ ability to communicate their need medicines. Commonly reported side effects include forpaincontrol,providefeedbackontheeffectivenessof constipation, sedation, and nausea. treatment,andcompliancewiththerequirementsofther- Belief that increasing pain signifies disease progression apy.Patients’limitedknowledgeof,beliefsaboutandat- causes patients who are unwilling to face this possibil- titudes towards pain and pain treatment may, therefore, ity to deny their cancer pain. Patients are also afraid to detract from optimal pain management. Several barriers bother their health care providers with symptoms they (Cleeland et al. 1997; Ward et al. 1993; Cleeland 1987) consider to be an expected part of their disease. Due to to the practice of goodpainmanagementhavebeeniden- the belief that pain is an inevitable part of cancer and tified. They include those associated with patients (re- that nothing can be done about it, patients are willing luctance to report pain and to take pain medications), the to accept and endure pain. In a population-based sur- health care system (low priority given to pain control), vey conducted several years ago (Levin et al. 1985), ap- and health care professionals (inadequate knowledge, proximately 50% of the respondents considered cancer reluctance to treat, fear of controlled-substance regula- to be an extremely painful disease. Approximately 40% tions). believed that cancer treatment is extremely painful, and Among cancer patients, studies have shown that pa- 37% rated cancer treatment as moderately painful. Fur- tients’ reluctance to report pain is a primary reason for thermore, over 70% thought that cancer pain could be so inadequatepain control. VonRoenn etal. (1993), Larson severe that one would consider suicide, and more than et al. (1993), and Cleeland (1987) have demonstrated 60% believed that cancer patients usually die a painful that both oncologists and oncology nurses identified death. Thesefindingsdocumentthemisconceptionssur- patient reluctance to report pain as one of the major rounding cancer pain. barriers to the adequate control of cancer pain. Patients also think that if they complain of symptoms, Patients are reluctant to report pain to their physicians their health care providers will be distracted from their or nurses for many reasons. Fear of addiction and de- efforts to cure the disease. A recent study specifically pendence is often rated as a number one concern is. investigated whether patients’ self-reports of pain vary Opioids are the cornerstone of cancer pain therapy. by treatment setting (Reyes-Gibby et al. 2003), in this First described in the World Health Organization’s case an outpatient chemotherapy clinic and an outpa- guidelines for cancer pain relief (World Health Organi- tient breast clinic. Medical charts of patients seen during zation 1986), the protocol for pain treatment provides the same day in both the outpatient chemotherapy clinic simple recommendations for the use of oral analgesics and the outpatient breast clinic were reviewed and pain and adjuvants: Non-opioids and adjuvants for mild ratings were abstracted. Statistically significant differ- pain; so-called “weak” opioids, often combined with ences in patients’ self-reports of pain were observed in a non-opioid and adjuvants, for moderate pain; and the two treatment settings. Fifty-one percent of patients’ so-called “strong” opioids, combined with adjuvants, self-reports of pain differed between the two treatment for moderate to severe pain. There is, however, a com- settings, with 38% reporting a pain score > 4 in the out- mon misconception among patients that opioids cause patient breast clinic, and 0 in the outpatient chemother- addiction. Often, patients and their family caregivers apy clinic. The authors suggested that the results may mistake the signs of withdrawal for addiction rather indicate that patients were reluctant to report pain in the than physical dependence, perpetuating the belief that chemotherapy clinic to avoid delaying their treatment. addiction is a sequela of taking opioids. Family mem- Another possible explanation for this finding is that pa- bers also fear that the patient will be thought of as an tients may have believed that the chemotherapy clinic addict, adding substantial pressure on the patient to was not set up for pain intervention (to contact a physi- refrain from taking opioids. cian for pain medication), and were thus reluctant to dis- The mistaken notion that pain medications taken early tract the clinic heath care professionals from adminis- will not be effective when pain gets worse further com- tering chemotherapy. pounds the problem. Some patients believe that if they Wanting to be labeled as “good patients” and not as take pain medication they will become tolerant to the ef- “complainers” also influences patients’ reporting of 262 Cancer Pain Management, Patient-Related Barriers pain. Many patients think that their behavior will influ- tions. Another important finding of this study was that a ence the quality of their care. Families may compound majority of patientsin both ethnic groupswouldwait un- the problem by trying to work out with the patient what til their pain severity was a 10 on a 10-point scale before is important to tell their physicians (Cleeland 1987). calling their health care provider. Not surprisingly, other frequently reported barriers are Other studies have identified religious beliefs, folk heal- forgetting to take pain medications and the belief that ers, non-drug interventions, and assistance from family one should be able to tolerate pain without medication members as important for pain management. A study of (Thomason et al. 1998). patients receiving analgesics from home health or hos- While most of the studies on patient-related barriers to pice agencies, found that Hispanic patients were more pain were conducted with non-Hispanic whites, studies likely than Caucasian patients to report beliefs (e.g. take in recent years explored the influence of sociocultural pain medicines only when pain is severe) that could hin- factors on patient-related barriers to adequate pain man- der effective pain management (Juarez et al. 1998a). A agement. There are many definitions of culture, but one qualitative study of Hispanic cancer patients receiving that is helpful for understanding the effects of culture on home health or hospice care also found that many pa- pain was offered by Hellman (1990). He defined culture tients believed that pain should be approached with sto- as “a set of guidelines (both explicit and implicit) that in- icism (Juarez et al. 1998b). dividuals inherit as members of a particular society, that While not directly related to patients’ attitudes and be- tells them how to view the world, how to experience it liefs,othernotablebarrierspatientsfaceincludesthecost emotionally, and how to behave in it in relation to other and limited availability of analgesics. Difficultywith co- people, and to natural and supernatural forces.” Helman payments or incidental costs associated with obtaining offered specific propositions as to the pervasive effects their prescriptions is especially relevant for those who of culture on pain: 1) Not all social or cultural groups re- lackinsurancecoverageorwhohavealimitedincome.In spond to pain in the same way, 2) How people perceive terms of availability, a study of pharmacies in New York and respond to pain, both in themselves and in others, found that only 25% of pharmacies in minority commu- can be largely influenced by their cultural background, nities stocked sufficient opioids for pain management, and3)How,andwhether,peoplecommunicatetheirpain compared to 72% of pharmacies in non-minority com- to health professionals and to others can also be influ- munities (Morrison et al. 2000). enced by cultural factors. These propositions underlie When patients’ attitudes and beliefs interfere with ef- the commonly held assertion that there may be signifi- fective pain management, patients can benefit from cant cultural and linguistic differences in the way people a number of interventions. Educational interventions feel, view, and report pain. that provide accurate information about pain and pain Although recent research suggests that culture does not treatments have shown some positive results. Rimer affect pain thresholds or pain intensity ratings, culture and colleagues (Rimer et al. 1987) used a randomized probably does impact people’s behavioral responses to Solomon Four-Group design to assess the effectiveness pain and their interpretations of the meaning of pain. A of a patient education intervention among 230 cancer study by Cleeland and colleagues (Cleeland et al. 1997) patients. The intervention consisted of nurse counseling of Hispanics and African-Americans who attended mi- and printed materials. Results showed that one month norityoutpatientclinics,showedthatHispanicsreported later, patients in the experimental group were more more concerns about taking too much pain medication likely to have taken their pain medicine on the correct and more concernsaboutpossible sideeffectsfromanal- schedule and to have taken the correct dosage. The gesics, as compared to African American patients. experimental group was significantly less likely to have A recent study by Anderson and colleagues (Anderson reported stopping the medicine when they felt better, et al. 2002) noted that, although the reasons for not tak- and were significantly less worried about tolerance and ing pain medications do not significantly vary among addiction to pain medicines as compared to the control African-Americans and Hispanic patients, differences group. The results of this study provide support for the exist between the two groups in terms of the meaning importance of educational interventions, augmented of cancer pain. African-Americans talked about the sen- with brief health care professional contact, in changing sory component of pain, describing pain as “hurt” and as pain-related beliefs and improving pain management. limited activity and impaired function. In contrast, His- panics tended to focus more on the emotional compo- References nentofpain,describingpainas“emotionalsuffering.”In 1. Anderson KO, Richman SP, Hurley J et al. (2002) Cancer terms of patient-related barriers to cancer pain manage- Pain Management among Underserved Minority Outpatients: ment, commonly stated barriers for both groups were: Perceived Needs and Barriers to Optimal Control. Cancer the need to be strong and not lean on pain medications; 94:2295–2304 concern about addiction and the possible development 2. Cleeland CS (1987) Barriers to the Management of Cancer Pain. Oncology 1:19–26 of tolerance to pain medications; concern about side ef- 3. Cleeland CS, Gonin R, Baez L et al. (1997) Pain and Treatment of fects; and family reactions to their use of pain medica- Pain in Minority Patients with Cancer. The Eastern Cooperative Cancer Pain Management, Principles of Opioid Therapy, Dosing Guidelines 263

Oncology Group Minority Outpatient Pain Study. Ann Intern morphine) or oral combination products (e.g. hydro- Med 127:813–816 codone/acetaminophen or oxycodone/acetaminophen). 4. Hellman C (1990) Culture, Health and Illness: An Introduction for Health Professionals. Wright, London The dose-limiting factor in these combination products 5. Juarez G, Ferrell B, Borneman T (1998a) Influence of Culture is acetaminophen. The total daily dose should be limited on Cancer Pain Management in Hispanic Patients. Cancer Pract to 4 grams, placing a limitation of 8–12 tablets per day, C 6:262–269 depending on the dose of acetaminophen. Short-acting 6. Juarez G, Ferrell B, Borneman T (1998b) Perceptions of Quality of Life in Hispanic Patients with Cancer. Cancer Pract 6:318–324 opioids are normally administered every 3–4 h, but 7. Larson PJ, Viele CS, Coleman S et al. (1993) Comparison of products such as immediate-release oxycodone or mor- Perceived Symptoms of Patients Undergoing Bone Marrow phine may be given as often as hourly in the situation Transplant and the Nurses Caring for Them. Oncol Nurs Forum of uncontrolled pain. 20:81–87 8. Levin DN, Cleeland CS, Dar R (1985) Public Attitudes toward Modified- or slow-release opioid products should be Cancer Pain. Cancer 56:2337–2339 used cautiously as an initial opioid treatment, given 9. Morrison RS, Wallenstein S, Natale DK et al. (2000) “We the potential for side effects and the longer elimination Don’t Carry That"- Failure of Pharmacies in Predominantly with these compounds. This is particularly true with Non-White Neighborhoods to stock Opioid Analgesics. N Engl J Med 342:1023–1026 the elderly and those with renal impairment, in whom 10. Reyes-Gibby CC, McCrory LL, Cleeland CS (2003) Variations opioid clearance may be decreased, causing increased in Patients’ Self-Report of Pain by Treatment Setting. J Pain and prolonged side effects with low doses of these Symptom Manage 25:444–448 products (Osborne et al. 1986). 11. Rimer B, Levy MH, Keintz MK et al. (1987) Enhancing Cancer Pain Control Regimens through Patient Education. Patient Educ Couns:267–277 Around-the-Clock Dosing 12. Thomason TE, McCune JS, Bernard SA et al. (1998) Cancer Theroutineadministrationofopioidsatregularintervals Pain Survey: Patient-Centered Issues in Control. J Pain Symptom Manage 15:275–284 has been an important part of cancer pain management 13. Von Roenn JH, Cleeland CS, Gonin R et al. (1993) Physician (Saunders 1963). In registration studies, investigators Attitudes and Practice in Cancer Pain Management. A Survey have found analgesic equivalence between immediate- from the Eastern Cooperative Oncology Group. Ann Intern Med release products and modified-release products at iden- 119:121–126 14. Ward SE, Goldberg N, Miller-McCauley et al. (1993) Patient- tical daily doses (Walsh et al. 1992). Improved patient RelatedBarriersto Management ofCancer Pain. Pain52:319–324 compliance, and, therefore, improved pain control, is 15. World Health Organization (1986) Cancer Pain Relief. WHO, anticipated with modified-release products. However, Geneva in the situation of limited resources, patients can be prescribed regularly-administered, immediate-release oral products with the anticipation of satisfactory pain control. Cancer Pain Management, Principles of Patients can be converted from immediate-release Opioid Therapy, Dosing Guidelines products to modified-release products. Some modified- release products have a biphasic release mechanism JAMES F. CLEARY that results in both immediate and more sustained pain University of Wisconsin Comprehensive Cancer relief. The dose of the modified-release formulation Center, Madison, WI, USA should be calculated by converting the daily dose of [email protected] immediate-release opioids (including those administered parenterally) to the modified-release formulation, which is then administered over the 24-h period accord- Characteristics ing to the medication’s dosing schedule. Opioids are the mainstay of cancer pain manage- There are now oral opioids approved for daily and twice ment. All patients with moderate to severe cancer pain daily dosing. The transdermal fentanyl patch has a du- should have access to opioids (Cleary 2000). The pri- ration of 2–3 days. With modified-release compounds, mary goal of opioid dosing is to establish pain relief dose escalation is usually best accomplished by increas- with regular dosing within a therapeutic window, the ing the dose rather than shortening the dosing interval. dose that maximises pain control with minimal side However, acarefulhistory should betakento explorethe effects. Opioids can be administered by various routes: conceptof “end of dose failure.” Apatientmayreportef- oral (immediate-release or modified-release products); fectiveanalgesiafor8–10hfollowingtheadministration transdermal; transmucosal; intravenous; subcutaneous of a modified-release opioid on a twice daily schedule. or intraspinal. Rather than increasing the dose and therefore increasing the risk of side effects, it may be preferable to decrease Initial Dosing the dosing interval to every 8 h. This also applies to once In most cases, the initial treatment with opioids begins daily oral products, with which twice daily dosing may with short-acting formulations. This may be in the be necessary. With the transdermal fentanyl patch, pa- form of opioid-only products (codeine, oxycodone or tients may report only one good day out of three despite 264 Cancer Pain Management, Principles of Opioid Therapy, Drug Selection increases in the dose delivered per hour. Changing the of life, it may also be appropriate to decrease the dose patchevery48hmayresultinmoreeffectivepaincontrol of morphine administered to reduce the risk of toxicity. (Payne et al. 1995) Breakthrough pain can usually be managed by pro- References viding a short-acting drug at a dose equal to 10–15% of 1. Cleary JF (2000) Cancer Pain Management Cancer Control 24-h daily dosing (Portenoy and Hagen 1990). Experi- 7:120–131 2. Cleary JF, Carbone PP (1997) Palliative Medicine in the Elderly. ence with oral transmucosal fentanyl citrate, however, Cancer 80:1335–1347 suggests that there is not a clear correlation between the 3. Davis MP (2004) Acute Pain in Advanced Cancer: An Opi- around-the-clock opioiddose andthe breakthroughpain oid Dosing Strategy and Illustration. Am J Hosp Palliat Care dose (Farrar et al. 1998). 21:47–50 4. Farrar JT, Cleary J, Rauck R et al. (1998) Oral Transmucosal Fen- tanyl Citrate: Randomized, Double-Blinded, Placebo-Controlled Dose Escalation Trial for Treatment of Breakthrough Pain in Cancer Patients J Natl Cancer Inst 90: 611–616 If pain is not well controlled and side effects are not se- 5. Jacox A, Carr DB, Payne R et al. (1994) Management of Cancer vere, the dose of opioid should be increased. The per- Pain: Clinical Practice Guideline No 9. Agency for Health Care centage escalation should be based on the severity of the Policy and Research. US Dept of Health and Human Services, pain, the side effects, and other medical factors. If pain Public Health Service AHCPr Publication 94-052 6. Osborne RJ, Joel SP, Slevin ML (1986) Morphine Intoxication is moderate, the increase should be 25–50% of the daily in Renal Failure: The Role of Morphine-6-Glucuronide. BMJ dose (Jacox et al. 1994). If pain is severe, a dose escala- 292:1548–1549 tion of 50–100%of the daily dose should be made. With 7. Payne R, Chandler S, Einhaus M (1995) Guidelines for the Clin- most oral products, this escalation can safely take place ical Use of Transdermal Fentanyl. Anticancer Drugs 6:50–53 8. Portenoy RK, Hagen NA (1990) Breakthrough Pain: Definition, every 24 h. In the case of the transdermal fentanyl patch, Prevalence and Characteristics. Pain 41:273–281 doseescalation should nottakeplacemoreoftenthanev- 9. Saunders C (1963) The Treatment of Intractable Pain in Terminal ery48h,althoughininpatientsettingswithcloseclinical Cancer. Proc R Soc Med 56:195–197 10. Walsh TD, MacDonald N, Bruera E et al. (1992) A Controlled supervision, dose increaseshave beensafely made every Study of Sustained-Release Morphine Sulfate Tablets in Chronic 24 h when needed (Payne etal. 1995).When opioidinfu- Pain from Advanced Cancer. Am J Clin Oncol 15:268–272 sions are used in the treatment of pain, dose escalations shouldtakeplacenomoreoftenthanthetimerequiredfor four half-lives, unless there is careful monitoring. In the Cancer Pain Management, Principles of case of morphine, this is every 10–16 h. Escalating the infusion rate more often than thismay result in increased Opioid Therapy, Drug Selection drug toxicity. Patients may use patient-controlled anal- MARIE FALLON gesia together with clinician-administered bolusesto ef- Department of Oncology, Edinburgh Cancer Center, fect better pain control, but it will still require 4–5 half University of Edinburgh, Edinburgh, Scotland lives to reach steady-state. [email protected]

Pain Emergency Definition In the case of a pain emergency, a loading dose may be Opioid is a general term that includes naturally occur- the most effective way to treat the pain (Davis 2004). ring, semisynthetic, and synthetic drugs that produce The loading dose should be established with frequent their effects by combining with opioid receptors and dosing administered either intravenously or subcuta- are stereospecifically antagonized by naloxone. Opioid neously. Many clinicians commence an opioid infusion drugs are the mainstay in the treatment of moderate to alone, but it will require 4–5 half-lives before maximal severe cancer pain. pain relief can be achieved. With the half life of morphine being 2.5–4 h, it would take 10–16 h to reach Characteristics steady state, and therefore potentially leave the patient Although concurrent use of other approaches and inter- with uncontrolled pain. If a loading dose is added to an ventions may be appropriate in many patients, and nec- opioid infusion, the ongoing opioid dose should be the essary in some, analgesic drugs are needed in almost ev- sum of the previous opioid regimen together with that ery patientwith cancer pain.Thekeystone of cancerpain calculated from the loading dose. management is a good assessment. Insight into the com- plexmultidimensionalfeaturesofcancerpain,andanap- Dosing in Special Situations preciationofthepatient’sclinicalandpsychosocialchar- Inthepresenceofrenalimpairment(Osborneetal.1986) acteristics, are fundamental for the success of any pain and in the elderly (Cleary and Carbone 1997), the clear- management strategy, pharmacological or otherwise. ance of either primary drug or metabolites may be Drugs whose primary clinical action is the relief of pain decreased. Therefore, both more cautious titration and are conventionally classified on the basis of their activ- longer dosing intervals may be necessary. Near the end ity at opioid receptors, as either opioid or non-opioid Cancer Pain Management, Principles of Opioid Therapy, Drug Selection 265 analgesics. A third class, adjuvant analgesics,are arm pain caused by radiation-induced brachial plex- drugs with other primary indications that can be effec- opathy may benefit when a tricyclic antidepressant is tive analgesics in specific circumstances. The major added to paracetamol (acetaminophen) (McQuay and group of drugs used in cancer pain management are the Moore 1997; Kalso et al. 1998). opioid analgesics. Patients who are relatively non-tolerant and present C Analgesic therapy with opioids, non-opioids and adju- with moderate pain, or who fail to achieve adequate vant analgesics is developed for the individual patient relief after a trial of a non-opioid analgesic, should be through a process of continuous evaluation, so that treated with an opioid conventionally used for mild to a favorable balance between pain relief and adverse moderate pain (formerly known as a “weak” opioid). pharmacological effects is maintained. The World This treatment is typically accomplished using a com- Health Organization (WHO) structured approach to bination product containing a non-opioid (e.g. aspirin drug selection for cancer pain, known as the WHO or paracetamol (acetaminophen)) and an opioid (such analgesic ladder, when combined with appropriate dos- as codeine, oxycodone or propoxyphene). This coming guidelines is capable of providing adequate relief to bination can also be coadministered with an adjuvant 70–90% of patients (World Health Organization 1986; analgesic. The doses of these combination products can Ventafriddaetal. 1987;Takeda1990;Walker etal. 1983; be increased until the maximum dose of the non-opioid Schug et al. 1990; Zech et al. 1995). This approach em- analgesic is attained (e.g. 4000–6000 mg paracetamol phasizes that the intensity of pain, rather than its specific (acetaminophen)); beyond this dose, the opioid con- etiology, should be the prime consideration in analgesic tained in the combination product could be increased selection. as a single agent, or the patient could be switched to an The WHO ladder was never intended to be used in opioid conventionally used in Step 3. isolation. Rather, it should be integrated with other Patients who present with severe pain, or who fail to approaches to cancer pain management such as ra- achieve adequate relief following appropriate admin- diotherapy, chemotherapy, anesthetic interventions, istration of drugs on the second step of the analgesic physiotherapy and relaxation techniques. ladder, should receive an opioid conventionally used for The WHO ladder approach advocates three basic steps moderate to severe pain (formerly known as a “strong” (Fig. 1): Patients with mild cancer-related pain should opioid). This group includes morphine, diamorphine, be treated with a non-opioid analgesic (also known fentanyl, oxycodone, phenazocine, hydromorphone, as a simple analgesic), which should be combined methadone, levorphanol, and oxymorphone. These with adjuvant drugs, if a specific indication for these drugs may also be combined with a non-opioid anal- exists. For example, a patient with mild to moderate gesicoranadjuvantdrug.Clearly,theboundarybetween opioids used in the second and third steps of the analgesic ladder is somewhat artificial, since low doses of morphine or other opioids for severe pain can be less effective than high doses of codeine or propoxyphene. Accordingly, some debate surrounds the usefulness of Step 2 of the WHO ladder. This is currently being examined in clinical studies. According to the WHO guidelines, a trial of opioid therapy should be given to all patients with chronic pain of moderate or greater severity. This approach has been subject to criticism concerning its evidence base and its use over time. Much of the evidence is based on components of the ladder examined in nonmalignant pain, e.g. an opioid combined with a non-opioid is more effective than either alone, or systematic reviews of adjuvant analgesics (which appear to suggest that the number needed-to-treat [NNT] for most of the commonly-used drugs is about three (McQuay and Moore 1998)). Some of the criticism may be related to the common misconception that the WHO ladder is a ‘recipe’ for cancer pain management. In fact, it is a set of principles that need to be applied appropriately with other non-pharmacological treatments to each individual situation. Cancer Pain Management, Principles of Opioid Therapy, Drug Selec- Themorphine-likeagonistdrugsarewidelyusedtoman- tion, Figure 1 WHO analgesic ladder. age cancer pain. Although they may differ from mor- 266 Cancer Pain Management, Principles of Opioid Therapy, Drug Selection phine in quantitative characteristics, they qualitatively trials would be needed to say there is good evidence for mimic the pharmacological profile of morphine, includ- the superiority of oxycodone (Kalso and Vainio 1990). ing both desirable and undesirable effects. Hydromorphone is another alternative to morphine if Comparative trials of opioids in cancer pain are ex- toxicity or drowsiness is problematic, but again, there tremely difficult to perform. While good quality ran- is no high quality evidence suggesting that one drug is domized trials to provide evidence for pharmacother- superior to another. apy of cancer pain are preferred, clinical decisions are Methadone is a synthetic opioid with unusual qualities currently based on limited trial evidence; basic pharma- and different pharmacologicalproperties from the other cology of the opioid and particular properties relating to opioids used in cancer pain. Steady-state plasma con- renal, hepatic and cognitive impairment; and progress centration is usually reached at one week, but may take in basic science which gives foundation to our belief up to 28 days. Serious adverse effects are avoided if the of genetic variability in response to opioid analgesia initialperiodofdosingisaccomplishedwith“asneeded” (Rossi et al. 1997). No strong evidence speaks for the administration, which is not the usual recommendation superiority of one opioid over another. For this reason, in cancer pain dosing regimens. When steady-state has the aforementioned factors, along with practical clinical been achieved, scheduled dose frequency should be issues such as possible routes of drug administration, determined by the duration of analgesia following each determine drug selection. dose. Although most cancer pain is responsive to opioid The equianalgesic dose ratio of morphine to metha- analgesia to some extent, the side effects experienced done has been the subject of controversy. Recent data by an individual are the practical limiting factors in suggest that the ratio correlates with the total opioid what is termed “ opioid-responsiveness.” While pure dose administered before switching to methadone. opioid agonists have no pharmacological ceiling dose, a Among patients receiving low doses of morphine the “ opioid pseudo-pharmacological ceiling dose exists ratio is 4:1. In contrast, for patients receiving more than in some situations because of dose-limiting side effects. 300 mg of oral morphine, the ratio is approximately The common side effects of all opioids are constipa- 10:1 or 12:1 (Ripamonti et al. 1998). tion, dry mouth, sedation, nausea and vomiting. The The therapeutic armamentarium for opioids has ex- first two often persist, but tolerance usually develops panded over time, and familiarity with a range of opioid to sedation, nausea and vomiting. Sedation, however, agonists and with the use of equianalgesic tables to tends to be the common limiting factor during opioid convert doses if switching opioids, is necessary (Ta- dose titration, particularly in genetically susceptible ble 1). It is clear that patients are at risk of under- or individuals, or in pain syndromes that usually require over-dosing by virtue of individual sensitivities; hence, larger doses of opioid e.g. neuropathic pain (Portenoy a logical, systematic approach to reassessment of the et al. 1990). entire clinical situation is the key to managing opioid Inindividualstroubledwithsideeffects,especiallyseda- adverse effects and/or uncontrolled cancer pain, rather tion, with one opioid, a switch to an alternative opioid than an automatic switch to another opioid. may result in an improved balance between analgesia and unwanted side-effects (Fallon 1997). It is impossible to predict such an improvement, but clinical expe- References rience with opioids makes this an acceptable strategy. In the case of neuropathic pain, use and titration of an 1. Fallon MT (1997) Opioid Rotation – Does It Have a Role? Palliat Med 11:176–178 appropriate adjuvant analgesic would seem another crit- 2. Kalso E, Tramer MR et al. (1998) Systemic Local Anaesthetic- icalstepinimprovingthebalancebetweenanalgesiaand Type Drugs in Chronic Pain: A Systematic Review. Eur J Pain side effects. 2:3–14 3. Kalso E, Vainio A (1990) Morphine and Oxycodone Hydrochlo- Therearenogooddatathatexaminearouteswitchrather ride in the Management of Cancer Pain. Clin Pharmacol Ther than an opioid switch as a beneficial strategy in the 47:639–646 managementof opioid adverse effects. Clinically, the 4. McQuay HJ, Moore RA (1997) Antidepressants and Chronic main benefit in switch to the spinal route of delivery is Pain. BMJ 314:763–764 5. McQuay H, Moore A (1998) An Evidence-Based Resource for the possibility of adding drugs to manage neuropathic Pain Relief. Oxford Medical Publications, Oxford pain and incident pain, such as local anesthetic. 6. Portenoy RK, Foley KM, Inturrisi CE (1990) The Nature of Opi- The transdermal route can be useful in patients having oid Responsiveness and its Implications for Neuropathic Pain: swallowing difficulties and in some cases of resistant New Hypotheses Derived from Studies of Opioid Infusions. Pain 43:273–286 constipation with oral opioids. Studies with transdermal 7. Ripamonti C, De Conno F et al. (1998) Equianalgesic Dose/Ratio fentanyl show a trend towards less constipation (Wong between Methadone and other Opioid Agonists in Cancer Pain: et al. 1997). Comparison of Two Clinical Experiences. Ann Oncol 9:79–83 There is one randomized, controlled trial comparing 8. Rossi GC, Leventhal L, Pan YX et al. (1997) Antisense Map- ping of MOR-1 in Rats. Distinguishing between Morphine and oxycodone favorably with morphine with regard to hal- Morphine-6 Beta-Glucuronide Antinociception. J Pharmacol lucinations, however, the numbers are small and larger Exp Ther 281:109–114 Cancer Pain Management, Principles of Opioid Therapy, Drug Selection 267

Cancer Pain Management, Principles of Opioid Therapy, Drug Selection, Table 1 Opioid analgesics (pure mu agonists) used for the treatment of chronic pain Morphine- Equi- Half-life Peak Duration Toxicity Comments Oral Active like agonists anal- (hr) Effect (hr) Bioavail- metabolites gesic (hr) ability dosesa (%) C

Morphine 10 s.c. 2–3 0.5–1 3–6 Constipation, Standard comparison for 20–30 M6G 20–60 2–3 1.5–2 4–7 nausea, sedation opioids; multiple routes p.o.b most common; available respiratory depression rare in cancer patients

Controlled- 20–60 2–3 3–4 8–12 20–30 M6G release p.o.b morphine Sustained- 20–60 2–3 4–6 24 Once-a-day morphine 20–30 M6G release p.o.b approved in some countries morphine Hydromorphone 1.5 s.c. 2–3 0.5–1 3–4 Same as morphine Used for multiple routes 35–80 No 7.5 p.o. 2–3 1–2 3–4

Oxycodone 20–30 2–3 1 3–6 Same as morphine Combined with aspirin 60–90 oxymorphone or acetaminophen, for moderate pain in USA; available orally without coanalgesic for severe pain

Controlled- 20–30 2–3 3–4 8–12 oxymorphone release oxycodone Oxymorphone 1 s.c. – 0.5–1 3–6 Same as morphine No oral formulation glucuronides 10 p.r. – 1.5–3 4–6

Meperidine 75 s.c. 2–3 0.5–1 3–4 Same as Not used for cancer pain 30–60 norpethidine (pethidine) morphine + CNS due to toxicity in higher excitation; doses and short half-life contraindicated in those on MAO inhibitors

Diamorphine 5 s.c. 0.5 0.5–1 4–5 Same as morphine Analgesic action due to Morphine metabolites, predominantly morphine; only available in some countries

Levorphanol 2 s.c. 12–16 0.5–1 4–6 Same as morphine With long half-life, No 4p.o. accumulation occurs after beginning or increasing dose

Methadonec 10 s.c. 12 ≥150 0.5– 4–8 Same as morphine Risk of delayed toxicity due 60–90 No 20 p.o. 1.5 to accumulation; useful to (see start dosing on p.r.n. text)

Codeine 130 2–3 1.5–2 3–6 Same as morphine Usually combined with 60–90 morphine s.c. non-opioid 200 p.o.

Propoxyphene – 12 1.5–2 3–6 Same as morphine Toxic metabolite 40 norpropoxy- HCI (Dextro- plus seizures with accumulates but not phene propoxyphene) overdose signiﬁcant at doses used clinically; usually combined with non-opioid

Propoxyphene –121.5–23–6Sameas Same as hydrochloride 40 norpropoxy- napsylate hydrochloride phene (Dextro- propoxyphene) 268 Cancer Pain Management, Radiotherapy

Cancer Pain Management, Principles of Opioid Therapy, Drug Selection, Table 1 (continued) Morphine- Equi- Half-life Peak Duration Toxicity Comments Oral Active like agonists analgesic (hr) Effect (hr) Bioavail- metabolites dosesa (hr) ability (%)

Hydrocodone – 2–4 0.5–1 3–4 Same as morphine Only available combined hydromor- with acetaminophen; only phone available in some countries

Dihydrocodone – 2–4 0.5–1 3–4 Same as morphine Only available combined with 20 morphine aspirin or acetaminophen in some countries

Fentanyl – 3–12 – – Same as morphine Can be administered as 25/buccal No a continuous I.V. or S.C. <2/oral infusion; based on clinical experience, 100 mcg/hr is roughly equianalgesic to morphine 4 mg/hr I.V.

Fentanyl – 13–22 – 48–72 Same as morphine Based on clinical experience 90/ No Transdermal 100 mcg/hr is roughly trans- System equianalgesic to morphine dermal 4 mg/hr; recent study indicates a ratio of oral morphine: transdermal fentanyl of 100:1 aDose that provides analgesia equivalent to 10 mg i.m. morphine. These ratios are useful guidelines when switching drugs or routes of administration bExtensive survey data suggest that the relative potency of i.m.:p.o. or s.c.:p.o., morphine of 1:6 changes to 1:2–3 with chronic dosing cWhen switching from another opioid to methadone, the potency of methadone is much greater than indicated on this table

9. Schug SA, Zech D et al. (1990) Cancer Pain Management Ac- Deﬁnition cording to WHO Analgesic Guidelines. J Pain Symptom Manage 5:27–32 Radiation is used to treat cancer and other diseases. 10. Takeda F (1990) Japan’s WHO Cancer Pain Relief Program. In: The radiation dose is described in terms of centigray Foley KM, Bonica JJ, Ventafridda V et al. (eds) Advances in (cGY) or Gray (Gy) (100 cGy = 1 Gy). For curative Pain Research and Therapy, vol 16. Raven Press, New York, pp 475–483 radiation, 5000–8000 cGy are generally prescribed over 11. Ventafridda V, Tamburini M, Caraceni A et al. (1987) A Valida- 5 treatments each week for 5–8 weeks of radiation. This tion Study of the WHO Method for Cancer Pain Relief. Cancer means that 180 cGy to 200 cGy of radiation are given 59:851–856 each day for a total of 25–40 fractions or treatments. 12. Walker VA, Hoskin PJ et al. (1983) Evaluation of WHO Analgesic Guidelines for Cancer Pain in a Hospital-Based Palliative Care When radiation is given with palliative intent, the dose Unit. J Pain Symptom Manage 3:145–149 usually rangesfrom asingle8 Gy fraction to 15 fractions 13. Wong JO, Chui GL, Tsao CJ et al. (1997) Comparison of Oral of 2.5 Gy over 3 weeks. Controlled-Release Morphine with Transdermal Fentanyl in Ter- There are many ways that radiation can be administered, minal Cancer Pain. Acta Anaesthesiol Sin 35:25–32 14. World Health Organization (1986) Cancer Pain Relief. World which are broadly classiﬁed as external radiation and Health Organization, Geneva brachytherapy. External radiation and brachytherapy 15. Zech DFJ, Grond S, Lynch J et al. (1995) Validation of World each have many forms of treatment. The goal of any Health Organization Guidelines for Cancer Pain Relief. A 10 type of radiation treatment is to limit the radiation dose Year Prospective Study. Pain 63:65–76 only to the involved areas.

External Beam Radiation External radiation treats the site of disease by using Cancer Pain Management, Radiotherapy different types of x-ray beams derived from a machine called a linear accelerator, which is built on the princi- 1 2 3 EDWARD CHOW ,STEPHEN LUTZ ,NORA JANJAN ples used in an x-ray machine. This is the most common 1Toronto Sunnybrook Regional Cancer Center, way that radiation is administered. Through the use of University of Toronto, Toronto, ON, Canada specialized blocks, a linear accelerator focuses the ra- 2Blanchard Valley Regional Cancer Center, Findlay, diation only on the area to be treated with millimeter Ohio, USA precision, and blocks radiation from affecting adjacent 3University of Texas M. D. Anderson Cancer Center, tissues. Houston, TX, USA Radiation loses energy as it passes through tissue, and [email protected] the characteristic of a radiation beam is described by the Cancer Pain Management, Radiotherapy 269 amount of energy that is lost as it passes through the tis- 60% of the radiation dose [60 cGy] is deposited at sue.ThetermDmaxreferstothedepthofthetissuewhere 10 cm of tissue below the skin surface. 100%of theradiation doseisdeposited.Only 50%ofthe prescribed radiation dose from a single beam may pene- Electron Beam Radiation trate to a tumor located 10 cm from the skin surface. To Electronbeamradiationisusedtotreatcancerslocatedin C overcome this, many beams of radiation are routinely the superficial tissues, like lymph nodes in the neck, the used to treat a tumor. The sum of the radiation doses at chest wall after a mastectomy, and skin cancers. It pro- the tumor gives a high total radiation dose. vides an important alternative to gamma rays, because The choice of the type of radiation used in a radiation underlying critical structures like the heart and spinal treatment plan depends on the location of the tumor and cord may not receive any radiation at all from electron critical structures near the tumor. The concept of inte- beam therapy. gral dose is used to describe the selection of the type of • radiation in order to maximize the radiation dose in the The depth of penetration in centimetersoftissue from tumor, yet minimize treatment of uninvolved adjacent an electron beam energy can be generalized by the tumors. following rule (Table 1): • Newer forms of radiation treatment planning, like three- 80%oftheradiationdosewillbedepositediftheelec- dimensional conformal radiation therapy and intensity tron beam energy is divided by three, and 95% of the modulated radiation therapy, apply the principles of in- radiation dose will be deposited if the electron beam tegral dose by targeting the tumor through multiple low- energy is divided by two. doseradiationbeams.Alltheradiationenergyfromthese – Forexample,a9MeVelectronbeamdeposits80% beams adds to give the tumor a very high radiation dose, of the dose 3 cm from the skin surface and 95% of buttheradiationdosefromtheindividualbeamsissolow the dose 4.5 cm from the skin surface. that there are minimal effects from the radiation in the adjacent normal tissues. External beam treatment planning involves the specific There are many types of external beam radiation that are selection of radiation beams to target the tumor and min- derived from a linear accelerator. These types of radia- imize treatment of adjacent normal tissues. Limiting the tion include gamma rays and electron beam radiation. dose of radiation to adjacent tissues is critical to avoid Gamma rays are used to treat tumors located deep in side effects from radiation. These treatment-related side thebody,whileelectronbeamradiationtreatssuperficial effects,especiallythosetomucosalsurfacesthatresultin cancers. mucositis, nausea and diarrhea, can significantly impact on the functional status of the patient. This is of particu- Gamma Rays lar concern in patients who are already debilitated from Gamma rays are penetrating forms of x-rays, and many their disease. energy levels of gamma rays are available for treatment Brachytherapy (Tables 1 and 2). In general: Brachytherapy is the placement of radioactive sources • High-energy gamma raysdeeplypenetrate the tissues in or adjacent to a tumor bed. These radioactive sources but spare the skin from radiation reactions like ery- can be permanently implanted in a tumor or placed tem- themaandmoistdesquamation.Thistypeofradiation porarilynearthetumorlocation.Permanentlyimplanted is used to treat deep-seated tumors in the abdominal radiation sources are used to treat prostate cancer. The and pelvic areas. Due to the characteristics of high- radiation dose gradually decays until no further radi- energy gamma rays, the skin receives little to no dose. ation is emitted. For lung cancer, radioactive sources • An example of a high-energy gamma radiation beam that are placed in a catheter are temporarily adjacent to is an 18 MV photon beam [a photon is a package of a tumor blocking the bronchus for a prescribed amount energy]. If 100 cGy is prescribed from one radiation of time to deliver a specific radiation dose. After the beam, 100 cGy is deposited 3.5 cm from the skin sur- prescribed amount of time, the radiation sources are face [Dmax] and 85% of the radiation dose [85 cGy] removed. Brachytherapy also uses high-dose rate [a is deposited at 10 cm of tissue below the skin surface. very strong radioactive source that gives radiation over • Low-energy gamma rays do not penetrate the tissues a few minutes] and low-dose rate [a radioactive source well and cause more skin reactions. This type of radi- that gives a low-dose of radiation over several hours]. ation is used to treat head and neck cancers and breast The choice of brachytherapyused primarily depends on cancers where there may be tumor infiltration of the the tumor location. The radiation dose is extremely lo- skin. calized because of the Inverse Square Law [Radiation • An example of a low energy gamma radiation beam is dose = 1/d2]. Applying this principle, the radiation dose a Cobalt-60 beam or a 6 MV photon beam. If 100 cGy dropsoffrapidlyasthedistancefromtheradiationsource isprescribed from one 6MVradiationbeam, 100cGy increases. For example, the radioactive dose 2 cm away isdeposited 1.5 cm fromtheskinsurface [Dmax],and from the radioactive source is only one-fourth the radia- 270 Cancer Pain Management, Radiotherapy

Cancer Pain Management, Radiotherapy, Table 1 Gamma Radiation – Prescribing 100 cGy for a tumor located 10 cm below the skin Type of Gamma Dmax [cm below %DepthDoseat Dose of radiation Dose of radiation Total dose of Beam skin surface] 10 cm below the [cGy] needed to at Dmax with each radiation to the skin surface give 100 cGy @ radiation fraction skin at Dmax [20 10 cm below the radiation fractions] skin

Cobalt-60 0.5 cm 57% 175 cGy 175 cGy 3500 cGy =∼ 0.5 cm

6 MV photons 1.5 cm 65% 154 cGy 154 cGy 3080 cGy =∼ 1.5 cm

18 MV photons 3.5 cm 80% 125 cGy 125 cGy 2500 cGy =∼ 3.5 cm

Dmax is the depth in cm below the skin surface where 100% of the prescribed radiation dose is given. The % depth dose at 10 cm is the % of the prescribed radiation that penetrates to a tumor located 10 cm below the skin surface = 100 cGy/% depth dose. 2000 cGy will be given to the tumor [located 10 cm from the skin surface] from an anterior radiation field. Another 2000 cGy will be given to the tumor from a posterior radiation field. This will deliver 4000 cGy to the tumor. Each radiation fraction will equal 200 cGy [100 cGy from the anterior and 100 cGy from the posterior field] and 20 fractions will be required to give a total radiation dose of 4000 cGy. 18 MV photons are more effective in treating abdominal and pelvic tumors and they cause little skin reaction. Cobalt-60 and 6 MV photons are effective in treating more superficial tumors like head and neck and breast cancers that may have tumor infiltration of the skin; in this case a higher radiation dose to the skin is essential to control the tumor.

Cancer Pain Management, Radiotherapy, Table 2 Electron Beam Radiation - Radiation is deposited over a short distance from the skin’s surface Type of Electron Beam Dmax [cm below skin surface] 80% of radiation dose 95% of radiation dose deposited within deposited within

6MeV 1.5cm 2cm 3cm

9MeV 2.3cm 3cm 4.5cm

12 MeV 3 cm 4 cm 6 cm

As an example, if a 100 cGy of radiation is administered with 6 MeV electron beam, 100 cGy would be given at 1.5 cm below the skin, only 20 cGy would be delivered 2 cm below the skin surface [80% of the radiation dose deposited within 2 cm of the skin surface] and only 5 cGy would be delivered 3 cm below the skin surface [95% of the radiation dose delivered within 3 cm of the skin surface]. Therefore, 80% of the radiation dose is given between 1.5 cm and 2 cm from the skin surface. Less than 5% of the radiation dose reaches structures more than 3 cm from the skin surface. tion dose next to the source. Brachytherapy is an impor- act mechanism of its action is still uncertain, although tant option in palliative care,because itcandeliverradia- tumor cell kill may be an important reason. However, tion over a few minutes to days instead of several weeks. the absence of a dose-response relationship, rapid re- As the radiation is well localized, brachytherapy can be sponses, and poor correlation of symptomatic relief usedtore-irradiatetissuesthathavepreviouslybeenirra- with radiosensitivity suggest that an effect on host diated. Treatment-related side effects with brachyther- mechanisms of pain could also be important. apy are limited. Markers of bone remodeling have been shown to be sup- Radioactive isotopes, which have affinity to specific pressed by anti-resorptive therapy, and the response of areas like the bone or thyroid, can also be injected these bone markers has been applied to monitoring ther- into the blood stream and are a form of brachytherapy. apy for bone metastases. The effects of the radiation are localized to the site of In the recent UK Bone Pain Radiotherapy Trial (Bone deposition and little radiation is administered to ad- Pain Trial Working Party 1999), 22 patients were en- jacent tissues. Like more conventional brachytherapy, tered into a supplementary study to establish the effects radioisotopes allow re-irradiation of previously irra- of local radiotherapy for metastatic bone pain on mark- diated areas because the radiation dose is concentrated ers of osteoclast activity, particularly the pyridinium in the site of disease. crosslinks pyridinoline and deoxypyridinoline, the Radiotherapy results in damage to cellular DNA. Ra- latter being specific for bone turnover. Urine samples diotherapy causes both direct and indirect damage to the were collected before and one month after radiotherapy. reproductive DNA material of the cell. Direct damage Patients were treated with either a single 8 Gy or 20 Gy takes place in the form of base deletions, single and in 5 daily fractions. Pain response was scored with double strand breaks in the DNA chain. Indirect damage validated pain charts completed by patients. occurs by the interaction of radiotherapy with water Urinary pyridinium concentrations were correlated molecules in the cell, which releases toxic free radicals. with pain response. In patients who did not respond to palliative radiation (non-responders), baseline con- Mechanisms of Action centrations of both pyridinoline and deoxypyridinoline Palliative radiotherapy is well established for the werehigher than thosewho responded (responders),and treatment of symptomatic bone metastases.Theex- rose further after treatment, whereas in responders, the Cancer Pain Management, Radiotherapy 271

Cancer Pain Management, Radiotherapy, Figure 1 Effect of Radiotherapy on Urinary Markers of Osteoclast Activity Related to Pain Response. Total: 22 patients, 8 with breast cancer and 14 with prostate cancer; 5 patients showed no response, 9 a partial response and 8 a complete response.

mean values remained unchanged (Fig. 1). This resulted Characteristics in significant differences between responders and non- responders for both indices after treatment (P = 0.027). External Beam Local Radiotherapy The authors concluded that radiotherapy-mediated inhi- Radiation therapy has long been employed in the man- bition of bone resorption, and thus osteoclastic activity, agement of bone metastases, including relief of bone could be a predictor for pain response. They also pro- pain, prevention of impending fractures and promotion posed that tumor cell killing reduces the production of of healing in pathological fractures. Stabilization osteoclast-activating factors, or there is a direct effect of bony destruction occurs in 80% and re-ossification upon osteoclasts within the radiation volume, distinct takes place in 50% of patients after radiotherapy. from tumor shrinkage. Their study supports the results Palliation of bone metastases comprises a significant from randomized trials that high dose radiotherapy is workload in the specialty of radiation oncology. Exter- not necessary for pain relief, and that single low-doses nalbeam radiation therapy iseffectiveandcost-effective of treatment are more than adequate for most patients in relieving symptomatic bone metastases. The most (Hoskin et al. 2000). commonly employed schemes to treat bone metastases 272 Cancer Pain Management, Radiotherapy include a single 8 Gy, 20 Gy in 5 daily fractions, 30 Gy respectively. The latter became 72.7% and 72.5%, rein 10 daily fractions and 40 Gy in 20 daily fractions. spectively, when the analysis was restricted to evaluated Numerous randomized trials have been conducted on patients alone (Wu et al. 2002). Most patients will ex- dose-fractionation schedules of palliative radiotherapy. perience pain relief in the first two to four weeks after Despite that, there is still no uniform consensus on the radiotherapy, be it single or multiple fractionations. optimal dose fractionation scheme. How, then, are radiation oncologists to prescribe treat- Retrospective series have documented prompt improvement? Despite the equivalence of single and multi- ment in pain in 80–90% of patients with various dose ple fractionations, recent surveys on the patterns of fractionations, without causing significant hematolog- practice of radiation oncologists do not suggest the ical or gastrointestinal side effects. One of the first implementation of employing single fractionation in randomized studies on bone metastases was conducted daily practice (Ben-Josef et al. 1998; Chow et al. 2000; by the Radiation Therapy Oncology Group (RTOG). Roos 2000). The initial analysisof thistrial (RTOG 74-02) concluded There is no doubt that in patients with short life ex- that a low dose short-course schedule was as effective pectancy, protracted schedules are a burden. However, in pain relief as more aggressive high-dose protracted inpatientswithalongerexpectedsurvival,suchasbreast schedules (Tong et al. 1982). However, this study was and prostate cancer patients with bone metastases only, criticized for using physician-based pain assessment. other parameters need to be taken into account. Since A re-analysis of the same set of data, grouping solitary re-treatment rates are known to be higher following a and multiple bone metastases, using the endpoint of single versus multiple fractions, about 25% versus 10% pain relief and taking into account analgesic intake and respectively, patients with good performance status may re-treatment, concluded that the number of radiation wish to share the decision-making process. A recent fractions was significantly associated with complete survey of patients with bone metastases suggested that pain relief. This conclusion was directly contrary to patients are not prepared to trade off long-term out- the initial report (Blitzer 1985), making the choice of comes in favor of a shorter treatment course. Durability endpoints very important in defining the outcome of of pain relief was more important than short-term “con- clinical trials (Chow et al. 2002). venience” factors. Patients prefer multiple treatments Several prospective randomized trials have subse- upfront in hopes of avoiding re-treatment (Barton et quently been performed that compared the efficacy of al.2001).However,theyneedtobeawareofthepotential different dose-fractionation schedules. They included physician bias of more readiness to retreat after single the recent large-scale multicenter trials comparing the fraction, accounting for the difference in re-treatment efficacy of a single 8 Gy treatment against multiple rates in the trials. treatments. The UK Bone Pain Working Party found no The anatomic location to be treated may also influence difference in the degree and duration of pain relief in theradiationschedulethatisused.Smallerdailydosesof a study of 765 patients randomized to receive either a radiation [250–300 cGy] are generally better tolerated single treatment or 5 fractionated treatments (Bone Pain when larger treatment fields are needed over mucosal Trial Working Party 1999). The Dutch Bone Metastases surfaces like those in the head and neck region, esoph- Study included 1171 patients, and found no difference agus, abdomen and pelvis. in pain relief or the quality of life following a single 8 Gy or 24 Gy in 6 daily radiation treatments (Steenland Re-Irradiation et al. 1999). As effective systemic treatment and better supportive One critical review on the subject of radiation dose- care result in improved survival, certain subsets of pa- fractionation suggested that protracted fractionated tientswithbonemetastaseshavelongerlifeexpectancies radiotherapy, given over 2–4 weeks, results in more than before. An increasing number of patients outlive complete and durable pain relief (Ratanatharathorn et the duration of the benefits of initial palliative radio- al. 1999). This review was performed because of con- therapy for symptomatic bone metastases, requiring cerns regarding the influence of length of survival on the re-irradiation of the previously treated sites. Addition- durability of pain relief. It was unclear whether higher ally, some patients fail to respond initially but may radiation doses were necessary for durable pain relief benefit from re-irradiation. in patients who survived longer. A recent meta-analysis Among the radiation trials comparing single versus showed no significant difference in complete and overall multiple fractionation schemes, re-irradiation rates var- pain relief between single and multi-fraction palliative ied from 11–42% following single fraction, and 0–24% radiotherapy for bone metastases. No dose-response following multiple-fraction schedules. There are at relationship could be detected. The meta-analysis re- least three scenarios of “failure” where re-irradiation ported that the complete response rates (absence of pain may be considered. Response to re-irradiation may be after radiotherapy) were 33.4% and 32.3% after sin- different for each of these scenarios: 1) no pain relief or gle and multi-fraction radiation treatment, respectively, pain progression after initial radiotherapy; 2) partial re- while the overall response rates were 62.1% and 58.7%, sponse with initial radiotherapy and the hope to achieve Cancer Pain Management, Radiotherapy 273 further pain reduction with more radiotherapy, and 3) to palliate bone pain and improve the quality of life in partial or complete response with initial radiotherapy these patients. These agents are particularly useful but subsequent recurrence of pain. among patients with multiple symptomatic metas- Available data support the re-irradiation of sites of tases. As the radiation is localized to the metastases, metastatic bone pain following initial irradiation, par- radioisotopes can be used for re-irradiation when there C ticularly where this follows an initial period of response. are concerns about normal tissue tolerance to further There is also limited evidence that a proportion of non- external beam radiation. Also, improved outcomes responders would respond to re-irradiation. However, and cost-effectiveness have been demonstrated when there remains a small group of patients who appear to be radioisotopes have been combined with external beam non-responsive to any amount of palliative radiother- radiation. The Trans-Canada Study, comparing external apy. Although the data do support the clinical practice beam radiation alone or in combination with Strontium- of re-irradiation, the preferred dose-fractionation at the 89 for bone metastases, demonstrated better pain relief time of re-irradiation is unknown. and a reduced need for external beam radiation to other sites in the latter group (Porter et al. 1993). Convenience Wide-Field/Half-Body External Beam Radiation (HBI) to the patient is the other key advantage, because radioisotope therapy is administered as a single injection. Patients with bone metastases can have multiple sites With normal bone marrow parameters, re-treatment of disease and present with diffuse symptoms affecting with radioisotope therapy is also possible because the several sites. Wide-field radiation /half-body external adjacent normal tissues do not receive any radiation beam radiation (HBI) hasbeenusedtotreat patientswith dose. multiple painful bone metastases. Single fraction HBI A flare of pain, like that seen with hormonal therapy has been shown to provide pain relief in 70–80% of pain breast cancer, may precede the relief of symptoms. tients. Pain relief is apparent within 24–48 h. Toxici- Itmaytakeupto1to2monthsbeforethereisrelief ties include minor bone marrow suppression and gas- of symptoms. Due to this, patients should have a life trointestinal side effects, such as nausea and vomiting in expectancy that allows the benefit of the relief of symp- upper-abdominalradiation. Pulmonary toxicity is mini- toms. Contraindications to bone-seeking radioisotopes mal provided the lung dose is limited to 6 Gy (corrected include compromised bone marrow tolerance defined dose). Fractionated HBI was investigated in a phase II as a platelet count < 60,000/mL, white blood cell count study that compared a single fraction (n = 14) with frac- <2.5×103/mL, disseminated intra-vascular coag- tionated HBI (25–30 Gy in a 9–10 fractions) (n = 15). ulation, or myelo-suppressive chemotherapy within Pain relief was achieved in over 94% of patients. At 1 previous month. As bone-seeking radioisotopes do not year, 70% in the fractionated and 15% in the single frac- penetrate to softtissues, they are also contraindicated for tion group had pain control; re-treatment was required treatment of soft tissue metastases or epidural extension in 71% and 13% for the single and fractionated group, with spinal cord compression. As with external beam respectively. A randomized trial of 499 patients com- radiation, an impending pathological fracture should pared local radiation alone versus local radiation plus a be evaluated for surgical stabilization. Impending or single fraction of HBI. The study documented a lower established pathological fractures and cord compres- incidence of new bone metastases (50% vs. 68%), and sions are acute emergencies to be managed by surgical fewer patients requiring further local radiotherapy at 1 or radiation oncology teams. Once the fracture or com- year after HBI (60% vs. 76%) (Poulter et al. 1992). pression is stabilized, radioisotopes may be appropriate therapy for on-going palliation of pain. Systemic Radiation – Radioisotopes Analternativeapproachtothepalliationofmultiplebone metastases is the administration of a bone seeking ra- Controlling Side Effects of Treatment dioactive isotope that is taken up at sites of bone metas- Radiation treatment planning is the most critical aspect tases with osteoblastic activity. The isotopes deliver the of reducing radiation side effects. Management of the radiation dose through the release of beta particles; their acute effects of radiotherapy requires attentive medical range of radiation isonly a few millimeters, therebycon- management that prevents expected side effect. Radia- centrating their dose within the bone metastases and de- tion side effects are specific to the area treated. No side livering little dose to the adjacent normal bone marrow. effects are observed when a femoral bone metastasis is The radiation half-life is about 50 days in the metastasis treated by radiation. Careful radiation treatment plan- and only 14 days in the normal bone marrow. Some ra- ning that avoids critical structures like mucosal surfaces dioisotopes also have a gamma component, so that the can prevent most side effects. uptake can be measured by conventional bone scan tech- Patients should be reassured that the unavoidable side niques. effects that they experience will resolve following the Systemic radiation using radioisotopes such as stron- completion of radiotherapy. Skin reactions are usually tium, samarium and rhenium has been increasingly used minimal during radiotherapy for bone metastases and 274 Cancer Pain Management, Radiotherapy are limited only to the radiation portal. Nausea and vom- Although radiotherapy provides pain relief and tumor iting, resulting from a radiation portal that includes the control, it does not restore bone stability. Postoperative abdomen, will usually respond to antiemetic therapy. radiotherapy is usually recommended after surgical sta- Diarrhea, resulting from abdominopelvic radiation, will bilizationofapathologicfracture.Patientswhoarewith- also usually respond to treatment. Local irritation from out visceral metastases and who have a relatively long mucositis of the oropharyngeal region may be relieved expected survival (e.g. > 3 months), are more likely to by soluble aspirin, analgesics or benzydamine mouth- benefit from post-op radiotherapy. As the entire bone is washes. Secondary infections, like Candida, should be at risk for microscopic involvement and the procedure treated. involved in rod placement may seed the bone at other The side effectsof electron beam radiation are more lim- sites, the length of the entire rod used for bone stabiliza- ited because they only treatsuperficialstructureslike the tion should be included in the radiation field. When the ribs, skin lesions, and superficiallymph nodes. Underly- radiation fields are more limited, instability of the rod, ing structures are spared with the selection of the proper resulting in pain and need for re-operation, can result electron beam energy. This characteristic is especially from recurrent osteolytic metastases outside the radia- important with re-irradiation to avoid injury to critical tion portal. structures like the spinal cord. The most prominent side effectof electron beam radiation isan erythematousskin Spinal Cord Compression and Cauda Equina Com- reactionandpossiblemoistdesquamation.Othersideef- pression fects listed above do not occur with electron beam radi- Malignant spinal cord and cauda equina compression ation because the radiation beam does not penetrate to is a devastating compression of advanced malignancy. these structures. Early diagnosis is essential. Presenting symptoms in- No side effects, other than a possible flare of pain in the clude radicular pain, paresis, paralysis, paresthesia first two weeks after administration, are observed with and bowel/bladder dysfunction. Surgery, radiation and systemic radioisotope therapy because all the radiation steroids are the standard treatment options in this con- is localized to the bone. This is a significant considera- dition (Loblaw et al., Group at CCOPGIN-ODS 2003). tion for patients who have symptoms of the disease or Radiotherapy results in pain relief in over 75% of other treatments. Side effects from external beam radi- patients. ation are also more severe when the radiation fields are Radiotherapy is indicated in patients without spinal in- large because more normal tissues are treated. Systemic stabilityorbonecompression,whensurgeryismedically radioisotopes can have significant advantage over large hazardous or technically difficult, and in patients who external beam radiation fields by reducing the risk for refuse surgery. side effects like nausea and diarrhea. Pre-existing co-morbidity, pre-treatment ambulatory status, the presence of bone compression and spinal instability, and patient preferences should be considered Radiotherapy for Complications of Bone Metastases in clinical decision making. Pathological and Impending Fractures The outcome of treatment depends mostly on the speed of diagnosis and neurological status at initiation of treat- Pathological fractures are handled with orthopedic sta- ment. Over seventy percent of patients are still ambula- bilization whenever possible. Surgery rapidly controls tory following radiation if they are ambulatory on pre- painandreturnsthepatienttomobility.Aselectiveortho- sentation. However, for those who are paralyzed when pedic stabilization has reportedly resulted in good pain theypresentfortreatment,lessthan30%willregainneu- relief and sustained mobility in up to 90% of patients, rologic function. earlyidentificationofpatientswithahighriskoffracture isespeciallyimportant.Prophylacticorthopedicfixation Conclusion is often advised to avoid the trauma of a pathological Manyformsofradiationtherapyarepossibleinthetreat- fracture. ment of bone metastases. Meeting the goal of palliative The criteria often used to determine fracture risk in long care, suffering can be effectively and efficiently relieved bones include: with the use of radiation. Ongoing trials continue to re- • Persistent or increasing local pain despite radiother- fine therapeutic approaches to determine the optimal ra- apy, particularly when aggravatedby functionalload- diation schedule and modalitiesused. Treatment-related ing side effects can be minimized through the use of radia- • A solitary, well-defined lytic lesion greater than tion treatment planning, and anticipating and preventing 2.5 cm known side effects. • A solitary, well-defined lesion circumferentially in- Comparedtootherapproaches,likesystemicchemother- volving more than 50% of the cortical bone apy, hormonal therapy and bisphosphonates, that ad- • Metastatic involvement of the proximal femur asso- minister treatment on an ongoing basis, all forms of ciated with a fracture of the lesser trochanter radiation therapy are completed within a day to several Cancer Pain Management, Rehabilitative Therapies 275 weeks with durable control of symptoms. Cost-benefit analyses demonstrate the benefit of radiation over other Cancer Pain Management, Rehabilitative forms of therapy for bone metastases. Furthermore, Therapies there is no evidence to support a survival benefit for the ANDREA CHEVILLE administration of systemic chemotherapy, hormonal Department of Rehabilitation Medicine, University of C therapy or bisphosphonates in metastatic disease. Con- Pennsylvania School of Medicine, Philadelphia, PA, sideringqualityoflifeissuesoftimespentundertherapy, USA toxicities of therapy and socioeconomic cost, radiother- [email protected] apy continues to be under-utilized in the treatment of bone metastases. Definition The potential role of rehabilitation in pain management is often overlooked. Rehabilitative techniques include References modalities that can directly influence pain (e.g. topical 1. Barton MB, Dawson R, Jacob S et al. (2001) Palliative Radiother- cold and desensitization techniques), and interventions apy of Bone Metastases: An Evaluation of Outcome Measures. J Eval Clin Pract 7:47–64 thatpreserveandrestorefunction.Thelatterarethefocus 2. Ben-Josef E, Shamsa F, Williams A et al. (1998) Radiotherapeu- of this essay. tic Management of Osseous Metastases: A Survey of Current Patterns of Care. Int J Radiat Oncol Phys 40:915–921 Characteristics 3. Blitzer P (1985) Reanalysis of the RTOG Study of the Palliation of Symptomatic Osseous Metastases. Cancer 55:1468–1472 Rehabilitative Goal Setting in Pain Management 4. Bone Pain Trial Working Party (1999) 8 Gy Single Fraction Aswithanyclinicalintervention,thetherapeuticgoalsof Radiotherapy for the Treatment of Metastatic Skeletal Pain: Randomized Comparison with Multi-Fraction Schedule over rehabilitation must be established prior to the initiation 12 Months of Patient Follow-Up. Radiother Oncol 52:111–121 oftherapytofacilitatereassessmentatfuturetimepoints. 5. Chow E, Danjoux C, Wong R et al. (2000) Palliation of Bone Dietz developed a structured approach to goal setting in Metastases: A Survey of Patterns of Practice among Canadian Radiation Oncologists. Radiother Oncol 56:305–314 cancer rehabilitation that is extremely useful and appli- 6. Chow E, Wu JS, Hoskin P et al. (2002) International Consensus cable in pain management (Dietz 1985). He identified on Palliative Radiotherapy Endpoints for Future Clinical Trials four broad categories of rehabilitation goals that can be in Bone Metastases. Radiother Oncol 64:275–280 used to define the purpose of interventions and to guide 7. Hoskin PJ, Stratford MRL, Folkes LK et al. (2000) Effect of Local Radiotherapy for Bone Pain on Urinary Markers of Osteoclast theirstrategicintegrationforoptimalresults.Asoutlined Activity. The Lancet 355:1428–1429 in Table 1, these include: 1) preventative rehabilitation 8. Loblaw DA, Laperriere NJ, Chambers A et al., Group that attempts to preclude or mitigate functional morbid- at CCOPGIN-ODS (2003) Diagnosis and Management ity resulting from pain, the pathophysiological process of Malignant Epidural Spinal Cord Compression (Evi- dence Summary Report No. 9-9). Cancer Care Ontario; driving it, or its treatment; 2) restorative rehabilitation http://www.ccopebc.ca./neucpg.html. Accessed: April 4, 2003 that describes the effort to restore the patient to a pre- 9. Porter A, McEwan A, Powe J (1993) Results of a Randomized morbid level of function when little or no long-term im- Phase III Trial to Evaluate the Efficacy of Strontium-89 Adjuvant pairment is anticipated; 3) supportive rehabilitation that to Local Field External Beam Irradiation in the Management of Endocrine Resistant Metastatic Prostate Cancer. Int J Radiat attempts to maximize function when long-term impair- Oncol Biol Phys 25:805–813 ment, disability, and handicap result from the pain, its 10. Poulter C, Cosmatos D, Rubin P et al. (1992) A Report of RTOG source, or its treatment; and 4) palliative rehabilitation, 8206: A Phase III Study of Whether the Addition of Single Dose which decreasesdependencyin mobility andself-care in Hemibody Irradiation to Standard Fractionated Local Field Irra- diation is More Effective than Local Field Irradiation Alone in association with the provision of comfort and emotional the Treatment of Symptomatic Osseous Metastases. Int J Radiat support. Many interventions (e.g. resistive and aerobic Oncol Biol Phys 23:207–214 exercise) may fall into more than one category, depend- 11. Ratanatharathorn V,Powers W,Moss W et al. (1999) Bone Metas- tasis: Review and Critical Analysis of Random Allocation Trials ing on the motivation for their use. For example, resis- of Local Field Treatment. Int J Radiat Oncol Biol Phys 44:1–18 tive exercise can be used preventatively to avoid decon- 12. Roos D (2000) Continuing Reluctance to use Single Fractions ditioning, restoratively to reverse it, and supportively to of Radiotherapy for Metastatic Bone Pain: An Australian and minimize it. The specifics of the therapeutic prescrip- New Zealand Practice Survey and Literature Review. Radiother Oncol 56:315–322 tionandanticipateddurationoftherapymayvarywidely, 13. Steenland E, Leer J, van Houwelingen H et al. (1999) The Effect contingent on goal definition. of a Single Fraction Compared to Multiple Fractions on Painful The effort to precisely define how these four general Bone Metastases: A Global Analysis of the Dutch Bone Metas- types of goals may apply to each patient is critical tasis Study. Radiother Oncol 52:101–109 14. Tong D, Gillick L, Hendrickson F (1982) The Palliation of Symp- for a number of reasons. It ensures that potentially tomatic Osseous Metastases: Final Results of the Study by the beneficial therapies will not be overlooked. It clarifies Radiation Therapy Oncology Group. Cancer 50:893–899 for both the clinician and the patient the purpose for 15. Wu J, Wong R, Johnston M, Bezjak A, Whelan T (2002) Meta- which therapies are prescribed. This allows objective Analysis of Dose-Fractionation Radiotherapy Trials for the Pal- liation of Painful Bone Metastases. Int J Radiat Oncol Biol Phys future assessment of whether a therapy has been suc- 55:594–605 cessful. If therapeutic goals have not been met after an 276 Cancer Pain Management, Rehabilitative Therapies

Cancer Pain Management, Rehabilitative Therapies, Table 1 Examples of goals and interventions that can be classiﬁed within the general therapeutic categories of preventive, restorative, supportive, and palliative rehabilitation

Preventative Rehabilitation The effort to restore the patient to a premorbid level of function when little or no long-term impairment is anticipated.

Goal Possible Intervention

Avoid development of secondary pain generators Normalize motor recruitment patterns

Minimize adverse effects of immobility

a.) deconditioning aerobic &resistive exercise

b.) contractures stretching, positioning

c.) osteopenia strategic loading of axial and appendicular structures

Correct maladaptive biomechanical patterns posture &gait modiﬁcation

Restorative Rehabilitation The effort to restore the patient to a premorbid level of function when little or no long-term impairment is anticipated.

Goal Possible Intervention

Eliminate musculoskeletal pain generators Myofascial release techniques

Restore power postoperatively to compromised Progressive resistive exercises muscle groups

Supportive Rehabilitation The attempt to maximize function when long-term impairment, disability, and handicap are anticipated.

Goal Possible Intervention

Optimize mobility status Provide patient with can, walker, etc.

Optimize ADL independence Instruction in compensatory strategies

Palliative Rehabilitation The effort to decrease dependency in mobility and self-care in association with the provision of comfort and support.

Goal Possible Intervention

Reduce dependency in toileting and grooming Provide appropriate ADL assistive devices

Preserve community integration Prescription of wheelchair or scooter adequate trial, the rationale for discontinuation can be functional status. Examples of the first four situations made evident to the patient. Definition of goals is also are given in Table 2. It is important to note that many useful in justifying therapy to third party payers, and musculoskeletal structures (e.g. the rotator cuff) can in anticipating the duration of therapy. The profound function in each of these categories. Rehabilitation heterogeneity of presentation encountered in pain man- is based on the fact that muscles, fascia, and bones agement confounds a rigidly algorithmic approach to respond to external forces that can be manipulated the prescription of rehabilitative therapies. The four with therapeutic intent. For example, muscles can be broad categories of clinical goals offer practitioners a stretched, strengthened, aerobically conditioned, or flexible structure in which to develop a comprehensive rendered more proprioceptively responsive, depending and integrated therapeutic plan for functional preserva- on the therapeutic demands to which they are subjected. tion. The correct choice of type, location and intensity of pressure(s) requires accurate identification, not only Rehabilitation, the Musculoskeletal System, and Pain of the involved anatomy and pathophysiological pro- The musculoskeletal system is the primary focus of cesses, but determination of precisely how these may virtually all pain-oriented rehabilitation approaches. be contributing to a patient’s global pain experienceand Dysfunction in the musculoskeletal system can: 1) pro- functional decline. It is critical that permissive factors duce a primary pain generator; 2) function as a primary (e.g. laxity, contractures, biomechanical malalignment) pain generator; 3) produce secondary pain generators; be identified and definitively addressed in order to 4) function as secondary pain generators; or 5) have prevent recurrence of the primary and development of no role in the pain syndrome, but undermine patients’ secondary pain generators. Cancer Pain Management, Rehabilitative Therapies 277

Cancer Pain Management, Rehabilitative Therapies, Table 2 Examples of musculoskeletal structures functioning as: 1) primary pain generators; 2) contributors to primary pain generator; 3) secondary pain generators; and 4) contributors to secondary pain generators Effects of Inactivity Primary pain generator Contributor to primary pain Secondary pain generator Contributor to secondary pain generator generator Structures that become painful Permissive factors (e.g. muscle Structures that become painful Permissive biomechanical factors C due to trauma, overuse, or weakness or tightness, or due to spasm, overuse or that arise consequent to the inﬂammation dysfunctional biomechanics) that inﬂammation related to the primary pain generator impose stress on the primary primary pain generator pain generator.

Rotator cuff tendonitis Weakness of scapular stabilizers Trazezius myofascial pain Premature upper trapezius recruitment

Osteoarthritis of the hip joint Flexibility deﬁcits of hip muscles Greater trochanteric bursitis Iliotibial band tightness

Myofascial pain of scapular retrac- Pectoralis muscle tightness Rotator cuff tendonitis Altered scapular biomechanics tors Discogenic lumbar nerve root Weakness of the abdominal Lumbar paraspinal muscle Lumbar hyperextension to reduce compression muscles spasm pain

Pain, particularly if associated with movement, en- Modalities genders inactivity. The many adverse consequences of inactivity have been well documented. They in- Although few blinded, prospective, randomized clinical clude: reduced cardiovascular endurance, diminished trials have been conducted to establish the efficacy of muscle strength and stamina, osteopenia with reduced most modalities, their routine integration into rehabili- fracture threshold, reduced peri-articular distensi- tative programs is the current standard of care. A review bility, articular cartilage degeneration, compromise of the few randomized controlled trials and the many of neural patterns required for coordinated activity, observational studies (Philadelphia Panel 2001) found reduced plasma volume, diminished proprioceptive evidence in support of a small, transient treatment effect acuity, and chemical alterations in connective tissue from the application of heat. The delivery of therapeu- (e.g. ligaments, tendons) causing failure with reduced tic heat is often characterized by depth of penetration loading. Studies characterizing these physiological (superficial and deep), or mechanism of transmission parameters have found that the rate of loss far ex- (conduction, convection, radiation, evaporation, and ceeds the rate of recovery once therapeutic activity has conversion). Superficial heat increases the temperature been initiated (Saltin et al. 1968; Noyes et al. 1974; in skin and subcutaneous fat to a depth of approxi- Beckman and Buchanan 1995). Some changes, partic- mately 1 cm. Superficial modalities include hot packs, ularly those in articular cartilage, may be irreversible. heating pads, fluidotherapy, and paraffin baths. Deep As inactivity has such profound and widespread ad- heating modalities increase temperature at a depth of verse effects, and because its consequences may be approximately 3.5–7.0 cm and can, therefore, influence slow and difficult to reverse, it is essential that pa- muscles, tendons, ligaments, and bones, while sparing tients preserve their activity levels within the limits the skin and subcutaneous fat. Although ultrasound is imposed by their pain. The prescription of preventa- the most commonly used deep heating modality, re- tive rehabilitation strategies can greatly facilitate this views offer little support of its efficacy, and its clinical goal. utility remains a subject of debate (Baker et al. 2001; Robertson and Baker 2001). Cryotherapy is a second modality used in the treat- Scope of Rehabilitation ment of cancer pain (Lehmann 1990). The majority of Rehabilitative interventions encompass a broad and cryotherapeutic modalities use superficial conduction. highly varied collection of therapies. Most can be used Cold packs come in the form of ice packs, hydrocolla- with supportive, restorative, preventive, or palliative tor packs, and endothermic packs that rely on chemical intent. The overarching goal of rehabilitation is func- reactions to lower temperature. Ice massage is the tional restoration and preservation. However, many application of ice directly to the skin’s surface. The approaches can be used to definitively address pain phases of reaction are coolness, aching, hypesthesia, generators, as with manual techniques for myofascial and analgesia. Cold (5–13˚C) water immersion is a pain. Interventions can be grouped into the following convection modality and vapocoolant sprays rely on categories: modalities, manual approaches, therapeutic evaporative cooling. Medical contraindications to cold exercise, provision of assistive devices, education in therapy include, but are not limited to, arterial insuffi- compensatory strategies, and orthotics. ciency, Raynaud’s phenomenon, cryoglobinemia, cold 278 Cancer Pain Management, Rehabilitative Therapies hypersensitivity, and paroxysmal cold hemoglobin- joint range of motion. Common manual techniques uria. include: Hydrotherapy involves the external application of wa- • Massage ter of any temperature to achieve therapeutic goals. Hy- • Myofascial release drotherapeutic modalities are often used for wound or • Soft tissue mobilization skindebridementandcleansing,aswellasinthesupport- • Manual lymphatic drainage ive and palliative care of pain related to arthritis, chronic • Acupressure inflammatory states, and myofascial syndromes. • Shiatsu Traction, the use of strategic displacing force to stretch • Rolfing soft tissue and separate articular surfaces, has been used • Reflexology for nonmalignant conditions, particularly those associ- • Craniosacral therapy ated with nerve root impingement. Despite decades of • Osteopathic manipulation researchregardingtheclinicalbenefitsofspinaltraction, • Joint mobilization thereisnoconsensusregardingitsutility.Primarymalig- • Muscle energy techniques nancies of bone or spinal cord, osteomyelitis or discitis, • Passive range of motion unstable spinal fractures, end-stage osteoporosis, central disc herniations, carotid or vertebral artery disease, The benefits of manual approaches are generally short- rheumatoid arthritis (cervical), and pregnancy (lumbar) lived if patients do not comply with a concurrent stretch- are absolute contraindications to the use of traction. ing, strengthening, and conditioning regimen. Physical Functional electrical stimulation (FES) applies electri- therapists, osteopathic physicians, massage therapists, cal stimulation via pad electrodes to depolarize motor acupuncturists, as well as a host of complementary and nerves, at either the axon or neuromuscular junction. It alternative practitioners, use manual techniques for pain has been used in patients with potentially painful condi- control. tions such as spinal cord injury (SCI), peripheral nerve When chronic pain affects the musculoskeletal sys- injury, spasticity, and cardiopulmonarydeconditioning. tem, a pain-spasm cycle begins. Nociception causes It has not been used in the management of cancer pain. reflexive muscle contraction, which in turn increases Transcutaneouselectrical nerve stimulation (TENS) in- nociception, and the cycle is set in motion leading fluences pain by stimulating large diameter, myelinated ultimately to painful, chronic muscle hypertonicity. Aβ nerve fibers. There is a large clinical experience sug- This results in muscle weakness, joint contractures, gesting that a subgroup does benefit. Multiple electrode aberrant biomechanics, and dysfunctional kinesthetic and stimulation configurations must be tested to ensure patterns. As patients attempt to perform normal daily an adequate trial. Studies of the technique have yielded activities, the compromised system becomes overused, inconsistent results (Fargas-Babjak 2001). For theoret- exacerbating the pain cycle and producing secondary ical reasons, patients are cautioned against stimulating pain generators. By normalizing joint and soft tissue directly over tumors. physiology, manual techniques can be used to break Iontophoresis allows charged molecules to penetrate this pain cycle and reestablish function biomechanics. cell membranes and enter tissue through the applica- Ideally, patient referral for manual techniques should tion of an electric field. Negative, positive and ground not be delayed until the pain-muscle spasm cycle is electrodes are secured to the patient, and a 10–30 m well established. current is used to transfer medication from the electrode Massage focuses on decreasing pain through increased into the surrounding tissues. This modality creates the circulation and mechanical movement of tissues. Tech- potential for medication delivery in the treatment of niques vary in the variety of hand strokes, applied spasticity, chronic inflammatory states, and myofascial pressure, and direction of force. Many beneficial phys- pain syndromes. There is no experience in the use of iological effects have been associated with massage this approach in medically ill patients. (Field 2002). In addition to its use in pain management, Phonophoresis also facilitates the transdermal delivery it has been adapted to the treatment of lymphedema and of topical medications, but uses ultrasound to facilitate contractures. medicationdelivery.Thetechniquehasbeenusedtotreat Myosfascial release is a technique that purportedly soft tissue inflammation. Again, there is no experience facilitates normal movement within the fascial system. in the cancer pain population. Fascia is the connective tissue that provides support throughout the body, and fascia that is injured or contracted could contribute to pain. Practitioners use vigor- Manual Therapies ous “hands on” compression and stretching techniques Manual therapies refer to a vast array of hands on to alter the mobility of affected tissues. techniques designed to normalize soft tissue and joint Several manual techniques are used to affect joint phys- mobility. Types of manual therapies include everything iology and normalize accessory movement. The most from massage to myofascial release, acupressure and basic technique is passive range of motion (PROM). Cancer Pain Management, Rehabilitative Therapies 279

A practitioner using PROM will move a joint through minimal resistive exercises, however, can lead to signif- its physiologic range of motion in an effort to maintain icant improvements in strength and functional status. and/or restore motion. In addition, PROM also stretches Brief isometric muscle contractions can be performed the soft tissues surrounding a joint and normalizes ac- in bed or in a chair against gravity or with gravity elim- cessory movements in a joint. By restoring normal joint inated. One brief isometric contraction per day was C mechanics on the accessory level, normal physiologic demonstrated to prevent loss of strength in bed-ridden motion can follow. There are five grades of joint mobi- rheumatoid arthritis patients (Atha 1981). lization based on the amplitude of movement through Stretching, or flexibility activities, can influence mus- the full range of accessory movement. Grades I and II cles by altering their length-tension relationships and provide the smallest amount of movement. These tech- resting tone. Stretching is an integral part of the treat- niques are used to prevent contractures and pain relief. ment of myofascial pain (Travell and Simons 1983) and Grades III and IV provide increased pressure within pain associated with muscle spasms. It is commonly the joint’s range of normal motion. These techniques used to achieve adequate range of motion for perfor- can help to promote normal physiologic motion as well mance of daily activities. Flexibility assessment must as providing pain relief. Grade V joint mobilization is consider patients’ overall level of muscle tightness, their known as a “manipulation.” Grade V manipulations required range of motion given their activity profile, and are performed at high velocity and intensity to the the impact of contracture-related asymmetry on move- end of the accessory range of motion. Physical ther- ment patterns. Two stretching techniques predominate apists, osteopathic physicians and chiropractors use in rehabilitation medicine: ballistic and static. Ballistic joint mobilization. In most cases, only chiropractors stretching involves repetitious bouncing movements use manipulations. at the end-range of joint range. Static stretching, in Muscle energy techniques (MET) are used to restore contrast, involves slow, steady soft tissue distension, normal joint and soft tissue movement through pa- which is maintained for several seconds. Comparisons tients’ own force. METs are based on the theory of suggest that static is superior to ballistic stretching, joint mobilization to facilitate movement, but recruit and that meaningful benefit can be achieved through patients’ own muscular force. The practitioner places three to five sessions per week (Sady et al. 1982). Pain the patient in a specific position, the patient is asked to patients require a slowly progressive approach to static push against the practitioner’s counterforce in order to stretching. Ballistic stretching is indicated only in un- facilitate movement in joints and soft tissues. usual cases and should be performed under the care of Acupressure involves the strategic application of pres- a physical medicine and rehabilitation specialist. sure to trigger points and derives from the theories of Resistive exercise is used to strengthen selected muscles acupuncture.Theuseofpressuretorelievetriggerpoints or muscle groups by forcing them to contract repeatedly has been incorporated into many soft tissue techniques. against resistance. Resistive training can beutilizedwith restorative, supportiveand/or preventativeintent. Goals Therapeutic Exercise must consider patients’ currentlevel ofconditioning,the The strategic use of exercise toenhance strength,coordi- prognosis for their pain and related medical comorbidi- nation, stamina, and flexibility is perhaps the most pow- ties, their past fitness histories, and the rigor of their an- erful intervention in rehabilitation medicine. The fact ticipated activity profile (e.g. vocational, avocational). that muscles and fascia respond predictably to imposed To induce strength gains, an intensity of at least 60% of external demands underlies this therapeutic approach. the one-repetition maximum must be used. Table 3 out- Musclechangesthatcanbeachievedthroughtherapeutic lines common parameters utilized in prescribing resis- exercise include: increased capillary density, enhanced tive exercise for generalized or focal weakness. neuromuscular responsiveness, normalization of mus- Aerobic conditioning differs from resistive exercise in clelength-tensionrelationships,alteredrestingtone,and itsemphasisoncontinuousrhythmiccontractionoflarge increased elaboration of mitochondrial and sarcoplas- muscle groups. Jogging and cycling are common exam- mic proteins (de Lateur 1996). ples. Aerobic training allows patients to perform daily For optimal benefit, the type, intensity, and frequency of activities with less effort, maintain greater indepen- exercise must be rationally chosen following a compre- dence, and enjoy an enhanced sense of well-being (NIH hensive clinical examination. The exercise prescription Consensus Developments Panel on Physical Activity will be determined by the presence, severity, and distri- and Cardiovascular Health 1996). If the medical condi- bution of flexibility and strength deficits, the degree of tion permits, regular physical activity may improve the deconditioning, and the presence abnormal segmental ability to perform physical activities and attenuate the biomechanics. An exercise program combining stretch- psychological morbidity associated with chronic pain. ing, aerobic conditioning, and strengthening should be A prescription for exercise should consider baseline tailored to each patient’s unique requirements. fitness levels, associated motor impairments and co- Patients may protest that the intensity of their pain morbidities, and patient tolerance. For deconditioned precludes participation in an exercise program. Even patients with chronic pain, the initial aerobic training 280 Cancer Pain Management, Rehabilitative Therapies

Cancer Pain Management, Rehabilitative Therapies, Table 3 Considerations in prescription of therapeutic resistive exercise Exercise Parameter Considerations and Recommendations

Choice of exercise Exercises strength deﬁcient muscle groups in multiple planes and across a range of length-tension relationships

Order of exercise Begin with large muscle group exercises. For circuit training start with legs

Number of sets Begin with one set and progress to three of more sets of each exercise

Rest between sets 3 min for heavy resistance, 2–3 for moderate resistance, 1–2 light resistance

Intensity 60% one repetition maximum, 6–15 repetitions

Rate of progression Increase 2.5–5% when level of resistance is perceived as “moderate”

Program variation Variations in intensity, positioning, order of exercises, choice of exercise should be adopted weekly to avoid overtraining

Speed speciﬁcity Intermediate velocity unless training goals involve rapid or slow velocity activities

Contraction speciﬁcity Isotonic training unless joint pain is prohibitive, then initiate training with isometric activities. Isometrics can be used to prevent loss of strength.

Joint angle speciﬁcity Loading should be maintained throughout entire functional range.

may entail walking slowly for 5–10 min. Exercise can position, to allow resolution of local inflammation, or also be used to enhance coordination, posture, propri- to rest painful muscles and/or tendons that act on the oception, balance, and the performance of integrated joint. They also can be used preventatively, when joints movement patterns. Much of the literature establishing or osseous structures are at risk of injury or contracture, the value of exercise for these applications derives from and patients are incapable, despite resistive exercise and sports and performing arts medicine. Techniques to proprioceptive enhancement, of protecting them. Such improve proprioception include use of a tilt or wob- circumstances often arise in the context of systemic ill- ble board, sideways walking or running, and agility ness. For example, spinal extension orthoses such as the drills. Balance enhancing activities include tossing and Jewitt or Cash brace limit spinal flexion, and thereby catching a ball while standing on heels, toes, or one prevent excessive loading and compression fracture of leg. Therapy balls can be utilized to address deficits the anterior vertebral bodies. Palliative splinting is used in truncal stability. Generally, patients sit on the ball to optimize comfort when function is no longer a pri- while shifting their weight in different directions or mary concern. An excellent example is the use of slings lifting their legs. There are many variations on balance to keep flaccid upper extremities tethered near the body activities. Their selection should consider the patients’ and out of harm’s way. Referral to an orthotist or physi- deficits and desired activity profile. The adage that the calmedicineandrehabilitationspecialistwillensurethat best training for an activity is the activity itself also patientsreceive appropriate orthoses. However, manyof holds true for coordination training. these professionals lack experience with pain patients. It is important to communicate the goals of treatment and Orthotics theprecisereason(s)whytheorthoticisbeingprescribed Orthotics are braces designed to alter articular mechan- to the rehabilitation professional. In this way, patients ics when their integrity has been compromised by pain, have the best chance of receiving an orthotist suited to weak muscles, impaired sensation, or other anatomical their unique requirements. disruption.Orthoticsmaybyusedtherapeuticallytopro- Many patients with chronic pain, particularly pain re- vide support, restore normal alignment, protect vulner- lated to chronic medical illness, require adaptive devices able structures, address soft-tissue contractures, substi- to enhance their safety, comfort and autonomy while tute for weak muscles, or maintain joints in positions of moving about the home or community. Ready access to least pain. Many orthotics are available pre-fabricated, such devices is essential if pain patients are to remain “off-the-shelf.” While such bracesoftensuffice,patients socially integrated within their communities. Adaptive mayrequiremoreexpensivecustomorthosesforoptimal equipment designed to augment mobility ranges from benefit.Orthoticscanbeusedtoaddresspathologyinvir- prefabricated single-point canes to complex motorized tuallyanyarticularstructure.Theuseofthesedevicesfor wheelchair systems. Hand-held assistive devices are pain patientsmustbe temperedbyconcernfor engender- generally variations on canes, crutches and walkers. ing long-term dependency and validating patients’ im- Devices can be customized to distribute weight bearing pairments. Orthotics are most often used in pain man- onto intact structures to minimize the pain. Patients agement on a transient basis, to keep joints in a fixed with severe deconditioning, paresis, osseous instabil- Cancer Pain Management, Treatment of Neuropathic Components 281 ity, or other sources of impaired mobility may require 12. Robertson V, Baker K (2001) A Review of Therapeutic Ultra- a wheelchair or scooter. Even when deficits are pre- sound: Effectiveness Studies. Phys Ther 81:1339–1350 13. Sady S, Wortman M, Blanke D (1982) Flexibility Training: sumed transient, a wheelchair can sustain community Ballistic, Static or Propriospective Neuromuscular Facilitation? integration and fragile social connections. Wheelchair Arch Phys Med Rehabil 63:261–263 tolerance and utilization depend on the prescription of 14. Saltin B, Blomqvist G, Mitchell JH et al. (1968) Response to Ex- C an appropriate model. ercise after Bed Rest and after Training: A Longitudinal Study of Adaptive Changes in Oxygen Transport and Body Composition. Assistive devices have also been developed to maxi- Circulation 38:VII1–78 mize patients’ independence and reduce pain during 15. Travell J, Simons D (1983) Myofascial Pain and Dysfunction. performance of activities of daily living (ADLs). De- The Trigger Point Manual. Williams and Wilkins, Baltimore pendence for self-care has been shown to erode quality of life across many medical diagnoses. Devices are available to assist patients with independent dressing, grooming, toileting, as well as performance of more Cancer Pain Management, Treatment of complex activities such as cooking and housekeeping. Neuropathic Components Conclusion 1 2 PAUL W. WACNIK ,RICHARD L. BOORTZ-MARX Cliniciansmustbecomediscriminatingconsumersofre- 1 Department of Pharmacology, College of Medicine, habilitation services if they are to optimally benefit their University of Minnesota, Minneapolis, MN, USA patients. This need arises from the fact that the delivery 2 Department of Neurosciences, Gundersen Lutheran of rehabilitation servicesoccurswithin asocioeconomic Health Care System, La Crosse, WI, USA context that imposes fiscal pressures upon its providers. [email protected], It is essential that clinicians question patients regarding [email protected] the particulars of their treatment and relay any concerns to the treating therapist. Including specific requirements on the therapy prescription can also help to ensure that Definitions patientsreceive appropriate care.Cliniciansmustrecog- nize that rehabilitation professionalsvarywidely intheir Painduetopathologicalfunctioningofeithertheperiph- levels of experience, biomechanical acumen, interper- eral nervous system (PNS) or the central nervous system sonal skill, and mastery of manual techniques. Ideally, (CNS) is classified as neuropathic. These processes may clinicians should refer patients to therapists with whom directly stimulate the pain system or damage nocicep- they are familiar and can readily enter into clinical di- tive pathways to shift the balance between painful and alogue. Most therapists welcome guidance from physi- nonpainful inputs to the CNS (Merskey and Bogduk cians and nurses and are highly motivated to cultivate 1994). Neurological symptoms of neuropathic pain the skills required to optimally serve pain patients. in cancer include continuous, burning, itching, aching and cramping or pain evoked by mechanical or thermal References stimuli. Such symptoms can be accounted for by an 1. Atha J (1981) Strengthening Muscle. Exerc Sport Sci Rev 9:1–73 intact, normally functioning nervous system sensing a 2. Baker K, Robertson V, Duck F (2001) A Review of Therapeutic noxious stimulus (in this case a tumor) manifesting Ultrasound: Biophysical Effects. Phys Ther 81:1351–1358 3. Beckman S, Buchanan T (1995) Ankle Inversion Injury and Hy- as somatic pain or by a component of the nervous permobility: Effect on Hip and Ankle Muscle Electromyography system damaged by the impact of previous antineo- Onset Latency. Arch Phys Med Rehabil 76:1138–1143 plastic therapies, such as surgery, chemotherapeutic 4. de Lateur BJ (1996) Therapeutic Exercise, pp 401–419 agents or radiation oncology or by progression of the 5. Dietz JJ (1985) Rehabilitation of the Patient with Cancer. In: Calabresi P, Schein PS, Rosenberg SA (eds) Medical oncology. disease (Portnoy 1991). Distinguishing between the Macmillan Publishing, New York, pp 1501–1522 two etiologies is often problematic. 6. Fargas-Babjak A (2001) Acupuncture, Transcutaneous Electrical Nerve Stimulation, and Laser Therapy in Chronic Pain. Clin J Pain 17:105–113 Characteristics 7. Field T (2002) Massage Therapy. Med Clin North Am Pain is but one symptom of many experienced with can- 86:163–171 8. Lehmann JF (1990) Therapeutic Heat and Cold. Williams & cer. However, if uncontrolled, the pain can profoundly Wilkins, Baltimore compromise quality of life and may interfere with anti- 9. NIH Consensus Developments Panel on Physical Activity and neoplastic treatment (Portenoy and Lesage 1999). Pain Cardiovascular Health (1996) Physical Activity and Cardiovas- in cancer can be either constant or variable in character, cular Health. JAMA 276:241–246 10. Noyes FR, Torvik PJ, Hyde WB et al. (1974) Biomechanics owing to the inevitability that cancer will involve tumor of Ligament Failure II. An Analysis of Immobilization, Exer- growth and progression, changes in the tissue surround- cise, and Reconditioning Effects in Primates. J Bone Joint Surg ing the tumor and therapeutic interventions intended to 56:1406–1418 control tumor growth. Although no overall “cure” exists 11. Philadelphia Panel (2001) Philadelphia Panel Evidence-Based Clinical Practice Guidelines on Selected Rehabilitation for Knee for most cancers, advances in anti-neoplastic therapies Pain. Phys Ther 81:1675–1700 have allowed patients to live longer with their disease, 282 Cancer Pain Management, Treatment of Neuropathic Components making long-term cancer pain therapy a considera- sensing systems in cancer. Although pain due to the tion of increasing importance. The incidence of cancer neoplasm is the focus of much investigation and treat- pain is high in patients with advanced disease as well as ment, there are considerable instances of pain observed in patients undergoing active treatment for solid tumors in cancer patients related to noxious interventions, in- (30–50% Portenoy and Lesage 1999). The intensity of cluding pain associated with diagnostic interventions, this pain is often overwhelming. In a multi-site cancer therapeutic interventions, lumbar puncture, analgesic pain study, two-thirds of patients rated their worst pain, techniques, chemotherapy toxicity, hormonal ther- using an 11 point numerical rating scale during a given apy and radiotherapy as well as post-operative pain. day, at7 outof a maximum 10, with an average painlevel The fact that cancer pain can evolve from one form to of 4.7 throughoutthe day, even though 91% of these pa- another with progression of the disease implies that tients were receiving opioid analgesics (Caraceni and analgesic treatment regimens must also evolve to match Portenoy 1999). This observation demonstrates that a changing etiology. most patients, even those receiving analgesic therapy, live with moderate to severe daily pain. One compli- Diagnoses of Neuropathic Components of Cancer Pain cation in understanding and treating cancer pain is its The diagnosis of neuropathic cancer pain is a clinical variable and complex nature (see Table 1). More than diagnosis. Based on the clinical presentation of the 25% of patients have nerve injury that occurs in tandem character and quality of pain, one is led to a provisional with damage to other structures and the pain has a mixed diagnosis of neuropathic cancer pain, which appropri- pathophysiology with more than one type of pain, most ately initiates therapeutic options, possibly including frequently somatic-nociceptive pain. Nociceptive anti-neuropathic pharmacotherapy. Some types of neu- pain involves direct ongoing activation of intact noci- ropathic injury produce aching, stabbing or throbbing ceptors (pain sensitive neurons) in either somatic or pain, but these syndromes often present with an unfa- visceral tissue. In essence, this is the intact, normally miliar quality or sensory distortion. Burning, shooting functioning nervous system sensing a noxious stimulus and tingling are suggestive of nerve involvement, but (in this case a tumor). On the other hand, pain due to not sufficient to make the diagnosis. Accompanying pathological function of either the peripheral or central abnormal sensations are often found on examination, nervous system is classified as neuropathic. In this case, including hypesthesia (increased threshold), hyperes- the presence of cancer induces a phenotypic change thesia (decreased threshold), paresthesias (spontaneous in the pain sensing system, increasing sensitivity of non-painful threshold), dysesthesia (spontaneous pain nerves to normally innocuous stimuli or exaggerating threshold), hyperpathia (prolonged stimulus response) the response to noxious stimuli. and allodynia (pain from a normally innocuous stimu- The findings of Boortz-Marx’s group in 2004 were lus). The presence of changes in small fibers on biopsy similar with 15% of cancer patients having neuropathic of the skin or peripheral nerves may be a useful confir- pain, 25% showing somatic-nociceptive pain and 60% mation, but has proven largely unnecessary in several showing mixed pain characteristics. This outcome clinical studies. underscores the complexity of the alterations in pain Pharmacological Treatment of Neuropathic Components of Cancer Pain Traditionally opioids have been utilized in the treatment Cancer Pain Management, Treatment of Neuropathic Components, Table 1 A compilation of pain types due to cancer from a multi-site study of cancer pain. However, their efficacy for neuropathic (Adapted from Caraceni and Portenoy 1999) pain states is controversial (McQuay 1999). The “mixed Cancer pain pathophysiology % Occurrence pain”statelendsitselftoeffectivetreatmentwithopioids (several preparations of long- and short-acting opioids Somatic nociceptive only 32.2 to be administered by different routes). These routes of Somatic and neuropathic 23.3 administration include oral, submucosal, subcutaneous, transdermal, rectal, parenteral, epidural and intrathecal. Visceral nociceptive only 15.2 Undesirable side effects of opioids (cognitive impair- Somatic and visceral 10.8 ment, somnolence, constipation, fatigue, hallucinations and myoclonus) may present without adequate analge- Neuropathic only 7.7 sia being achieved. Somatic, visceral, and neuropathic 5.2 The adjuvant group of analgesics (pharmacotherapy Visceral and neuropathic 3.6 designed for other purposes, but producing analgesia in certain circumstances) has proved to be effective in the Unknown only 1.7 treatment of neuropathic cancer pain. Traditionally, the Other with psychogenic 1.5 tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine and doxepin) have demon- Psychogenic only 0.3 strated efficacy in the treatment of neuropathic pain Cancer Pain Management, Treatment of Neuropathic Components 283 states. The side effect profile of this group has led hol (chemical neurolysis in specific cases) administered individuals not to consider these medications as first around nerves or ganglia (Chong 1997; Eisenach 1995; line therapy. The predominance of anticholinergic side Stubhaug 1997; Rowbotham 1994; Galer 1999; Watson effects (dry mouth, somnolence, cognitive impairment, 1988). cardiac arrhythmias, urinary retention and constipation) MostrecentlyBoortz-Marxandcolleaguespublishedre- C is often dose related, but can have advantages in patients sults of a multicenter study looking at the impact of in- afflicted with disrupted sleep architecture. Often doses trathecaldrugdeliveryoncancerpain(Smithetal.2002). needed for treatmentof neuropathic painstatesare much Mixtures of drugs including opioid agonists, local anes- lower than those needed for the treatment of depression. thetics and alpha-2 adrenergic agonists were applied as Other antidepressants such as the serotonin selective intrathecal preparations. Patients enrolled in this study reuptake inhibitors (SSRIs), atypical antidepressants reported reduced pain, reduced toxic side effects, im- and monoamine oxidase inhibitors (MAOIs) have not proved quality of life and a trend toward extended life proven efficacious unless predominant depression ac- expectancy. companies the neuropathic pain state. Most recently, a selective norepinephrine reuptake inhibitor (SNRI) Non-Pharmacological Treatment of Neuropathic Components received approval for treatment of painful diabetic pe- of Cancer Pain ripheral neuropathy.One of the authors (RB-M) has not Non-pharmacological treatment options serve as a experienced added benefit with this class of drugs in successful adjunct in the treatment of neuropathic the treatment of painful neuropathic pain states related cancer pain. The International Association for the to cancer. Study of Pain (IASP) has characterized chronic pain Several anticonvulsant medications constitute the main- as a “bio-psycho-social-spiritual” process. Chronic stay in the treatment of most neuropathic pain states, pain affects all patients at all stages of their cancer including neuropathic pain accompanying cancer. The disease. Non-pharmacological strategies including pa- traditional anticonvulsants (phenytoin, carbamazepine tient psychoeducation, supportive psychotherapy and and valproate) have fallen from favor because of their cognitive-behavioral interventions have been demon- toxic side effects related to bone marrow suppression; strated to be effective in the cancer pain patient. These this side effect is particularly unwelcome in a patient therapies lead to patient empowerment, improved population that has already received a toxic impact stress management and improved patient recognition from chemotherapeutic agents used in the treatment and modification of factors contributing to physical and of their disease state. A newer class of anticonvul- emotional distress (Thomas and Weiss 2000). Other ma- sants has recently evolved that employs varying modes jor non-pharmacological modalities that have demon- of activity relating to voltage gated channels (alpha- strated efficacy include therapeutic touch, massage, 2/delta subunit of voltage gated calcium channels and aromatherapy, reflexology, relaxation, guided imagery, voltage gated sodium channels) and glutamate gated visualization, meditation, biofeedback, acupuncture channels of the AMPA subtype. These agents include and music therapy (O’Callaghan 1996; Penson and pregabalin and gabapentin, which target the calcium Fisher 1995). channels, topiramate, tiagabine, levetiracetam, lamotrigine, oxcarbazepine and zonisamide, which target the Modeling Aspects of Persistent Cancer Pain sodium channels and glutamate receptors. Drugs such In order to understand the basic mechanisms involved in as gabapentin have few drug-drug interactions, are well cancer pain and ultimately to provide insight into mech- tolerated (starting at a low dose and escalating slowly) anism based therapies, several groups have developed and have produced favorable outcomes. rodent models of tumor induced hyperalgesia. The clas- Other adjuvant medications used or tested in the treat- sification of pain in cancer can be either neuropathic or ment of neuropathic cancer pain have included alpha-2 nociceptive (somatic), but is often mixed (Caraceni and adrenergic agonists (tizanidine and clonidine) ad- Portenoy 1999). This distinction is a familiar theme, not ministered orally, epidurally or intrathecally, local only clinically, but also in pain models. Neuropathic anesthetics (lidocaine, mexiletine, bupivacaine, ropiva- pain models in rodents have mostly focused on mechan- caine, tetracaine) administered perineurally (conductive ical trauma to the sciatic or spinal nerves; similarly, in block of major nerve trunks), parenterally, epidurally, animal models of cancer pain, the tumor mass itself may intrathecally or orally, NMDA receptor antagonists impose structural damage on nearby nerve bundles. (dextromethorphan and ketamine) administered orally or parenterally or (ketamine only) intrathecally, GABA Neural Plasticity in Cancer Pain Models agonists (e.g. baclofen) or facilitators (e.g. diazepam) Plasticity in pain processing within the CNS can lead administered orally or intrathecally, corticosteroids to pathological pain states that manifest not only as (prednisone and dexamethasone) administered par- increased nociceptive sensitivity at the injury site, but enterally or orally, topical agents (EMLA, gabapentin, also as secondary hyperalgesia and referred pain. In morphine, lidocaine and capsaicin) and phenol or alco- models of cancer pain, the potential for both peripheral 284 Cancer Pain Management, Treatment of Neuropathic Components and central plasticity is likely, particularly when tumor tive somatic/visceral). Although the malignant mass cells are implanted into the distal femur, where hyper- begins as a single entity, it may manifest pain via several algesia both at the tumor site (Schwei et al. 1999) and means and via complex interactions. Accordingly, work secondarily in the paw (Wacnik et al. 2001) are measur- towards a mechanistic classification of cancer pain must able. Schwei et al. (1999) and Shimoyama et al. (2005) take these various means and interactions into account. found increased immunoreactivity for dynorphin and c-fos protein in the dorsal horn correlated with tumor References growth, possibly signaling neuroplastic changes. In a rat model of cancer pain where tumors are implanted 1. Bruera E, Roca E, Cedaro L (1985) Action of Oral Methylpred- nisolone in Terminal Cancer Patients: A Perspective Randomized in the tibia, Urch et al. (2003) demonstrated increased Double-blind Study. Cancer Treat Rep 69:751–754 responses to mechanical, thermal and electrical (A beta, 2. Caraceni A, Portenoy R (1999) An international survey of cancer C-fiber and post-discharge evoked response) stimuli pain characteristics and syndromes. Pain 82:263–274 in wide dynamic range dorsal horn neurons in tumor 3. Chong SF, Bretsher ME, Mailliard JA, et al. (1997) Pilot Study Evaluating Local Anesthetics Administered Systemically for bearing animals, but no changes in nociceptive specific Treatment of Pain in Patient with Advanced Cancer. J Pain neurons. Tumor induced peripheral neuropathies in- Symptom Manage 13:112–117 clude aberrant firing of peripheral nociceptors adjacent 4. Cain DM, Wacnik PW, Turner M et al. (2001) Functional interac- to the tumor, identified by spontaneous activity in 34% tions between tumor and peripheral nerve: changes in excitability and morphology of primary afferent fibers in a murine model of of cutaneous C-fibers and an increase in epidermal cancer pain. J Neurosci 21:9367–9376 nerve branching concomitant with a decrease in the 5. Eisenach JC, DuPen S, Dubois M et al. (1995) Epidural Clonidine actual number of fibers in skin overlying the tumor Analgesia for Intractable Cancer Pain. The Epidural Clonidine (Cain et al. 2001). Furthermore, immunohistochemical Study Group. Pain 61:391–399 6. Foley KM (2000) controlling cancer pain. Hosp Pract (Off Ed) analysis of tumors revealed innervation of tumors with 35:101–108, 111–-102 CGRP-immunoreactive nerve fibers. The density of 7. Galer BS, Rowbotham MC, Pcrander J et al. (1999) Topical Li- these tumor-nerve appositions was positively corre- docaine Patch Release Post-Herpetic Neuralgia More Effectively than a Vehicle Topical Patch: Results of an Enriched Enrollment lated with the level of hyperalgesia, whereas that of Study. Pain 80:533–538 blood vessels was inversely correlated (Wacnik et al. 8. McQuay, H (1999) Opioids in Pain Management. Lancet 2005). 353:2229–2232 9. Merskey H, Bogduk N (1994) Classification of Chronic Pain, Models of Chemotherapy Induced Neuropathic Pain 2nd edn. IASP Press, Seattle 10. O’Collaghan CC (1996) Complimentary Therapies in Terminal In cancer patients, neuropathic pain is frequently as- Care: Pain, Music, Creativity, and Music Therapy in Palliative sociated with direct tumor invasion of the peripheral Care. Am J Hospice Palliative Care 13:43–49 nerve or spinal cord or secondarily caused by can- 11. Penson J, Fisher R (1995) Complimentary Therapies in Palliative Care for People with Cancer. Arnold, London, pp 233–245 cer chemotherapy. Several rodent models have been 12. Portenoy RK (1991) Cancer Pain General Design Issues. In: Max developed to model painful chemotherapy induced neu- M, Portenoy R, Laska E (eds) Advances in Pain Research and ropathy, using for example, vincristine or paclitaxel. In Therapy. Raven Press, New York, pp 233–266 the periphery, vincristine has been shown to enhance 13. Rowbotham MC (1994) Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts in Critical Issues. C-fiber responsiveness and to induce structural changes IASP Press, Seattle to large diameter sensory neurons and myelinated axons 14. Schwei MJ, Honore P, Rogers SD et al (1999) Neurochemical (Topp et al. 2000). In the CNS, vincristine promotes and cellular reorganization of the spinal cord in a murine model central sensitization in the dorsal horn of the spinal of bone cancer pain. J Neurosci 19:10886–10897 15. Shimoyama M, Tatsuoka H, Ohtori S et al. (2005) Change of cord, as indicated by increased spontaneous activity, dorsal horn neurochemistry in a mouse model of neuropathic increased responsiveness to C- and Aδ-fiber activity cancer pain. Pain 114:221–230 and abnormal “wind-up” in response to afferent C-fiber 16. Smith TJ, Staats PS, Pool G et al. (2002) An implantable drug delivery system for refractory cancer pain improves pain control, activity (Weng et al. 2003). drug-related toxicity, and survival compared to comprehensive medical management. American Society of Clinical Oncology, Conclusions May 2002. Proceedings of the American Society of Clinical On- Pain categories say little about the actual underlying cology 21:360a 17. Stubhaug A, Breivik H (1997) Long-term Treatment of Chronic mechanisms. Whether the category is neuropathic or Neuropathic Pain with NMDA (N-Methyl-D-Aspartate) Recep- nociceptive, the tumor or antecedent chemotherapy is tor Antagonists Ketamine. Acta Anaesthesiol Scand 41:329–331 ultimately the genesis of the pain. Damage to several 18. Thomas EM, Weiss SM (2000) Non-pharmacological Inter- different tissue types is part of tumorigenesis, and this ventions with Chronic Cancer Pain in Adults. Cancer Control 7:157–164 damage in turn may make different contributions to 19. Urch CE, Donovan-Rodriguez T, Dickenson AH (2003) Alter- the resulting pain. There is a high likelihood that a ations in dorsal horn neurones in a rat model of cancer-induced tumor could damage the nerve through compression, bone pain. Pain 106:347–356 stretching or infiltration (i.e. neuropathic), as well as 20. Wacnik PW, Eikmeier LJ, Ruggles TR et al. (2001) Functional interactions between tumor and peripheral nerve: morphology, by invading somatic or visceral structures and releasing algogen identification, and behavioral characterization of a new mediators that activate nociceptive fibers (i.e. nocicep- murine model of cancer pain. J Neurosci 21:9355–9366 Cancer Pain Management, Undertreatment and Clinician-Related Barriers 285

21. Wacnik PW, Baker C, Blazar BR et al. (2005) Tumor-induced of 13,625 US nursing home residents with cancer and mechanical hyperalgesia involves CGRP receptors and altered daily pain, factors that were predictive of undertreat- innervation and vascularization of DsRed2 ﬂuorescent hindpaw tumors. Pain 115:95–106 ment included poor cognitive status, polypharmacy, 22. Weng HR, Cordella JV, Dougherty PM (2003) Changes in sen- and advanced age (age > 85) (Bernabei et al. 1998). sory processing in the spinal dorsal horn accompany vincristine- Factors that were predictive of undertreatment of pain C induced hyperalgesia and allodynia. Pain 103:131–138 in the ECOG study of ambulatory oncology patients included minority status, discrepancy between patient and physician rating of pain severity, age, female sex Cancer Pain Management, and poor performance status. Undertreatment and Clinician-Related Undertreatment of Cancer Pain in Special Populations Barriers Elderly and Minority Patients

SEAN O’MAHONY Undertreatment of cancer pain has been reported in Montefiore Medical Center and Albert Einstein minorities and the elderly in ambulatory patients, hos- College of Medicine, Bronx, New York, NY, USA pitalized patients and residents of nursing homes (Von somahony@montefiore.org Roenn et al. 1994; Bernabei et al. 1998). Elderly patients with cancer pain often have comorbidities. In Definitions conjunction with polypharmacy, this can account for a greater susceptibility of adverse drug events. Cog- Cancerpainispainthatcanbeattributedtoamalignancy, nitive impairment and impaired communication also or complication of a malignancy, or its treatment. render some elderly patients with pain susceptible to undertreatment. Characteristics Despite the high prevalence of cancer pain in the el- Cancer pain affects 17 million people worldwide (Coyle derly, they tend to be excluded from analgesic trials. etal. 1990;Dautand Cleeland 1982). Prevalence ratesof Between 1987 and 1990, 83 randomized clinical trials 30–40% are reported for patients receiving active treat- of anti-inflammatory drugs in 10,000 patients included ment, and 70–90% for patients with advanced cancer only 203 patients over the age of 65. The occurrence of (Kelsenetal.1995).Cancerpainoccursatmultiplesites; complications of cancer pain in the elderly has not been in onestudy of 2266 cancer patients, 70%of patientshad extensively studied, including gait disturbance, falls, pain at 2 or more sites (Zeppetella et al. 2000). The du- delayed rehabilitation, malnutrition, polypharmacyand ration of cancer pain varies, but it can extend to several cognitive impairment. months or years (Petzke et al. 1999). In the U.S., an East- Ambulatory cancer patients treated at centers that pre- ern Cooperative Oncology Group survey of 1308 am- dominantly treat minority patients in the U.S., have been bulatory cancer patients found that 67% reported recent reported to be three timeslesslikely than patientstreated pain, and 36% reported their pain severity as sufficient elsewhere to receive adequate cancer pain management to interfere with their function (Von Roenn et al. 1994). (VonRoenn et al. 1994). Access to analgesic medication is impaired by lower availability of opioid medications Undertreatment of Cancer Pain in pharmacies located in predominantly minority neigh- Although reviews of the literature confirm that cancer borhoods. Clinician adherence to racial stereotypes is pain may be relieved in 70–90% of patients, an increas- implicated in reports of disparities in morphine equiva- ing body of evidence suggests that cancer pain remains lent doses for different ethnic groups undertreated internationally. Deficits in the treatment of cancer pain extend across specialty and level of Cancer Pain in the Developing World experience. A French national questionnaire study of It has been predicted that 10 of the 15 million new cases general practitioners and specialists indicated that only of cancer worldwide in the year 2015 will occur in the 10% of patients treated by general practitioners, and Third World; as many as 90% of these will continue to 21% of patients treated by specialists, were receiving present with advanced disease. The World Health Orga- treatment regimens appropriate to their pain severity nization assesses progress in cancer pain management (Vainio 1995). An analysis of the computerized medi- by national per capita morphine consumption. Fifty cal records of more than one million German patients percent of countries use little or no morphine (U.N. revealed that only 1.9% of patients with cancer were International Narcotics Control Board (United Na- receiving prescriptions for strong opioid medications, tions International Narcotics Control Board 1992). The and many patients with cancer were receiving medi- ten countries consuming 57% of all morphine in 1991 cations at inappropriate intervals and often on an “as have ranked highest in morphine consumption for many needed” basis (Zenz et al. 1995). years. However, 100 of the poorest countries with the Fear of addiction and respiratory depression appear majority of the world’s population used just 14% of to limit physician’s use of strong opioids. In a study all morphine. Many of these countries lack economic 286 Cancer Pain Management, Undertreatment and Clinician-Related Barriers resources and medical infrastructure to produce and unintentional effect of such policies may be the pre- distribute oral opioid medications. Restrictions exist on mature admission of chronically ill patients to skilled the duration that a patient can receive oral morphine or long term nursing care facilities (Soumerai et al. 1987). the locations where opioid medications can be received. In many countries, oral opioids and long-acting for- When available orally, the available formulations of mulations of opioid medications, in particular, are morphine (e.g. 10 mg controlled-release formulations prohibitively expensive when consideration is given to in the Philippines) may predispose to underdosing. average incomes. Even in wealthy countries, availability of inpatient pal- Barriers to Effective Pain Management liative care beds is limited. In Germany, it was estimated Clinician Educational Needs in 1996 that the national need for palliative care beds Barriers to effective pain management are often con- was about 4000 beds. Only 230 were available, and at ceptualized in terms of healthcare provider, patient, the same time patients described spending an average of family, institutional and societal factors. About 50% of 2 years with cancer pain prior to having access to a pain physicians are reported as having erroneous assump- clinic (Strumpf et al. 1996). tions about the use of opioids for cancer pain (Fife Historically, in the U.S., healthcare insurance compa- et al. 1993). These misconceptions include concerns nies have paid for procedures at the expense of compre- about tolerance, addiction, the role of various routes of hensive medication coverage. Medicare, the prevailing administration and the prevalence and management of carrier for patients with chronic illness and for the el- side effects. As many as 20% of physicians are reported derly, will pay for the cost of home infusions of opioid to regard cancer pain as inevitable and something that medications at a cost of US $250–300 per day. However, cannot be effectively managed (Fife et al. 1993). These the same medications administered orally are often not misconceptions extend across disciplines and medical reimbursed (Witteveen et al. 1999). specialties. More than one-third of doctors and nurses Inconsistent access to effective pain management rein a U.S. survey of 971 clinicians believed that the use sources commonly result in unnecessary hospital ad- of opioid medications should be restricted based on the missions for pain and symptom management. At one stage of a patient’s illness (Elliott and Elliott 1992). hospital alone, it was reported that 4% of the hospital’s Knowledge deficits do not appear to correlate with the admissions were for uncontrolled pain, at an annual cost level of exposure to cancer pain and training in palliative of US $5.1 million. Little work exists on the impact of care. Despite their widespread availability, physicians cost shifting to patients and their families, in terms continue to be reluctant to use validated assessment of family income or lost work days for cancer pain instruments. management in the community. The rising cost of opioid medications, for long-acting Patient and Family Barriers formulations in particular, may place severe strains on Many patients and families have unrealistic concerns the budgets of hospice organizations. Hospices may about the use of pain medications, and inadequate also be negatively impacted by requirements to destroy knowledge of cancer pain management. Patients often opioid medications after a patient dies. Recommended regard opioids as a last resort to be reserved for intol- changes include alterations in federal guidelines to erable pain, which they believe will be an inevitable enable pharmacies to partially dispense if a patient is sequela of their illness. Patient barriers are stronger in resident in a long-term care facility or has a documented older patients and in patients with lower educational terminal illness. and income levels. References Economic Considerations 1. Bernabei R, Gambassi I, Lapane KF (1998) Pain Management in Elderly Patients with Cancer. JAMA 279(23): 1877–1882 Internationally, reimbursement of patients for analgesic 2. Coyle N, Adelhardt J, Foley KM et al. (1990) Character of Ter- medications is limited. Reimbursement by prevailing minal Illness in the Advanced Cancer Patient: Pain and Other medical payers also does not cover operational costs Symptoms in the Last 4 Weeks of Life. 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(1995) Pain and De- restrictions on the number of refills on prescriptions, pression in Patients with Newly Diagnosed Pancreas Cancer J Clin Oncol 13:748–755 the number of dosage units of a medication, or the 7. Petzke F, Radbruch L, Zech D, Loick G, Grond S (1999) Tem- number of medications that a patient can receive. An poral Presentation of Chronic Cancer Pain: Transitory Pains on Cancer Pain Model, Bone Cancer Pain Model 287

Admission to a Multidisciplinary Pain Clinic. J Pain Symptom Characteristics Manage 17:391–401 8. Soumerai SB, Avorn J, Ross-Degnan D et al. (1987) Payment Re- Animal models of bone cancer pain have only been de- strictions for Prescription Medications under Medicaid. N Engl veloped in rodents (i.e. mice and rats). One advantage of J Med 317:550–556 murine models is that mice are commonly used to study 9. Strumpf M, Zenz M, Donner B (1996) Germany: Status of Cancer Pain and Palliative Care. J Pain Symptom Manage 12:109–111 cancer biology, so that many cancer cell lines are avail- C 10. United Nations International Narcotics Control Board (1992) able for use in mice. Many strains of mice have been Narcotic Drugs: Estimated World Requirements for 1993, Statis- genetically modified, and these strains may be used to tics for 1991. United Nations, Vienna determine the role of specific biochemicals in bone can- 11. Vainio A (1995) Treatment of Terminal Cancer Pain in France: A Questionnaire Study. Pain 62:155–162 cer pain. The advantage of using rats in a model of bone 12. Von Roenn JH, Cleeland CS, Gonin R et al. (1994) Pain and its cancer pain is that rats are commonly used in pain re- Treatment in Outpatients with Metastatic Cancer. N Engl J Med search, so their nociceptive systemshave been wellstud- 330:592–596 ied. Many nocifensive behavioral assays used to test 13. Witteveen PO, Van Groenestijn MAC, Blijham GH et al. (1999) Use of Resources and Costs of Palliative Care with Parenteral rodents with bone cancer pain were initially developed Fluids and Analgesics in the Home Setting for Patients with End- inratsandhavebeenusedinmodelsofinflammatoryand Stage Cancer. Annals Oncology 10:161–165 neuropathicpain.Thus,comparisonsbetweenthemech- 14. Zenz M, Zenz T, Tryba M et al. (1995) Severe Under-Treatment anisms underlying inflammatory, neuropathic, and bone of Cancer Pain: A 3 Year Survey of the German Situation. J Pain Symptom Manage 10:187–190 cancer pain can be made more easily. Finally, because of 15. Zeppetella G, O’Doherty CA, Collins S (2000) Prevalence and its larger size, it is easier to perform surgical procedures Characteristics of Breakthrough Pain in Cancer Patients Admit- on a rat than a mouse. ted to a Hospice. J Pain Symptom Manage 20:87–95 In these rodent models of bone cancer pain, tumor cells are implanted into different bones. In three of the four models, tumor cells are implanted into bones of the Cancer Pain Model hind limb, specifically the femur, tibia, and calcaneous bones. Use of the hind limb is advantageous because many behavioral tests of nociception apply the stim- Definition ulus to the hind paw of rats, and thus the responses to A clinically relevant model used to study the mecha- these stimuli have been well characterized. It is easier nisms and neurobiology of cancer-induced pain. Often, to apply stimuli to the hind paw than the forepaw in but not exclusively, these models are developed in rodents because the hind paw is larger and away from rodents or mammalians. the animal’s line of sight. The lumbar enlargement Cancer Pain, Animal Models of the spinal cord is easier to access than the cervical Cancer Pain Management, Treatment of Neuropathic enlargement, and so it is easier to apply drugs to or Components record electrophysiological activity from dorsal Cancer Pain Model, Bone Cancer Pain Model horn neurons. The lumbar and cervical enlargements are where primary afferents/neurons that innervate the hind limb and forelimb terminate, respectively. As a result, the electrophysiological responses and neuro- Cancer Pain Model, Bone Cancer Pain chemical characteristics of the dorsal horn neurons that Model have receptive fields on the hind limb have been better characterized than those innervating the forelimb. As DARRYL T. HAMAMOTO,DONALD A. SIMONE the hind limb is longer than the forelimb in rodents, University of Minnesota, School of Dentistry, Moos surgical preparation for electrophysiological record- Tower, Minneapolis, MN, USA ing from primary afferent fibers is easier. Thus, the [email protected], [email protected] electrophysiological responses of the primary afferent fibers that innervate the hind paw, and the neurochem- Definition ical characteristics of their associated dorsal root ganglion neurons, have been better studied. Bone is the third most common site for tumor metastases(Rubens1998),andpainisthemostfrequentsymp- tom for patients with metastatic bone cancer (Pecher- Femur Model storfer and Vesely 2000). Bone cancer pain is often diffi- The first reported animal model of bone cancer pain cult to treat (Mercadante 1997). Animal models have re- used NCTC 2472 cells, derived from a spontaneous cently been developed to elucidate the underlying mech- connective tissue tumor, which were implanted through anisms of bone cancer pain. A better understanding of an arthrotomy in the knee joint into the medullary cavity these mechanisms may lead to the development of novel of one femur of C3H/he mice (Schwei et al. 1999). The and more effective approaches to treating bone cancer hole in the articular surface of the distal femur, through pain. which the sarcoma cells are implanted, is sealed to 288 Cancer Pain Model, Bone Cancer Pain Model keep the cells within the medullary cavity (Honore changes that were similar to those found in the femur et al. 2000a). Implantation of sarcoma cells produces model in mice. an increase in both the number of osteoclasts and in A murine model of bone cancer pain, produced by osteoclast activation, which results in osteolytic lesions implantation of NCTC 2472 sarcoma cells through a in the implanted femur and invasion of the sarcoma skin incision into the tibia of C3H/he mice, has also cells into the adjacent soft tissues (Clohisy et al. 1996). been reported (Menendez et al. 2003). The hole in the Micewithsarcomacellsimplantedintothefemurexhibit tibia through which the sarcoma cells are implanted is spontaneous guarding and flinches, movement-evoked not sealed. Implantation of sarcoma cells results in an nocifensive behaviors during spontaneousor forced am- increase in the number of osteoclasts. At the time when bulation, and mechanical allodynia, as evidenced by the sarcoma cells erode through the bone and grow flinching, guarding, fighting, and vocalization produced into the surrounding soft tissue, mice exhibit thermal by normally non-noxious palpation of the affected limb hypoalgesia (i.e. increased paw withdrawal latencies (Schwei et al. 1999; Honore et al. 2000a; Luger et al. when on a hot plate). As the tumor mass grows, and 2001). The frequency of palpation-induced nocifensive the extent of bone destruction increases, mice exhibit behaviorswascorrelatedwiththeextentofbonedestruc- thermal hyperalgesia. tion (Schwei et al. 1999). In both of these models, test stimuli are applied to the One feature of this model is that the sarcoma cells are hind paw, a site distant from the location of the tumor sealed in the bone. This is similar to the clinical situa- cells. Increased responses to stimuli applied distant to tion in which tumor cells metastasize to the medullary the site of implantation of the tumor cells suggesting a cavity of a bone. Also, nociceptive stimuli are applied neuropathic injury or central sensitization may underlie to the distal femur, the location where the sarcoma cells these tumor-evoked behaviors. erode through the bone, suggesting that the nociceptive behaviorsare due to excitation of nociceptorsin the area. Calcaneous Model However,itisnotclearwhetherexcitationofnociceptors Implantation of NCTC 2472 sarcoma cells percuta- located in bone, muscle, or skin is responsible for evok- neously into and around the calcaneous bone of C3H/he ing the nocifensive behaviors. Interestingly, implanta- mice produces osteolysis and evokes mechanical hyper- tion of sarcoma cells into the femur also produced me- algesia (Wacnik et al. 2001). Mechanical hyperalgesia chanical allodynia at the plantar surface of the hind paw, was observed upon stimulation of the plantar surface as shown by a decrease in the threshold force required of the ipsilateral hind paw with von Frey monofil- to evoke a hind paw withdrawal (Honore et al. 2000b). aments. These mice also exhibited cold hyperalgesia This finding suggests that the sarcoma cells may be in- (i.e. enhanced paw withdrawal responses when placed juring nerve trunks passing through the area, resulting on a 5˚C plate). Histological examination shows that in a neuropathic pain condition as well as releasing po- sarcoma cells are found under the skin of the plantar sur- tentialalgogens. Alternatively, excitation of nociceptors face of the hind paw, and that the number of nerve fibers located near the sarcoma cells might produce sensitiza- in the epidermis (i.e. epidermal nerve fibers) above the tion of dorsal horn neurons (i.e. central sensitization) tumor decreases (Cain et al. 2001). Interestingly, the thatalso have cutaneousreceptive fieldson the hindpaw. proportion of neuropeptide containing primary afferent fibers increases suggesting that the sarcoma cells affect Tibia Model subclasses of primary afferent fibers differently. A model of bone cancer pain in rats was developed in One advantage of this model of bone cancer pain is that whichmammaryglandcarcinomacells(MRMT-1)were the effect of the sarcoma cells on the electrophysiologi- implanted through an incision in the skin into the tibia, cal responses of primary afferent fibers innervating the 5 mm distal to the knee joint of one hind limb in fe- tissue near the tumor can be determined. In fact, a pro- male (Medhurst et al. 2002) or male (Urch et al. 2003) portion of nociceptive C-fibers innervating the plantar Sprague-Dawley rats. Theholethrough which thebreast surface of the hind paw exhibit spontaneous activity, carcinoma cells were implanted is sealed. Implantation which may produce central sensitization and contribute of these breast carcinoma cells produces an increase in to the mechanical hyperalgesia observed (Cain et al. the number of osteoclasts-like cells and time-dependent 2001). Thus, interactions between the sarcoma cells bone destruction. Tumor bearing rats exhibit mechani- and primary afferent fibers can be examined using both cal hyperalgesia (i.e. paw pressure) and allodynia (i.e. histological and electrophysiological methods. von Fey stimulation to the plantar surface of the hind This model differs from the models using the femur and paw), cold allodynia (i.e. acetone applied to the plantar tibia in that the sarcoma cells are not sealed in the bone surface of the hind paw), a decrease in weight bearing but are implanted both in and around the calcaneous on the implanted limb, and ambulatory-evoked pain (i.e. bone. As a practical issue, the calcaneous bone in mice limpingandguardingonaRotarodtreadmill)(Medhurst is small and the volume of its medullary cavity is low, et al. 2002; Urch et al. 2003). Thus, this model of bone making it difficult to keep the cell suspension within cancer pain in rats produces histological and behavioral the medullary cavity. Additionally, sarcoma cells are Cannabinoid 289 implanted without making an incision through the skin. 6. Medhurst SJ, Walker K, Bowes M et al. (2002) A Rat Model of To seal the hole would require an incision to expose the Bone Cancer Pain. Pain 96:129–140 7. Menendez L, Lastra A, Fresno MF et al. (2003) Initial Thermal calcaneous bone, which might produce inflammation Heat Hypoalgesia and Delayed Hyperalgesia in a Murine Model and mechanical hyperalgesia. Moreover, implantation of Bone Cancer Pain. Brain Res 969:102–109 of sarcoma cells into the tissues around the calcaneous 8. Mercadante S (1997) Malignant Bone Pain: Pathophysiology and C bone produced less mechanical and cold hyperalgesia Treatment. Pain 69:1–18 9. Mercadante S, Maddaloni S, Roccella S et al. (1992) Predictive than when the sarcoma cells were implanted into the Factors in Advanced Cancer Pain Treated only by Analgesics. bone (Wacnik et al. 2001). These findings suggest that Pain 50:151–155 interactionofthesarcomacellswiththecalcaneousbone 10. Pecherstorfer M, Vesely M (2000) Diagnosis and Monitoring of is important for full development of the mechanical and Bone Metastases: Clinical Means. In: Body J-J (ed) Tumor Bone Diseases and Osteoporosis in Cancer Patients. Marcel Dekker cold hyperalgesia observed in this model. Inc., New York, pp 97–129 11. Rubens RD (1998) Bone Metastases - The Clinical Problem. Eur Humerus Model J Cancer 34:210–213 12. Schwei MJ, Honore P, Rogers SD et al. (1999) Neurochemical Movement-related cancer pain is thought to be a pre- and Cellular Reorganization of the Spinal Cord in a Murine Model dictor of poor response to routine pharmacotherapy in of Bone Cancer Pain. J Neurosci 19:10886–10897 cancer patients (Mercadante et al. 1992). Thus, a model 13. Urch CE, Donovan-Rodriguez T, Dickenson AH (2003) Alter- of deep tissue cancer pain may be ideal for studying ations in Dorsal Horn Neurones in a Rat Model of Cancer-Induced Bone Pain. Pain 106:347–356 this specific characteristic of cancer pain. Implantation 14. Wacnik PW, Eikmeier LJ, Ruggles TR et al. (2001) Functional of NCTC 2472 sarcoma cells through the proximal Interactions between Tumor and Peripheral Nerve: Morphology, end of each humerus bone in C3H/he mice produces Algogen Identification, and Behavioral Characterization of a movement-related hyperalgesia, observed as a reduc- New Murine Model of Cancer Pain. J Neurosci 21:9355–9366 15. Wacnik PW, Kehl LJ, Trempe TM et al. (2003) Tumor Implanta- tion in forelimb grip force (Wacnik et al. 2003) (see tion in Mouse Humerus Evokes Movement-Related Hyperalge- Muscle Pain Model, Inflammatory Agents-Induced). sia Exceeding that Evoked by Intramuscular Carrageenan. Pain This reduction in grip force can be attenuated with 101:175–186 morphine (Wacnik et al. 2003), and is possibly due to sensitization of nociceptors in the triceps muscles. Aninterestingadvantageofthehumerusmodelisthatthe Cancer Survivorship effectivenessof an analgesic treatmentisindicated by an increase in response. That is, as the tumor grows, mice Definition exhibit a decrease in grip force that is reversed by effec- The period of time during which an individual’s life is tive analgesics. In other nocifensive behavioral tests, the defined from the moment of diagnosis with cancer until animal shows an increase in responsiveness with tissue death. Often in pediatriconcology thefocusislong-term injury that is reversed by effective analgesic treatment. survivorship, defined as a specified period of time after However, a decrease in paw withdrawal response or vo- treatment during which the individual is disease free. calization could also be due to sedation or motor effects Cancer Pain, Assessment in Children of the test treatment. In the humerus model, sedation and motor impairment would be likely to produce a decrease in grip force, resulting in the analgesic effects of a treatment being more easily separated from any sedative ef- Cancer Therapy fects or motor impairment. Definition References Referstoanti-cancerchemotherapy,radiationtreatment, 1. Cain DM, Wacnik PW, Turner M et al. (2001) Functional Inter- surgery or endocrine/hormonal treatment to cure or con- actions between Tumor and Peripheral Nerve: Changes in Ex- trol cancer and its progression. citability and Morphology of Primary Afferent Fibers in a Murine Cancer Pain Management Model of Cancer Pain. J Neurosci 21:9367–9376 2. Clohisy DR, Ogilvie CM, Carpenter RJ et al. (1996) Localized, Psychiatric Aspects of the Management of Cancer Tumor-Associated Osteolysis Involves the Recruitment and Ac- Pain tivation of Osteoclasts. J Orthop Res 14:2–6 3. Honore P, Luger NM, Sabino MA et al. (2000a) Osteoprotegerin Blocks Bone Cancer-Induced Skeletal Destruction, Skeletal Pain and Pain-Related Neurochemical Reorganization of the Spinal Cannabinoid Cord. Nat Med 6:521–528 4. Honore P, Rogers SD, Schwei MJ et al. (2000b) Murine Models Definition of Inflammatory, Neuropathic and Cancer Pain each Generates a Unique Set of Neurochemical Changes in the Spinal Cord and Cannabinoids are derivatives of 9-tetrahydrocanna- Sensory Neurons. Neuroscience 98:585–598 binol (9-THC), the constituent of marijuana that is 5. Luger NM, Honore P, Sabino MA et al. (2001) Osteoprote- gerin Diminishes Advanced Bone Cancer Pain. Cancer Res responsible for its psychoactive effects. 61:4038–4047 Evoked and Movement-related Neuropathic Pain 290 Cannabinoid Receptors

The substance is widely used as an experimental model Cannabinoid Receptors of cutaneous hyperalgesia Amygdala, Pain Processing and Behavior in Animals Definition Atypical Facial Pain, Etiology, Pathogenesis and Receptors that are activated by the active constituent of Management cannabis sativa, 9–tetrahydrocannabinol (9–THC). Autologous Thrombocyte Injection as a Modelof Cu- These receptors can also be activated by endogenous taneous Pain ligands such as anandamide (so-called „endocannabi- Exogenous Muscle Pain noids“).Twotypesofreceptorhavebeenidentified,CB1 Freezing Model of Cutaneous Hyperalgesia and CB2, which are G-protein coupled. CB1 receptors Human Thalamic Response to Experimental Pain are found in several brain areas. (Neuroimaging) Nociceptive Neurotransmission in the Thalamus Inflammation, Modulation by Peripheral Cannabi- noid Receptors Mechano-Insensitive C-Fibres, Biophysics Muscle Pain Model, Ischemia-Induced and Hyper- Capacity tonic Saline-Induced Nociceptors in the Orofacial Region (Skin/Mucosa) Definition Opioid Modulation of Nociceptive Afferents In Vivo PET and fMRI Imaging in Parietal Cortex (SI, SII, In- An individual’s ability to execute a task or an action, the ferior Parietal Cortex BA40) highest probable level of functioning that a person may Polymodal Nociceptors, Heat Transduction reach in a given domain, at a given moment. Sensitization of Muscular and Articular Nociceptors Disability, Functional Capacity Evaluations Species Differences in Skin Nociception Spinothalamic Tract Neurons, Glutamatergic Input Spinothalamic Tract Neurons, Role of Nitric Oxide Capitated Care Sympathetically maintained Pain and Inflammation, Human Experimentation Definition Toxic Neuropathies TRPV1 Modulation by p2Y Receptors A provider receives a set fee for each patient assigned to TRPV1, Regulation by Nerve Growth Factor the practice through an insurance carrier.Thefee isoften TRPV1, Regulation by Protons called a per-member-per-month, and is independent of the care the patient requires. Disability Management in Managed Care System

Capsaicin Receptor Capsaicin ANTONIO VICENTE FERRER-MONTIEL Institute of Molecular and Cell Biology, University Definition Miguel Hernández de Elche, Alicante, Spain The pungent ingredient of chili peppers (8-methyl N- [email protected] vanillyl 6-nonenamide) from the capsicum family, which can be used to selectively activate nociceptive sensory neurones via its activation of a ligand-gated Synonyms cation channel TRPV1 (originally called the VR1 TRPV1; vanilloid receptor subunit 1; Heat Sensor channel, which can also be stimulated with heat and physical abrasion, permits cations to pass), present on these neurones. Stimulation of the cutaneous peripheral Definition terminals of these nerve fibers with capsaicin can be The capsaicin receptor is a calcium permeable non- used to produce neurogenic inflammation. It is also selective cation channel that is gated by noxious heat applied to the skin in order to treat neuropathic pain (≥ 42˚C), vanilloid compounds such as capsaicin and such as post herpetic neuralgia. Suggested mechanism protons. As a molecular sensor of painful stimuli at of action is by activation of C fiber mechano-heat noci- the peripheral endings of nociceptive, primary sensory coeptors, causing depletion of its neurotransmitters, e.g. neurons, the capsaicin receptor transduces noxious substance P, thus stopping the function of the neuron. chemical and thermal signals into action potentials. Plants produce the compound to deter predation. Cap- Thus, the capsaicin receptor is a key molecular compo- saicin is classified among the secondary metabolites. nent of the pain pathway. Capsaicin Receptor 291

Characteristics In situ hybridisation, immunocytochemicalanalysisand drug binding assays have shown TRPV1 expression in The capsaicin receptor is a member of the transient ≈50% of dorsal root and trigeminal ganglion neurons, receptor potential (TRP) mammalian gene superfam- in the dorsal horn of the spinal cord and in the caudal nu- ily (Caterina and Julius 2001). These channels are cleus of the spinal trigeminal complex. The majority of C considered molecular gateways in sensory systems, TRPV1 positive neurons also colocalise with the nerve since several of these proteins transduce chemical and growth factor (NGF) receptor trkA, the lectin IB4 and physical stimuli into neuronal activity, i.e. membrane the neuropeptides involved in nociceptive transmission potential changes. The capsaicin receptor gave its name such as substance P (SP) and calcitonin gene related to the vanilloid subfamily (TRPV) of TRP channels. peptide (CGRP) (Caterina and Julius 2001; Nagy et al. This sensory receptor is an integrator of noxious thermal 2004; Szallasi and Appendino 2004). Vanilloid sensi- stimuli aswell asof irritant chemicalssuch asvanilloids, tive nociceptors are peptidergic, small diameter neurons protons and pro-algesic substances (Caterina and Julius that give rise to unmyelinated C fibres, although some 2001;Szallasiand Appendino 2004). Temperaturegates Aδ fibres are responsive to vanilloid derivatives (Nagy the channel by shifting the voltage-dependent activa- et al. 2004; Szallasi and Appendino 2004). Somatic and tion towards the neuronal resting potential (Voets et al. visceral primary afferents express TRPV1 at both the 2004). In contrast, chemical activators of the receptor spinal and peripheral terminals. In addition to a subset such as capsaicinoid and vanilloid-like molecules and of nociceptors, the capsaicin receptor is present in neu- acidosis act as gating modifiers, reducing the temper- rons of the central nervous system and in non-neuronal ature threshold of channel gating from 42˚C to below cells. For instance, TRPV1 mRNA or protein is widely body temperature (36˚C). This is the underlying mech- expressed in brain regions such as the olfactory nuclei, anism for the characteristic pungency of capsaicin and cerebral cortex, dentate gyrus, central amygdala, stria- related molecules. tum, centromedian and paraventricular thalamic nuclei, Molecularly,thefunctionalchannelisatetramericmem- hypothalamus, substantia nigra, reticular formation, lo- brane protein with four identical subunits assembled cus coeruleus, inferior olive and cerebellar cortex (Nagy around a central aqueous pore. Each receptor subunit et al. 2004). Furthermore, the receptor is expressed in a displays a membrane domain composed of six trans- variety of epithelial tissues such as the skin, human hair membrane segments (S1–S6) with an amphipathic follicles, lungs, uroepithelium of the urinary bladder, region between the fifth and sixth segment that forms the vascular system and the inner ear (Nagy et al. 2004). the channel conductive pore (Caterina and Julius 2001; Taken together, all these observations underscore the Ferrer-Montiel et al. 2004). The protein also has cyto- notion that TRPV1 is a widely expressed protein whose plasmic N- and C-termini (Fig. 1). In the N-terminus, function is critical for diverse physiological conditions. TRPV1 channels exhibit three ankyrin domains that The pivotal role of TRPV1 in nociceptive transduc- mediate protein-protein interactions with cytosolic pro- tion has suggested a contribution of the channel to teins and consensus sequences for protein kinases. The diverse pathophysiological processes. In particular, protein displays a cytosolic C-terminusdomain contain- cumulative evidence is substantiating the tenet that ing phosphoinositide, and calmodulin binding (CAM) nociceptor sensitisation by pro-inflammatory agents domains, as well as phosphorylation sites (Caterina is primarily achieved by the capsaicin receptor. This and Julius 2001; Ferrer-Montiel et al. 2004; Nagy et al. protein is the endpoint target of intracellular signalling 2004). In addition, the C-end has a TRP-like motif that cascades triggered by inflammatory mediators that functions as an association domain for receptor subunits lead to remarkable potentiation of its channel activ- (Garcia-Sanz et al. 2004). The receptor has two abun- ity which, in turn, promotes the hyperexcitability of dant single nucleotide polymorphisms that produce nociceptors (Planells-Cases et al. 2005; Julius and amino acid substitutions, one in codon 315 (Met315 Ile) Basbaum 2001; Davis et al. 2000). Enhancement of at the N-terminus domain and the other at amino acid TRPV1 function by pro-algesic agents may be accom- 585 (Ile585 Val) located in the fifth transmembrane seg- plished either by direct activation of the channel or ment. Interestingly, gender, ethnicity and temperament by its posttranslational modification by intracellular seem to contribute to individual variation in thermal metabolic cascades (Planells-Cases et al. 2005; Julius and cold pain sensitivity by interactions in part with and Basbaum 2001). Direct activation of TRPV1 re- these TRPV1 single nucleotide polymorphisms (Kim sponses has been reported for lipid mediators such as et al. 2004). arachidonic acid metabolites including anandamide, N- The capsaicin receptor is widely expressed in neuronal arachidonyl-dopamine(NADA) and N-oleyldopamine. and non-neuronal cells of both endodermal and meso- Similarly, several eicosanoids, particularly those de- dermal origin, implying that the receptor is involved rived from the enzymatic action of 5-lipoxygenase or in diverse physiological functions. These include ther- 12-lipoxygenase, are capable of activating TRPV1. mosensory transduction, as well as chemical signalling In particular, 12-(hyperoxy)eicosatetraenoic acid (12- presumably mediated by endovanilloid compounds. HPETE) and leukotriene B4 (LTB4) have exhibited the 292 Capsaicin Receptor

Capsaicin Receptor, Figure 1 Molecular model of the capsaicin receptor subunit. The figure displays a membrane domain composed of six transmembrane segments (S1–S6) with an amphipathic region between the fifth and sixth segment that forms the channel conductive pore, which also contains the glutamic acids (E600 and E648) responsible for the pH-induced channel gating. The protein also has cytoplasmic N- and C-termini. In the N-terminus, TRPV1 channels exhibit three ankyrin domains and consensus sequences for PKA and Src. The capsaicin-binding site is located at the N-end of the S3 segment, near S502, a serine residue phosphorylated by PKA, PKC and CaMKII. The protein displays a cytosolic C-terminus domain containing phosphoinositide (PIP2), and calmodulin binding (CAM) domains and phosphorylation sites for PKC (T704, S800) and CaMKII (T704). In addition, the C-end has a TRP domain that may contribute to the association of receptor subunits. The higher Ca2+permeability with respect to Na+and K+is also depicted. most potent agonistic activity. In addition, the acidosis sion is up-regulated in tissue samples from patients that develops in inflamed tissues is also a direct activator with inflammatory bowel disease and Crohn’s disease of the TRPV1 channel activity (van der Stelt and Di and also in patients with rectal hypersensitivity, as well Marzo 2004). The potency and efficacy of each singular as in those affected by vulvodynia (see ref. in Nagy et mediator is quite low but in inflammatory conditions al. 2004; Szallasi and Appendino 2004; Planells-Cases several of these modulators are simultaneously re- et al. 2005). Thus, TRPV1 receptors are critical deter- leased and act synergistically. Therefore, direct gating minants of the sensitisation of primary afferents after of TRPV1 responses by inflammatory agents acting injury or inflammation. The involvement of TRPV1 as channel agonists notably increases the excitability in heat hypersensitivity is underscored by the reduced of nociceptors, resulting in a hyperalgesic condition. thermal hyperalgesia of TRPV1 null mice (Caterina et Prolonged activation of the receptor, leads to an intra- al. 2000), and by the attenuation of this inflammatory as- cellular [Ca2+] rise that, in turn, activates intracellular sociated phenomenon by non-competitive antagonists signalling that triggers the release of pro-inflammatory of the TRPV1 channel (Garcia-Martinez et al. 2002). agents at peripheral terminals. This dual action further Accordingly, the important contribution of TRPV1 increases the excitability of the nociceptors. In addi- receptor to the onset and maintenance of neurogenic tion, inflammation-evoked activation of intracellular inflammation has validated it as a therapeutic target protein networks results in TRPV1 phosphorylation, for inflammatory pain management and a tremendous release of tonically inhibited receptors and an incre- effort is being carried out to develop clinically useful ment in the surface expression of functional channels, modulators of the receptor dysfunction characteristic all being major events underlying the nociceptor ac- of human diseases (Szallasi and Blumberg 1999). tivation and sensitisation that leads to hyperalgesia Polymodal Nociceptors, Heat Transduction (Planells-Cases et al. 2005). Indeed, TRPV1 expres- TRPV1 Receptor, Species Variability Carotid Arteries 293

TRPV1, Regulation by Nerve Growth Factor among astrocytes. In addition to decoupling gap junc- TRPV1, Regulation by Protons tions, carbenoxolone can also exert non-specific effects, including inhibition of11-beta-hydroxysteroid dehydro- References genase, at higher doses. Peri-spinal administration of 1. Caterina MJ, Julius D (2001) The vanilloid receptor: A molecular carbenoxolone blocks mirror-image pain. C gateway to the pain pathway. Annu Rev Neurosci 24:487–517 Cord Glial Activation 2. Caterina MJ, Leffler A, Malmberg AB et al. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313 3. Davis JB, Gray J, Gunthorpe MJ et al. (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Cardiac Stress Response Nature 405:183–187 4. Ferrer-Montiel A, Garcia-Martinez C, Morenilla-Palao C et al. (2004) Molecular architecture of the vanilloid receptor. Insights for drug design. Eur J Biochem 271:1820–1826 Postoperative Pain, Pathophysiological Changes in 5. García-Martínez C, Humet M, Planells-Cases R et al. (2002). Cardiovascular Function in Response to Acute Pain Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc Natl Acad Sci USA 99:2374–2379 6. Garcia-Sanz N, Ferández-Carvajal A, Morenilla-Palao C et al. (2004) Identification of tetramerization domain in the C-terminus of the vanilloid receptor. J Neurosci 24:5306–5314 Cardiac Surgery 7. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210 8. Kim H, Neubert JK, San Miguel A et al. (2004) Genetic influence on variability in human acute experimental pain sensitivity as- Definition sociated with gender, ethnicity and psychological temperament. All cardiac surgical procedures performedwith or with- Pain 109:488–496 9. Nagy I, Sántha P, Jancsó G et al. (2004) The role of the vanilloid out cardiopulmonary bypass. (capsaicin) receptor (TRPV1) in physiology and pathology. Eur Postoperative Pain, Thoracic and Cardiac Surgery J Pharmacol 500:351–369 10. Planells-Cases R, García-Sanz N, Morenilla-Palao C et al. (2005) Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflugers Arch Eur J Physiol 21 May, Epub ahead of print. PMID Career Assessment 15909179 11. Stelt M van der, Di Marzo V (2004) Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem 271:1827–1834 Vocational Assessment in Chronic Pain 12. Szallasi A, Appendino G (2004) Vanilloid receptor TRPV1 antagonists as the next generation of painkillers. Are we putting the cart before the horse? J Med Chem 47:1–7 13. Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–211 Caregiver 14. Voets T, Droogmans G, Wissenbach U et al. (2004) The principle of temperature–dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–754 Definition Any person who assesses and provides care to the individual experiencing pain (health care professionals, Capsazepine family member, friend). As it pertains to the newborn infants, the maternal caregiving relationship during in- Definition fancy is considered a key mediator and moderator of risk factors on infant development. Capsazepine is a classical capsaicin antagonist, identi- Pain Assessment in Neonates fied by a combinatorial chemical screen. Interacts with TRPV1, the capsaicin receptor. Capsaicin Receptors TRPV1, Regulation by Protons Carotid Arteries

Deﬁnition Carbenoxolone The common carotid artery divides into the internal and external carotid arteries in the neck. The former supplies Deﬁnition the forebrain with blood and the latter supplies the face Carbenoxolone is a gap junction decoupler. When ad- and scalp. ministered over the spinal cord, it disrupts gap junctions Primary Cough Headache 294 Carotidynia

proximal to the wrist, and therefore abnormal sensibil- Carotidynia ity of the thenar skin is not included in the definition of carpal tunnel syndrome. Motor symptoms include com- Definition plaints of clumsiness in the use of the thumb, as the me- A poorly defined syndrome with unilateral anterolateral dian nerve’s motor branch innervates the abductor pol- cervical pain and local tenderness. licis brevis, the opponens pollicis, and the short head Headache due to Dissection of the flexor pollicis brevis. When the wrist is flexed, pressure increases upon the median nerve, causing decreased blood flow within the median nerve, and the resulting ischemia causes transmission of neural impulses Carpal Tunnel Syndrome interpretedasnumbnessortingling(paresthesia),and,in some patients, actually as pain, causing them to awaken Definition at night. Acute onset of pain in the distribution of the me- Chronic compression of the median nerve as it passes dian nerve is not included in the definition of carpal tun- through the carpal tunnel in the wrist. The pressure nel syndrome, and indicates acute compression with ax- placed on the median nerve could be caused by exces- onal loss, rather than chronic compression and demyeli- sive pressure due to tendon or tissue inflammation and nation. excessive fluid in the wrist. The condition normally Characteristics results in reduced nerve conduction velocity, and pain and numbness in the thumb, index and middle fingers, Carpal tunnel syndrome is themost common example of sometimes the ring finger, but not the little finger. With chronic nerve compression, with a prevalence of at least use of the hand, these symptoms can become disturbing 2% in the general population, 14% in diabetics without during the daytime. Carpal tunnel syndrome has been peripheral neuropathy, and 30% in diabetics with pe- associated with repetitive work and frequent forceful ripheral neuropathy (Perkins et al. 2003). The physical exertions, as well as several systemic health conditions examination findings required to confirm a diagnosis in such as diabetes and pregnancy. The symptoms are the first patient reported to have a carpal decompression over the palmar side of the hand, and not the dorsum. were blisters on the tips of the thumb, index and mid- These include night-time awakening with numbness or dle finger, due to anesthesia, and wasting of the thenar tingling. muscles (Woltman 1941). The patient was an acrome- Carpal Tunnel Syndrome galic with hypertrophic neuropathy as the cause of the Ergonomics Essay compressionofthemediannerve,andJamesLearmonth, NeuropathicPain Model, ChronicConstrictionInjury a neurosurgeon at the Mayo Clinic, divided the transverse carpal ligament. In 1950, George Phalen, a surgeon in Cleveland, described a series of patients with carpal tunnel syndrome, which has become the classic Carpal Tunnel Syndrome description. Today a history of numbness or paresthe- A. LEE DELLON sias in the thumb and index finger, associated with night Department of Plastic Surgery and Neurosurgery, timeawakeninghasbecometheclassichistory.Theclas- Johns Hopkins University, Baltimore, MD, USA sic physical examination findings are a positive Phalen [email protected] sign (symptoms provoked with wrist flexion for 1 min) or a positive Tinel sign (distally radiating sensory phe- Synonyms nomenon when the median nerve is tapped at the wrist) (Mackinnon and Dellon 1988). It is unusual today for Median nerve compression at the wrist; Entrapment a patient to have sufficient chronicity of symptoms or Neuropathies, Carpal Tunnel Syndrome severity of compression to have thenar muscle wasting at the time or presentation. Definition Documentation of carpal tunnel syndrome requires ei- Carpal tunnel syndrome is a combination of patient ther electrodiagnostictesting(EDT)or neurosensory complaintsrelatedtochroniccompressionofthemedian testing (NST). EDT is objective, but remains with sig- nerve within the carpal tunnel. Since the carpal tunnel is nificant number of false negative findings, such that a at the wrist, the painful symptoms of which the patient meta-analysis done by the American Neurologic Asso- complains are related to the small and large myelinated ciation (AAEM 1993) found that just 66% of patients nerve fibers that supply the palmar, but not thenar, skin using clinical symptoms and findings as the gold stan- along an axis that is radial to the longitudinal axis of the dard had positive EDT. In contrast, quantitative sensory ringfinger,andthedistaldorsaltipsoftheindexandmid- testing has been demonstrated to be valid, reliable, cordle finger. The thenar skin is innervated by the palmar relate well with patient symptoms, and to be painless cutaneousbranch of the median nerve,which arises5cm (Arezzo et al. 1993). Thermal threshold testing docu- Carpal Tunnel Syndrome 295 ments the presence of small nerve fiber pathology, and the tarsal tunnel syndrome. This numerical grading sys- does not become abnormal until late in the pathology tem permits statistical comparison of treatment options of carpal tunnel syndrome. Vibratory threshold testing for the wide range of clinical symptoms and findings documents the presence of large fiber pathology, but, usually seen in carpal tunnel syndrome, or other nerve because the stimulus is a wave, it can give ambiguous entrapment syndromes. For the mild degrees of com- C information when used to stimulate the index finger pression, non-operative treatment is appropriate with or the thumb: these fingers are innervated by both the splinting of the wrist in a neutral position, non-steroidal radial sensory and the median nerve, both of which anti-inflammatory medication, change of activities of will be stimulated by the waveform. NST is a form daily living, and cortisone injection. Failure of this of quantitative sensory testing that measures the cuta- approach, manifested by persistence or progression of neous pressure threshold for one and two-point moving symptoms is an indication for surgical decompression and static-touch. This testing found a clear distinction of the median nerve at the wrist. Another indication for between the 99% upper confidence limit in the nor- surgery is if more severe degrees of compression are mal age-matched population, from those patients with present initially, such as the axonal loss associated with even a mild degree of carpal tunnel syndrome (Dellon abnormal two-point discrimination or muscle atrophy. and Keller 1997), suggesting that this methodology Randomized prospective studies (Gerritsen et al. 2001; would have a high sensitivity in evaluating patients Trumbleetal.2002),ingeneral,agreethat80–90%ofpa- with chronic nerve compression. This was confirmed tients can achieve good to excellent symptomatic relief in a blinded, prospective study evaluating the ability of througheitheratraditionalopenorthenewerendoscopic EDT versus NST with the Pressure-Specified Sensory approach. In experienced hands, the complications for Device to identify patients with carpal tunnel syndrome each procedure are similar. These complicationsinclude from an asymptomatic population (Weber et al. 2000). failure of the procedure to achieve the desired result, in- That study found that the sensitivity of NST vs. EDT jury to the median nerve or its branches, and a painful in- was 92% vs. 81%, and the specificity of NST vs. EDT cision.Forcertainoccupations,theendoscopicapproach was 82% vs. 77%. Since NST is painless, the patient appears to permit a slightly earlier return to work. is willing to have repeated studies in those clinical Based upon pre-operative staging, a routine intra- situations in which they may be necessary, e.g. when operative internal neurolysis does not improve results non-operative treatment is first prescribed, or there is (Mackinnon et al. 1991), however, adding an internal workplace environment modification (ergonomics), microsurgical neurolysis based upon intra-operative treatment failure, or evaluation of impairment for a pathology, has not been evaluated in a prospective disability rating. study. An internal neurolysis may be indicated, Another indication for NST is the differential diag- therefore, and is utilized by this author, for intraneural nosis of failure to improve following carpal tunnel fibrosis typically identified in the setting or recurrent decompression, in which a proximal source of median median nerve entrapment (Chang and Dellon 1993), nerve compression, such as the pronator syndrome, is or that observed in diabetics with superimposed nerve considered. EDT has a high false negative percentage compression (Aszmann et al. 2000; Dellon 1992). with this nerve compression, with up to 75% false Results of median nerve decompression in diabetics negative in many studies, whereas NST, by measuring give excellent results in the majority of patients. In the the cutaneous pressure threshold of the thenar emi- presence of neuropathy, EDT cannot reliably identify nence, can document this proximal site of compression the presence of carpal tunnel syndrome, and clinical (Rosenberg et al. 2001). Evaluation of the cutaneous decision making, based upon the presence of the Phalen pressure threshold over the dorsoradial aspect of the and Tinel sign, is still considered valid (Perkins et al. hand can identify the presence of radial sensory nerve 2002). entrapment, another nerve compression to be considered in the differential diagnosis of “failed carpal tunnel decompression”. In those patients in whom a References C6 radiculopathy is being considered in the differential 1. AAEM Quality Assurance Committee (1993) Literature Review diagnosis, the electromyographic component of EDT of the Usefulness of Nerve Conduction Studies and Electromyo- is still the critical method required for documentation. graphy for the Evaluation of Patients with Carpal Tunnel Syn- The treatment of carpal tunnel syndrome is clearly drome. Muscle Nerve 16:1392–1414 defined based upon staging the degree of compres- 2. Arezzo JC, Bolton CF, Boulton A et al. (1993) Quantitative Sen- sory Testing: A Consensus Report from the Peripheral Neuropa- sion (Dellon 2001). Measurement of peripheral nerve thy Association. Neurol 43:1050–1052 function permits a numerical grading system which in- 3. Aszmann OC, Kress K, Dellon AL (2002) Results of Decompres- corporates both the motor and sensory systems, and can sion of Peripheral Nerves in Diabetics: A Prospective, Blinded be applied to other upper extremity nerve compressions Study Utilizing Computer-Assisted Sensorimotor Testing. Plast Reconstr Surg 106:816–822 like the ulnar nerve at the elbow, cubital tunnel syn- 4. Chang B, Dellon AL (1993) Surgical Management of Recurrent drome, or the lower extremity tibial nerve compression, Carpal Tunnel Syndrome. J Hand Surg 18:467–470 296 Carrageenan

5. Dellon AL (1992) Treatment of Symptoms of Diabetic Neuropa- the joint. Degradation of cartilage is a key characteristic thy by Peripheral Nerve Decompression. Plast Reconstr Surg of osteoarthritis. 89:689–697 6. Dellon AL (2001) Clinical Grading of Peripheral Nerve Prob- Arthritis Model, Osteoarthritis lems. Neurosurg Clinics N Amer 12:229–240 7. Dellon AL, Keller KM (1997) Computer-Assisted Quantitative Sensory Testing in Carpal and Cubital Tunnel Syndromes. Ann Plast Surg 38:493–502 Case Control Study 8. Gerritsen AAM, Uitdehaag BMJ, Geldere D van et al. (2001) Systematic Review of Randomized Clinical Trials of Surgical Treatment for Carpal Tunnel Syndrome. Br J Surg 88:1285–1295 Definition 9. Mackinnon SE, Dellon AL (1988) Carpal Tunnel Syndrome. In: Mackinnon and Dellon (eds) Surgery of the Peripheral Nerve. A study that starts with the identification of persons with Thieme, New York, pp 149–170 the disease (or outcome variable) of interest, and a suit- 10. Mackinnon SE, McCabe S, Murray JF et al. (1991) Internal Neu- rolysis Fails to Improve Results of Primary Carpal Tunnel De- able control (comparison) group of persons without the compression. J Hand Surg 16:211–216 disease (Last, 1988). 11. Perkins BA, Olaaleye D, Bril V (2002) Carpal Tunnel Syn- Prevalence of Chronic Pain Disorders in Children drome in Patients with Diabetic Polyneuropathy. Diabetes Care 25:565–569 12. Rosenberg D, Conolley J, Dellon AL (2001) Thenar Eminence Quantitative Sensory Testing in Diagnosis of Proximal Median Nerve Compression. J Hand Therap 14:258–265 Case Rate 13. Trumble TE, Diao E, Abrams RA et al. (2002) Single-Portal En- doscopic Carpal Tunnel Release Compared with Open Release. J Bone Joint Surgery 84:1107–1115 Definition 14. Weber R, Weber RA, Schuchmann JA et al. (2000) A Prospec- tive Blinded Evaluation of Nerve Conduction Velocity versus Flat fee paid for a patient’s treatment, based on the di- Pressure-Specified Sensory Testing in Carpal Tunnel Syndrome. agnosis and/or presenting problem. Ann Plast Surg 45:252–257 Disability Management in Managed Care System 15. Woltman HW (1941) Neuritis Associated with Acromegaly. Arch Neurol Psych 45:680–682

Caspases Carrageenan Definition Definition Caspases are a family of cysteine proteases that cleave A colloidal extract from carrageen seaweed and other proteins after aspartic acid residues. They are the main red algae, s. also Carrageenan Inflammation. executorsof apoptosisor programmedcelldeath(PCD), Amygdala, Pain Processing and Behavior in Animals and cause the characteristic morphological changes of the cell during apoptosis such as shrinkage, chromatin condensation and DNA fragmentation. Carrageenan Inflammation NSAIDs and Cancer

Definition Carrageenan is an inflammatory irritant utilized to CAT Scan mimic inflammatory pain. Carrageenan can be injected into the paw, muscle or joint. Carrageenan inflammation CT Scanning is associated with heat and mechanical hyperalgesia. ArthritisModel,Kaolin-CarrageenanInducedArthri- tis (Knee) TENS, Mechanisms of Action Catabolism, Destructive Metabolism

Postoperative Pain, Pathophysiological Changes in Cartilage Metabolism in Response to Acute Pain Deﬁnition Connective tissue that surrounds the ends of bones as they meet to form a joint. The cartilage serves to form Catalogue a smooth surface around the bones, providing for cush- ioning and allowing for smooth and easy movement of Taxonomy Catastrophizing 297

Most of the research demonstrating an association be- Catastrophic Cognitions tween catastrophizing and pain has been correlational in design, thus precluding the nature of causal inferences Catastrophizing that can be drawn. However, a few studies have shown that measures of catastrophizing prospectively predict C pain outcomes. Keefe et al. (1989) assessed catastro- Catastrophic Thinking phizing and various pain-related outcomes in a sample of patients with rheumatoid arthritis at two points in time, separated by a 6-month interval. Catastrophizing Catastrophizing predicted pain and functional disability even when controlling for initial pain and disability. In a sample of injured workers, Sullivan and Stanish (2003) showed that Catastrophizing treatment-related reductions in catastrophic thinking were associated with increased probability of returning MICHAEL J.L. SULLIVAN,HEATHER ADAMS to work. In several experimental studies, Sullivan and Department of Psychology, University of Montreal, colleagues showed that catastrophizing, measured in a Montreal, QC, Canada pain-free state, prospectively predicted pain responses [email protected], to painful procedures conducted as long as 6 weeks fol- [email protected] lowing initial assessment of catastrophizing (Sullivan et al. 2001). Although these findings do not rule out Synonyms the possibility that catastrophizing may be reactive to Catastrophic thinking; catastrophic cognitions; mal- variations in pain experience, they do nevertheless high- adaptive coping light that the assessment of catastrophizing can permit prediction of future pain and pain-related disability. Definition Functions of Catastrophizing Pain catastrophizing has been defined as an exagger- Early conceptualizations of pain catastrophizing ap- ated negative ‘mental set’ that is brought to bear during pealed to cognitive constructs such as appraisals, an actual or anticipated pain experience (Sullivan et cognitive errors and schema activation to account al. 2001). Pain catastrophizing is considered to be a for the relation between catastrophizing and pain (Sul- multidimensional construct that includes elements of livan et al. 1995). It was suggested that, as a function rumination (i.e. excessive focus on pain sensations), of a learning history characterized by heightened pain magnification (i.e. exaggerating the threat value of experience, catastrophizers may develop expectancies pain sensations), and helplessness (i.e. perceiving about the high threat value of painful stimuli (i.e. pri- oneself as unable to cope with pain symptoms). mary appraisal), and about their inability to effectively Characteristics manage the stress associated with painful experiences (i.e. secondary appraisal). Once activated, catastro- Catastrophizing, Pain and Disability phizers’ ‘pain schema’ could influence emotional or To date, approximately 200 studies have been published cognitive functioning in a manner that contributed to documenting a relation between catastrophizing and heightened pain experience. pain. A relation between catastrophizing and pain has More recently, it has been suggested that catastro- been observed in diverse clinical and experimental pop- phizers might engage in exaggerated displays of their ulations (Sullivan et al. 2001). Catastrophizing has been pain-related distress as a means of coping with pain associated with increased pain and pain behavior, (Sullivan et al. 2001). This ‘communal coping’ model increased use of health care services, longer hospi- of pain catastrophizing draws on recent theoretical tal stays, increased use of analgesic medication, and discussions of the interpersonal dimensions of coping, higher rates of unemployment. In samples of chronic suggesting that individuals differ in the degree to which pain patients, catastrophizing has been associated with they adopt social or relational goals in their efforts to heightened disability, predicting the risk of chronicity cope with stress. Catastrophizers’ expressive displays and the severity of disability better than illness-related of distress might be used, consciously or unconsciously, variables or pain itself (Sullivan et al. 2001; Buer and to maximize proximity, or to solicit assistance or em- Linton 2002; Picavet et al. 2002). A relation between pathic responses from others in their social environment catastrophizing and pain-related outcomes has been ob- (Sullivan et al. 2004a). served in children as young as 7 years (Gil et al. 1993). For a comprehensive review of current research and Mechanisms of Action: Catastrophizing and Pain theory on pain catastrophizing, the reader is referred to The role of attentional factors has been discussed as one Sullivan et al. (2001) and Vlaeyen and Linton (2000). mechanism through which castastrophic thinking might 298 Catastrophizing exert its influence on the pain experience. For example, Self-report measures have also been developed for as- several investigations have shown the rumination sub- sessing catastrophizing in children and adolescents (Gil scaleofthePCSismorestronglycorrelatedtopaininten- et al. 1993; Crombez et al. 2003). Interview methods sity ratings than the magnification or helplessness sub- have also been used; however, their application to clin- scales (Sullivan et al. 2001). In other words, the endorse- ical settings has been limited. ment of items, such as ‘I keep thinking about how much it hurts’ and ‘I can’t seem to keep it out of my mind’ is Treatment associated with higher pain ratings. The robust relation between catastrophizing and pain Crombezetal.(1997)foundthat,inanticipationofapain has prompted a growing number of clinicians and re- stimulus,catastrophizersshowedgreaterinterferenceon searchers to identify catastrophizing as a central factor an attention-demanding task than non-catastrophizers. in the clinical management of disabling pain condi- Heyneman et al. (1990) reported that pain catastrophiz- tions. Following multidisciplinary treatment for pain, ers were unsuccessful in using attention diversion cop- reductions in catastrophizing are often noted (Burns et ing strategies to reduce their pain. Other investigations al. 2003). Recently, intervention programs have been have provided data suggesting that catastrophizers may developed that specifically target catastrophic thinking be impaired in their ability to divert attention away from as a primary goal of treatment. Thorn et al. (2002) pain (Sullivan et al. 2001; Van Damme et al. 2002). have described a 10–week, cognitive behavioral intervention designed to reduce catastrophic thinking in Mechanism of Action: Catastrophizing and Disability headache sufferers. In this treatment program, thought The role of emotional factors, specifically fear, has been recording and cognitive restructuring techniques are discussedasonemechanismthroughwhichcatastrophic used as a means of monitoring and modifying catas- thinking might exert its influence on pain-related dis- trophic thoughts. Sullivan and Stanish (2003) described ability. It has been suggested that following injury, indi- a 10–week, cognitive-behavioral program designed to viduals who engage in catastrophic thinking are likely facilitate return-to-work following occupational injury. to develop heightened fears of pain, movement and re- In the latter program, activity mobilization strate- injury (Vlaeyen and Linton 2000). By contributing to gies and cognitive restructuring are used to minimize the development of pain-related fears, catastrophizing catastrophic thinking and facilitate progress toward might heighten the risk for different aspects of disabil- occupational re-integration. ity, such as activity discontinuation and activity avoid- Cognitive-Behavioral Perspective of Pain ance (Picavet et al. 2002). Research suggests that pain- Coping and Pain related fears do not mediate the relation between catas- Ethics of Pain, Culture and Ethnicity trophizing and pain experience, but do mediate the re- Psychological Aspects of Pain in Women lation between catastrophizing and disability (Sullivan Psychological Treatment in Acute Pain et al. 2004b; Picavet et al. 2002). Psychological Treatment of Headache

Assessment References Several assessment instruments have been developed to 1. Buer N, Linton SJ (2002) Fear-Avoidance Beliefs and Catastro- assess pain catastrophizing. Considerable research on phizing: Occurrence and Risk Factor in Back Pain and ADL in catastrophizing has used the Coping Strategies Ques- the General Population. Pain 99:485–491 tionnaire (CSQ) (Rosenstiel and Keefe 1983). The CSQ 2. Burns JW, Kubilus A, Bruehl S, Harden RN, Lofland K (2003) Do Changes in Cognitive Factors Influence Outcome following consists of 7 coping subscales, including a 6–item catas- Multidisciplinary Treatment for Chronic Pain? A Cross-Lagged trophizing subscale. Respondents are asked to rate the Panel Analysis. J Consult Clin Psychol 71:81–91 frequencywithwhichtheyusethedifferentstrategiesde- 3. Crombez G, Bijttebier P, Eccleston E, Mascagni GM, Goubert L, Verstraeten K (2003) The Child Version of the Pain Catastrophiz- scribed by scale items. The catastrophizing subscale of ing Scale (PCS-C): A Preliminary Validation. Pain 104:639–646 the CSQ contains items reflecting pessimism and help- 4. Crombez G, Eccleston C, Baeyens F, Eelen P (1997) When So- lessness in relation to coping with pain (i.e. “It’s terrible matic Information Threatens, Catastrophic Thinking Enhances and it’s never going to get any better”, “There’s nothing Attentional Interference. Pain 74:230–237 5. Gil KM, Thompson RJ, Keith BR, Tota-Faucette M, Noll S, Kin- I can do to reduce the intensity of the pain”). ney TR (1993) Sickle Cell Disease Pain in Children and Ado- The Pain Catastrophizing Scale (PCS) (Sullivan et lescents: Change in Pain Frequency and Coping Strategies Over al. 1995) is another commonly used measure of catas- Time. J Ped Psychol 18:621–637 trophizing that adopts a multidimensional view of the 6. Heyneman NE, Fremouw WJ, Gano D, Kirkland F, Heiden L (1990) Individual Differences and the Effectiveness of Different construct. The PCS is a 13–item self-report question- Coping Strategies for Pain. Cog Ther Res 14:63–77 naire that assesses three dimensions of catastrophizing: 7. Keefe FJ, Brown GK, Wallston KA, Caldwell DS (1989) Cop- rumination (“I can’t stop thinking about how much it ing with Rheumatoid Arthritis: Catastrophizing as a Maladaptive hurts”), magnification (“I worry that something serious Strategy. Pain 37:51–56 8. Picavet HS, Vlaeyen JW, Schouten JS (2002) Pain Catastrophiz- may happen”), and helplessness (“It’s awful and I feel ing and Kinesiophobia: Predictors of Chronic Low Back Pain. that it overwhelms me”). Am J Epidemiol 156:1028–1034 Causalgia 299

9. Rosenstiel AK, Keefe FJ (1983) The Use of Coping Strategies in Chronic Low Back Pain Patients: Relationship to Patient Char- Caudal Epidural Blocks acteristics and Current Adjustment. Pain 17:33–44 10. Sullivan MJL, Adams H, Sullivan ME (2004a) Communicative Dimensions of Pain Catastrophizing: Social Cueing Effects on Deﬁnition Pain Behaviour and Coping. Pain 107:220–226 C 11. Sullivan MJL, Bishop, SR, Pivik J (1995) The Pain Catastro- Sensory and motor block of the thoracic, lumbar or phizing Scale: Development and Validation. Psychological As- sacral nerves achieved by injecting local anesthetic sessment 7:524–532 12. Sullivan MJL, Stanish WD (2003) Psychologically Based Occu- (0.5-1 mg/kg) via needle or catheter inserted through pational Rehabilitation: The Pain-Disability Prevention Program. the sacral hiatus into the epidural space. Clin J Pain 19:97–104 Acute Pain in Children, Post-Operative 13. Sullivan MJL, Thorn B, Haythornthwaite JA, Keefe FJ, Martin M, Bradley LA, Lefebvre JC (2001) Theoretical Perspectives on the Relation between Catastrophizing and Pain. Clin J Pain 17:52–64 14. Sullivan MJL, Thorn B, Rodgers W, Ward C (2004b) Path Model of Psychological Antecedents of Pain Experience: Experimental and Clinical Findings. Clin J Pain 20:164–173 Caudal Epidural Steroids 15. Thorn BE, Boothy J, Sullivan MJL (2002) Targeted Treatment of Catastrophizing in the Management of Chronic Pain. Cogn Behav Pract 9:127–138 16. Van Damme S, Crombez G, Eccleston C (2002) Retarded Disen- Epidural Steroid Injections gagement from Pain Cues: The Effects of Pain Catastrophizing and Pain Expectancy. Pain 100:111–118 17. Vlaeyen JWS, Linton SJ (2000) Fear-Avoidance and its Conse- quences in Chronic Musculoskeletal Pain: A State of the Art. Pain 85:317–332 Caudal Injection

Epidural Steroid Injections for Chronic Back Pain Categorization of Nociceptors

Nociceptor, Categorization Caudate Nucleus

Definition Cauda Equina One of the main nuclei of the basal ganglia; part of the striatum connected principally with prefrontal and other association areas of cortex. Definition Nociceptive Processing in the Nucleus Accumbens, Neurophysiology and Behavioral Studies A syndrome of fluctuating weakness and sensory loss Parafascicular Nucleus, Pain Modulation caused by ischemia of the lumbosacral roots in a narrow spinal canal. It also refers to a collection of spinal roots descending from the lower spinal cord and occupying the vertebral canal below the cord. Chronic Back Pain and Spinal Instability Causalgia Radiculopathies

Deﬁnition A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often com- Caudal Analgesia or Anesthesia bined with vasomotor and sudomotor dysfunction and later trophic changes. Causalgia, Assessment Deﬁnition Complex Regional Pain Syndrome and the Sympa- Regional anesthesia by injection of local anesthetic so- thetic Nervous System lution or other drugs into the epidural space via sacral Complex Regional Pain Syndromes, General Aspects hiatus. Sympathetically Maintained Pain in CRPS II, Human Postoperative Pain, Epidural Infusions Experimentation 300 Causalgia, Assessment

Arendt-Nielsen 2003). Electrodiagnostic studies are Causalgia, Assessment capable of demonstrating the peripheral nerve injury of ELLEN JØRUM causalgia or CRPS–II (Devor 1983). Neurography does The Laboratory of Clinical Neurophysiology, not evaluate the function of thin nerve fibres such as A Rikshospitalet University, Oslo, Norway δ mediating cold/sharp pain and C-fibres mediating the [email protected] sensation of heat, heat pain and some forms of tactile pain. These nerve fibres may be evaluated by quantitative sensory testing (QST) (Gracely et al. 1996). It is Definition important to note that the number of nerves available for Causalgia is defined as “A syndrome of sustained neurography is restricted. Neurography will routinely burning pain, allodynia and hyperpathia after be performed on the major nerves of the upper extrem- a traumatic nerve lesion, often combined with ity (median, ulnar and radial nerves) and in the lower vasomotor and sudomotor dysfunction and later extremity (peroneal, tibial and sural nerves); it is also trophic changes.” (Classification of chronic pain 1994) possible, to some extent, to perform neurography of a This is an old term and causalgia will now be called few proximal sensory nerves in both upper and lower complex regional pain syndrome type 2 – CRPS–II extremity. EMG is also a helpful method in evaluating (with nerve lesion). neurogenic affection of muscles, and since it may be Causalgia, or complex regional pain syndrome, is as performed in a large extent of muscles, more nerves the name implies a complex pain syndrome, being may hereby be examined. characterized by the presence of spontaneous pain, Assessment of Clinical Pain alterations in sensibility including allodynia and hyperpathia, as well as symptoms and signs of autonomic The pain in causalgia will have the same possible char- dysfunction. acteristicsaspain following neuropathic painin general, Since this chapter will be dealing with “assessments” including the presence of spontaneous and evoked pain. the complicated neurophysiological mechanisms will Althoughpainfollowingnervelesionshasoftenbeende- not be mentioned. The aetiology is given, since we are scribed as burning, there are no pain descriptors which talking about a traumatic nerve lesion. This may occur are specific to neuropathic pain (and thereby to causal- in relation to all sorts of injuries. gia). Pain in causalgia may be described by a large number Characteristics of adjectives, of which burning, throbbing, aching are only a few examples. Spontaneous pain may be ongoing Assessment of Nerve Lesion and/or paroxysmal, and the intensity may be evaluated Thisisapainsyndromeoccurringafteratraumaticnerve by a visual analogue score (0–10 cm) or (0–100 mm), lesion, and much emphasis will have to be put on the where 0 representsno pain and10or100 the worst think- identification of a specific nerve lesion. able pain. Pain intensity may spontaneously vary in in- The best way to detect and to assess a peripheral nerve tensity, but is often aggravated by physical activity and lesion is to perform a detailed clinical neurological exposure to cold. Lightly touching the painful area will, examination of the patient, including investigation of in most cases, provoke a severe pain, but pain may also motor and sensory function and myotatic reflexes. Since beevokedbythermalstimuli(frequentlycold,notsofre- pain may arise following either a sensory or a mixed quently heat.) motor and sensory nerve, a detailed mapping of motor and sensory deficits is crucial. In most cases, there Assessment of Allodynia/Hyperpathia will be a lesion of sensory nerve fibres, and a careful Since causalgia may be characterized by the presence study of the innervation territory of sensory deficit is of allodynia and hyperpathia, an assessment of these warranted. However, because of the involvement of cen- phenomena is important. Both are described elsewhere, tral sensitization-mechanisms, the sensory deficit may but it is briefly repeated here that allodynia is defined as sometimes exceed the innervation territory of the nerve; “pain dueto astimuluswhichdoesnotnormally provoke one may proceed by admitting the patient to a clinical pain” and hyperpathia as “a painful syndrome charac- neurophysiologist for EMG (electromyography) and terized by an abnormally painful reaction to a stimulus, neurography. By neurography, measurements of con- especially a repetitive stimulus, as well as an increased duction velocities and other variables such as distal threshold” (Classification of chronic pain 1994). Al- delay, motor and sensory amplitudes and latency of late lodynia and hyperpathia to both tactile stimuli and volleys such as the H– and F– wave are measured. Nerve thermal stimuli may be tested. In clinical practice, conduction studies play an important role in precisely allodynia to light touch is the easiest to perform. One delineating the extent and distribution of a peripheral may apply a cotton swab or a brush, gently moving it nerve lesion, and give some indication of nerve-root over the painful area, and record whether this normally pathology (by evaluation of late reflexes) (Jørum and non-painful stimulus evokes pain or not. Hyperpathia Causalgia, Assessment 301 to light touch may also be present, but in general the and the dynamic alterations may also include diurnal two phenomena may coexist. For the determination of fluctuations. The evaluation of autonomic dysfunction allodynia and hyperpathia to thermal stimuli, special may in most cases be performed by a clinical examina- equipment is generally needed. One may obtain some tion, but laboratory tests may prove helpful. These can indication of the presence or not of allodynia to cold measure changes in autonomic function with higher C or heat by applying thermorollers over the skin, rollers sensitivity and more objectivity. Most laboratory stud- which are set at fixed temperatures, i.e. 25 and 40˚C. ies of autonomic dysfunction in patients with CRPS The rollers are first and foremost manufactured for test- have been conducted on patients with CRPS type 1 ing reduced sensibility, and since heat pain is normally (formerly reflex sympathetic dystrophy). One must add perceived at temperatures around 42–43˚C, it may be that a general assumption is that CRPS–l or CRPS–II, difficult to conclude with heat allodynia if pain is per- do not differ in the changes believed to be dependent ceived at 40˚ C. Cold allodynia, on the other hand, may on the sympathetic nervous system (Stanton-Hicks et be easier to demonstrate. In the upper extremity, cold al. 1995). Various tests may be employed to assess pain will normally be seen at a threshold of 10–15˚C, the function of the autonomic nervous system, both while in the lower extremity, it will be below 10˚C. For well validated routine tests as well as more experi- more accurate determinations of thresholds for cold mental procedures. For the assessment of sudomotor allodynia or heat allodynia, quantitative sensory testing function, sympathetic skin response and quantitative (QST) may be performed with the use of a thermotest. sudomotor axon reflex test (QSART) may be employed. Cold allodynia will be the most prominent finding, and Recordings of skin potentials from the foot or hand may will not be different from cold allodynia in other cases be made following a stimulus such as electric shock, of neuropathic pain (Jørum et al. 2003). a noise, a cough or an inspiratory gasp. The advan- Heat allodynia may exist, but is seen less frequently. Hy- tage of this method is that it is easy to perform in a peralgesia/hyperpathia to pinprick may also be demon- routine clinical neurophysiological laboratory. The strated, and as for allodynia to light touch, it may be of disadvantage is its large variability, the tendency of the value to map the area, by moving the von Frey hair or a responses to habituate, and that it has little sensitiv- needle from normal skin centripetally towards the area ity, especially compared with the more sophisticated of hyperalgesia. QSART. In the latter test, the sweat output in response to iontophoretic application of 10% acetylcholine is Assessment of Vasomotor and Sudomotor Dysfunction recorded by a sudorometer. The major advantage is that The inclusion of possible vasomotor and sudomotor the test is sensitive and reproducible in controls and in dysfunction is essential for the diagnosis of CRPS–II patients with neuropathy (Low 2003). The disadvan- or causalgia. The clinician should look for signs like tage is that the equipment has only recently become oedema (Fig. 1), sweat dysregulation (usually increased commercially available and is not yet represented in sweating, but also possibly reduced sweating), alter- many laboratories. In a study of 102 patients with ations in skin temperature (cooler or warmer) reflecting CRPS–I by Sandroni and co-workers (1998), they vasomotor changes, and trophic changes of the skin, found that some of the indices that correlated most hair and nails. The diagnosis of a full developed CRPS reliably with clinical data, and with each other, were is not difficult. However, the diagnosis of milder cases QSART and skin temperature reductions. The authors may prove difficult, especially since the patients’ clini- computed the sudomotor index from the change in cal picture may change over time (vasodilatation at first, sweat volume, latency and persistent sweat activity. then vasoconstriction and finally dystrophic changes), QSART was positive at a single site if the affected side

Causalgia, Assessment, Figure 1 Oedema in the right hand in a patient with CRPS. 302 Cawthorne and Cookseys’ Eye-Head Exercises showed changes 50% greater than the non-affected (eds) Textbook of Clinical Pain Management. Arnold, London, side. pp 27–38 6. Jørum E, Warncke T, Stubhaug A (2003) Cold Allodynia The assessment of vasomotor (vasoconstriction/vaso- and Hyperalgesia in Neuropathic Pain: The Effect of N- dilatation) dysfunction may be performed by indi- methyl-D-aspartate (NMDA) Receptor Antagonist Ketamine: rect methods, such as measuring of skin tempera- A Double-Blind, Cross-Over Comparison with Alfentanil and ture or thermography and by more sophisticated laser Placebo. Pain 101:229–235 7. Low P (2003) Testing the Autonomic Nervous System. Seminars doppler–examinations. The measurement of skin tem- in neurology 23:407–421 perature is an easy but indirect way to detect changes 8. Sandroni P, Low PA, Ferrer T, Opfer-Gehrking T, Willner in vasomotor function, where a difference between the C, Wilson PR (1998) Complex Regional Pain Syndrome affected and non-affected extremity exceeding 1˚C will (CRPS 1): Prospective Study and Laboratory Evaluation. Clin J Pain 14:282–289 be regarded as significant. Thermography is also easy 9. Stanton-Hicks M, Jänig W, Hassenbusch S et al. (1995) Re- to perform, but has the disadvantage that it will be reflex Sympathetic Dystrophy: Changing Concepts and Taxonomy. garded as an indirect way of testing vasomotor function. Pain 63:127–133 Laser doppler investigations are also easy to perform, 10. Weber M, Birklein F, Neundörfer B, Schmelz M (2001) Facili- tated Neurogenic Inflammation in Complex Regional Pain Syn- by measuring flow at a limited area or by scanning a drome. Pain 91:251–257 larger area, but interpretations of data related to pathophysiology may be difficult. Elegant examinations are performed with laser doppler examination, as described in a paper by Weber et al. (2001), in combination with trancutaneous electrical stimulation. They found that Cawthorne and Cookseys’ Eye-Head the vasodilatation as a response to electrical stimulation Exercises of the skin increased significantly (more pronounced vasodilatation) in a group of mainly CRPS type 1 patients compared to normal controls. There have been Coordination Exercises in the Treatment of Cervical many critical comments to the IASP diagnostic criteria Dizziness for CRPS in general, and many authors have questioned the specificity of the criteria. In a study by Bruehl and co-workers (1999) of 117 patients meeting the IASP criteria for CRPS, and 43 pa- CBT tients with neuropathic pain from diabetic neuropathy, they found that signs or symptoms of oedema versus colour changes versus sweat dysregulation satisfied Cognitive-Behavioral Therapy three criteria, and discriminated between the groups. Although diagnostic sensitivity was high at 98%, specificity was poor at 36%. The diagnosis of CRPS was likely to be correct in only 40% of the cases, and the results of this study suggested that the criteria used by CCI IASP had inadequate specificity and were likely to lead to over-diagnosis. However, it was again emphasized that this study was performed on patients with CRPS Chronic Constriction Injury of both type 1 (approximately two thirds) and type 2. Chronic Constriction Injury Model NeuropathicPain Model, ChronicConstrictionInjury

References 1. Bruehl S, Harden RN, Galer BS, Saltz S, Betram M, Backonja M, Gayles R, Rudin N, Bhugra MK, Stanton-Hicks M (1999) External Validation of IASP Diagnostic Criteria for Complex Re- CCK gional Pain Syndrome and Proposed Research Diagnostic Cri- teria. Pain 81:147–154 2. Merskey H, Bogduk N (1994) Classiﬁcation of Chronic Pain. Cholecystokinin IASP Press, Seattle 3. Devor M (1983) Nerve Pathophysiology and Mechanisms of Pain in Causalgia. J Autonom Nerv Syst 7:371–384 4. Gracely RH, Price DD, Rogers WJ, Bennett GJ (1996) Quanti- tative Sensory Testing in Patients with Complex Regional Pain Syndrome (CRPS) l and ll. In: Jänig W, Stanton-Hicks M (eds) Reﬂex Sympathetic Dystrophy: A Reappraisal, Progress in Pain CDH Research and Management, vol 6. IASP Press, Seattle, p 151 5. Jørum E, Arendt-Nielsen L (2002) Sensory Testing and Clin- ical Neurophysiology. In: Breivik H, Campell W, Eccleston C Chronic Daily Headache in Children Cell Therapy in the Treatment of Central Pain 303

Definition Celiac Plexus Block Cell therapy is the use of transplanted cells from pri- maryorimmortalizedsourcestoreverseorreducesymp- Definition toms or causes of pain arising from injury to the cen- The celiac plexus is involved in nociceptive pain trans- tral nervous system. Cell grafts used in this therapy can C mission from intraabdominal organs from the distal be placed near the original injury, such as in or near the esophagus to the transverse, and sometimes to the de- spinal cord, or further away, depending on the intended scending colon. Interruption of nociceptive signals by mechanism to be targeted for therapeutic intervention. injection of phenol or alcohol onto the plexus may Primary cell sources are derived from a single cohort provide excellent and prolonged pain relief for pa- donor and cannot be expanded or kept in vitro for ex- tients suffering particularly from gastric and pancreatic tended periods. Immortalized cell sources are derived carcinoma. from any animal or human source, but have been engi- Cancer Pain Management, Anesthesiologic Interven- neered to be, or are naturally, expandable in vitro. tions, Neural Blockade Cancer Pain Management, Overall Strategy Characteristics Even with continuous improvements in surgical management, physical therapy and the availability of newer pharmacological agents, many patients following in- Cell Adhesion jury to the central nervous system continue to suffer from difficult to treat chronic pain. Newer treatments to modulate and reduce central pain are likely to in- Definition clude cell grafts that release antinociceptive molecules synthesized by transplanted cells. Cell therapy to treat An intercellular connection by which cells stick to other neuropathic pain after spinal cord injury (SCI) is in cells or non-cellular components of their environment. its infancy, but the development of cellular strategies Cell adhesion generally requires special protein com- that would replace or be used as an adjunct to current plexes at the surface of cells. pharmacological treatments for neuropathic pain NSAIDs and Cancer have progressed tremendously over the past 20 years. One strategy involves the placement of grafts in the spinal cord where a variety of antinociceptive substances are released. Presumably, these cell grafts act Cell Grafts as “cellular minipumps” that are able to release neuroactive antinociceptive molecules in the spinal cord and effect pain processing pathways. Cell lines, rather Cell Therapy in the Treatment of Central Pain than primary cell grafts, can also offer a renewable and possibly safe to use source of cells. Grafts of either primary or immortalized sources could be expected to reduce or eliminate side effects associated with large Cell Minipumps doses of pharmacological agents typically required for centrally acting pain reducing agents, such as opioids or antidepressants. Cell Therapy in the Treatment of Central Pain The earliest studies using cell transplants for pain therapy were developed with the idea of mimicking descending or local spinal inhibitory neurotransmitter modulation of sensory information. In these studies Cell Therapy in the Treatment of Central agents released by cell grafts after injury resulted in Pain antinociception. A variety of neurotransmitters, peptides and more recently neurotrophins,have MARY J. EATON been implicated in spinal inhibition. These include Miller School of Medicine at the University of Miami, the endogenous neurotransmitters serotonin (5-HT), Miami, FL, USA noradrenaline and γ-aminobutyric acid (GABA), the [email protected] endogenous opioid β-endorphin, enkephalins, endogenous peptides such galanin and neurotrophins such as brain derived neurotrophic factor (BDNF). Many of the Synonyms commonly used pharmacological therapies target re- Cell Transplantation; Cell Grafts; Cell Minipumps ceptors and re-uptake mechanisms of these substances 304 Cell Therapy in the Treatment of Central Pain in order to increase or mimic their presence in acute ropathic pain (Eaton et al. 1997). Transplants of similar and chronic pain. In the early 1980’s it was recognized murine cell lines genetically engineered to synthesize that these agents could be supplied by grafts of autolo- and secrete potentially antinociceptive molecules such gous primary adrenal medullary chromaffin cells after the inhibitory peptide galanin, the neurotrophin BDNF nerve injury ( autologous graft). Chromaffin cells and the inhibitory neurotransmitter GABA have been contain a cocktail of antinociceptive agents, peptides tested successfully in the same partial nerve injury pain and neurotrophins (Wilson et al. 1981). To use chro- model (Eaton 2000). maffin cell therapy in humans, adrenal chromaffin cell The same bioengineered rat serotonergic cell line men- grafts were prepared from xenogenic bovine sources tioned above has been successfully used to reduce neu- and tested for antinociception after nerve injury (Sagen ropathic pain and improve locomotor function follow- et al. 1993). There have also been a number of animal ing SCI (Hains et al. 2001). Pain reduction requires that studies using primary medullary tissue or dissociated cellsbeplacedinthesubarachnoidspace,wheretheycan chromaffin cultures placed in the subarachnoid space affect dorsal horn pathways and reduce spinal neuronal to reduce behavioral hypersensitivity in models of hyperexcitability (Hains et al. 2003), probably modu- SCI-induced pain (Brewer and Yezierski 1998). Un- latedthroughspecific5-HTreceptors.Asimilarbioengi- fortunately, non-human, xenogenic tissue sources are neering approach was used to immortalize primary em- not likely to be used clinically, even if they are more bryonic rat and bovine chromaffin cells, using the tsTag abundant, given their increased risk of antigenicity for immortalization. Grafts of these cells placed in the and rapid rejection by the human host. Adult human subarachnoid space in a model of neuropathic pain after chromaffin tissue has been transplanted and tested in nerve injury reduced pain without forming tumors in the humans for terminal cancer pain (Pappas et al. 1997), host animal (Eaton et al. 2000). For such an approach to which is often neuropathic pain in nature. In these be completely safe as a clinical method for cell therapy, studies when the immune response in the human host it will be necessary to remove the oncogene completely was examined after graft placement, it was concluded before grafting. The next advance in the creation of cell that further purification or immunoisolation of grafts lines for therapeutic use has been the development of re- would be needed in order to use such tissues in multiple versibly immortalized cell lines, as modeled by rat chro- transplants, given the antigenicity of the diverse cell maffin cell lines with an excisable oncogene. sources. Chromaffin cells from primary tissue sources Studies exploiting site specific DNA recombination are not likely to be homogeneous, since they are often and Cre/lox excision have suggested that cells can be obtained from multiple donors. The ability to use and targeted in vitro and in vivo for removal of deleteri- manipulate immortalized cell lines as a defined and ous genes, including the large T antigen. Reversible stable source of cells will most probably permit the immortalization with Tag and Cre/lox technology was implementation of cell therapy for pain in a clinical first reported in human fibroblasts by Westerman and setting. Leblouch (1996) and more recently in human myo- A number of immortalized cell lines have been derived genic cells and hepatocytes (Kobayashi et al. 2000). from the rat brainstem to model how such cell line Introduction of the gene for Cre recombinase into a grafts might function in models of pain after grafting cell’s genome allows for Cre to excise any recom- near the spinal cord. A common feature of these cells is binant sequences present that are flanked by small the expression of an oncogene, such as the temperature loxP sequences. Using this strategy, rat chromaffin sensitive allele of large T antigen (tsTag) that con- cells have been immortalized with an oncogenic tsTag fers immortalization and allows for the expansion construct, utilizing retroviral infection of these early of cells at low temperatures in vitro. This oncogene is chromaffin precursors with the tsTag construct flanked down-regulated at higher transplant temperatures in the by loxP sequences (floxed). Following isolation of animal. One of these rat neural precursor cell lines was immortalized cells, they were further infected with a isolated from embryonic day 12.5 rat brainstem and retrovirus expressing the CrePR1 gene, which encodes immortalized with the tsTag sequence. This cell line has for a fusion protein that combines Cre activity with the been made to synthesize and secrete the neurotrophin mutant human steroid receptor, hPRB891. After incu- BDNF by the addition of the sequence for rat BDNF bation of the cells with the synthetic steroid RU486, to its genome, causing these cells to have improved the fusion protein is translocated to the cell nucleus, survival in vitro and in vivo and develop a permanent allowing Cre to excise the tsTag oncogene and effec- serotonergic phenotype. Since additional5-HTwaspos- tively dis-immortalize the cells in vitro. Such reversibly tulated to have a beneficial effect on neuropathic pain, immortalized chromaffin cells, which express many cells were placed in a lumbar subarachnoid space after features of the primary chromaffin cell, are able to re- sciatic nerve injury. Grafts of these serotonergic cells verse neuropathic pain after spinal cord transplantation placed 1 week after nerve injury and the development in a nerve injury model (Eaton et al. 2002). Such studies of severe hypersensitivity to thermal and tactile stimuli model the use of reversibly immortalized cell lines in were able to permanently reverse the symptoms of neu- humans. Cellular Adhesion Molecules 305

Anentirelydifferentapproachwithcelllinesistheuseof 4. Eaton MJ (2000) Emerging cell and molecular strategies for the human neural lines that contain an oncogene that can be study and treatment of painful peripheral neuropathies. J Peripher Nerv Sys 5:59–74 down-regulated with agents such as retinoic acid (RA). 5. Eaton MJ, Dancausse HR, Santiago DI et al. (1997) Lumbar trans- An example of such a human neural cell line is the NT2 plants of immortalized serotonergic neurons alleviates chronic line (Andrews 1984), which after differentiation with neuropathic pain. Pain 72:59–69 C RAfor more than 2 weeksin vitro, differentiatesintosta- 6. Eaton MJ, Martinez M, Frydel B et al. (2000) Initial characterization of the transplant of immortalized chromaffin cells for the at- blehumanneuralcellsthatneverformtumorsaftergraft- tenuation of chronic neuropathic pain. Cell Transplant 9:637–656 ing and have been used to ameliorate a variety of trau- 7. Eaton MJ, Herman JP, Jullien N et al. (2002) Immortalized chro- maticandneurodegenerativeconditions(Trojanowskiet maffin cells disimmortalized with Cre/lox site-directed recom- al. 1997). Such cells represent immortalized stem cells bination for use in cell therapy for pain. Exp Neurol 175:49–60 8. Hains BC, Johnson KM, McAdoo DJ et al. (2001) Engraftment of or neural progenitors that have been spontaneously im- immortalized serotonergic neurons enhances locomotor function mortalized and only differentiate after RA into the non- and attenuates pain-like behavior following spinal hemisection tumor, neural phenotype. These cells offer great poten- injury in the rat. Exp Neurol 171:361–378 tial for the treatment of central pain, since they appear 9. Hains BC, Johnson KM, Eaton MJ et al. (2003) Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitabil- safe and can be easily used in the clinical setting, being ity of dorsal horn neurons after spinal hemisection in rat. Neu- placed via spinal tap into the subarachnoid space. rosci 116:1097–1110 Finally, there are no published successful methods for 10. Kobayashi N, Miyazaki M, Fukaya K et al. (2000) Treatment treating human central pain with stem cells or precur- of surgically induced acute liver failure with transplantation of highly differentiated immortalized human hepatocytes. Cell sors. The promise of this strategy lies in the future and Transplant 9:733–735 will probably require a degree of genetic or laboratory 11. Pappas GD, Lazorthes Y,Bes JC et al. (1997) Relief of intractable manipulation. Regenerative medicine and the use of hu- cancer pain by human chromaffin cell transplants: experience at two medical centers. Neurol Res 19:71–77 man embryonic stem cells also currently engender eth- 12. Sagen J, Wang H, Tresco PA et al. (1993) Transplants of ical considerations. But, with rapid advances in knowl- immunologically isolated xenogenic chromaffin cells provide edge about the basic biology of and ability to manipulate a long-term source of pain-reducing neuroactive substances. J embryonic stem and precursor cells derived from CNS Neurosci 13:2415–2423 13. Trojanowski JQ, Kleppner SR, Hartley RS et al. (1997) Trans- andothertissues,thefuturewillprobablyhaveaplacefor fectable and transplantable postmitotic human neurons: poten- the use of cell therapy. For example, adrenal chromaffin tial “platform” for gene therapy of nervous system diseases. Exp progenitors can be kept proliferating by growth factors Neurol 144:92–97 invitro(BesandSagen2002),suggestingthattheymight 14. Westerman KA, Leboulch P (1996) Reversible immortalization of mammalian cells mediated by retroviral transfer and site- provide an alternative source for cell therapy, different specific recombination. Proc Nat Acad Sci USA 93:8971–8976 frombioengineered,immortalizedchromaffincelllines. 15. Wilson S, Chang K, Viveros O (1981) Opioid peptide synthe- Thenearfuturewillprobablyprovidenewchallengesfor sis in bovine and human adrenal chromaffin cells. Peptides 2 the implementation of cell therapy for those who suf- Suppl:83–88 fer chronic pain. Some of the challenges common to all forms of cell transplantation include immune rejection versuslong-termsurvivalandefficacyinthehumanhost, Cell Transplantation dependable, well characterized cell sources for grafts, cells that can safely integrate into or near the CNS without danger of tumors or significant deleterious effects, Cell Therapy in the Treatment of Central Pain abilitytocontroltheantinociceptiveoutputofcellgrafts, ideally increasing with the cyclic episodes of pain, and efficacy in a wide variety of pain causalities. Cell therapy for thetreatmentof pain offersmuch promiseasare- Cell-Mediated Immunity placement or adjunct to current clinical methodologies. The efficacy of this strategy will depend on a better un- Definition derstanding of the mechanisms of pain, so that such bio- An arm of the immune system that recognizes cell- engineered cellular tools can be used appropriately. associated antigens and consists of T-cells, phagocytes References and NK cells as cellular effectors. Viral Neuropathies 1. Andrews PW (1984) Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro. Dev Biol 103:285–293 2. Bes JC, Sagen J (2002) Dissociated human embryonic and fetal adrenal glands in neural stem cell culture system: open fate for Cellular Adhesion Molecules neuronal, nonneuronal, and chromaffin lineages? Ann N Y Acad Sci 971:563–572 3. Brewer KL, Yezierski RP (1998) Effects of adrenal medullary Synonyms transplants on pain-related behaviors following excitotoxic spinal cord injury. Brain Res 798:83–92 CAMs 306 Cellular Targets of Substance P

Deﬁnition Central Changes after Peripheral Nerve Cellular adhesion molecules (CAMs) are cell surface proteins involved in the binding of cells, usually leuko- Injury cytes, to each other, to endothelial cells, or to extracel- MARSHALL DEVOR lular matrix. Most of the CAMs characterized so far fall Department of Cell and Animal Biology, Institute into three general families of proteins: the immunoglob- of Life Sciences, and Center for Research on Pain, ulin (Ig) superfamily, the integrin family, or the selectin Hebrew University of Jerusalem, Jerusalem, Israel family. The Ig superfamily of adhesion molecules, [email protected] including ICAM–1, ICAM–2, ICAM–3, VCAM–1, and MadCAM–1, bind to integrins on leukocytes and Synonyms mediate their ﬂattening onto the blood vessel wall, with their subsequent extravasation into the surrounding Transsynaptic Changes after Peripheral Nerve Injury; tissue. central sensitization; central hyperexcitability state; Cytokine Modulation of Opioid Action Centralization; CNS Changes after Peripheral Nerve Injury

Definition Cellular Targets of Substance P Following nerve injury, including injury associated with chronic pain, numerous structural, neurochemical and Definition electrophysiological parameters are altered in the central nervous system (CNS), especially in the spinal cord Possible sources of NK1 receptor stimulated NGF and brainstem areas that receive direct primary afferent biosynthesis including mast cells, which have been input. This has led to the conviction that at least some of reported to be prominent sources of skin NGF, although these central changes contribute to chronic neuropathic the expression of NK1 receptors on these cells is unsure. paineitherdirectly,bygeneratingectopicpain-signaling There are only a few reports suggesting the presence of impulses, or indirectly, byamplifyingorotherwisemod- NK1 receptors on mast cells. However, it has to be taken ulating pain signals generated in the peripheral nervous into account that, depending on anatomic site, mast cells system (PNS). In most instances we do not know with show variations in cell size, cytoplasmic granule ultra- confidence whether or not a particular central change structure, mediator content, sensitivity to stimulation plays an important part in neuropathic pain. by secretagogues, and in their susceptibility to various pharmacological agents. Thus, it has been shown re- Characteristics cently that functional NK1 receptors are induced by Central Sensitization and Pain Centralization IL-4 and stem cell factor, suggesting that under certain conditions, like those accompanying inflammation, “Centralsensitization”referstoanalteredstateofcentral mast cells could gain increased responsiveness to NK1 neuralprocessing in which nociceptive signalsthatenter agonists. Keratinocytes have been shown to express the CNS from the periphery are amplified, or in which beta adrenoceptors and to produce NGF in response to signals carried centrally by low threshold mechanore- substance P. However, there are diverging reports as to ceptorafferents(afferentsthatnormallyprovokeasensa- the type of tachykinin receptor primarily expressed by tionoftouch)insteadprovokeasensationofpain(Camp- murine keratinocytes. Other possible sources of NGF belletal. 1988;Devor etal. 1991;Woolf 1983). Thecon- include macrophages/monocytes that express NK1 re- cept that pain hypersensibility in inflamed tissue and in ceptors and can be stimulated by substance P to produce neuropathymay be due, at least in part, to abnormalsig- cytokines. nal processing in the CNS, has a long history in neurol- NGF, Regulation during Inflammation ogy. The idea waspromoted in particular by Hardy, Wolf and Goodell in the 1950s (Hardy et al. 1952), but was marginalized at the time, with most investigators favor- ingthealternativehypothesisofhyperexcitablenocicep- Cementum tive afferent endings in the periphery (Lewis 1942). The conviction that the CNS makes an important contribution was revived in the 1980s, partly under the influence Definition of Melzack and Wall’s “Gate control theory” and partly Cementum is the mineralized tissue that covers the root duetotheappearanceofagreatdealofnewdatabasedon of a tooth. At the level where it abuts the enamel of the experimental observations in humans and animal prepa- crown it is very thin and often abraded, exposing the un- rations. derlying sensitive dentin. When first introduced, the term central sensitization DentalPain, Etiology, PathogenesisandManagement referred to a spinal pain hypersensitivity state triggered Central Changes after Peripheral Nerve Injury 307 by afferent input entering the CNS on nociceptive C- given the dissonant name “extraterritorial pain” The afferents, and perhaps also nociceptive Aδ-afferents. concept can be extended still further. Pathology in one This hypersensitivity state comes on rapidly following organ, for example, can cause hyperesthesia in neigh- onset of the nociceptive stimulus (seconds or minutes), boring ones, and meningeal inflammation in migraine and on cessation of the stimulus rapidly dissipates can cause tenderness on the scalp. Some authors have C (minutes or hours). It can be maintained indefinitely, gone even further, positing that broad expanses of the however, by continuous barrages of nociceptive input central somatosensory representation can become per- such as may occur in chronic inflammatory conditions sistently hyperexcitable. This is a popular explanation and neuropathy. Thus, as originally conceived, central for widely distributed global pain symptoms such as in sensitization is a labile, dynamic state dependent on an fibromyalgia (Banic et al. 2004; McDermid et al. 1996). ongoing barrage of nociceptive afferent input (Gracely et al. 1992; Ji et al. 2003; Koltzenburg et al. 1994; Varieties of Central Change Torebjork et al. 1992). Numerous central changes have been documented in an- Research into neural mechanisms that might underlie imal models of neuropathic (and inflammatory) pain. In central sensitization, however, revealed that a large va- principle, itoughtto be possible to determinethe relative riety of candidate processes are triggered by peripheral contribution of each such change by spinal delivery of inflammation and neuropathy, and that some of these are agents that counter the changes, one at a time. Each such neither transient and rapidly reversible, nor apparently agent should block a fraction of the neuropathic pain dependent on ongoing afferent input. The discovery of symptoms, and the appropriate combination of agents such durable central changes coincided with the revival should block the pain entirely. In practice, however, this ofanotherclassicalconcept,“ paincentralization”Be- approach has not produced clear results. In many cases, lievers in pain centralization claim that persistent severe appropriate blocking drugs are not available. In others, paincan“burnitselfinto”theCNS,inthesamewaythata the application of drugs intended to reverse individual torrential stream can carve a canyon through solid rock. central changes has been claimed to eliminate neuro- Persistent pain thus creates a central hyperexcitability pathic pain entirely. This suggests that experimental re- statethatbecomesindependentofafferentinputfromthe sults might have been exaggerated, or perhaps tested un- periphery. If true, this is an important matter, because it der highly specific, idiosyncratic circumstances. Alter- implies that pain relief has a deadline; if it is not relieved natively, pain symptoms may have a threshold such that soon enough it centralizes and may become intractable, partial suppression of many independent processes in- permanent (Kalso 1997). deed yields complete pain suppression. It is unlikely that pain, per se, can in fact cause perma- Anotherproblemiswiththeagentsthemselves.Pharma- nent changes in central somatosensory processing. If it cological agents that show a high degree of specificity did, then severe pain would persist after removal of a when tested under specific in vitro conditions, often clearperipheralsourcesuchaspassageofakidneystone, prove to have unanticipated effects when tested in com- childbirth, or replacement of an osteoarthritic hip. Pe- plex behavioral paradigms, in vivo. This also extends ripheral nerve injury, in contrast, may well induce per- to newer transgenic technologies. Finally, few authors manent CNS changes and intractable pain. In the con- check whether the agents they deliver to the spinal cord text of neuropathy, the idea of durable centralization has actually act there. Ectopic impulse discharge originat- mergedwiththeoriginaldynamicconceptofcentralsen- inginthe DRG is thought to play an important role in sitization. Thus, “central sensitization” has become an the initiation and maintenance of central sensitization, umbrella term that coversall peripherallyevokedcentral particularly in animal models of neuropathy. Since the changes that contribute to neuropathic pain, labile and DRG shares the epidural and the intrathecal space with durable. This will be the use of the term in the present the spinal cord, spinally delivered drugs access primary essay. Note that central changes underlying neuropathic sensory neurons as well as CNS neurons. It is essential pain probably encompasssomeprocessesthatarenotin- to document that the spinally administered drug being volved in central sensitization evoked by acute noxious tested does not silence peripheral ectopia because this events, or by peripheral tissue inflammation. alone would be expected to relieve pain symptoms, Central sensitization was originally conceived of as without regard to the central process being tested. Such being regionally circumscribed. For example, follow- confirmation is rarely done. ing a localized burn, allodynia and hyperalgesia spread What follows is a list of central changes induced by pe- somewhat beyond the area of primary injury into a ripheral nerve injury that might reasonably be predicted surrounding zone termed the area of “ secondary hy- to affect pain processing. Most have been documented peralgesia”. Likewise, if the precipitating injury is to a in one, or only a few neuropathic pain models, or are particular nerve or sensory ganglion, central sensitiza- inferred from models of inflammation, and are not nec- tion can cause the pain to extend into the distribution essarily universal. Some may appear paradoxical. For of neighboring nerves, or nearby dermatomes. Pain example, a priori one might presume that depletion of extending beyond the triggering source is sometimes an excitatory transmitter, or increased expression of an 308 Central Changes after Peripheral Nerve Injury inhibitory one, is unlikely to cause pain. However, since also undergo changes in gene expression. All of these thesetransmittersmightbeactingoninhibitoryinterneu- are candidates, but few have been subjected to even ronsin thespinalcord, acontributionto painhypersensi- minimal functional analysis. tivitybysuchchangescannotberuledout.Thelistbelow is presented with a minimum of annotation (and without references due to editorial limitations imposed on all es- Changes in the Neurochemistry and Gene Expression says in this volume). It is almost certainly incomplete at of CNS Neurons and Glia after Peripheral Nerve Injury the time of writing, and new changes are being identified • A number of activity-regulated immediate early ata rapid rate. Some changesmayoverlap, be redundant, genes are upregulated in postsynaptic neurons in the or describe the same processusing alternative functional dorsal horn including c-fos and jun-B. These tend to markers. be transcription factors and hence probably affect the expression of numerous other, still unidentified, Changes in the Neurochemistry of Primary Afferent downstream genes. Terminals in the Spinal Cord after Peripheral Nerve • Many transmembrane and intracellular signaling Injury cascades in postsynaptic neurons are activated by • Levels of the excitatory peptide neurotransmit- the phosphorylation of protein kinases such as ERK, ter/neuromodulator substance P (SP), and ex- MAPK, and CREB. More than 500 protein kinase pression of its precursor gene preprotachykinin, are genes are present in the mammalian genome (Man- reduced in small diameter nociceptive DRG neu- ning et al. 2002). rons and their central terminals. However, there is a • Levels of cyclooxygenase (COX–1 and COX–2) in concomitant increase in medium and large diameter thedorsalhornarealteredwithconsequentchangesin DRG neurons. arachidonic acid metabolites including (excitatory) • Expression of the excitatory peptide neurotransmit- prostanoids and leukotrienes. ter/neuromodulator CGRPisdecreasedinsmalldi- • Expression of certain Na+ channel types is upregu- ameter DRG neurons and their central terminals. lated in postsynaptic spinal neurons following nerve • Expression of the inhibitory peptide neurotransmit- injury. Such changes are expected to increase the exter/neuromodulator galanin is increased. citability of the affected neurons. • Cellular content of the excitatory peptide neurotrans- • A decrease in μ opiate receptors on postsynaptic dor- mitters/neuromodulators neuropeptide Y (NPY) salhornneuronsfollowingnerveinjurymayoccasion and vasoactive intestinal peptide (VIP) is increased, decreased intrinsic spinal inhibition. as is that of a variety of proinflammatory cytokines. • P2X4 receptors are upregulated in dorsal horn mi- • Expression of the μ opioid morphine receptor gene croglia, potentially enhancing response to the exci- (MOR) is reduced in DRG neurons and μ receptor is tatory neurotransmitter ATP. depleted in afferent terminals • There is an increase in the spinal content of pro- • The Ca 2+ channel subunit α2δ-1 is upregulated in ax- inflammatory cytokines including IL1β,IL6,TNFα, otomized primary afferent neurons, perhaps enhanc- but also in the anti-inflammatory cytokine IL10. ing synaptic release. These compounds are synthesized in activated as- • Expression of the transducer/ion channels TRPV1 trocytes and microglia and are released into the and P2X3 is depressed in afferent terminals extracellular space. Some may also be produced • Tissue plasminogen activator is induced in primary in neurons. Proinflammatory cytokines can sensi- afferent neurons by axotomy and released from their tize and directly excite postsynaptic dorsal horn terminal endings. This increases the excitability of neurons. dorsal horn neurons. • There is an alteration in the content of many neu- • Expression of the TTX -S Na+ channel Nav1.3 is rotransmitters in postsynaptic dorsal horn neurons, upregulated in axotomized DRG neurons while that some inhibitory (e.g. 5-HT, NA, GABA, glycine) of TTX-R Nav1.8 and Nav1.9 is downregulated. All and some prohyperalgesic (e.g. dynorphin). There three channels contribute to the membrane excitabil- is also an increase in the spinal content of many ity of primary afferent neurons and their central ter- bioactive molecules of uncertain function in pain minals. processing such as certain lectins and GAP43 • The preceding are high-profile examples of changes • Increased nocistatin decreases spinal GABA inhibi- ingeneexpressioninDRGneurons,andingeneprod- tion. uct density in afferent terminals, following axotomy. • As with primary sensory neurons, studies using Recent studies using oligonucleotide arrays indi- oligonucleotide arrays suggest that very large num- catethatmorethanonethousandtranscriptsareup-or bers of transcripts are up- or down-regulated in the down-regulated in axotomized DRG neurons (Costi- spinal cord as a consequence of nerve injury. Few of gan et al. 2002; Xiao et al. 2002), and that “intact” these have been subjected to even minimal functional neighboring neurons that have not been axotomized analysis. Central Changes after Peripheral Nerve Injury 309

Structural Changes in the CNS after Peripheral Nerve sible that some specific components of the ascending Injury volley are enhanced. • • Central terminals of axotomized primary afferent NMDA type glutamate receptors on postsynaptic neurons show a morphologically distinct “degen- dorsal horn pain signaling neurons are normally eration atrophy”. The functional significance is blocked and non-functional at resting membrane po- C uncertain, but the change might be associated with tential. Primary afferent nociceptive input produces altered synaptic release or even degeneration. a prolonged, shallow depolarization, probably due to • There are reports that intraspinal terminals of low the release of SP (and other peptides) which relieves threshold mechanoreceptive Aβ afferents enter a the block, enables the NMDA-Rs, and enhances growth mode, extending sprouts dorsally into spinal postsynaptic response to Aβ touch input. • laminae 1 and 2, where they may form ectopic Nociceptive afferent input induces PKC-dependent synaptic contacts with pain signaling spinal neu- phorphorylation of NMDA-R subunits contributing rons. This finding is controversial, however, as it to spinal pain hypersensitivity. might simply reflect axotomy-induced enhancement • There is also activation of non-NMDA glutamate re- of the visualization of afferent connections present ceptors (kainate receptors) in the spinal cord follow- normally. ing nociceptive afferent input. • • Thereisalossof neuronsthatimmunolabelfor thein- Since the nociceptive mediators SP,NPY,and BDNF hibitory neurotransmitters glycine and GABA. This come to be expressed in low threshold mechanore- β mayreflectpermanentlossofinhibitoryinterneurons. ceptive A afferents, activity in these afferents might • Time-dependent loss of many functionally unidenti- come to directly activate pain signaling dorsal horn fiedneuronsinthedorsalhornhasbeenreported(neu- neurons. • rodegeneration), but the magnitude and significance For the same reason, these afferents may acquire the of this effect has been disputed. ability to trigger and maintain central sensitization. • • Transsynaptic atrophy and cell loss has been reported There is increased release of the excitatory neuro- in somatotopically appropriate supraspinal projec- transmitter glutamate in the dorsal horn. • tion systems including the primary somatosensory “Glycinespillover”facilitatestheresponseofNMDA cortex (in long term amputees). receptors to glutamate, including glutamate released β • Large numbers of astrocytes and microglia in the from A touch afferents. • – dorsal horn are “activated”, shortly after nerve injury, Suppression of the Cl pump, and the consequentde- – showing hypertrophy, increased numbers (hyperpla- polarizingshiftoftheCl reversalpotential,cancause sia), and altered expression of neuroactive molecules the normally inhibitory neurotransmitter GABA to including proinflammatory cytokines. yield excitation. • Immune cells from the peripheral circulation, includ- • Manysynapsespresentondorsalhornneuronsarerel- ing macrophages and lymphocytes, invade the dor- atively ineffective at driving the postsynaptic neuron sal horn grey matter. They may release excitatory cy- (“silent synapses”). These can be strengthened by a tokines and activate dorsal horn neurons. variety of mechanisms, opening new functional path- • ATP,an excitatory neurotransmitter, is released from ways including Aβ access to ascending nociceptive astroglia activated following nerve injury.ATP isalso circuitry. hydrolysedintotheinhibitoryneuroactivetransmitter • BDNF released from afferent terminals, and perhaps adenosine. synthesized locally, sensitizes postsynaptic neurons in the superficial dorsal horn. • Elevatedbackgroundafferentactivity(ectopia)depo- Electrophysiological and Functional Changes in the larizes neurons, bringing them closer to spike thresh- CNS after Peripheral Nerve Injury old. This increases the level of spontaneous activity • The dorsal root potential (DRP) and primary affer- generatedwithinthedorsalhorn,andenhancesthere- ent depolarization (PAD), two measures of spinal sponse of dorsal horn neurons to weak residualinputs presynaptic inhibition, are suppressed following from the periphery. nerve injury. Reduced inhibition increases spinal • Repetitive stimulation at low frequency reveals response. homosynaptic facilitation ("windup"). This is aug- • Receptive fields (RF) of dorsal horn neurons expand, mented after nerve injury. increasing the RF overlap between neighboring neu- • Long term potentiation (LTP) is facilitated by nerve rons. A given peripheral stimulus now activates more injury. spinal cord neurons. • The duration of spinal postsynaptic potentiation is • The overall impulse volley that ascends in the spinal augmented by nerve injury. cord towards the brain upon electrical stimulation of • Injury discharge triggered by acute transection of a peripheralnerve isreduced by about50%beginning primary afferent axons may selectively damage in- 1–2 weeks following nerve injury. However, it is pos- hibitory spinal interneurons, perhaps by the sudden 310 Central Changes after Peripheral Nerve Injury

release of high levels of glutamate (excitotoxic cell these signaling molecules released or incorporated into death). the membrane might be regulated by spike-evoked exo- • Nerve injury is associated with reduced GABA re- cytosis, or perhaps by constitutive processes unrelated lease in the dorsal horn following electrical nerve to afferent impulse traffic (Battaglia et al. 2003; Fields stimulation. et al. 2001). • Spontaneousdischarge,particularlyinaburstymode, isaugmented in dorsalhornpostsynapticneuronsand Perspective also in supraspinal relays. Some of this activity may Only a generation ago there was little concept of the be generated within the CNS, rather than reflecting processes that might underlie neuropathic pain. The elevated peripheral drive. situation has since reversed so that today we are awash • Brainstem descending inhibition may be reduced fol- with candidate theories. It is a high priority to develop lowing nerve injury. strategies for prioritizing central changes in terms of • Brainstem descending facilitation may be enhanced their relative contribution to pain symptomatology. following nerve injury. Likewise, it is essential to establish the mechanism(s) • The gate control theory predicts that selective loss by which nerve injury triggers CNS changes. If all of large diameter low threshold afferent neurons will or most central changes are due to abnormal primary bias the spinal gate towards augmented nociception. afferent input, it may be possible to prevent or reverse the central changes by controlling afferent input. Alter- How Does Nerve Injury Trigger Central Change? natively, key central changes might offer opportunities for direct therapeutic intervention. Little is know with confidence about how peripheral nerve injury triggersand maintainscentralsensitization. Acknowledgements There are three fundamental possibilities: Thanks to Linda Watkins and Zsuzsanna Wiesenfeld- Depolarization due to Impulse Trafficperse Hallin for helpful commentson the manuscript. I wish to The resting potential of postsynaptic neurons is deter- apologize to the numerous colleagues whose work was mined, in part, by the constant barrage of excitatory noted in this essay but not specifically cited because of and inhibitory postsynaptic potentials impinging on editorialrestrictionsonthenumberofreferencespermit- their dendritic arbor (spatial and temporal summated. tion). Ectopic afferent activity in neuropathy enhances the barrage, depolarizes the neuron, and brings rest- References ing potential closer to firing threshold. This increases 1. Banic B, Petersen-Felix S, Andersen OK et al. (2004) Evidence spontaneous firing and response to normal and ectopic for Spinal Cord Hypersensitivity in Chronic Pain after Whiplash afferent input. Injury and in Fibromyalgia. Pain 107:7–15 2. Battaglia AA, Sehayek K, Grist J et al. (2003) EphB Receptors OtherActionsofTransmittersReleasedbyAfferentIm- and Ephrin-B Ligands Regulate Spinal Sensory Connectivity and Modulate Pain Processing. Nat Neurosci 6:339–340 pulse Traffic 3. Campbell JN, Raja SN, Meyer RA et al. (1988) Myelinated Af- Neurotransmitter and neuromodulator molecules re- ferents Signal the Hyperalgesia Associated with Nerve Injury. leased from afferent terminals during spike activity may Pain 32:89–94 4. Costigan M, Befort K, Karchewski L et al. (2002) Replicate High- have postsynaptic effects beyond the moment to mo- Density Rat Genome Oligonucleotide Microarrays Reveal Hun- ment modulation of the membrane potential. Coupling dreds of Regulated Genes in the Dorsal Root Ganglion after Pe- may be via ligand-gated ion channels (and consequent ripheral Nerve Injury. BMC Neurosci 3:16–28 membrane depolarization), or transmembranesignaling 5. Devor M, Basbaum A, Bennett G et al. (1991) Mechanisms of Neuropathic Pain following Peripheral Injury. In: Basbaum A, pathways that are independent of membrane potential. Besson J-M (eds) Towards a New Pharmacology of Pain, Chich- ester: Dahlem Konferenzen, Wiley, pp 417–440 Trophic Interactions 6. Fields RD, Eshete F, Dudek S et al. (2001) Regulation of Gene More speculatively, nerve injury might bring about Expression by Action Potentials: Dependence on Complexity in Cellular Information Processing. Novartis Found Symp central changes completely independent of impulse 239:160–172 traffic and synaptic release. During embryonic de- 7. Gracely R, Lynch S, Bennett G (1992) Painful Neuropathy: Al- velopment, the very survival of primary sensory and tered Central Processing, Maintained Dynamically by Peripheral second order CNS neurons is dependent on mutual Input. Pain 51:175–194 8. Hardy JD, Wolf HG, Goodell H (1952) Pain Sensations and Re- neurotrophic interactions. Beyond a critical period the actions. William and Wilkins, New York neurons lose their acute dependence on neurotrophic 9. Ji RR, Kohno T, Moore KA et al. (2003) Central Sensitization and support, but even in adulthood neuronal phenotype is LTP: Do Pain and Memory Share Similar Mechanisms? Trends altered by changes in the provision of developmental Neurosci 26:696–705 10. Kalso E (1997) Prevention of Chronicity. In: Jensen TS, Turner neurotrophins (Boucher et al. 2001). Both soluble and JA, Wiesenfeld-Hallin ZH (eds), Proceedings of the 8th World membrane bound recognition molecules could be in- Congress on Pain. Progress in Pain Research and Management, volved (neurotrophins, NCAMs, ephrin). Amounts of vol 8. IASP Press, Seattle, pp 215–230 Central Nervous System Stimulation for Pain 311

11. Koltzenburg M, Torebjork, H, Wahren L (1994) Nociceptor Modulated Central Sensitization Causes Mechanical Hyper- Central Medial Nucleus (CM) algesia in Acute Chemogenic and Chronic Neuropathic Pain. Brain 117:579–591 12. Lewis T (1942) Pain. MacMillan, New York Definition 13. Manning G, Whyte DB, Martinez R et al. (2002) The Pro- C tein Kinase Complement of the Human Genome. Science A nucleus within the internal medullary lamina, located 298:1912–1934 ventrally to the central lateral nucleus and lateral to the 14. McDermid AJ, Rollman GB, McCain GA (1996) Generalized Hypervigilance in Fibromyalgia: Evidence of Perceptual Ampli- parafascicular nucleus. fication. Pain 66:133–144 Thalamus, Visceral Representation 15. Torebjork H, Lundberg L, LaMotte R (1992) Central Changes in Processing of Mechanoreceptive Input in Capsaicin-Induced Secondary Hyperalgesia in Humans. J Physiol 448:765–780 16. Woolf CJ (1983) Evidence for a Central Component of Post- Injury Pain hypersensitivity. Nature 306:686–688 17. Xiao HS, Huang QH, Zhang FX et al. (2002) Identification of Central Nervous System Map Gene Expression Profile of Dorsal Root Ganglion in the Rat Pe- ripheral Axotomy Model of Neuropathic Pain. Proc Nat Acad Sci USA: 998360–998365 Definition The organizationof locations on or in the brain or spinal cord that represent the characteristics of a stimulus, such Central Gray/Central Grey as the receptive field, or of motor output, such as stimulation evoked movement. Thalamus,ReceptiveFields,ProjectedFields,Human Opioid Electrophysiology in PAG

Central Hyperexcitability Central Nervous System Portion of a Cranial Nerve Central Changes after Peripheral Nerve Injury Visceral Pain Model, Esophageal Pain Definition The proximal portion of a cranial nerve over which myelin is associated with glial (oligodendroglial) cells Central Lateral Nucleus (CL) rather than with the Schwann cells, which are associated with myelin in the periphery. Trigeminal, Glossopharyngeal, and Geniculate Neu- Definition ralgias The intralaminar complex is a group of thalamic nuclei composed of neurons that are located within the internal medullary lamina, a nerve fiber sheet that can be used to subdivide different parts of the thalamus. The central lateral nucleus is one of the rostral group of intralaminar Central Nervous System Stimulation for nuclei of the primate thalamus. Itreceives inputfrom the Pain spinothalamic tract and projects broadly to the sensori- 1, 2 2, 3 LUC JASMIN ,PETER T. OHARA motor cortex, as well as to the striatum. 1 Spinothalamic Input, Cells of Origin (Monkey) Department of Surgery, Division of Neurosurgery, University of Texas Medical Branch, Galveston, TX, Spinothalamic Terminations, Core and Matrix Thalamotomy for Human Pain Relief USA 2Department of Anatomy and, Thalamus, Visceral Representation 3the W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA, USA Central Lobe [email protected], [email protected]

Insular Cortex, Neurophysiology and Functional Synonyms Imaging of Nociceptive Processing CNS Stimulation in Treatment of Neuropathic Pain 312 Central Nervous System Stimulation for Pain

Definition the cessation of the electric current (minutes to hours). Electrical stimulation of the central nervous system is a This persistent analgesia is thought to depend not only non-destructiveand reversible therapy for certain forms on an effect on neurons adjacent to the stimulating of difficult to treat chronic pain. Candidates have to fail a electrode, but also on long neural loops linking the trial of the more conventional therapies. An electrode is spinal cord to the brain. The result is the inhibition of placed over the spinal cord, cerebral cortex or in the tha- spinothalamic projection neurons (Gerhart et al. 1984). lamus, hypothalamus or central gray matter. Analgesia Clearly, when the underlying disease involves a loss is produced when a small current is delivered through of large fiber activity (as in multiple sclerosis or post- this electrode and usually persists for some time after cordotomy dysesthesia), stimulation is less likely the current is turned off. to work. Another often cited mechanism is that spinal cord stimulation blocks sympathetic nervous system Characteristics fibers. This latter action would explain the favorable Both clinical and experimental studies have determined results obtained in complex regional pain syndrome that electrical stimulation of the spinal cord or brain (CRPS) and in angina pectoris. Other indications are is analgesic. Considering the complexity of chronic neuropathic leg pain (not back pain) associated with pain, it is often perplexing that such a simple technique failed back syndrome, diabetic neuropathy, ischemic results in relieving pain syndromes often deemed “in- leg pain not treatable by vascular surgery, phantom tractable”, while complex pharmaceutical approaches, limb pain, post-herpetic neuralgia, spinal cord injury often because of their side effects, end in failure. Since pain, tabes dorsalis and spinal cord injury pain. the 1960s the technology associated with electrical Long term, moderate relief can be obtained in many stimulation for pain has remained essentially the same, patients. although the quality of the components has improved. In spite of the use of electrical stimulation to control The two main components are the electrode and the pain in large number of patients, there have been only current generator, both of which are internalized (i.e. a few placebo-controlled evaluations of this treatment all inside the patient). The electrode (4 to 8 contacts) is (Mailis-Gagnon et al. 2004). A significant placebo ef- usually placed over the dorsal aspect (dorsal columns) fect might exist in patients utilizing SCS, and the relief of the spinal cord, in the brain parenchyma (thalamus, might be related to the distraction of stimulation. Test- hypothalamus or periaqueductal gray matter [PAG]), ing of this possibility is undermined by the difficulty or over the surface of the motor cortex. The current in controlling for placebo response in a therapy that generator, which is presently about the size of a pace- depends on the production of a sensory phenomenon maker (4 cm × 4 cm × 1 cm), is concealed under the skin to work (i.e. patients feel a tingling or paresthesia in and connected to the electrode through subcutaneous the stimulated area when the current generator is on). wires. The current generator (including a rechargeable Although it is important to understand the exact mech- battery) is programmed by telemetry using a handheld anism of pain relief, it will probably not matter to the computer and an antenna laid over the appropriate skin patient whether it is via placebo or some other mech- area. Voltage, frequency, pulse width and times of the anism. While all agree that better clinical studies are day the system is on can be adjusted after the system is needed to confirm the effectiveness of SCS, especially implanted. since the benefits appear moderate, its continued use appears justified since it decreases the cost of treating Spinal Cord Stimulation (SCS) pain (Taylor et al. 2005). Spinal cord stimulation (SCS) was first performed in 1967 and since then several hundred thousand patients Deep Brain Stimulation (DBS) have received this treatment worldwide. About 10,000 Deep brain stimulation (DBS) has been out of favor individuals will be implanted in the United States this since 1999 when Medtronic (Medtronic Inc. Min- year alone. While the mechanism remains to be fully neapolis, MN) decided not to pursue FDA approval for elucidated, a widely regarded explanation is the gate this therapy due to the lack of conclusive clinical data control theory. This theory, dating from the 1960s sug- (Coffey 2001). In spite of this, DBS is still used “off- gests that nociceptive information entering the CNS label” here and in other countries for selected patients is reduced by the activity of innocuous (low threshold (Nandi and Aziz 2004). Electrodes are implanted in large fibers) sensory afferents or brain activity. The the ventropostero-lateral thalamus, posterior limb of effect of electrically stimulating neural pathways ca- the internal capsule, periventricular gray including the pable of inhibiting nociceptive information is to “close posterior hypothalamus or PAG. Stimulation in these the gate” on the noxious input and result in analgesia. areas is reported as fairly successful in patients with Accordingly, the electrode is positioned at the level of failed back syndrome, trigeminal neuropathy other the spinal cord corresponding to the dermatome or than tic douloureux, certain forms of central pain viscerotome where the pain is felt. Interestingly, the (post-stroke pain), peripheral neuropathy, anesthesia analgesia produced by stimulation often lasts long after dolorosa and post-cordotomy dysesthesia. Central Nervous System Stimulation for Pain 313

As with dorsal column stimulation, the neural mecha- The rationale that guided surgeons to attempt cortical nisms underlying DBS-induced analgesia are a matter stimulation was based on the results of many decades of speculation. Marchand and colleagues (Marchand of experimentation, which demonstrated that electrical et al. 2003) studied the effect of placebo stimulation stimulation of the cerebral cortex affects spinal and in patients with thalamic electrodes installed for pain trigeminal afferent sensory transmission and that this C control. Their key finding is that placebo analgesia is a effect is, in part, presynaptic on somatic afferents, insignificant element of DBS and that this is reinforced cluding nociceptive afferents (Abdelmoumene et al. by the degree of paresthesia felt during the stimulation. 1970). The effect of stimulation of the cerebral cortex The study of Marchand and colleague supports the con- on spinothalamic neurons however, can be inhibitory, tention that further controlled investigations are needed excitatory or both (Yezierski et al. 1983). Because to understand the mechanisms by which stimulation of the latency of excitation is significantly shorter than the central nervous system produces analgesia. the latency of inhibition, inhibition could be polysy- Recently DBS has experienced a rebirth based on the naptic via inhibitory interneurons and/or presynaptic finding that stimulation of the hypothalamus can re- processes on primary afferent terminals. Finally, ex- duce the occurrence of cluster headaches (Horton’s perimentation in cats has also shown that motor cortex headaches). Cluster headaches are a vascular type of stimulation blocks spontaneous burst activity induced pain, occurring more commonly in males and charac- by spinothalamic deafferentation (Tsubokawa et al. terized by unilateral headaches lasting 30 to 90 minutes 1991). and recurring 1 to 6 times a day for several weeks. The most common indication for cortical stimulation Between attacks, patients can be asymptomatic for is central pain syndrome. Dejerine recognized the syn- months. The pain is reported as excruciating and char- drome a century ago while an intern at the Salpêtrière acteristically located around the eye, which is visibly hospital in Paris. Because all of his patients with this congested and tearing. While some measures, such as previously unrecognized pain syndrome were found to avoiding alcohol and tobacco, reduce the frequency of have strokes in the posterolateral thalamic area at au- the attacks, in many patients the prevention and treat- topsy, Dejerine and Roussy, coined the term “thalamic ment of cluster headaches presents a challenge. In 1998 syndrome” A complete thalamic syndrome is uncom- the positron emission tomography (PET) observation mon and subsequently the term “thalamic pain” was that the symptomatic phase of cluster headaches was usedforallpainconditionsthatarosefromboththalamic accompanied by the activation of a region of the ipsi- and non-thalamic CNS lesions. Since the majority of lateral medio-caudal hypothalamus led to the idea that central pain syndromes occur after an ischemic stroke, stimulation of this area might be of therapeutic value the designation ‘central post-stroke pain’ (CPSP) is (Ekbom and Waldenlind 2004, Leone et al. 2004). often employed. The current definition of central pain Unilateral or bilateral electrodes and high frequency has become quite broad and accommodates etiologies stimulation have been effective in reducing the occur- of central pain such as Parkinson’s disease or epilepsy, renceand duration of theattacks. PET imagingin cluster in which there is no thalamic lesion or interruption of headache has revealed that during hypothalamic stimu- thalamic afferents. It should be noted that “central pain” lation, some pain activated areas such as the ipsilateral differs from “centralized pain”, which is considered to anterior cingulate, primary somatosensory cortices and result from remodeling of the CNS as a consequence of the insular cortex bilaterally are inactive (May et al. a peripheral injury. One example of centralized pain for 2003). While, DBS does not bring a cure to individuals which cortical stimulation has recently been shown to with cluster headaches, for some it is the best treatment be successful is trigeminal deafferentation pain (Brown available. For neuroscientists, it is a further indication and Pilitsis 2005). of the validity of electrical stimulation for pain and an Although it is important to optimize patient selection for incentive to purse basic research in this field as a means motor cortex stimulation, there is no unequivocal way of understanding pain mechanisms. to separate the responders from the non-responderspre- operatively. Only patients with an intact motor cortex and corticospinal projections should be chosen. In pa- Motor Cortex Stimulation (MCS) tients with large lesions of the motor cortex or pyramidal Motor cortex stimulation (MCS) has also yielded tractonthesideoppositetothesymptoms,stimulationof positive results in treating patients with central pain the ipsilateral motor cortex has been shown to produce following ischemic brain or spinal injury and with analgesia. Stimulation is usually ineffective, however, deafferentation pain in the trigeminal or spinal ter- in subjects with profound sensory loss. Imaging studies ritories. Here an electrode is laid over the part of the have also been recommended prior to surgery in order to motor cortex (usually over the dura rather than directly confirm the presence of cortical hypoperfusion and as- on the pia mater) that corresponds to the area where the certainthesiteofimplantation,sincecorticalstimulation pain is felt on the opposite side of the body (according isassociatedwithacorticalreperfusion.Finally,atrialof to the homunculus). non-invasive stimulation using a transcranial magnetic 314 Central Neuropathic Pain coil over the motor cortex could also be a helpful way 11. May A, Leone M, Boeker H et al. (2003) Deep brain stimulation of selecting the potential responders. in cluster headache: preventing intractable pain by activating the pain network. Cephalalgia 23:656 12. Nandi D, Aziz TZ (2004) Deep brain stimulation in the manage- Vagal Nerve Stimulation (VNS) ment of neuropathic pain and multiple sclerosis tremor. J Clin Vagal nerve stimulation (VNS) acts indirectly to stim- Neurophysiol 21:31–39 13. Taylor RS, Van Buyten JP, Buchser E (2005) Spinal cord stimulate the CNS through sensory afferents to the caudal ulation for chronic back and leg pain and failed back surgery brainstem. VNS is currently used to treat certain forms syndrome: a systematic review and analysis of prognostic fac- ofepilepsyandisunderinvestigationaspossibletherapy tors. Spine 30:152–160 fordepression.Itmightalsobecomeanacceptedmethod 14. Tsubokawa T, Katayama Y, Yamamoto T et al. (1991) Treatment of thalamic pain by chronic motor cortex stimulation. Pacing Clin for treating cluster headaches and migraine (Mauskop Electrophysiol 14:131–134 2005) and possibly other pain disorders. Because it can 15. Yezierski RP, Gerhart KD, Schrock BJ et al. (1983) A further ex- decrease the nociceptive threshold in depressed individ- amination of effects of cortical stimulation on primate spinotha- uals(Borckardtetal. 2005) and depressionoftenaccom- lamic tract cells. J Neurophysiol 49:424–441 panies pain, patient selection for this technique will be critical. Central Neuropathic Pain Conclusion DAV I D BOWSHER Further clinical studies are needed to validate CNS stim- Pain Research Institute, University Hospital Aintree, ulation as an effective treatment of pain, mainly because Liverpool, UK most of the evidence is anecdotal or retrospective. Basic [email protected] or [email protected] research is critically needed to establish the mechanism of action and it is possible that stimulation induced anal- Synonyms gesia might open the door to a new, unforeseen understanding of the means by which pain operates. DBS is Dejerine and Roussy (1906) described three cases of currently gaining popularity for the treatment of move- pain following strokes involving the thalamus, and ment disorders, a field where much greater understand- named the condition “thalamic syndrome” – a name ing of the neural circuitry has fostered unique cooper- that has, unfortunately, remained in the literature – ation between clinicians and basic scientists. The same because it was later shown that similar pain follows in- type of teamwork could benefit the developmentof new farction of other, non-thalamic, telencephalic areas such ideas and advances in the field of pain. as the cortex (Foix et al. 1927). Infarction in brainstem or the anterolateral medulla oblongata can also cause pain in the condition known as Wallenberg’s syndrome References (Ajuriaguerra 1937). 1. Abdelmoumene M, Besson JM, Aleonard P (1970) Cortical areas The onset of pain following central lesions is not exerting presynaptic inhibitory action on the spinal cord in cat restricted to supraspinal pathology. Central pain in and monkey. Brain Res 20:327–329 syringomyelia has been reported by Spiller (1923) 2. Borckardt JJ, Kozel FA, Anderson B et al. (2005) Vagus nerve stimulation affects pain perception in depressed adults. Pain Res and was indistinguishable from central pain of cere- Manag 10:9–14 bral origin. Unfortunately, recognition of the fact that 3. Brown JA, Pilitsis JG (2005) Motor cortex stimulation for central central pains following spinal cord damage, such as and neuropathic facial pain: a prospective study of 10 patients and observations of enhanced sensory and motor function during anterolateral cordotomy (White and Sweet 1969), and stimulation. Neurosurgery 56:290–297; discussion 290–297 of course spinal cord injury (SCI) are similar to those 4. Coffey RJ (2001) Deep brain stimulation for chronic pain: re- of supraspinal origin was slow to develop. sults of two multicenter trials and a structured review. Pain Med 2:183–192 Definition 5. Ekbom K, Waldenlind E (2004) Cluster headache: the history of the Cluster Club and a review of recent clinical research. Funct Leijon et al. (1989) proposed the name “Central Post- Neurol 19:73–81 Stroke Pain” (CPSP) to cover all these contingencies – 6. Gerhart KD, Yezierski RP, Wilcox TK et al. (1984) Inhibition of however, this name does not encompass cases caused by primate spinothalamic tract neurons by stimulation in periaqueductal gray or adjacent midbrain reticular formation. J Neuro- conditions other than stroke. The post-mortem anatom- physiol 51:450–466 ical pathology of eleven cases in which lesions of the 7. Leone M, Franzini A, Broggi G et al. (2004) Long-term follow- central nervous system, including cortical lesions, two up of bilateral hypothalamic stimulation for intractable cluster tumours and one multiple aneurysm, resulted in the headache. Brain 127:2259–2264 8. Mailis-Gagnon A, Furlan AD, Sandoval JA et al. (2004) Spinal onset of pain was described in detail by Davison and cord stimulation for chronic pain. Cochrane Database Syst Schick (1935). Subarachnoid haemorrhage, multiple Rev:CD003783 sclerosis, tumour, cerebral abscess, Behçet’s disease, 9. Marchand S, Kupers RC, Bushnell MC et al. (2003) Analgesic Parkinson’s disease, and arteriovenous aneurysm have and placebo effects of thalamic stimulation. Pain 105:481–488 10. Mauskop A (2005) Vagus nerve stimulation relieves chronic re- all been implicated as causes of central pain. It is well- fractory migraine and cluster headaches. Cephalalgia 25:82–86 known that syringomyelia is associated with central Central Neuropathic Pain 315 pain (Madsen et al. 1994), and central pain caused by tional stress; while 38 % were alleviated by relaxation spinal cord injury (SCI) has been described in a number (which is why most patients with CNP can fall asleep of reports (Yezierski 1996). Painful post-cordotomy without difficulty, even though they may wake in pain) dysaesthesia was recognised by White and Sweet and 15 % by warmth (Bowsher 1996a). The most impor- (1955), who stated that 20 % of patients undergoing tant feature of CNP,as noted above, is that it occurs in an C anterolateral cordotomy and surviving for more than area of sensory change (partial or total deficit of one or a year developed painful dysaesthesia. Siddal et al. moresomatosensorymodalities);thisisindeedanessen- (1999) concluded that 50 % of patients with spinal cord tial criterion. The pain is experienced within the area of injury (SCI) suffer central neuropathic pain, as do most sensory change, i.e. it is smaller than the area exhibit- patients with syringo/hydro-myelia. ing sensory change. Of course patients do not present It can convincingly be argued that the seat of pathophys- with sensory loss, but with pain; so this will be dealt with iology in neuropathic pains due to insult of peripheral first. About 40 % of CPSP patients begin to experience nerves (e.g. painful diabetic neuropathy, complex re- pain immediately after their stroke; the other 60 % have gional pain syndromes, and postherpetic neuralgia) a later onset, which may be up to 2 years after stroke, but is in the central nervous system; the symptomatology the median is 3 months (Bowsher 1996a). In the case of certainly fulfils the criterion enunciated in the next spinal cord injury, a similar pattern is observed: pain is paragraph. However, they will not be dealt with in de- immediate in about a third of cases, with later onsets up tail in this chapter. Thus, it would perhaps be better to to 2 years, but a median of 3 months (Widerström-Noga recognise a category of central neuropathic pain (CNP), 2003). due to (unspecified) damage to any part of the neuraxis. Early descriptions emphasised burning pain as a promi- That such pains be recognised as neuropathic requires nent characteristic of central pain. Close interrogation one more criterion: the pain occurs in an area of sensory reveals that this is most frequently paradoxical burning change (total or, much more frequently, partial deficit). (ice-burn). While this type of pain, when it occurs, is indeed characteristic of central pain, and is much em- Incidence phasised because patients say “It’s like nothing I ever While it has long been known that not all cases of experienced before”, burning pain is not a sine qua non spinal cord injury or Wallenberg’s syndrome necessar- of neuropathic pain. Only 47 % of 111 personal CPSP ily suffer spontaneous neuropathic pain, it is important patients complained of burning pain (Bowsher 1996a). to emphasise the findings of Bogousslavsky and his Others experienced aching or throbbing pain (35 %) or colleagues (1988): only 25 % of patients with thalamic shooting/stabbing pain (7 %); no type of pain was per- infarcts involving the thalamic somatosensory relay ceived to be more intense than any other ( Visual Ana- nucleus (VPL, Vc) actually develop pain. In a prospec- logue Scale, VAS). Background pain was exacerbated tive study, Andersen et al. (1995) reported that about by emotional stress or environmental cold in about half 8 % of all surviving stroke patients develop CNP. In a of patients (28 % by both). Following spinal cord injury, population of 250 million (e.g. USA), there are 250,000 burning and aching pain were found in almost equal pro- strokes p.a., of whom about 170,000 survive. Thus, the portions (Widerström-Noga 2002). annual incidence of CPSP is approximately 11,000 new cases. Since most patients with CPSP do not have very Sensory Change severe or life-threatening motor impairment (only 8 % Some somatosensory modalities may be entirely lost, of 111 of our CPSP patients were plegic, and only 29 % while in others the sensation may still be present, but paretic), the prevalence must be very much higher. At with a raised threshold compared to the mirror-image least 30 % of MS patients have central pain, and in area on the unaffected side. There is frequently disso- spinal cord injury (SCI) CNP is present in about two ciation between various somatosensory submodalities. thirds of patients. SCI pain has been subdivided into From the point of view of spontaneous pain in CPSP,the pain at, above, and below the level of injury in an at- modalities most concerned appear to be those subserv- tempt to develop a more meaningful taxonomy (Siddall ing innocuous thermal sensations (Bowsher 1996b) and Loeser 2001). Thus, despite the fact that far from and sharpness discrimination (tested with weighted all patients with injury to the CNS develops CNP, the needles); pain intensity correlated with thermal (partic- overall prevalence is very high – yet it is regarded as ularly warmth) and sharpness discrimination threshold a rarity by most members of the medical and allied elevation. Patients with aching pain had a significantly professions. higher perception threshold for tactile (von Frey) stimuli than those with burning pain, while the latter had Characteristics much higher thresholds for innocuous warmth and cold Central pain is greatly influenced by autonomic factors. (but not for painful heat). Both had higher thresholds Seventy-nine CPSP patients were asked to identify fac- for sharpness and innocuous thermal modalities than tors that exacerbated or alleviated their pain: 59 % found patients suffering from strokes with sensory loss but their pain was exacerbated by cold and 57 % by emo- no pain; and additionally patients with burning pain, 316 Central Neuropathic Pain but not those with aching pain, had a very much higher as a result of a further stroke (which may also suppress threshold for warmth than did pain-free stroke patients other neurogenic pains such as postherpetic neuralgia). (Bowsher 1996a). Successful treatment with tricyclic antidepressants Eide et al. (1996) found that CNP in SCI patients was (TCAs) is time-dependent, as with several other neu- correlated with intensity of sensory deficit. Central ropathic pains – i.e. if treatment is initiated within 6 pain does not accompany loss of only Aβ modalities months of pain onset (NOT of stroke occurrence), 89 % (touch, innocuous pressure, vibration), as those sub- of our patientsgained relief;within12months, 67%;but served by smaller peripheral fibres (Aδ,C)arealso thereafter less than 50 %. Ami- and nor- tryptiline are compromised. It was noted that in cordotomised pa- poorly tolerated, and produce disagreeable side-effects. tients with malignant disease, where non-neuropathic Success has been reported with a more recent and pain due to the neoplasm returned, pinprick (sharpness) less noxious antidepressant, venlafaxine. This is also threshold also returned towards that on the unaffected adrenergically active; it should be noted that selective side, while in those patients who developed neuro- serotonergic reuptake inhibitors (SSRIs), which have pathic post-cordotomy pain, the deficit in sharpness no SNRI activity, are ineffective in neuropathic pains sensation remained (Lahuerta et al. 1994). Indeed, so (e.g. Max et al. 1992). Unlike peripheral neuropathic far as central pain is concerned, it is irrelevant whether pain (PHN), the presence or absence of allodynia does or not sensations subserved by Aβ fibres are affected. not influence the therapeutic response to tricyclics. Contrarily, stroke patients with sensory deficits but no Older Anticonvulsant(Agent),notablycarbamazepine, pain frequently have a very marked tactile deficit, but have proven themselves ineffective (Leijon and Boivie much less extensive thermal and sharpness deficits. 1989) in the treatment of central neuropathic pain. Allodynia is defined as pain produced by innocuous Membrane-stabilising drugs such as lignocaine (infu- stimulation. As it only occurs in patients with peripheral sions) and mexiletine (Awerbuch and Sandyk (1990) or central neuropathic pain, it is pathognomonic when have been effective; mexiletine added to a TCA has found. However, unfortunately for the diagnostician, it been shown to be beneficial in CPSP (Bowsher 1995b) is found in only about half of patients with supraspinal in some cases unresponsive to TCAs alone. Lignocaine CNP.Byfarthecommonestformofallodyniaisdynamic (lidocaine) is a local anaesthetic that blocks sodium mechanical or tactile: allodynia caused by a moving channels. Boas et al. (1982) reported its analgesic effect tactile stimulus, subserved by Aβ fibres. The provoking when given systemically (I.V.) in conditions with neu- stimulus may be the movement of clothes across the ropathic pain. Among newer anticonvulsants, which skin or a breeze on the face. Other forms of stimulus do not block sodium channels, gabapentin monother- that may produce allodynia are thermal (particularly apy is now widely used, though no statistics are yet cold, which unlike other forms of allodynia is twice available. Lamotrigine has also shown promise, per- as common in males as in females; warmth-provoked haps especially when added to a TCA. Of the opioids, allodynia is rare). The threshold for innocuous warmth dextromethorphan, in combination with gabapentin, is significantly higher in CPSP patients with allodynia is the most widely used; favourable claims have also (all forms) than in those without. Movement related been made for methadone. NMDA receptor antagonists allodynia also occurs in CPSP, provoked by active or (a minor additional property of dextromethorphan and passive movement, so presumably initiated from stretch methadone) are said to be effective, as shown by use receptors. of the short-acting ketamine; relief of CPSP by oral While the pain of allodynia usually occurs in the area ketamine has been reported (Vick and Lamer 2001), stimulated, it may occur in a remote area, even one and there is a report of relief of syringomyelic pain by which itself is neither spontaneously painful nor allo- intravenous ketamine (Cohen and DeJesus 2004). dynic. When somatosensory thresholds in patients with Surgical treatment has varied from thalamic lesioning mechanical allodynia are compared with thresholds in to the implantation of stimulating electrodes – thalamic, pain-free stroke patients, it is found that the signifi- periaqueductal, or spinal; and more recently on the mo- cance of the difference in thresholds between affected tor cortex (Tsubokawa et al. 1993), which is the most and unaffected mirror-image areas between the two promising of the stimulation methods, with a reported groups is 0.02 for sharpness, 0.007 for warmth, 0.047 success rate of 60–70 %. Additional treatments of pain for cold, and 0.004 for heat pain; but is non-significant associated with spinal cord injury are dealt with in the for mechanical modalities (Bowsher 1996a). volume edited by Yezierski and Burchiel (2002). Re- laxation therapy, which has a known beneficial effect, Treatment should not be overlooked in all forms of CNP. The mainstay of treatment until recently has been adrenergically-active tricyclic antidepressants,i.e. Possible Mechanisms of Neuropathic Pain principally ami- or nor- tryptiline, in relatively low We have to explain a condition that differentially and doses (Leijon and Boivie 1989). Spontaneous recovery variably affects somatosensory submodalities and auto- undoubtedly occurs (usually unreported), sometimes nomic function; which followsinsult to the central or pe- Central Neuropathic Pain 317 ripheral nervous system, but not ineluctably – indeed, in a) Why, in what is apparently the same condition, does onlyaminorityofcases;andinwhichthesensorychange one form of therapy succeed in some cases but fail in may or may notbe accompaniedby neuropathicpain(al- others, in which another form of therapy (a different though, as discussed above, the presence or absence of drug)iseffective?(e.g.TCAs,whichactonserotoner- pain does appear to depend on the intensity of innocuous gicandadrenergicsystems,versusgabapentin,which C thermal loss, particularly for warmth). acts on subunits of voltage-dependentCa++ channels It strikes the present author that the cardinal fact about b) It is fairly widely reported that patients with CPSP neuropathic pain (central or peripheral) is that only a mi- may have their pain alleviated by a second stroke; nority of individuals who suffer apparently appropriate we have also seen the pains of both post-herpetic insulttothecentralorperipheralnervoussystemactually and trigeminal neuralgias relieved by a subsequent develop neuropathic pain. This is equally true, it would stroke. Such events are hardly going to increase seem, of nerve ligation experiments in animals, by no levels of Transmitter X or densities of Receptor Y! means all of which show signs or symptoms of neuro- Although progress has been made in understanding pathic pain. the mechanisms responsible for central pain, there are It was suggested earlier (Bowsher 1995b) that the best- clearly additional questions to address, the answers to fit theoretical model for central pain would appear to which will hopefully provide new insights into more be one in which a widely-distributed transmitter/ligand effective treatment strategies. in the central nervous system, and/or its specific recep- Spinal Cord Injury Pain Model, Hemisection Model tors may become depleted; possible changes in receptor function were also mentioned by Siddall and Loeser (2001),specificallyinrelationtospinalcordinjury.Ithas References been known for a long time that some transmitters, such 1. Ajuriaguerra J de (1937) La Douleur dans les Affections du Sys- as serotonin, have both a global function, disturbance tème Nerveux Central. Doin, Paris of which may be reflected in some psychiatric disorders, 2. Andersen G (1995) Incidence of Central Post-Stroke Pain. Pain 61:187–194 and a specific one, disturbance of which is seen in partic- 3. Awerbuch GI, Sandyk R (1990) Mexiletine for Thalamic Pain ular “focal” conditions such as migraine; enhanced pain Syndrome. Int J Neurosci 55:129–133 sensitivity following injury may be regulated by spinal 4. Boas RA, Covino BG, Shanharian A (1982) Analgesic Response NK1 receptor expressing neurons (Suzuki et al. 2002), to I. V. Lignocaine. Br J Anaesth 54:501–505 5. Bogousslavsky J, Regli F, Uske A (1988) Thalamic Infarcts: Clin- while spinal5HT3 receptorsmediate descendingexcita- ical Syndromes, Etiology, and Prognosis. Neurol 38:837–848 tory controls on spinal neurones activated in some neu- 6. 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Foix C, Chavany J-A, Lévy M (1927) Syndrome pseudo- up- or down- regulation, may occur following nervous thalamique d’origine pariétale. Lésion de l’artère du sillon interpariétal (Pa P1P2 antérieures, petit territoire insulo- system injury. Following appropriate insult, transmit- capsulaire). Rev Neurol (Paris) 35:68–76 ters and/or receptors may undergo sudden and massive 16. Lahuerta J, Bowsher D, Buxton PH, Lipton S (1994) Percuta- depletion, leading to immediate onset of CNP; or one neous cervical cordotomy: A review of 181 operations in 146 or other or both may deplete slowly, giving rise to patients, including a study on the location of “pain fibers” in the second cervical spinal cord segment of 29 cases. J Neurosurg later onset of pain; they may recover their original 80:975–985 levels/concentrations/density, so that the pain “sponta- 17. 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19. Max M, Lynch SA, Muir J et al. (1992) Effects of Desipramine, Characteristics Amitriptyline, and Fluoxetine on Pain in Diabetic Neuropathy. New Eng. J Med 326:1250–1256 Prevalence 20. McCleane GJ, Suzuki R, Dickenson AH (2003) Does a Single In- The prevalence of central neuropathic pain following travenous Injection of 5HT3 Receptor Antagonist Ondansetron have an Analgesic Effect in Neuropathic Pain? A Double- SCI is relatively high. In the first six months following Blinded, Placebo-Controlled Cross-Over Study. Anesth Analg SCI, it has been reported that 35 % of patients have 97:1474–1478 at-level neuropathic pain and 25 % of patients have 21. Moss A, Blackburn-Munro G, Garry EM et al. (2002) A Role of below-level neuropathic pain. At five years following the Ubiquitin-Proteosome System in Neuropathic Pain. J Neu- rosci 22:1363–1372 injury, there is little change in these numbers, with 22. Siddall PJ, Loeser JD (2001) Pain following Spinal Cord Injury. 42 % having at-level neuropathic pain and 34 % having Spinal Cord 39:63–73 below-level neuropathic pain (Siddall et al. 2003). This 23. Siddall PJ, Taylor DA, McClelland JM et al. (1999) Pain Re- increase in numbers of people reporting pain reflects port and the Relationship of Pain to Physical Factors in the First 6 Months following Spinal Cord Injury. Pain 81:187–197 the lack of success in alleviating the pain. It also reflects 24. Suzuki R, Morcuende S, Webber M et al. (2002) Superficial the late onset of neuropathic pain, even years follow- NK1-Expressing Neurons Control Spinal Excitability through ing injury, in many people. The prospective study by Activation of Descending Pathways. Nat Neurosci 5:1319–1326 Siddall et al. (2003) also indicates a strong correlation 25. Taylor CP, Gee NS, Su T-Z et al. (1998) A Summary of Mech- anistic Hypotheses of Gabapentin Pharmacology. Epilepsy Res between the presence of both types of neuropathic pain 29:233–249 within six months and at five years following injury. 26. Tsubokawa T, Katayama Y,Yamamoto T, Hirayama T, Koyama S This unfortunately suggests that if either of these pain (1993) Chronic motor cortex stimulation in patients with thalamic types is present at six months, then there is a strong pain. J Neurosurg 78:393–401 27. Vick PG, Lamer TJ (2003) Treatment of Central Post-Stroke Pain likelihood that it will be present at 5 years. with Oral Ketamine. Pain 92:311–313 28. Wang H, Sun H, Della Penna K et al. (2002) Chronic Neuropathic Pain is accompanied by Global Changes in Gene Expression and Diagnosis Shares Pathobiology with Neurodegenerative Diseases. Neurosci 114:529–546 A taxonomy of pain following SCI was proposed by the 29. White JC, Sweet WH (1955) Pain: Its Mechanisms and Neuro- International Association for the Study of Pain (IASP) surgical Control. CC Thomas, Springfield Ill 30. Widerström-Noga EG (2002) Evaluation of Clinical Characteris- Task Force on SCI pain, and identifies five main types tics of Pain and Psychosocial Factors after Spinal Cord Injury. In: of pain that occur following SCI (Siddall et al. 2002). Yezierski RP, Rurchiel KJ (eds) Spinal Cord Injury Pain: Assess- Theseare:musculoskeletal,visceral,above-levelneuro- ment, Mechanisms, Management. IASP Press, Seattle, pp 53–82 pathic,at-levelneuropathicandbelow-levelneuropathic 31. Widerström-Noga EG (2003) Chronic Pain and Non-Painful Sensations following SCI: Is there a Relationship? Clin J Pain pains. The presence of neuropathic pain is suggested by 19:39–47 descriptors such as electric, shooting and burning with 32. Yezierski RP (1996) Pain following Spinal Cord Injury: The Clin- pain located in or adjacent to a region of sensory loss. ical Problem and Experimental Studies. Pain 73:115–119 Central neuropathic pain will usually present at or be- 33. Yezierski RP, Burchiel KJ (2002) Spinal Cord Injury Pain: As- sessment, Mechanisms, Management. IASP Press, Seattle low the level of injury and will thereforefall into the last 34. Yu X-M, Salter MW (1999) Src, A Molecular Switch Governing two groups. Above-levelneuropathic painusually refers Gain Control of Synaptic Transmission Mediated by N-methyl- to neuropathic pain arising from damage to peripheral D-aspartate Receptors. Proc-Natl Acad Sci USA 96:7697–7704 nerves above the level of injury. Therefore, many types of above-levelneuropathic pain are peripheral in origin. However, some types of above-level neuropathic pain Central Neuropathic Pain from Spinal may be central in origin. For example, syringomyelia Cord Injury may give rise to central neuropathic pain that is located in dermatomes above the level of injury. PHILIP SIDDALL At-level neuropathic pain occurs as a band of pain in the Pain Management Research Institute, University of dermatomes adjacent to the level of injury, and is there- Sydney, Royal North Shore Hospital, Sydney, NSW, fore sometimes referred to as segmental, end-zone or Australia border zone pain. It may be due to damage to nerve roots [email protected] and therefore be a form of peripheral neuropathic pain. However, animal models have clearly demonstrated that Definition at-level neuropathic pain may occur in the absence of Central pain from spinal cord injury (SCI) refers to nerve root damage, and therefore it may be central in neuropathic pain that occurs following traumatic or origin. atraumatic injury to the spinal cord. It may be due to dys- Below-level neuropathic pain occurs more diffusely, in function occurring at spinal and/or supraspinal levels. a bilateral distribution below the level of the spinal cord Twomaintypesofcentralneuropathicpainaredescribed lesion in the region of sensory disturbance, and is some- following SCI. These are at-level neuropathic pain times referred to as central dysesthesia syndrome. It is and below-levelneuropathicpain(Siddalletal.2002). most likely due to changes in the spinal cord and brain Central Neuropathic Pain from Spinal Cord Injury 319 following SCI. Therefore, below-level neuropathic pain Treatment is generally regarded as a central neuropathic pain. There are relatively few studiesthat havespecifically ex- Mechanisms amined the effectiveness of treatments for pain follow- At-level neuropathic pain may be due to nerve root ing SCI, and in these situations subject numbers are gen- C compression. The mechanisms of pain associated with erally low. Therefore, there is little definitive evidence nerve root compression are similar to other forms of to guide management. In the few randomized controlled peripheral neuropathic pain and are described else- trials that have been done, many of the treatments were where. However, at-level neuropathic pain may also be no more effective than the placebo, and therefore ade- due to changes within the spinal cord itself as a conse- quatecontrolofcentralneuropathicSCIpainisgenerally quence of injury. The specific mechanisms underlying difficult (Finnerup et al. 2001). Principles of treatment both at-level and below-level neuropathic pain are in- are derived largely from the treatment of other neuro- completely understood. However, there are a number pathic pain conditions. of secondary changes that occur as a consequence of It is traditionally stated that opioids are relatively inef- spinal cord damage, which may result in the generation fective for the treatment of neuropathic pain. However, or amplification of nociceptive signals (Vierck et al. there is increasing evidence that they may be effective 2000, Yezierski 2003). These include: if an appropriate dose is used. A randomized controlled trial of intravenous morphine (9–30 mg) found a signifi- 1. Damage to the spinal cord may result in increased cant reduction in brush-evoked allodynia, but no signif- levels of glutamate which activates N-methyl D- icant effect on spontaneous neuropathic SCI pain (At- aspartate (NMDA), non-NMDA and metabotropic tal et al. 2002). Long term use of opioids may also be glutamate receptors. This activation of glutamate a problem because of side effects such as constipation, receptors results in activation of a cascade of sec- which may be more of an issue in individuals with SCI. ondary processes within neurons, which ultimately Although there is little direct evidence in SCI pain, tra- result in increased neuronal excitability. madol may also be an option because of its serotonergic 2. Alternatively, increased neuronal excitability may and noradrenergic effects, which may provide an advan- be a consequence of reduced inhibition within the tage in the treatment of neuropathic pain. spinal cord. Several mechanisms have been pro- Intravenous or subcutaneous infusion of local anaes- posed, including reduced function of inhibitory thetics such as lidocaine (lignocaine), are also widely neurotransmitters and receptors such as γ aminobu- used for the treatment of neuropathic pain and may be tyric acid (GABA) and glycine. This may occur effective for neuropathic SCI pain. One of the actions through reduction in inputs from surrounding re- of local anaesthetics is to produce sodium channel gions that normally exert an inhibitory action on the blockade. This reduces the amount of ectopic impulses region, which has lost inputs (inhibitory surround). generated by activity at these receptors. Relatively Loss of inhibition may also occur through disruption low concentrations of local anaesthetic are required to inhibitory neurotransmitter production, release to reduce ectopic neural activity in damaged nerves. or uptake as a consequence of spinal cord damage. There is evidence from a randomized controlled trial A reduction in inhibition may also be due to a de- supporting the efficacy of intravenous lidocaine in treat- crease in the levels of inhibitory controls exerted by ing neuropathic SCI pain (Attal et al. 2000). Although descending antinociceptive pathways. its mode of action is different from local anaesthetics, 3. Injury to the spinal cord will also initiate inflamma- propofol is another agent that may be administered tory and immune responses, which will have both di- systemically and has been shown to provide effec- rect and indirect effects on the long-term integrity of tive relief of neuropathic SCI pain (Canavero et al. spinal cord structures, as well as functional changes 1995). in sensory processing. As mentioned above, SCI may result in an increased re- Bothincreasedexcitationandlossofinhibitionmaygive lease of glutamate and activation of NMDA receptors, rise to a population of neurons close to the site of in- resulting in central neuronal hyperexcitability. NMDA jury that have an increased responsiveness to peripheral receptor antagonists such as ketamine have been used stimulation and may even fire spontaneously. These al- as a treatment for neuropathic pain following SCI (Eide terations in the properties of spinal neurons may give et al. 1995). Administration is generally by infusion via rise to the phenomenon of hyperaesthesia ( allodynia the intravenous or subcutaneous route. One of the main and hyperalgesia) and spontaneouspain, respectively. problems with the use of ketamine is the occurrence of As well as alterations at a spinal level, alterations in the disturbing side effects such as hallucinations, although chemistry and firing properties of supraspinal neurons benzodiazepines may help reduce these symptoms. Al- havealsobeendemonstrated.Themainsitethathasbeen though careful monitoring can help to minimize the rate investigated is the thalamus (Ralston et al. 2000; Ohara of occurrence of these side effects, they can be distress- et al. 2002). ing to the person when they do occur. 320 Central Pain

Oral rather than systemic administration of a number of 4. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, drugs is also possible, and may be preferred. Unfortu- Loeser JD (2002) Efficacy of Amitriptyline for Relief of Pain in Spinal Cord Injury: Results of a Randomized Controlled Trial. nately, most studies suggest that these oral agents are Pain 96:365–373 less effective than drugs used systemically. Most of the 5. Chiou Tan FY, Tuel SM, Johnson JC, Priebe MM, Hirsh DD, evidence for the effectiveness of opioids for the treat- Strayer JR (1996) Effect of Mexiletine on Spinal Cord Injury mentofneuropathicpaincomesfromstudiesusingacute Dysesthetic Pain. Am J Phys Med Rehabil 75:84–87 6. Davidoff G, Guarracini M, Roth E, Sliwa J, Yarkony G. (1987) intravenous administration. Local anaesthetics are not Trazodone Hydrochloride in the Treatment of Dysesthetic Pain in availableinoralform,andthelocalanaestheticcongener Traumatic Myelopathy: A Randomized, Double-Blind, Placebo- mexiletine does not appear to be as effective as lidocaine Controlled Study. Pain 29:151–161 inreducingneuropathicSCIpain(ChiouTanetal.1996). 7. Eide PK, Stubhaug A, Stenehjem AE (1995) Central Dyses- thesia Pain after Traumatic Spinal Cord Injury is Dependent Similarly, ketamine is difficult to administer orally and on N-methyl-D-aspartate Receptor Activation. Neurosurgery other NMDA antagonists available for administration 37:1080–1087 via the oral route, such as dextromethorphan, are also 8. Finnerup NB, Yezierski RP, Sang CN, Burchiel KJ, Jensen TS not as effective. (2001) Treatment of Spinal Cord Injury Pain. Pain Clinical Up- dates 9:1–6 Several agents that are used widely for the treatment 9. Finnerup NB, Sindrup SH, Flemming WB, Johannesen IL, Jensen of persistent neuropathic pain are not available for sys- TS (2002) Lamotrigine in Spinal Cord Injury Pain: A Random- temic administration but are available in the oral form. ized Controlled Trial. Pain 96:375–383 These include the tricyclic antidepressants such as 10. OharaS, GaronzikI, HuaS, LenzFA(2002) Microelectrode Stud- ies of the Thalamus in Patients with Central Pain and in Control amitriptyline, prothiaden and nortriptyline and anticon- Patients with Movement Disorders. In: Yezierski RP, Rurchiel KJ vulsants such as carbamazepine, valproate, lamotrigine (eds) Spinal Cord Injury Pain: Assessment, Mechanisms, Man- and gabapentin. However, specific evidence of efficacy agement. IASP Press, Seattle, pp 219–236 11. Siddall PJ, Molloy AR, Walker S, Mather LE, Rutkowski SB, in the treatment of neuropathic SCI pain is limited. Cousins MJ (2000) Efficacy of Intrathecal Morphine and Cloni- Randomised controlled trials of trazodone (Davidoff dine in the Treatment of Neuropathic Pain Following Spinal Cord et al. 1987) and amitriptyline (Cardenas et al. 2002) Injury. Anesth Analg 91:1493–1498 both failed to find an effect greater than placebo, al- 12. Siddall PJ, Yezierski RP, Loeser JD (2002) Taxonomy and Epi- demiology of Spinal Cord Injury Pain. In: Yezierski RP, Rurchiel though numbers in the trazodone study were low and KJ (eds) Spinal Cord Injury Pain: Assessment, Mechanisms, the amitriptyline study contained subjects who had Management. IASP Press, Seattle, pp 9–24 both musculoskeletal and neuropathic pains. A ran- 13. Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ (2003) domised controlled trial of sodium valproate also failed A Longitudinal Study of the Prevalence and Characteristics of Pain in the First 5 Years Following Spinal Cord Injury. Pain to demonstrate a significant analgesic effect (Drewes 103:249–257 et al. 1994). Lamotrigine has been demonstrated to 14. Ralston DD, Dougherty PM, Lenz FA, Weng HR, Vierck CJ, be effective, but only for the evoked component of Ralston HJ (2000) Plasticity of the Inhibitory Circuitry of the neuropathic SCI pain (Finnerup et al. 2002). Primate Ventrobasal Thalamus Following Lesions of Somatosen- sory Pathways. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Consideration may be given to spinal administration of Z (eds) Proceedings of the 9th World Congress on Pain, IASP drugsiforalapproachesareunsuccessful.Intrathecalad- Press, Seattle, pp 427–434 ministration of morphine and clonidine has been helpful 15. Umlauf RL (1992) Psychological Interventions for Chronic Pain Following Spinal Cord Injury. Clin J Pain 8:111–118 in some people with neuropathic SCI pain (Siddall et al. 16. Vierck CJ, Siddall PJ, Yezierski RP (2000) Pain Following 2000). Spinal Cord Injury: Animal Models and Mechanistic Studies. Spinalcordinjuryrequiresamajorpsychologicaladjust- Pain 89:1–5 ment.Awarenessoftheseissuesisimportantintheevalu- 17. Yezierski RP (2002) Pathophysiology and Animal Models of Spinal Cord Injury Pain. In: Yezierski RP, Rurchiel KJ (eds) ationofthepersonwithpain.Aswithanypaincondition, Spinal Cord Injury Pain: Assessment, Mechanisms, Manage- psychological factors may contribute to the perception ment. IASP Press, Seattle, pp 117–136 and expression of pain. Pain reportmaybe an expression of difficulty in adjustment, and therefore psychological approaches that attempt to deal with these issues may be Central Pain helpful. Utilisation of pain management strategies and cognitive behavioural therapy (CBT) may be helpful in achieving optimal pain management (Umlauf 1992). Definition Central pain is defined by the International Association References for the Study of Pain (IASP) as: „Regional pain caused 1. Attal N, Guirimand F, Brasseur L, Gaude V,Chauvin M, Bouhas- by a primary lesion or dysfunction in the central nervous sira D (2002) Effects of IV Morphine in Central Pain – A Ran- domized Placebo-Controlled Study. Neurology 58:554–563 system, usually associated with abnormal sensibility to 2. Attal N, Gaudé V, Brasseur L et al. (2000) Intravenous Lido- temperature and to noxious stimulation“. caine in Central Pain: A Double-Blind, Placebo-Controlled, Psy- Cell Therapy in the Treatment of Central Pain chophysical Study. Neurology 54:564–574 Central Nervous System Stimulation for Pain 3. Canavero S, Bonicalzi V,Pagni CA et al. (1995) Propofol Analge- sia in Central Pain - Preliminary Clinical Observations. J Neurol Central Pain, Diagnosis and Assessment of Clinical 242:561–567 Characteristics Central Pain and Cancer 321

Central Pain, Human Studies of Physiology leptomeningeal disease (Delatte et al. 1989). A more Central Pain in Multiple Sclerosis recent study by Gonzales et al. described the prevalence Central Pain, Outcome Measures in Clinical Trials and causes of central pain in patients with cancer (Gon- Central Pain, Pharmacological Treatments zales et al. 2003). In this study conducted in a cancer Central Pain Syndrome center, a relatively high number of general oncology C Diagnosis and Assessment of Clinical Characteristics patients admitted to the Neurology Service (2%) or of Central Pain seen in consultation by the Pain Service (4%) were DREZ Procedures found to have CP. It is important to underscore that the Functional Changes in Sensory Neurons Following prevalence of central pain seen in these patients is not Spinal Cord Injury in Central Pain representative of the true prevalence of central pain in Pain Treatment, Motor Cortex Stimulation hospitalized patients with cancer, as these patients were Percutaneous Cordotomy selected by their referral to the pain service or admis- Post-Stroke Pain Model, Thalamic Pain (Lesion) sion to the neurology ward. In this study, spinal cord SecondarySomatosensoryCortex(S2)andInsula,Ef- lesions were by far more likely to cause CP compared fectonPainRelatedBehaviorinAnimalsandHumans to brain and brainstem lesions, as is the case in patients Stimulation Treatments of Central Pain with non-cancer causes of central pain (Gonzales et al. 2003). When a patient with cancer has radiological documen- Central Pain and Cancer tation of a lesion within the CNS, pain in a distribution compatible with the CNS lesion, and no other lesions 1, 2 1 PAOLO L. MANFREDI ,GILBERT R. GONZALES that could potentially cause pain in the same area, a di- 1Department of Neurology, Memorial Sloan-Kettering agnosisof CPcan be made. Inorder tobe classified asCP Cancer Center, New York, NY, USA related to cancer the inciting CNS lesion must be caused 2Essex Woodlands Health Ventures, New York, NY, by cancer or its treatment. USA PaindescriptorssuggestiveofCPsuchasburning,numb, [email protected], [email protected] cold, pins and needles, electric shock can also help with the diagnosis. Definition On physical examination it may be possible to elicit different neurological abnormalities, depending on the lo- In order to be diagnosed with Central Pain (CP) asso- cation and size of the CNS lesion. The finding of altered ciated with cancer, patients must have a lesion within temperature sensation in the painful area is consistently the Central Nervous System (CNS) caused by cancer or seen in all CP patients with cancer, as expected from the its treatment, pain in a distribution compatible with the experience with non-malignant causes of CP (Gonzales CNS lesion, and no other lesions that could potentially and Casey 2003; Gonzales et al. 2003). A detailed sen- cause pain in the same area (Casey 1991; Gonzales and sory examination is therefore essential. Casey 2003; Gonzales et al. 2003). Central pain may be delayed by days to years after CNS This definition includes pathology in the spinal cord, injury (Gonzales 1995). In one cancer patient, CP was brainstem, or cerebral hemispheres. Lesions in the found to be delayed by up to 6 years after the diagnosis peripheral nervous system can produce CNS changes, and treatment of the spinal cord tumor (Gonzales et al. but these are secondary CNS changes and are not cat- 2003). This is much longer than the delay usually seen egorized as CP syndromes (Casey 1991; Gonzales and in non-malignant causes of spinal cord CP. Casey 2003). The most common causes of CNS injuries The treatment strategies in patients with cancer and that result in CP are stroke, spinal cord trauma and mul- CP may include anti-tumor therapies such as radiation, tiple sclerosis (Casey 1991). However, cancer and its chemotherapy, surgical resection and steroids to de- treatment can also cause CP (Gonzales et al. 2003). crease edema. Aside from addressing the treatment of the tumor, the treatment of CP in patients with cancer Characteristics can be approached as with non-malignant CP (Gonza- Although CP occurs infrequently, over 15% of patients les and Casey 2003; Gonzales et al. 2003) and include with systemic cancer have metastases to the brain or antidepressants, anticonvulsants, opioids, clonidine, spinal cord (Clouston et al. 1992), making it possible for baclofen, acetaminophen, and NSAIDs. some of these patients to go on and develop CP. Central pain caused by cancer is mostly described through case References reports, such as the study of thalamic tumors by Cheek 1. Casey KL (1991) Pain and Central Nervous System Disease: and Taveras (Cheek et al. 1966). Pagni and Canavero A Summary and Overview. In: Casey KL ed. Pain and Central (1993), and Gan and Choksey (2001) have reported Nervous System Disease: The Central Pain Syndromes. Raven Press, New York CP from extra-axial tumors such as meningiomas. 2. Cheek WR, Taveras JM (1966) Thalamic Tumors. J Neurosurg Delattre and colleagues have reported CP caused by 24:505–513 322 Central Pain, Diagnosis

3. Clouston PD, DeAngelis LM, Posner J (1992) The Spectrum arising from the damaged peripheral nerve. The distinc- of Neurological Disease in Patients with Systemic Cancer. Ann tionismostclearwhentheprecipitatinginjuryofdisease Neurol 31:268–273 4. Delattre JY,Walker RW, Rosenblum MK (1989) Leptomeningeal is obviously in the central nervous system.In such cases Gliomatosis with Spinal Cord or Cauda Equina Compression: A the term –central pain, applies unambiguously. Completion of Supratentorial Gliomas in Adults. Acta Neurol Scand 79:133–139 5. Gan YC, Choksey MS (2001) Parafalcine Meningioma Present- Examples ing with Facial Pain: Evidence for Cortical Theory or Pain? Br Classical examples of central pain are the pain of J Neurosurg 15:350–352 brachial plexus avulsion, spinal cord injury pain, pain 6. Gonzales GR (1995) Central Pain: Diagnosis and Treatment Strategies. Neurology 45:11–16 after stroke, and pain due to infarction of thalamic 7. Gonzales GR, Casey KL (2003) Central Pain Syndromes. In: Rice nuclei. The latter is known as thalamic pain syndrome ADS, Washeld CA, Justins D et al. (eds) Clinical Pain Manage- or the Dejerine-Roussy syndrome. Complex regional ment Chronic Pain. Arnold Press, London 8. Gonzales GR, Tuttle S, Thaler HT et al. (2003) Central Pain in pain syndrome is the most ﬂorid example of central Patients with Cancer. J Pain 4:351–354 pain. 9. Pagni CA, Canavero S (1993) Paroxysmal Perineal Pain Resem- Othersexamplesinclude postherpetic neuralgia,periph- bling Tic Doubureux, only Symptom of a Dorsal Meningioma. eralnerve injury, and painfulperipheralneuropathy.The Ital J Neurol Sci 14:323–324 10. Tasker RR, DeCorvalho G, Dostrovosky JO (1991) The History of latter, however, are contentious, for it is not always evi- Central Pain Syndromes, with Observations Concerning Patho- denttheextenttowhichthepainiscentralinoriginordue physiology and Treatment. In: Casey KL (ed) Pain and Central to peripheral mechanisms such as neuroma, or ectopic Nervous System Disease: The Central Pain Syndromes. Raven impulse generation in peripheralnervesortheir dorsal Press, New York, pp 31–58 root ganglia.

Mechanism Central Pain, Diagnosis Central pain is believed to result from deafferentation: DAV I D VIVIAN whenneuronsinthecentralnervoussystemlosetheirac- Metro Spinal Clinic, Caulfield, VIC, Australia customed afferent input, either from a peripheral nerve [email protected] or from an ascending sensory tract. In particular, partial deafferentation is considered most likely to be associ- Synonyms ated with the development of central pain. Deafferentation seems to induce plastic changes in the Thalamic Pain; Dejerine-Roussy Syndrome; deaf- central nervous system. Numerous theories describe ferentation pain these plastic changes in terms of: removal of local inhi- Definition bition, changes in neuronal membrane excitability, and synaptic reorganisation. These changes occur rapidly Central pain is pain whose source lies in the central ner- after central nervous system damage. However, it is voussystem,i.e.thebrain,brainstem,orspinalcord.The typical for central pain to occur some time after such cardinal defining feature is that the pain is not evoked by an injury (days to weeks). neural activity in peripheral nerves. Experiments in animals have been conducted in which recordings are established from dorsal horn neurons Characteristics that respond to input from particular peripheral nerves. In terms of clinical features, central pain has particular If those nerves are then severed, the dorsal horn neurons characteristics. The pain is typically spontaneous and no longer respond to peripheral stimuli but exhibit a va- burning in quality, associated with abnormal sensations. riety of changes (Anderson et al. 1971; Macon 1979; 3). The latter may include: They become spontaneously active, and eventually no longer become responsive to typical neurotransmitters. • hyperaesthesia (increased sensitivity to touch) These features suggest that their membranes become • hyperalgesia (increased sensitivity to noxious stim- unstable, and the neurons no longer maintain receptors uli) when denied their accustomed input. The latter feature • allodynia (touch and brush are perceived as painful) probably underlies the notorious resistance of central • paraesthesiae (sensation of pins and needles) pain to pharmacological therapy. • formication (sensation of ants crawling on skin) and Spontaneousactivityhasbeenconfirmedinhumanswith • diminished topoesthesia (ability to locate a sensation central pain. When subjects with spinal cord injury pain somatotopically) have been explored with electrodes, spontaneously ac- In these respects central pain resembles neuropathic tive neurons have been found in the spinal cord immedi- pain, and the taxonomic distinction between the two ately above the level of injury (Loeser et al. 1968). Sim- conditions is not always clear. Some forms of neuro- ilar activity has been recorded after experimental spinal pathic pain are likely to be central in origin rather than cord injury in cats (Loeser and Ward 1967). Central Pain, Diagnosis 323

Theabnormalsensationsassociatedwithcentralpainare Diagnosis most likely due to disinhibition. Sensory perception is Thediagnosisofcentralpainrestslargelyontherecogni- normally subject to a variety of central excitatory and tion of the clinical features and history of the pain. Spon- inhibitory controls. These are mediated by the dorsolat- taneous burning pain associated with abnormal, exag- eral tract and by tracts in the anterior funiculus of the gerated sensations implies a central mechanism. If the C spinalcord. When peripheralnervesare severed, the bal- history indicates disease or injury to the central nervous ance between these central modulating influences is dis- system, the diagnosis is confirmed. The diagnosis is less turbed, sometimes with contrasting effects. certain if injury to the central nervous system is not ev- Disinhibition results in sensitization of Second Order ident, or when the injury or disease affects peripheral Neurons. Sensations mediated by intact nerves become nerves. exaggerated. This is manifest in the form of hyperaes- A presumptive test for central pain is the administration thesia, hyperalgesia, and allodynia. of lignocaine by systemic intravenous infusion.Such an In experimental animals, the effects of sectioning the infusion is believed to suppress the spontaneous activity trigeminal nerve (Denny-Brown et al. 1973), spinal in the central nervous system believed to be responsible nerves (Denny-Brown and Yanagisawa 1973) or the for central pain. spinal cord (Denny-Brown 1979), can be modulated pharmacologically and surgically. Discrete sectioning Treatment of the lateral portion of the dorsolateral tract results Central pain is notoriously difficult to treat. Standard in shrinkage of the area of sensory nerve loss (Denny- analgesics seem to have little or no effect, which corre- Brown and Yanagisawa 1973; Denny-Brown et al. lates with the lack of receptors found in animals with 1973). Conversely, sectioning the medial portion of spontaneously active neurons after deafferentation. the dorsolateral tract increases the area (Denny-Brown Agents that suppress ectopic activity, or which stabilize and Yanagisawa 1973; Denny-Brown et al. 1973). Sec- nerve-cell membranes, are more likely to relieve central tioning both anterior funiculi reverses the sensory loss pain, provided that side-effects can be tolerated. Such caused by spinothalamic tractomy, but the restored agents include local anaesthetic agents, administered sensation is hyperaesthetic (Denny-Brown 1979). Ad- either by systemic infusion or orally; and membrane- ministering L-dopareducessensoryloss(Denny-Brown stabilizing agents such as gabapentin and lamotrigine. et al. 1973), as does a subconvulsive dose of strychnine: Otherwise, central pain can be treated, with reasonable an antagonist of the inhibitory transmitter – glycine success, by neuroaugmentive surgical procedures such (Denny-Brown 1979; Denny-Brown and Yanagisawa as dorsal column stimulation, dorsal root entry zone le- 1973; Denny-Brown et al. 1973. sioning, and deep brain stimulation. In humans who have undergone dorsal root section for pain but whose pain recurs, administration of L-dopa in- References creases their pain but decreases the area of cutaneous 1. Anderson LS, Black RG, Abraham J et al. (1971a) Neuronal Hy- anaesthesia (Hodge and King 1976). Reciprocally, ad- peractivity in Experimental Trigeminal Deafferentation. J Neu- ministration of methyldopa decreases pain but increases rosurg 35:444–451 2. Anderson LS, Black RG, Abraham J et al. (1971b) Neuronal Hy- numbness. Similarly, tryptophan – a serotonin precur- peractivity in Experimental Trigeminal Deafferentation. J Neu- sor–reducespainbutincreasesanaesthesia(King1980). rosurg 35:444–451 These phenomenons indicate that the effects of deaf- 3. Cesaro P, Mann MW, Moretti JL et al. (1991) Central Pain and ferentation are not fixed, but are subject to a complex Thalamic Hyperactivity: A Single Photon Emission Computer- ized Tomographic Study. Pain 47:329–336 variety of controls. Release of these controls, following 4. Denny-Brown D (1979) The Enigma of Crossed Sensory Loss peripheral nerve injury or central nervous injury, under- with Cord Hemisection. In: Bonica JJ et al. (eds) Advances in Pain lies the varied appearance of pain and altered sensations Research and Therapy, vol 3. Raven Press, New York,pp 889–895 5. Denny-Brown D, Kirk EJ, Yanagisawa N (1973a) The Tract associated with central pain. of Lissauer in Relation to Sensory Transmission in the Dorsal For the central pain of thalamic syndrome, a variety Horn of Spinal Cord in the Macaque Monkey. J Comp Neurol of explanations have been advanced; but they, too, re- 151:175–199 volve around deafferentation and disinhibition. Cells 6. Denny-Brown D, Yanagisawa N (1973b The Function of the De- scending Root of the Fifth Nerve. Brain 96:783–814 in the ventroposterior thalamic nuclei become spon- 7. Hodge CJ, King RB (1976) Medical Modification of Sensation. taneously active, and produce pain in the area of the J Neurosurg 44:21–28 body that they subtend (Lenz et al. 1987; Lenz et al. 8. King RB (1980) Pain and Tryptophan. J Neurosurg 53:44–52 1989). Experimental stimulation of these cells evokes 9. Lenz FA, Tasker RR, Dostrovsky JO (1987) Abnormal Single Unit Activity Recorded in the Somatosensory Thalamus of a pain in the deafferented region Lenz et al. 1988). The Quadriplegic Patient with Central Pain. Pain 31:225–236 abnormal activity is believed to arise because of loss 10. Lenz FA, Dostrovsky JO, Tasker RR et al. (1988) Single-Unit of inhibition of medial thalamic nuclei by the reticular Analysis of the Human Ventral Thalamic Nuclear Group: So- nucleus (Cesaro et al. 1991; Mauguiere and Desmedt matosensory Responses. J Neurophysiol 59:299–316 11. Lenz FA, Kwan HC, Dostrovsky JO et al. (1989) Characteristics 1988). Damage to the spinothalamic tract seems to be of the Bursting Pattern of Action Potential that Occurs in the the precipitating factor for these changes. Thalamus of Patients with Central Pain. Brain Res 496:375–360 324 Central Pain, Diagnosis and Assessment of Clinical Characteristics

12. Loeser JD, Ward AA (1967) Some Effects of Deafferentation on Characteristics Neurons of the Cat spinal cord. Arch Neurol 17:629–636 13. Loeser JD, Ward AA, White LE (1968) Chronic Deafferentation TheThalamicRegionofVcanditsImportanceinPainProcess- of Human Spinal Cord Neurons. J Neurosurg 29:48–50 ing 14. Macon JB (1979) Deafferentation Hyperactivity in the Monkey Spinal Trigeminal Nucleus: Neuronal Responses to Amino Acid Several lines of evidence demonstrate that the ventral Iontophoresis. Brain Research 161:549–554 caudal nucleus of the human sensory thalamus (Vc), the 15. Mauguiere F, Desmedt JE (1988) Thalamic Pain Syndrome human analog of monkey ventral posterior (VP) nucleus of Dejerine-Roussy: Differentiation of Four Subtypes As- (Hirai and Jones 1989), is an important component in sisted by Somatosensory Evoked Patients Data. Arch Neurol 45:1312–1320 human pain-signaling pathways. Studies of patients at autopsy following lesions of the STT show the densest STT termination in the Vc region including: posterior and inferior subnuclei of Vc, suprageniculate, and pos- Central Pain, Diagnosis and Assessment terior subnuclei (Bowsher 1957; Mehler 1962; Walker 1943). In monkeys, the STT originating in dorsal horn of Clinical Characteristics lamina I, in part, terminates in Vmpo (Craig et al. 1994; Graziano and Jones 2004). In humans, cells responding Diagnosis and Assessment of Clinical Characteristics to noxious and temperature stimuli can be located in all of Central Pain of these areas (Davis et al. 1999; Lee et al. 1999; Lenz et al. 1993). Thus, both anatomic and physiologic data demonstrates the presence of a distributed group of thalamic nuclei with pain related activity. Central Pain, Functional Changes in Sensory Neurons Following Spinal Cord Is Thalamic Functional Mode Altered in Chronic Pain States? Injury Spike-bursting activity refers to a particular pattern of interspike intervals (ISI) between action potentials, such that a spike-burst begins after a relatively long ISI, Functional Changes in Sensory Neurons Following and is comprised of a series of action potentials with a Spinal Cord Injury in Central Pain short ISI (typically < 6 ms) (Lenz et al. 1994; Steriade et al. 1990). Thereafter, the ISIs progressively increase in length so that the cell’s firing decelerates throughout the spike-burst. Central Pain, Human Studies of In patients with spinal transection, the highest rate of burstingoccursincellsthatdonothaveperipheralrecep- Physiology tive fields, and that are located in the thalamic represen- A. TAGHVA,S.H.PATEL,A.FERNANDEZ, tation of the anesthetic part of the body. Since the pain is N. WEISS,FREDERICK A. LENZ also in the anesthetic part of the body, this bursting may Department of Neurosurgery, Johns Hopkins Hospital, be due to loss of sensory input or be the cause of pain Baltimore, MD, USA or both. These cells also have the lowest firing rates in fl[email protected] the interval between bursts (principal event rate) (Lenz et al. 1994). The low firing rates suggest that these cells have decreased tonic excitatory drive and are hyperpo- Definition larized, perhaps due to loss of excitatory input from the Spontaneous thalamic cellular activity is often cate- STT(Blomqvistetal.1996;Doughertyetal.1996;Eaton gorized as either bursting activity ( spike-bursts, and Salt 1990). Therefore, the available evidence sug- bursting mode) or as tonic firing mode (tonic mode) gests that thalamic cells deafferentated by spinal tran- (Steriade et al. 1990). Many studies have suggested section (lesions) are dominated by spike-bursting and that increased spike-bursting occurs in the thalamus of low firing rates between bursts, consistent with mem- patients with chronic neuropathic pain (Jeanmonod et brane hyperpolarization (Lenz et al. 1998; Steriade et al. 1994; Lenz et al. 1994, 1998; Rinaldi et al. 1991). al. 1990). Thalamic bursting has also been reported in monkeys Spike-bursting activity is maximal in the region poste- with interruption of the spinothalamic tract (STT), riorandinferiortothecorenucleusofVc(Table4inLenz which sometimes develop sensory abnormalities simi- etal.1994).Stimulationinthisareamayevokethesensa- lar to those seen in patients with similar lesions (Weng tion of pain more frequently than does stimulation in the et al. 2000). This bursting is certainly associated with core of Vc (Dostrovsky et al. 1991; Hassler 1970; Ohara lesions of the somatic sensory pathways to thalamus, and Lenz 2003). Thus, increased spike-bursting activity and is perhaps associated with the pain that develops may be correlated with some aspects of abnormal sensa- following such lesions. tions (e.g. dysesthesia or pain) that these patients expe- Central Pain, Human Studies of Physiology 325 rience. However, in patients with spinal transection, the from both human and animal studies for a correlation painful area and the area of sensory loss overlap (Lenz between central pain following spinal cord injury and et al. 1994). Thus, the bursting activity might be related an altered thalamic neuronal action potential firing pat- to deafferentation of the thalamus from the input from tern. It appears that there is an increase in spike-burst the STT, rather than to pain. firing in patients with pain following spinal injury. The C Thesefindingsaboutspike-burstingactivityinspinalpa- exact physiologic relationships which link the pattern of tients have been called into question by a recent study in thalamic firing to the human perception of pain in this patients with chronic pain (Radhakrishnan et al. 1999). condition are still unclear. It has been reported that the number of bursting cells per trajectory in patients with movement disorders (con- Acknowledgement trols) is not different from that in patients with chronic Supported by grantsto FAL fromtheNIH:NS39498and pain. However, there are significant differences between NS40059. the two studies (Lenz et al. 1994; Radhakrishnan et al. 1999) in terms of: (1) patient population (spinal cord in- References jury vs. mixed chronic pain); (2) location of cells stud- 1. Beric A, Dimitrijevic MR, Lindblom U (1988) Central Dysesthe- ied (Vc vs. anterior and posterior to Vc); and (3) analysis sia Syndrome in Spinal Cord Injury Patients. Pain 34:109–116 methods (incidence of bursting cells vs. bursting param- 2. Blomqvist A, Ericson AC, Craig AD et al. (1996) Evidence for Glutamate as a Neurotransmitter in Spinothalamic Tract Termi- eters). Clearly, the increase in bursting activity demon- nals in the Posterior Region of Owl Monkeys. Exp Brain Res stratedintheearlierstudyismoreapplicabletotheregion 108:33–44 of the principal somatic sensory nucleus in patients with 3. Bowsher D (1957) Termination of the Central Pain Pathway in central pain from spinal transection (Lenz et al. 1994). Man: The Conscious Appreciation of Pain. Brain 80:606–620 4. Craig AD, Bushnell MC, Zhang ET et al. (1994) A Thalamic Further support for increased spike-bursts occurring Nucleus Specific for Pain and Temperature Sensation. Nature in spinal cord injured patients is found in thalamic 372:770–773 recordings from monkeys with thoracic anterolateral 5. Davis KD, Lozano AM, Manduch M et al. (1999) Thalamic Relay Site for Cold Perception in Humans. J. Neurophysiol cordotomies (Weng et al. 2000). Some of these animals 81:1970–1973 showed increased responsiveness to electrocutaneous 6. Dostrovsky JO, Wells FEB, Tasker RR (1991) Pain Evoked by stimuli, and thus may represent a model of central pain Stimulation in Human Thalamus. In: Sjigenaga Y (ed) Interna- (Vierck 1991). The most pronounced changes in firing tional Symposium on Processing Nociceptive Information. El- sevier, Amsterdam, pp 115–120 pattern were found in thalamic multi-receptive cells, 7. Dougherty PM, Li YJ, Lenz FA et al. (1996) Evidence that Ex- which respond to both cutaneous brushing and com- citatory Amino Acids Mediate Afferent Input to the Primate So- pressive stimuli, with activity that is not graded into matosensory Thalamus. Brain Res 278:267–273 the noxious range. In comparison with normal controls, 8. Eaton SA, Salt TE (1990) Thalamic NMDA Receptors and Nociceptive Sensory Synaptic Transmission. Neurosci Lett multi-receptive cells in monkeys with cordotomies 110:297–302 showed significant increases in the number of bursts 9. Graziano A, Jones EG (2004) Widespread Thalamic Termina- occurring spontaneously or in response to brushing or tions of Fibers Arising in the Superficial Medullary Dorsal Horn compressive stimuli. The changes in bursting behavior of Monkeys and their Telation to Calbindin Immunoreactivity. J Neurosci 24:248–256 were widespread, occurring in the thalamic represen- 10. Hassler R (1970) Dichotomy of Facial Pain Conduction in the tation of upper and lower extremities, both ipsilateral Diencephalon. In: Walker AE (ed) Trigeminal Neuralgia. Saun- and contralateral to the cordotomy. ders, Philadelphia, pp 123–138 Although there is an increase in spike-burst activity in 11. Hirai T, Jones EG (1989) A New Parcellation of the Human Tha- lamus on the Basis of Histochemical Staining. Brain Res Rev centralpain secondary tospinalinjury,there doesnotap- 14:1–34 pear to be a direct relationship between spike-burst fir- 12. Jeanmonod D, Magnin M, Morel A (1994) A Thalamic Concept ing and pain. Spike-bursts are also found in the thalamic of Neurogenic Pain. In: Gebhart GF, Hammond DL, Jensen TS (eds) Proceedings of the 7th World Congress on Pain. Progress representation of the monkey upper extremity and of the in Pain Research and Management, vol 2. IASP Press, Seattle, representation of the arm and leg ipsilateral to the cor- pp 767–787 dotomy. Pain is not typically experienced in these parts 13. Lee J-I, Antezanna D, Dougherty PM et al. (1999) Responses of of the body in patients with thoracic spinal cord tran- Neurons in the Region of the Thalamic Somatosensory Nucleus to Mechanical and Thermal Stimuli Graded into the Painful Range. section or cordotomy (Beric et al. 1988). Spike-bursts J Comp Neurol 410:541–555 are increased in frequency during slow wave sleep and 14. Lenz FA, Gracely RH, Baker FH et al. (1998) Reorganization of drowsiness in all mammals studied (Steriade et al. 1990) Sensory Modalities Evoked by Stimulation in the Region of the including man in the absence of pain (Zirh et al. 1997). Principal Sensory Nucleus (Ventral Caudal-Vc) in Patients with Pain Secondary to Neural Injury. J Comp Neurol 399:125–138 However, such bursting could cause pain if stimulation 15. Lenz FA, Kwan HC, Martin R et al. (1994) Characteristics of in the vicinity of the bursting cells produced the sensa- Somatotopic Organization and Spontaneous Neuronal Activity in tion of pain. This finding has been reported in a study the Region of the Thalamic Principal Sensory Nucleus in Patients of sensations evoked by stimulation of the region of Vc with Spinal Cord Transection. J.Neurophysiol 72:1570–1587 16. Lenz FA, Seike M, Lin YC et al. (1993) Neurons in the Area of in patients with central pain, including those with spinal Human Thalamic Nucleus Ventralis Caudalis Respond to Painful cord injuries (Lenz et al. 1998). Thus, there is evidence Heat Stimuli. Brain Res 623:235–240 326 Central Pain in Multiple Sclerosis

17. Lenz FA, Zirh AT, Garonzik IM et al. (1998) Neuronal Activ- patients have pain caused by spasticity; while others re- ity in the Region of the Principle Sensory Nucleus of Human port pain is not a common problem. According to recent Thalamus (Ventralis Caudalis) in Patients with Pain Following Amputations. Neurosci 86:1065–1081 research, however, 44%–79% of all MS patients have 18. Mehler WR (1962) The Anatomy of the So-Called “Pain Tract” problems with pain (Ehde et al. 2003; Österberg 2005; in Man: An Analysis of the Course and Distribution of the As- Svendsen 2003), and about half of these patients have cending Fibers of the Fasciculus Anterolateralis. In: French JD, central pain, according to the only study in which cen- Porter RW (eds) Basic Research in Paraplegia. Thomas, Spring- field, pp 26–55 tral pain has been specifically investigated (Österberg 19. Ohara S, Lenz FA (2003) Medial Lateral Extent of Thermal and et al. 2005). Pain Sensations Evoked by Microstimulation in Somatic Sensory In two postal surveys about pain, responses were re- Nuclei of Human Thalamus. J Neurophysiol 90:2367–2377 ceived from 442 and 508 MS patients (Ehde et al. 20. Radhakrishnan V, Tsoukatos J, Davis KD et al. (1999) A Com- parison of the Burst Activity of Lateral Thalamic Neurons in 2003; Svendsen et al. 2003). In the American study Chronic Pain and Non-Pain Patients. Pain 80:567–575 44% reported persistent, bothersome pain as a result of 21. Rinaldi PC, Young RF, Albe-Fessard DG et al. (1991) Sponta- MS. Pain was of moderate to severe intensity in 63%, neous Neuronal Hyperactivity in the Medial and Intralaminar and interfered with life moderately or severely in 49% Thalamic Nuclei in Patients with Deafferentation Pain. J Neu- rosurg 74:415–421 (Ehde et al. 2003). In the Danish study, no significant 22. Steriade M, Jones EG, Llinas RR (1990) Thalamic Oscillations difference in the total proportion of individuals with and Signaling. Wiley, John & Sons, New York pain were found between MS patients and controls 23. Vierck CJ (1991) Can Mechanisms of Central Pain Syndromes (79% and 75%), but when responses were analyzed it be Investigated in Animal Models? In: Casey KL (ed) Pain and Central Nervous System Disease: the Central Pain Syndromes. became clear that pain was more severe in MS patients Raven Press, New York, pp 129–141 (Svendsen et al. 2003). In this study the impact of pain 24. Walker AE (1943) Central Representation of Pain. Res Publ As- on daily life ranged from moderate to severe in 45% and soc Res Nerv Ment Dis 23:63–85 25. Weng HR, Lee J-I, Lenz FA et al. (2000) Functional Plasticity 7% of the patients, respectively. Results from studies in Primate Somatosensory Thalamus Following Chronic Lesion over the last twenty years in which neurologists have of the Ventral Lateral Spinal Cord. Neurosci 101:393–401 interviewed and examined MS with regard to pain point 26. Zirh AT, Lenz FA, Reich SG et al. (1997) Patterns of Bursting in the same direction. Seven studies from the last 20 Occurring in Thalamic Cells during Parkinsonian Tremor. Neu- rosci 83:107–121 years have shown the prevalence of pain in MS patients has been found to be 54%–86% (Table 1). In a systematic study of central pain in MS, the preva- Central Pain in Multiple Sclerosis lence of CP in a population of 364 MS patients was found to be 27.5%, including 4.9% with TN (Österberg JÖRGEN BOIVIE et al. 2005). An additional 15 patients had possible Department of Neurology, University Hospital, CP. If the patients with probable CP had been included Linköping, Sweden the outcome would have been a prevalence of 31.6%. [email protected] These figures compare well with results of previous studies (Moulin et al. 1988; Moulin 1989; Vermonte et Synonyms al. 1986). Central neuropathic pain in multiple sclerosis. Previ- ously equated with dysesthetic pain, since there was a Features of Central Pain belief that all central pain in multiple sclerosis (MS) In the study by Österberg et al. (2005) many aspects of was of dysesthetic quality, this has been shown to be CP in MS were investigated, including: incorrect. • The prevalence of CP increased with age and disease Definition duration with peaks between 40 and 60 years-of-age and 10–20 years of disease duration, but not with a Central pain (CP) is neuropathic pain caused by pri- higher degree of disability. The prevalence of CP was marylesions(e.g.MSlesions)inthecentralnervoussys- ashigh as31%ten yearsafter onsetofMS, and almost tem (CNS), either in the brain or spinal cord. the same after 11–20 years of disease, thereafter the Characteristics prevalence of CP decreased to 14% – 18%. Thus, it appears that neither age nor duration of MS increases Epidemiology the risk of developing CP. This partly contradicts the Contrary to what was previously claimed in the liter- results of previous studies, where it was found that ature, several studies from the last two decades have the pain prevalence increased with age (Clifford and shown that many patients with MS have pain, and that Trotter1984;Moulinetal.1988;Stenageretal.1991), pain is a major problem for many MS patients. In the disease duration (Kassirer and Osterberg 1987) and early literature it was recognized thata small minority of disability (Stenager et al. 1995). Prospective studies MS patients have trigeminal neuralgia (TN) and even are needed to give more reliable information on these fewer painful tonic seizures. Furthermore, some MS matters. Central Pain in Multiple Sclerosis 327

Central Pain in Multiple Sclerosis, Table 1 Results from prevalence studies on pain in MS. Ages and durations in years. Prevalence in percent of the total population. The prevalence ﬁgures for central pain are estimates made from descriptions of pain, and were not calculated by the authors themselves. Study Vermote Kassirer Moulin Stenager Indaco Stenager Österberg 1986 1987 1988 1991 1994 1995 2005 C Nr of pats 83 28 159 117 122 49 364

Mean age - 49 47 43 38 - 54

MS duration - 29 13 8 13 - 23

Allpain 54755565578665

CP incl. TN 31 64* 29 - - - 28

TN 3,6 18** 5,9 3 9*** 14 4,9

Dysaesthetic pain - - 29 - 22 20 -

Pain in extremities 15 64 - 22 - 55 21

Spasm induced pain - 53 13 21 19 4 1

Non-trig. paroxysmal pain 4 - 5 7 5 41 2

Pain qualities Burning Burning Burning ---Aching Pricking Tingling Tingling Burning Stabbing Aching Pricking Dull Stabbing Smarting Squeezing

TN=trigeminal neuralgia. *Neurogenic origin, **Including atypical facial pain, ***Neuralgic pain (face and head)

• There was a large span in the time interval between • More than 80% of MS patients with CP experienced clinicalonsetof MSand the onsetof CP,ranging from two or more pain qualities, which is similar to that 7 years before other symptoms to 25 years after other found by Leijon et al. (1989) for central post-stroke symptoms. In 57% of patients with CP, pain started pain.Themostcommonqualitieswereburning(40%) within 5 years of onset of the disease, and after 10 and aching (40%). Thus, no pain qualities or combi- years the figure was 73%. nation of pain qualities are pathognomonic for CP in • In some patients, CP was the first symptom of MS MS. before any other symptom, while in others CP ap- • Out of 364 patients only 2% had pain caused by spas- peared together with other symptoms. CP preceded ticity. Instead, it was found that many patients with other symptoms in 6% of patients, and it was part of CP also have spasticity, but it was not the cause of the onset symptoms in 20% of these patients and in pain. This conclusion is shared by many clinicians. 5.5% of all MS patients. • A large majority of patients experienced daily pain As for other MS symptoms, CP can be one of several (88%);only30%hadpain-freemoments,lastingmin- symptomsinarelapse,ortheonlysymptom.Cliffordand utes to hours. Trotter(1984)reportedthisphenomenon,intwopatients • The intensity of pain varied somewhat, and 44% of withtemporaryburningpainduringarelapseofMS.The patientsexperiencedaconstantintensity.Thisandthe distribution of the three forms of MS in patients with CP irritating quality of the pain, contribute to the fact that does not generally differ among MS patients (relapsing- patients rate their pain as a heavy burden (Ehde et al. remitting, secondary progressive, primary progressive). 2003). Fromtheliteratureitisknownthatemotionalstress,light • More than one third of patientsexperiencedCP intwo touch,coldandphysicalactivitycanincreaseCP(Boivie to four separate pain loci, often with differing modal- 1999). This aspect has not been systematically studied ity, time of onset and intensity (TN excluded). in MS, but it has been noted that many MS patients ex- • The most common location of CP was in the lower perience worse pain after physical activity. extremities(87%)andintheupperextremities(31%). Some patients with MS who have pareses, spasticity and • Half the patients experienced pain both superficially dyscoordination of movement will develop nociceptive inskinandindeeperpartsofthebody,whichissimilar musculoskeletal pain. In a recent study, 21% of MS pa- to that found in central post-stroke pain (Leijon et al. tients were found to have nociceptive pain (Österberg 1989). et al. 2005), which is in the same range found in pre- 328 Central Pain in Multiple Sclerosis vious studies (14%–39%; Kassirer and Osterberg 1987, anisms of central pain stating that “central pain is due Moulin 1989; Vermote et al. 1986). to the disruption of thermosensory integration and the loss of cold inhibition of burning pain”, which in turn Sensory Abnormalities is caused by a lesion of the spinothalamic projection The most common neurological sign in patients with activated by cold receptors in the periphery. The dis- non-trigeminal CP is sensory disturbance. Almost all rupted fibres are thought to tonically inhibit nociceptive patients have at least one abnormal finding in the sen- thalamocortical neurones, increasing discharge and sory examination, with a decrease in sensibility to cold producing pain. Like several other hypotheses, this occurring more often than any other sub-modalities might be applicable in some patients, but not others, (Österberg and Boivie, in preparation). In this study because of the location of the lesions and character of of 62 patients with non-trigeminal CP, both clinical the pain. and quantitative methods were used to test sensibil- One can only speculate about the location of lesions re- ity. There was a large variation between patients with sponsible for the development of CP in MS, because, as regard to degree and submodality of abnormalities. shown with MRI, practically all patients have dissemi- Some patients had severe defects in all submodalities, nated lesions in both the brain and spinal cord. However, whereas only one or two were affected in others. In based on clinical grounds, it is proposed that much of the the quantitative tests, all patients except two (97%) CP located in the lower extremities is due to lesions in had abnormal sensibility to temperature and/or pain. the spinal cord. The bilateral nature of pain supports this Significant differences in abnormalities were found idea. between regions with CP and regions without CP for the following perception thresholds: difference limen Treatment (i.e. innoxious temperature), warmth, cold, cold pain. The treatment of MS with interferons and similar sub- No significant differences were found in the thresholds stances do not appear to have any symptomatic effect on for heat pain. central pain, or on any other symptom. Among patients who did not perceive non-noxious Several treatment modalities are used in the manage- warmth at all, but could feel heat pain, the burning ment of CP in general, but almost no controlled clini- sensation of heat struck patients suddenly and with cal trials have been performed in MS, and only a few high intensity as the temperature reached threshold. in other forms of CP. The only exception is the study of This was observed in 19% of patients. A corresponding oral cannabinoid dronabinol in 28 MS patients. A statis- sensation did not appear with cold. Eight patients had tically significant, but weak effect was found (Svendsen noxious cold evoked paradoxical heatpain. Non-painful et al. 2004). dysesthesias were commonly evoked by noxious heat TreatmentsthatareusedforCParelistedabove,butmost or cold. of them are based on clinical experience and tradition, The results from the sensory tests indicate that most MS rather than on results from controlled clinical trials. This patientswithCPhavelesionsaffectingthespinothalamo- means that no evidence based recommendations can be cortical pathways (temperature and pain), but to a lesser made for the management of CP in MS. Tricyclic an- degree affect the medial lemniscal pathways (tactile, tidepressants have been found to be effective for many position sense and vibration). patients with central post-stroke pain (see essay on this pain condition), but the experience is that many MS pa- Mechanisms tients get severe side effects from these drugs. The cellular mechanismsunderlyingcentralpainin general, and definitely for MS, are largelyunknown. Several Treatment Modalities Used for Central Pain investigators have reported that CP develops as a result Among antidepressants and antiepileptics, the most fre- of lesions affecting the spino- and quintothalamic path- quently used are listed. ways, i.e. pathways most important for the sensibility • Antidepressant drugs (AD) of pain and temperature. Furthermore, lesions of these pathways can be located at any level of the neuraxis (for – Amitriptyline references see Boivie 1999). The results from examina- –Desipramine tion of the sensibility in MS patients with CP support –Doxepine this hypothesis. It has been proposed that the crucial le- –Imipramine sionisonethataffectsneospinothalamicprojections,i.e. – Nortriptyline projectionstotheventroposteriorthalamicregion(Bow- sher 1996). The effects of such a lesion involve neurones • Antiepileptic drugs (AED) of the spinothalamic pathway which become hyperexcitable due to reduced tonic inhibition. – Carbamazepine Based on results from experimental studies, Craig – Gabapentin (1998) proposed a similar hypothesis about the mech- – Lamotrigine Central Pain, Outcome Measures in Clinical Trials 329

– Oxcarbazepine 10. Stenager E, Knudsen L, Jensen K (1991) Acute and Chronic Pain – Pregabalin Syndromes in Multiple Sclerosis. Acta Neurol Scand 84:197–200 11. Stenager K, Knudsen L, Jensen K (1995) Acute and Chronic Pain Syndromes in Multiple Sclerosis. A 5-Year Follow-Up Study. Ital • Analgesics J Neurol Sci 16:629–632 12. Svendsen K, Jensen T, Bach F (2004) Does the Cannabinoid C – Morphine Dronabinol Reduce Central Pain in Multiple Sclerosis? Ran- domised Double Blind Controlled Crossover Trial. Br Med J – Oxycontine 329:253 – Codeine 13. Svendsen K, Jensen T, Overvald K (2003) Pain in Patients with Multiple Sclerosis: A Population-Based Study. Arch Neurol 60: 1089–1094 • Sensory stimulation 14. Vermote R, Ketelaer P,Carton H (1986) Pain in Multiple Sclerosis Patients. Clin Neurol Neurosurg 88: 87–93 – Transcutaneous electrical stimulation (TENS) – Spinal cord stimulation (SCS) – Deep brain stimulation (DBS) – Motor cortex stimulation (MCS) Central Pain Mechanisms, Molecular Contributions Among the antiepileptic drugs, carbamazepine is effective for trigeminal neuralgia associated with MS, Molecular Contributionsto the Mechanism of Central but does not appear to relieve non-trigeminal central Pain pain (Österberg and Boivie, in preparation). Lamotrig- ine was shown to relieve CP in stroke, but it has not been tested in MS patients. Many neurologists have Central Pain Model tried gabapentin with some success in non-trigeminal CP, but in the literature only case reports support its Spinal Cord Injury Pain Model, Ischemia Model use. In one study with I.V. morphine, ten patients with CP from MS, and ﬁve patientsfrom stroke were tested. Only Central Pain, Outcome Measures in a trend to pain relief was found, and during the following 12 weeks open treatment period only three patients Clinical Trials experienced a positive effect (Attal 2002). From clini- EVA WIDERSTRÖM-NOGA cal experience it appears that some MS patients obtain The Miami Project to Cure Paralysis, Department of long-term relief from weak opioids, but no systematic Neurological Surgery University of Miami, VAMC, observations support this. The experience with TENS Miami, FL, USA for CP is meagre and positive results have not been re- [email protected] ported. The same is true for spinal cord stimulation and deep brain stimulation. Synonyms Effectiveness Measure References Deﬁnition 1. Boivie J (1999) Central Pain. In: Wall PD, Melzack R (ed) Textbook of Pain 4th edn. Churchill Livingstone, Edinburgh, An outcome measure is a performance indicator that as- pp 879–914 sesses patient health status subsequent to, and resulting 2. Bowsher D (1996) Central Pain: Clinical and Physiological Char- from, a health care treatment, procedure, or other ther- acteristics. J Neurol Neurosurg Psychiat 61:62–69 apeutic interventions. 3. Clifford DB, Trotter JL (1984) Pain in Multiple Sclerosis. Arch. Neurol 41:1270–1272 4. Craig AD (1998) A New Version of the Thalamic Disinhibition Characteristics Hypothesis of Central Pain. Pain Forum 7:1–14 Central neuropathic pain (CNP) is a result of trauma 5. Ehde DM, Gibbons LE, Chwastiak L (2003) Chronic Pain in a Large Community Sample of Persons with Multiple Sclerosis. or neurological disease involving the central nervous Multiple Sclerosis 9:605–611 system (CNS) (Bowsher et al. 1998). This type of pain 6. Indaco A, Iachetta C, Nappi C (1994) Chronic and Acute Pain can be a prominent feature in the complex clinical Syndromes in Patients with Multiple Sclerosis. Acta Neurol picture associated with disease or trauma involving the (Napoli) 16:97–102 7. Kassirer M, Osterberg D (1987) Pain in Chronic Multiple Scle- CNS, e.g. stroke, multiple sclerosis, epilepsy, rosis. J Pain Symptom Manag 2:95–97 tumors, syringomyelia, brain or spinal cord trauma, 8. Moulin DE (1989) Pain in Multiple Sclerosis. Neurologic Clinics or Parkinson’s disease (Boivie 2003). CNP is com- 7:321–331 monly associated with both spontaneous non-painful 9. Österberg A, Boivie J, Thuomas K-Å (2005) Central Pain in Multiple Sclerosis – Prevalences, Clinical Characteristics and sensations and evoked pain (Widerström-Noga 2002), Mechanisms. Eur J Pain 9:531–542 which further contribute to its unpleasant character. 330 Central Pain, Outcome Measures in Clinical Trials

Due to the refractory nature of CNP (Bowsher 1999), on a combination of clinical characteristics, and signs there is an obvious risk for a significantly decreased and symptoms of neurological dysfunction. This evalu- health-related quality of life (HRQOL). Therefore, ation is particularly relevant for people who have CNP, clinical trials examining treatments, or combina- since they frequently experience different types of pain tions of treatments, which may lead to more effective simultaneously,withpresumablydifferentmechanisms. strategies for pain management in these patient popu- Even though a clinicaltrialmay be designed primarily to lations are urgently needed. Although CNP is common target CNP, an improvement in physical and emotional in specific syndromes, the prevalence in the general function may be caused by a decrease in the severity of population is relatively low (Boivie 2003). However, less refractory pain types, rather than a direct effect on with increased awareness and more advanced diag- central pain. Different types of pain may also influence nostic procedures this number can be expected to pain-related impairment and function to various degrees increase. (Marshall et al. 2002). Therefore, it is important to dif- The low numbers of people who experience CNP make ferentiate between the consequences of different pain it difficult to obtain sufficient numbers of participants types to determine treatment effects on specific types of for definitive clinical trials. Consequently, few large pains. scale, randomized, controlled clinical trials have been In central pain, the evaluation of neurological dysfunc- conducted in persons with CNP. This further empha- tion includes the quantification and determination of sizes the need for clinical trial designs that permit sensory, motor, and autonomic function (Cruccu et al. comparisons between trials. To achieve this goal, it is 2004). This evaluation is of primary importance for the particularly important to evaluate outcomes of treat- diagnosis, and thus provides a basis for mechanism- ments in a comprehensive and consistent manner. The based tailored treatments. However, the role of these use of standard sets of outcome measures in clinical tri- types of assessments as outcome measures in clinical als involving people with CNP would greatly facilitate trials is less clear. Specifically, more research is needed the interpretation and application of research results to to establish reliability of the various ways of assessing the management of CNP. and quantifying neurological dysfunction. In addition, In a recent report, the Initiative on Methods, Measure- the relationship between neurological dysfunction and ment, and Pain Assessment in Clinical Trials (IMM- improvement in spontaneous neuropathic pain needs to PACT) (Turk et al. 2003) recommended that clinical be further elucidated. trials designed to evaluate the effectiveness of a therapy in relieving chronic pain, should consider including a Physical Functioning core set of 6 outcome domains. The combination of Because CNP is associated with neurological disease these domains would generate more complete reports of or trauma, physical functioning is often impaired. Al- results, and therefore facilitate the overall risk-benefit though a general measure applicable to various pain evaluation. The suggested domains include: populations would allow for better comparisons, physical functioning in chronic pain populations afflicted 1. Pain with neurological disease or trauma may be influenced 2. Physical functioning more by the neurological impairment per se, than by 3. Emotional functioning chronic pain. One of the commonly used measures for 4. Participants ratings of improvement and satisfaction the evaluation of function in disabled populations is with treatment the Functional Independence Measure (FIM). The FIM 5. Symptoms and adverse effects was developed to provide a uniform measurement of 6. Participant disposition. disability (Granger 1998) and assesses independent The authors emphasized those complementary mea- performance in self-care, sphincter control, transfers, sures appropriate for specific patient populations should locomotion, communication, and social cognition. be added as needed. Below is a brief description of the However, the usefulness of this measure in CNP popu- six domains recommended to be included in the design lations needs to be determined. Moreover, the relative of clinical trials for chronic pain. contribution of CNP to the overall perceived disability in physically impaired central pain populations is not Pain clear, and is also an important area for future research. Ratings of pain intensity, or pain severity by means of Pain Interference measures may provide more useful numerical rating or visual analogue scales,arethe alternatives or complements to instruments that assess most widely used primary outcome measures in clinical general functional disability. For example, the extent pain trials (Farrar et al. 2001). However, other clinical to which pain hinders or interferes with daily activities features of pain (i.e. location, quality temporal pattern) may provide more specific information in populations commonly evaluated in the pain history (Wincent et afflicted with physical impairment (Widerström-Noga al. 2003) may also be useful for the evaluation of treat- et al. 2002). These measures can be used as comparisons ment outcome. The differentiation of pain types is based to samples of able-bodied chronic pain patients. Central Pain, Outcome Measures in Clinical Trials 331

Emotional Functioning disease-specific and related to other sequela of neuro- Emotional distress (e.g. depressed mood, anxiety, logical disease and trauma. anger, irritability) is intimately linked to the experience of chronic pain, although no consistent causal rela- Health Related Quality of Life tionship has been proven. In neurological disease or In CNP, complete remission of pain is unlikely to oc- C trauma, such as in traumatic brain injury (Jorge et al. cur either spontaneously or due to treatment (Bowsher 2004), depression and anxiety levels are often elevated. 1999). Therefore, measures that assess factors that may Similar to physical functioning, it is not clear to what influence HRQOL are of particular interest. HRQOL is extent pain itself contributes to affective distress in the a subjective concept, which is based on personal prefer- complicated clinical syndromes associated with a neu- encesandvaluesconcerningmultipledimensionsoflife, rological injury. Since affective distress is an important including well-being and enjoyment of life. HRQOL in factor in the pain experience, this may have a significant diverse populations has been categorized into the fol- impact on HRQOL, and additional research in this area lowing groups: is warranted. 1. Physical functioning 2. Social functioning Participants Ratings of Global Improvement and Satisfaction 3. Role limitations due to physical problems with Treatment 4. Role limitations due to emotional problems Related to the risk-benefit ratio, is the participant’s 5. Mental health personal estimation of how beneficial a treatment in- 6. Vitality tervention is, namely, participants rating of global 7. Bodily pain improvement and satisfaction with treatment. Although 8. General Health (Ware and Sherbourne 1992). this rating can be influenced by a variety of factors that are difficult to control for (e.g. social desirability, recall The IMMPACT group (Turk et al. 2003) suggested bias, etc.), it still provides valuable and useful infor- that assessing some of these HRQOL dimensions (e.g. mation (Farrar et al. 2001), incorporating the patient’s physical and emotional functioning and pain severity) own unique view about the benefit and overall meaning would provide a basis for a multidimensional evaluation of a treatment. of pain. However, in CNP populations with physical impairments, the inclusion of additional dimensions Symptoms and Adverse Effects (i.e. changed roles due to physical problems and general health) may be needed to determine the relative The assessment of adverse effects in a clinical trial aims contribution of CNP to the perception of HRQOL. Fur- to determine the risk-benefit of the treatment. Adverse thermore, increased understanding of the interaction effects can be directly caused by the treatment, or indi- between the variousdomainsmayimprovemanagement rectlybyworseninganunderlyingillnessorcompromis- of these complex pain syndromes. ing previously impaired function. In people with CNP, the latter scenario may need special consideration, since Conclusion adverse effects that have a relatively minor impact in able-bodied populations can cause significant problems The assessment domains recommended by the IMM- when there are pre-existing impairments. For example, PACT appear to also be appropriate for CNP popu- a decrease in cognitive function in a person with cogni- lations. Due to the fact that people who have CNP tive impairment due to a traumatic brain injury, or con- frequently have varying degrees of physical impair- stipation in a person who has impaired bowel function ment, specific assessment of pain-related interference due to spinal cord injury, may cause difficulties that hin- with physical and emotional functioning may be more der adequate dosing as well as adherence to treatment. useful than general measures of physical and emotional Therefore, it is important to monitor not only severity of function. A set of core outcome measures in combi- adverseeffects,butalsoimpactonpre-existingproblems nation with more disease specific measures would be associated with the neurological disease or trauma. useful for the purpose of comparison of clinical trials in these populations. In the selection of specific instru- Participant Disposition ments to be used as core outcome measures, not only validity and reliability must be considered, but also To adequately interpret the results of a trial and to deter- whether the instrument can be used with diverse CNP mine whether obtained results are representative and ap- populations associated with a variety of diseases and plicable to larger population, details concerning partici- traumas. pants screened for enrollment (e.g. reasons for drop-out and non-compliance etc.) need to be provided (for de- tailsseethe CONSORTstatement(Moheretal.2001). References This is particularly important in CNP populations, since 1. Boivie J (2003) Central Pain and the Role of Quantitative Sensory the reasons for withdrawal and non-adherence may be Testing (QST) in Research and Diagnosis. Eur J Pain 7:339–343 332 Central Pain Pathways

2. Bowsher D, Leijon G, Thuomas KA (1998) Central Poststroke central pain in spinal cord injury (SCI), multiple scle- Pain: Correlation of MRI with Clinical Pain Characteristics and rosis, perhaps Parkinson’s and Huntington’s disease, Sensory Abnormalities. Neurology 51:1352–1358 3. BowsherD(1999)CentralPain Following Spinal andSupraspinal AIDS, and brain trauma. In spinal cord injury, central Lesions. Spinal Cord 37:235–238 neuropathic pain is experienced at and/or below the 4. Cruccu G, Anand P, Attal N et al. (2004) EFNS Guidelines on level of a lesion, and may be difficult to separate from Neuropathic Pain Assessment. Eur J Neurol 11:153–162 peripheral neuropathic pain components caused by root 5. Farrar JT, Young JP Jr, LaMoreaux Le et al. (2001) Clinical Im- portance of Changes in Chronic Pain Intensity Measured on an lesions. Pain associated with this pathology is generally 11-Point Numerical Pain Rating Scale. Pain 94:149–158 felt at the level of injury. Since different types of SCI 6. Granger CV (1998) The Emerging Science of Functional Assess- pain are usually not separated, this review includes all ment: Our Tool for Outcomes Analysis. Arch Phys Med Rehabil trials on the treatment of pain associated with spinal 79:235–240 cord injury. 7. Jorge RE, Robinson RG, Moser D et al. (2004) Major Depres- sion Following Traumatic Brain Injury. Arch Gen Psychiatry Anylesionalongthespinothalamocorticalpathwaymay 61:42–50 lead to central pain, and neuronal hyperexcitability 8. Marshall HM, Jensen MP, Ehde DM et al. (2002) Pain Site and caused by increased excitation and/or decreased inhi- Impairment in Individuals with Amputation Pain. Arch Phys Med Rehabil 83:1116–1119 bition is an additional mechanism, which provides the 9. Moher D, Schulz KF, Altman DG (2001) The CONSORT mechanistic basis for the use of drugs for neuropathic Statement: Revised Recommendations for Improving the Qual- pain. Most pharmacological agents developed for treat- ity of Reports of Parallel-Group Randomised Trials. Lancet ment of this condition act by depressing neuronal activ- 357:1191–1194 10. Turk DC, Dworkin RH, Allen RR et al. (2003) Core Outcome ity, modulating sodium or calcium channels, increasing Domains for Chronic Pain Clinical Trials: IMMPACT Recom- inhibition with γ-aminobutyric acid (GABA), seroton- mendations. Pain 106:337–345 ergic, noradrenergic, or enkephalinergic agonists, or de- 11. Ware JE Jr, Sherbourne CD (1992) The MOS 36-Item Short- creasing activation via glutamate receptors, especially Form Health Survey (SF-36). I. Conceptual Framework and Item Selection. Med Care 30:473–483 the N-methyl-D-aspartate (NMDA) receptor. 12. Widerström-Noga EG (2003) Chronic Pain and Nonpainful Sen- sations after Spinal Cord Injury: Is there a Relation? Clin J Pain Characteristics 19:39–47 13. Widerström-Noga EG, Duncan R, Felipe-Cuervo E et al. (2002) Tosuggestanevidence-basedtreatmentalgorithmbased Assessment of the Impact of Pain and Impairments Associated on randomized double-blind placebo-controlled with Spinal Cord Injuries. Arch Phys Med Rehabil 83:395–404 trials on central pain is difficult, considering the fact that 14. Wincent A, Liden Y, Arner S (2003) Pain Questionnaires in the Analysis of Long Lasting (Chronic) Pain Conditions. Eur J Pain although new trials are emerging, there are still only a 7:311–321 few, small sized studies on central pain (Table 1 and 2). Number needed to treat (NNT) and number needed to harm (NNH) (in this text defined as treatment-related Central Pain Pathways withdrawals) are used to compare efficacy and harm of individual drugs. Definition Antidepressants The pathways that carry information about noxious Tricyclic antidepressants block the reuptake of nore- stimuli to the brain, includes the spinalthalamic tract pinephrine or serotonin, but activation on NMDA and trigeminal system. receptors and sodium channels may also play a role Thalamic Nuclei Involved in Pain, Human and Mon- in their analgesic actions. The tricyclic antidepres- key sant amitriptyline has been studied in two controlled trials. In a three-way cross-over study, amitriptyline 75 mg daily was effective in relieving pain (Leijon and Boivie 1989). The pain-relieving effect correlated Central Pain, Pharmacological well with total plasma concentration a with high num- Treatments ber of responders, b having plasma concentrations 1 2 exceeding 300 nmol/L. In patients with SCI, amitripty- NANNA BRIX FINNERUP ,SØREN HEIN SINDRUP line 10–125 mg daily had no effect on different types of 1Department of Neurology and Danish Pain Research pain, including nociceptive pain (Cardenas et al. 2002), Centre, Aarhus University Hospital, Aarhus, Denmark but the average amitriptyline dose was low, as were 2Department of Neurology, Odense University serum concentrations (mean 92 ng/ml), i.e. below the Hospital, Odense, Denmark level associated with response in CPSP. The hetero- fi[email protected], [email protected] cyclic antidepressant trazodone 150 mg daily had no effect on neuropathic pain in spinal injury (Davidoff Definition et al. 1987). The possibility of preventing CPSP was Central pain can be a consequence of different dis- studied using amitriptyline (10 mg the first day after the eases and includes central post-stroke pain (CPSP), onset of stroke was diagnosed, titrated to 75 mg within Central Pain, Pharmacological Treatments 333

Central Pain, Pharmacological Treatments, Table 1 Randomized, double-blind, placebo-controlled trials on oral drugs in central pain Active drug, daily dose Study Condition Design, no. of Outcome NNT NNH patients (95% CI) (95% CI)

Amitriptyline Leijon and Boivie 1989 CPSP Cross-over Ami > pla 1.7 ∞ 75 mg 15 (1.2–3.1) C Amitriptyline Cardenas et al. 2002 SCI pain Parallel Ami = pla - 9.2 10–125 mg 84 (4.2–∞)

Trazodone Davidoff et al. 1987 SCI pain Parallel Tra = pla - NA 150 mg 18

Carbamazepine Leijon and Boivie 1989 CPSP Cross-over 15 Carb = pla - 15.0 800 mg (5.2–∞)

Lamotrigine Vestergaard et CPSP Cross-over 30 Ltg > pla NA 10.0 200 mg al. 2001 (4.8–∞)

Lamotrigine Finnerup et al. 2002 SCI pain Cross-over 22 Ltg = pla - ∞ 200–400 mg

Valproate 600–2400 mg Drewes et al. 1994 SCI pain Cross-over 20 Val = pla - ∞

Gabapentin Tai et al. 2002 SCI pain Cross-over 7 Gab = pla - 14.0 (4.8–∞) up to 1800 mg Gabapentin Levendoglu et al. 2004 SCI pain Cross-over 20 Gab > pla NA ∞ up to 3600 mg Mexiletine Chiou-Tan et al. 1996 SCI pain Cross-over 11 Mex = pla - ∞ 450 mg Dronabinol Svendsen et al. 2004 Multiple Cross-over 24 Dro > pla 3.4 ∞ 5–10 mg sclerosis (1.8–23.4)

CPSP, central post-stroke pain; SCI, spinal cord injury; CI, confidence interval three weeks) or placebo administered to 39 stroke pa- actions. The effect of valproate 600–2400 mg daily tients for one year (Lampl et al. 2002). Within this year, was examined in a cross-over study in patients with CPSP developed in three patients receiving amitripty- spinal injury (Drewes et al. 1994). Although a trend line (VAS 5.0), and in four receiving placebo (VAS 5.4). toward improvement was observed, valproate was not Two patients in the amitriptyline group and three pa- significantly better than placebo in relieving pain. Lam- tients in the placebo group developed allodynia. With otrigine inhibits voltage dependent sodium channels to an expected 8% incidence of CPSP, this sample size is stabilize neuronal membranes and inhibits release of probably too small to detect an effect, but this was the excitatory amino acids, principally glutamate. In CPSP, first study of its kind and more are encouraged. lamotrigine 200 mg daily reduced pain with a mean reduction of 30% (Vestergaard et al. 2001). Lamotrigine Antiepileptic Drugs also reduced cold evoked allodynia assessed by an Antiepileptic drugs include a broad spectrum of drugs acetone droplet. In spinal cord injury pain (SCIP), lam- used in the managementof epilepsy, and exert their anal- otrigine 200–400 mg daily was not more effective than gesic actions through multiple mechanisms, by either placebo in reducing pain, although a subgroup of pa- reducing excitation and/or enhancing inhibition. Carba- tients with incomplete injury and evoked pain reported mazepine blocks voltage dependent sodium channels, an effect on spontaneous pain (Finnerup et al. 2002). and may have minor effects on calcium channels and Gabapentin, which is thought to exert its analgesic α δ serotonergic systems. In a three-way cross-over study of actions by binding to an 2 subunit of voltage gated amitriptyline, carbamazepine 800 mg and placebo, car- calcium channels, has been studied in two cross-over bamazepine did not reduce CPSP compared to placebo trials in SCIP. In a small study with seven patients, (Leijon and Boivie 1989). However, both amitriptyline gabapentin up to 1800 mg had no significant effect on and carbamazepine treatments gave a 20% lower mean pain intensity (Tai et al. 2002). There was, however, pain intensity score during the last week of treatment. a trend toward improvement, and a significant effect Based on the relatively small number of patients in this on unpleasant feeling. In another study, gabapentin study,asignificanteffectofcarbamazepineinCPSPcan- up to 3600 mg reduced the intensity and frequency of not be excluded. Valproate has several pharmacological pain and several pain descriptors in 20 paraplegics with effects, including GABAergic and anti-glutamatergic complete SCI (Levendoglu et al. 2004). Gabapentin in 334 Central Pain, Pharmacological Treatments

Central Pain, Pharmacological Treatments, Table 2 Randomized, double-blind, placebo-controlled trials on non-oral drugs in central pain Active drug, dose administration Study Condition Design, no. of Outcome patients

Lidocaine IV 5 mg/kg Attal et al. 2000 CPSP/ Cross-over Lid > pla SCI pain 16

Lidocaine IV 2.5 mg/kg Kvarnstrøm et al. 2004 SCI pain Cross-over Lid = pla 10

Lidocaine SA 50–100 mg Loubser and Donovan 1991 SCI pain Cross-over Lid > pla 21

Ketamine IV60 µg/kg + Eide et al. 1995 SCI pain Cross-over Ket > pla 6 µg/kg/min 9

Ketamine IV 0.4 mg/kg Kvarnstrøm et al. 2004 SCI pain Cross-over Ket > pla 10

Alfentanil IV 7 µg/kg + Eide et al. 1995 SCI pain Cross-over Alf > pla 0.6 µg/kg/min 9

Propofol IV 0,2 mg/kg Canavero and Bonicalzi 2004 CPSP/ Cross-over Pro > pla SCI pain 44

Morphine IV 9-30 mg Attal et al. 2002 CPSP/ Cross-over Mor = pla SCI pain 15

Morphine IT 0.2–1.5 mg Siddall et al. 2000 SCI pain Cross-over Mor = pla Clonidine IT 50–100 µg 15 Clo = pla or 300–500 µg Mor + clo > pla

Naloxone IV up to 8 mg Bainton et al. 1992 CPSP Cross-over Nal = pla 20

Baclofen 50 µg Hermann et al. 1992 SCI pain Cross-over Bac > pla 6

CPSP, central post-stroke pain; SCI, spinal cord injury; IV, intravenous; SA, subarachoidal; IT, intrathecal

(similar mechanism as gabapentin) reduced SCIP in a large study which is not yet published (Siddall et al. 2005). Oxcarbazepine (similar mechanism as carbamazepine), and other newer anticonvulsants such as tiagabine, levetiracetam, and zonisamide, have not been tested in controlled trials in central pain.

Other Oral Drugs Thecannabinoiddronabinol(asyntheticδ-9-tetrahydrocannabinol) has been studied in 24 patients with central pain caused by multiple sclerosis. It significantly relieved central pain (Svendsen et al. 2004). Mexiletine, a sodium channel blocker, did not relieve pain in eleven patients with SCIP in doses of 450 mg daily (Chiou-Tan et al. 1996). Central Pain, Pharmacological Treatments, Figure 1 L’Abbé plot of controlled trials in central pain. Number of patients receiving active and Non-Oral Drugs placebo treatments are indicated by circle sizes (lower right corner). Note that the two trials showing a pain relieving effect of lamotrigine (Vestergaard Sodium channel blockers may play a role in the treat- et al. 2001) and gabapentin (Levendoglu et al. 2004) are not included in ment of central pain. Lidocaine in doses of 2.5 mg/kg, the figure because dichotomized data were not provided. administeredintravenouslyover40minutes,hadnopain relieving effect on pain in spinal cord injury patients combination with the NMDA antagonist dextromethor- (Kvarnstrom et al. 2004), while 5 mg/kg administered phan was found to be superior to placebo, and to either intravenously over 30 minutes significantly decreased component alone, in patients with neuropathic pain spontaneous ongoing pain, brush-evoked allodynia, following spinal injury (Sang et al. 2001). Pregabalin and static mechanical hyperalgesia, but was no better Central Pain, Pharmacological Treatments 335 than placebo against thermal allodynia and hyperalge- treatment algorithm for central pain is still based on sia in patients with CPSP or SCIP (Attal et al. 2000). It effective treatments for peripheral neuropathic pain. was also found that lidocaine 5 mg/kg over 30 minutes Antidepressants and anticonvulsants (Table 3) are first- relieved spontaneous pain in spinal cord injury patients line drugs for central pain. In many cases, treatment with (n=12) and without (n=12) evoked pain, and that provides only partial or no relief, and other types of C lidocaine relieved pain felt at and below the level of drugs, combination therapy, intrathecal therapy, and injury (Finnerup et al. 2005). Subarachnoid infusion of different non-pharmacological approaches may be lidocaine was significantly better than placebo in re- considered in these cases. lieving SCIP (Loubser and Donovan 1991). Adequate spinal anesthesia, proximal to the level of spinal injury, seems important for a positive response to lidocaine, References suggesting the existence of a ‘pain generator’ in the 1. Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, spinal cord of some patients. Bouhassira D (2000) Intravenous Lidocaine in Central Pain: A NMDA receptor antagonists given intravenously were Double-Blind, Placebo-Controlled, Psychophysical Study. Neu- rology 54:564–574 reported to relieve SCIP in two studies (Eide et al. 1995; 2. Attal N, Guirimand F, Brasseur L, Gaude V,Chauvin M, Bouhas- Kvarnstrom et al. 2004). Studies on opioids in central sira D (2002) Effects of IV Morphine in Central Pain: A Ran- pain trials have yielded diverging results. Intravenous domized Placebo-Controlled Study. Neurology 58:554–563 morphine was reported to have an effect on brush- 3. Bainton T, Fox M, Bowsher D, Wells C (1992) A Double-Blind Trial of Naloxone in Central Post-Stroke Pain. Pain 48:159–162 evoked allodynia, but not on spontaneous pain in CPSP 4. Canavero S, Bonicalzi V (2004) Intravenous Subhypnotic Propo- and SCIP patients (Attal et al. 2002), intravenous alfen- fol in Central Pain: A Double-Blind, Placebo-Controlled, Cross- tanil was effective in relieving SCIP (Eide et al. 1995), over Study. Clin Neuropharm 27:182–186 and finally, morphine given intrathecally was effective 5. Cardenas DD, Warms CA, Turner JA, Marshall H, Brooke MM, Loeser JD (2002) Efficacy of Amitriptyline for Relief of Pain in in SCIP patients, but only in combination with cloni- Spinal Cord Injury: Results of a Randomized Controlled Trial. dine (an α2-adrenergic agonist) (Siddall et al. 2000). Pain 96:365–373 No effect of naloxone in CPSP was found (Bainton 6. Chiou-Tan FY, Tuel SM, Johnson JC, Priebe MM et al. (1996) Effect of Mexiletine on Spinal Cord Injury Dysesthetic Pain. Am et al. 1992). Propofol, a GABAA-receptor agonist, J Phys Med Rehabil 75:84–87 injected as a single intravenous bolus of 0.2 mg/kg, 7. Davidoff G, Guarracini M, Roth E, Sliwa J, Yarkony G (1987) relieved spontaneous pain and allodynia in 44 patients Trazodone Hydrochloride in the Treatment of Dysesthetic Pain in with spinal cord injury and post-stroke pain (Canavero Traumatic Myelopathy: A Randomized, Double-Blind, Placebo- Controlled Study. Pain 29:151–161 and Bonicalzi 2004). Intrathecal baclofen, a GABAB 8. Drewes AM, Andreasen A, Poulsen LH (1994) Valproate for receptor agonist, was also reported to relieve dyses- Treatment of Chronic Central Pain after Spinal Cord Injury. A thesia in six patients with SCI or multiple sclerosis double-blind cross-over study. Paraplegia 32:565–569 (Herman et al. 1992). 9. Eide PK, Stubhaug A, Stenehjem AE (1995) Central Dyses- thesia Pain after Traumatic Spinal Cord Injury is Depen- dent on N-methyl-D-aspartate Receptor Activation. Neuro- Conclusions surgery 37:1080–1087 10. Finnerup NB, Sindrup SH, Bach FW, Johannesen IL, Jensen TS Tricyclic antidepressants, sodium channel blockers, (2002) Lamotrigine in Spinal Cord Injury Pain: A Randomized NMDA antagonists, GABA agonists, calcium channel Controlled Trial. Pain 96:375–383 blockers, and cannabinoids, are shown to relieve central 11. Finnerup NB, Biering-Sorensen F, Johannesen IL et al. (2005) Intravenous lidocaine relieves spinal cord injury pain: a random- pain. In randomized controlled trials on oral treatment, ized controlled trial. Anesthesiology 102:1023–30 amitriptyline, lamotrigine, gabapentin, and dronabinol 12. Herman RM, D’Luzansky SC, Ippolito R (1992) Intrathecal Ba- have been effective in relieving pain, but large scale clofen Suppresses Central Pain in Patients with Spinal Lesions. randomized controlled studies are lacking, and the A Pilot Study. Clin J Pain 8:338–345

Central Pain, Pharmacological Treatments, Table 3 First-line treatment options for central pain Drug class and name Dosage Common side effects and cautions

Tricyclic antidepressants e.g. 25 mg daily initially, increasing by 25 mg every Dry mouth, constipation, and urinary retention, imipramine or amitriptyline two weeks, usually up to 150 mg daily in one to orthostatic hypotension, sedation, and increased two divided doses. Plasma drug levels should be spasticity is reported. Contraindicated in patients with monitored (optimal plasma levels of imipramine plus heart failure, cardiac conduction blocks (ECG before desipramine is 300–750 nM). start) and epilepsy.

Gabapentin 300 mg daily initially, increasing by 300 mg every Dizziness, sedation, ataxia, and occasional peripheral third day, to 1800–4800 mg daily. edema. Renal impairment requires dosage adjustment.

Lamotrigine 25 mg daily initially, increasing the dose with 25 mg Dizziness, sedation, ataxia diplopia, and nausea. Risk every two weeks, later with 50 mg every week to of rash and potentially life-threatening hypersensitivity 400 mg daily reactions requires slow dose escalation 336 Central Pain Syndrome

13. Kvarnstrøm A, Karlsten R, Quiding H, Gordh T (2004) The Anal- the spinal dorsal horn, to sensory stimulation. Cen- gesic Effect of Intravenous Ketamine and Lidocaine on Pain after tral sensitization may be induced by conditioning Spinal Cord Injury. Acta Anaesthesiol Scand 48:498–506 14. Lampl C, Yazdi K, Röper C (2002) Amitriptyline in the Prophy- noxious stimulation such as trauma, inflammation, laxis of Central Poststroke Pain. Stroke 33:3030–3032 nerve injury or electrical stimulation of sensory nerves 15. Leijon G, Boivie J (1989) Central Post-Stroke Pain – A Controlled at C-fiber strength. It is considered to contribute to Trial of Amitriptyline and Carbamazepine. Pain 36:27–36 afferent-induced forms of hyperalgesia and allodynia. 16. Levendoglu F, Ögün CÖ, Özerbil Ö, Ögun TC, Ugurlu H (2004) Gabapentin is a First Line Drug for the Treatment of Neuropathic Proposed spinal mechanisms include reduced inhibi- Pain in Spinal Cord Injury. Spine 29:743–751 tion, excessive primary afferent depolarization (PAD), 17. Loubser PG, Donovan WH (1991) Diagnostic Spinal Anaesthesia and enhanced strength at excitatory synapses in pain in Chronic Spinal Cord Injury Pain. Paraplegia 29:25–36 pathways (synaptic long-term potentiation: LTP). 18. Sang CN, Dobosh L, Miller V, Brown R (2001) Combination Therapy for Refractory Pain following Spinal Cord Injury Us- ArthritisModel,Kaolin-CarrageenanInducedArthri- ing the Low Affinity N-methyl-D-aspartate (NMDA) Receptor tis (Knee) Antagonist Dextromethorphan and Gabapentin. Abstract 20th Cancer Pain Model, Bone Cancer Pain Model Annual Scientific Meeting APS. J Pain 2:10 Central Changes after Peripheral Nerve Injury 19. Siddall PJ, Molloy AR, Walker S, Rutkowski SB (2000) The Efficacy of Intrathecal Morphine and Clonidine in the Treatment Chronic Pelvic Pain, Musculoskeletal Syndromes of Pain after Spinal Cord Injury. Anesth Analg 91:1–6 Drugs Targeting Voltage-Gated Sodium and Calcium 20. Siddall PJ, Cousins M et al. (2005) Pregabalin safely and effec- Channels tively treats chronic central neuropathic pain after spinal cord Exogenous Muscle Pain th injury. Abstr IASP 11 World Congress on Pain Formalin Test 21. Svendsen KB, Jensen TS, Bach F (2004) Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? GABA Mechanisms and Descending Inhibitory Randomised double blind placebo controlled crossover trial. Mechanisms BMJ 329:253–258 Gynecological Pain, Neural Mechanisms 22. Tai Q, Kirshblum S, Chen B, Millis S et al. (2002) Gabapentin in the Treatment of Neuropathic Pain after Spinal Cord Injury: Hypersensitivity Maintained Pain A Prospective, Randomized, Double-Blind, Cross-over Trial. J Long-Term Potentiation and Long-Term Depression Spinal Cord Med 25:100–105 in the Spinal Cord 23. Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen TS Metabotropic Glutamate Receptors in Spinal Noci- (2001) Lamotrigine for Central Poststroke Pain: A Randomized Controlled Trial. Neurology 56:184–190 ceptive Processing Muscle Pain Model, Inflammatory Agents-Induced Pain Modulatory Systems, History of Discovery Postherpetic Neuralgia, Pharmacological and Non- Central Pain Syndrome Pharmacological Treatment Options Postoperative Pain, Acute Neuropathic Pain Definition Psychiatric Aspects of Pain and Dentistry A neurological condition caused by damage to or dys- Psychological Treatment of Headache function of the central nervous system, most commonly Quantitative Sensory Testing following a thalamic stroke, s. also Central Pain. Referred Muscle Pain, Assessment Lateral Thalamic Lesions, Pain Behavior in Animals Restless Legs Syndrome Spinothalamic Neuron Spinothalamic Tract Neurons, Role of Nitric Oxide Central Pattern Generator Transition from Acute to Chronic Pain

Deﬁnition Cellular networks in the brainstem that are organized to Central Sulcus initiate and maintain motor activity through pattern generation and rhythm generation. Orofacial Pain, Movement Disorders Synonyms Rolandic Sulcus

Central Sensitization Deﬁnition The convolutions of the cerebral cortex have a general Deﬁnition organization that is similar for all humans. One constant Central sensitization is an umbrella term for a number and readily recognizable sulcus is the central sulcus (of of phenomena, all of which are characterized by an Rolando),andmarksthedivisionbetweenthefrontaland increase in the responsiveness of nociceptive neurons parietal lobes. in the central nervous system, best characterized in Motor Cortex, Effect on Pain-Related Behavior Cerebrospinal Fluid 337

Central Trigger Point Cephalalgia

Synonyms Headache CTrP C

Definition Clinically, central trigger point is characteristically Ceramide a very tender, circumscribed nodule-like spot in the mid-portion of a palpable taut band of skeletal muscle Definition fibers and it usually refers pain when compressed. This trigger point may be active or latent and can induce An intracellular signaling molecule liberated by activa- attachment trigger points. tion of the sphingomyelin pathway. This pathway is ac- Myofascial Trigger Points tivated by NGF via its action on the p75 receptor. Nerve Growth Factor, Sensitizing ActiononNocicep- tors Centralization

Central Changes after Peripheral Nerve Injury Cerebellum

Definition Central-Peripheral Distal Axonopathy The cerebellum is located dorsal to the brainstem and pons, and inferior to the occipital lobe. It mainly serves Definition sensory-motor integration, by providing constant feed- Peripheral nerve disorders beginning from degeneration back signals to adapt fine-tune movements according to of the most terminal parts of both central and periph- momentary muscle length and tone and body posture. eral processes of neurons, the major pathology of toxic Functional Imaging of Cutaneous Pain neuropathies; also dying-back neuropathy and distal axonopathy. Toxic Neuropathies Cerebral Cortex

Centrifugal Control of Nociceptive Deﬁnition Processing The cerebral cortex is the thin, convoluted surface layer of nerve cell bodies (also called gray matter) of the cere- GABA Mechanisms and Descending Inhibitory bral hemispheres responsible for receiving and analyz- Mechanisms ing sensory information, for the execution of voluntary SpinothalamicTractNeurons,DescendingControlby muscle movement, thought, reasoning and memory. Brainstem Neurons Cingulate Cortex, Functional Imaging Clinical Migraine with Aura Descending Circuitry, Transmitters and Receptors Nociceptive Processing in the Cingulate Cortex, Be- Centrifugal Control of Sensory Inputs havioral Studies in Humans PET and fMRI Imaging in Parietal Cortex (SI, SII, In- Deﬁnition ferior Parietal Cortex BA40) Regulation of the access of sensory information to the centralnervoussystemiscarriedoutbytheactionofneu- ral pathwaysthat inhibit or facilitate sensory processing. Such regulatory pathways can be intrinsic to the spinal Cerebrospinal Fluid cord (and trigeminal nuclei) or can originate from a variety of structures in the brain. SpinothalamicTractNeurons,DescendingControlby Synonyms Brainstem Neurons CSF 338 Cervical Discogram

Deﬁnition Provocation discography is the only means by which to Fluid within the 4 brain ventricles, mainly produced test if a cervical disc is painful or not. The procedure in- by the choroid plexus. The average pressure (in lateral volves injecting contrast medium into the nucleus pulposus of the disc, in an effort to reproduce the patient’s recumbent position) is 150–250mmH2O, depending on CSF secretion & absorption, intracranial arterial and pain. Although the contrastmediumoutlinestheinternal venous pressure, hydrostatic pressure, brain bulk and structure of the disc, this is not seminal to the diagnosis. status of surrounding coverings. The critical component of the procedure is reproduction Cancer Pain Management, Anesthesiologic Interven- of the patient’s pain. tions, Neural Blockade Studies in normal volunteers and in patients have Headache due to Low Cerebrospinal Fluid Pressure demonstrated that cervical discs can produce neck pain, under experimental conditions (Schellhas et al. 1996; Cloward 1959; Grubb and Kelly 2000) Referred pain patterns encompass areas that are topographically sep- Cervical Discogram arated from the site of pathology. Furthermore, discs at particular segmental levels produce pain in fairly Cervical Discography consistent regions (Schellhas et al. 1996; Grubb and Kelly 2000) (Fig. 1). The C2–3 disc typically refers to the occiput. The C3–4 disc typically refers to the area of the C7 spinous process, with spread toward the side Cervical Discography of the neck. The C4–5 disc typically refers toward the superior angle of the scapula, but may spread from the DAV I D DIAMANT base of the neck to the top of the shoulder. The C5–6 Neurological and Spinal Surgery, Lincoln, NE, USA disc refers to the center of the scapular border, and the [email protected] C6–7 disc refers to the inferior angle of the scapula, but both may spread over the entire scapula, across the Synonyms shoulder and into the proximal upper limb. These pain Cervical Discogram; Provocation Discogram; provoca- patterns can be used to plan which segmental levels tive discography should be targeted for investigation. If stimulation of the disc reproduces the patient’s pain Deﬁnition pattern (concordantpain), it may be presumed that such is their pain generator. If stimulating the disc is not Cervicaldiscographyisadiagnosticproceduredesigned painful, or produces an atypical (non-concordant) pain to determine if a cervical intervertebral disc is the source pattern,thisdiscispresumednottobethepaingenerator. of a patient’s neck pain. It involves injecting contrast medium into the disc in an attempt to reproduce the patient’s pain.

Characteristics Principles The cervical intervertebraldiscs are innervated by nociceptive ﬁbers from the cervical sinuvertebral nerves, the vertebral nerves, and the cervical sympathetic trunks (Bogduk et al. 1989; Groen et al. 1990; Mendel et al. 1992). Being endowed with a nerve supply, the cervical discs are potentially a source of neck pain. There are no conventional means by which to determine if a patient’s neck pain arises from a cervical interverte- braldisc.Therearenosignson musculoskeletalexam- ination by which this can be established, and no signs on medical imaging. Abnormalities evident on magnetic resonanceimaging (MRI) correlate poorly with whether thediscispainfulor not(Parfenchuck andJanssen 1994; Schellhas et al. 1996). Furthermore, ﬁssures that may be present across the posterior aspect of cervical discs are a normal age change (Oda et al. 1988), and do not con- Cervical Discography, Figure 1 Patterns of distribution of pain after stitute a painful lesion (Parfenchuck and Janssen 1994; stimulation of cervical intervertebral discs at the segments indicated. Re- Schellhas et al. 1996). produced courtesy of the International Spinal Intervention Society. Cervical Discography 339

Cervical Discography, Figure 2 Radiographs showing needles placed into cervical intervertebral discs in preparation for discography. (a) Anterior view. (b) Lateral view. Reproduced courtesy of the International Spinal Intervention Society.

Cervical Discography, Figure 3 Radiographs of cervical discography after injecting of contrast medium. (a) Anterior view. (b) Lateral view. Reproduced courtesy of the International Spinal Intervention Society.

Technique the target disc, until it reaches the centre of the nucleus The patient lies supine and the neck is prepared for an (Fig. 2). Thereupon, contrast medium is injected, both aseptic procedure. The operator inserts a needle through to verify correct placement (Fig. 3), and to test for re- the skin of the neck and into the anterolateral aspect of production of pain. The nucleus pulposus of a typical 340 Cervical Discography cervical intervertebral disc will admit 0.2–0.4cc of in- Applications jectate (Kambin et al. 1980). Whether the patient devel- The primary purpose of cervical discography is to de- ops concordant pain or not is the critical component of termine if cervical discs are the source of patient’s neck the procedure. pain. It is indicated, therefore, in patients whose cause of pain cannot be established by other means, who have Validity not benefited from conservative therapy, and for whom In order to be valid, the International Association for a diagnosis is desired or required. the Study of Pain (Merskey and Bogduk 1994) recom- A secondary purpose of cervical discography is to help mendsthatcervicaldiscographybesubjectedtoanatom- physicians plan interventional management. One treat- ical controls. Not only does provocation of the interver- ment option is anterior cervical discectomy and fusion. tebral disc need to reproduce the individual’s pain con- For this procedure, surgeons are not only interested in cordantly, but also provocation at adjacent levels must if a disc hurts, but also if other discs hurt. The greater not reproduce such pain. Additional criteria have been thenumbersofdiscsthatappearpainful,thelessinclined recommended by the International Spinal Intervention surgeonsaretoundertakesurgery.Notonlyismulti-level Society (2004) pertainingtotheintensity of the painpro- fusionmoretechnicallydemandingforthesurgeons,and duced during disc stimulation, and the potential role of more hazardous to the patient, its outcomes are less fa- other structures in the generation of pain. vorable than fusion at a single level. Cervical discs in normal, asymptomatic volunteers can be made to hurt by discography (Schellhas et al. 1996). Utility However, in such individuals the evoked pain is not severe. They rate the pain as typically less than 6 on a Cervical discography was originally developed with the 10–pointscale. In contrast, patientswith discpain report prospect of finding one, or perhaps only two, discs that reproduction of moderate or severe pain, which they were painful, so that fusion might be undertaken to re- typically rate as greater than 7, Schellhas et al. 1996). lieve the patient’s pain. Accordingly, cervical discogra- Accordingly, it is recommended that for cervical disc phy was expected to have positive predictive value. Sub- stimulation to be considered positive, the evoked pain sequent studies, however, have thwarted this aspiration. must have an intensity of 7 or greater (International Ithasbecome evidentthatcervicaldiscsareinfrequently Spinal Intervention Society 2004). This criterion serves symptomatic at single levels (Grubb and Kelly 2000). to prevent minor pain from an asymptomatic disc, being More commonly, discs at three levels, and even four or considered positive. more levels, are symptomatic. This pattern essentially Provocation of the intervertebral disc may elicit con- precludes surgical therapy. Consequently, in practice, cordant pain, yet other sources of such pain can be the cervical discography has more of a negative predictive actual pain generator. As such, the issue of diagnostic value. It serves far more often to prevent surgery than to specificity of this procedure is questionable. As they encourage it. Indeed, in one series, only 10% of patients share a similar segmental innervation, the cervical zy- proceeded to surgery in the light of their responses to gapophysial joints can refer pain to similar regions as cervical discography (Grubb and Kelly 2000). the intervertebral discs (Bogduk and Aprill 1993). Con- sequently, cervical discography can be false-positive in References patients whose pain originates from the zygapophysial joints at the same segment as the disc stimulated. Some 1. Bogduk N, Aprill C (1993) On the Nature of Neck Pain, Discogra- phy and Cervical Zygapophysial Joint Blocks. Pain 54:213–217 40% of patients with positive responses to discogra- 2. Bogduk N, Windsor M, Inglis A (1989) The Innervation of the phy have their pain relieved by blocks of the cervical Cervical Intervertebral Discs. Spine 13:2–8 zygapophysial joints (see Cervical Medial Branch 3. Cloward RB (1959) Cervical Diskography. A Contribution to the Aetiology and Mechanism of Neck, Shoulder and Arm Pain. Ann Blocks), which is not compatible with the disc being Surg 130:1052–1064 the primary source of their pain. Accordingly, it has 4. Groen GJ, Baljet B, Drukker J (1990) Nerves and Nerve Plexuses been recommended that cervical discography be under- of the Human Vertebral Column. Am J Anat 188: 282–296 taken only when the cervical zygapophysial joints, at 5. Grubb SA, Kelly CK (2000) Cervical Discography: Clinical Im- plications from 12 Years of Experience. Spine 25:1382–1389 the areas of concern, have been excluded as the source 6. International Spinal Intervention Society (2004). Cervical of the patient’s pain (International Spinal Intervention Discography. In: Bogduk N (ed) Practice Guidelines for Spinal Society 2004). Diagnostic and Treatment Procedures (2004) International Additionally, there are other pitfalls that may compro- Spinal Intervention Society, San Francisco 7. Kambin P, Abda S, Kurpicki F (1980) Intradiskal Pressure and mise the validity of cervical discography. Technical er- Volume Recording: Evaluation of Normal and Abnormal Cervi- rors will compromise the diagnostic validity of cervical Disks. Clin Orthop 146: 144–147 cal discography. The needle tip must be in the nucleus 8. Mendel T, Wink CS, Zimny ML (1992) Neural Elements in Hu- pulposus—otherwise, stimulation of the anulus fibrosus man Cervical Intervertebral Discs. Spine 17:132– 135 9. Merskey H, Bogduk N (1994) Classification of Chronic Pain. will be likely to yield a painful response, regardless of Descriptions of Chronic Pain Syndromes and Definition of Pain whether that disc is the pain generator or not. Terms, 2nd ed. IASP Press Seattle, p 108 Cervical Medial Branch Blocks 341

10. Oda J, Tanaka H, Tsuzuki N (1988) Intervertebral Disc Changes with Aging of Human Cervical Vertebra from the Neonate to the Eighties. Spine 13:1205–1211 11. Parfenchuck TA, Janssen ME (1994) A Correlation of Cervi- cal Magnetic Resonance Imaging and Discography/Computed Tomographic Discograms. Spine 19:2819–2825 12. Schellhas KP, Smith MD, Gundry CR, Pollei SR (1996) Cervical C Discogenic Pain. Prospective Correlation of Magnetic Resonance Imaging and Discography in Asymptomatic Subjects and Pain Sufferers. Spine 21:300–312

Cervical Facet Blocks

Cervical Medial Branch Blocks

Cervical Facet Denervation Cervical Medial Branch Blocks, Figure 1 A lateral radiograph of the cervical spine. The course of the third occipital nerve and the medial branches of the C3 to C7 dorsal rami across the articular pillars is indicated with dotted lines. Cervical Medial Branch Neurotomy

Characteristics Rationale Cervical MBBs At typical cervical levels, the medial branchesof the cervical dorsal rami pass across the waist of the ipsiseg- mental articular pillar (Fig. 1). They innervate the zy- Cervical Medial Branch Blocks gapophysial joints above and below, before supplying the posterior muscles of the neck (Bogduk 1982). The third occipital nerve and the C7 medial branch cross the joint that they supply. The zygapophysial (“Z”) joints are the only structures Cervical Medial Branch Blocks supplied by these nerves that are affected by disorders JAYANTILAL GOVIND that can be a source of chronic pain (Barnsley and Bog- Department of Anaesthesia, Pain Clinic, Liverpool duk1993).Thesedisorderscannotbediagnosedbymus- Hospital, University of New South Wales, Sydney, culoskeletal examination or by medical imaging. Diag- NSW, Australia nostic blocks are the only validated means by which the [email protected] Z joints can be implicated or excluded as the source of pain. In order to anaesthetise a given joint, both nerves that innervate it must be blocked. Synonyms Technique Cervical Zygapophysial Joint Blocks; Cervical Facet Blocks; Cervical MBBs; Z Joint Blocks Theblocksareperformedwiththepatientlyinginacom- fortable position, prone, supine, or on their side. Under fluoroscopic guidance, a fine needle is inserted through Definition the skin and muscles of the neck and onto the articular Cervical medial branch blocks (MBBs) are a diagnostic pillar where the target nerve lies (Fig. 2). The nerve can test to determine if a patient’s neck pain is mediated by be anaesthetised with as little as 0.3 ml of local anaes- one or more of the medial branches of the cervical dorsal thetic. rami. This is achieved by anaesthetising the target nerve withaminutevolumeoflocalanaesthetic.Intheabsence Principles of evidence to the contrary, a positive response to MBBs The primary objective of cervical MBBs is to establish impliesthatthepatient’spainstemsfromthezygapophy- if anaesthetising the target nerves relieves the patient’s seal joint innervated by the nerves anaesthetised. pain. If the pain is not relieved, the targeted joint can be 342 Cervical Medial Branch Blocks

trolled. Single diagnostic blocks are associated with an unacceptably high rate of false-positive responses (Barnsley et al. 1993a). Although placebo controls can be used, these may not be practical under conventional circumstances, but comparative local anaesthetic blocks can be used (International Spinal Intervention Society 2004; Barnsley et al. 1993b; Lord et al. 1995). On separate occasions, the same block is repeated using local anaesthetics with different durations of action. The test is negative if the repeat block fails to relieve pain. If both blocks relieve the pain, the relief may be concordant or discordant, and can be either prolonged or not (Barnsley et al. 1993b). Concordant relief is short-lasting relief when a short- acting agent is used and long-lasting relief when a long- acting agentisused. When relief islongeraftertheshort- acting agent is used, the response is classed as discordant. If the relief substantially outlasts the expected duration of action of either agent, the response is classed as prolonged. Discordant and prolonged responses are probably due to local anaesthetics, particularly lignocaine, acting on “open” sodium channels (Butterworth Cervical Medial Branch Blocks, Figure 2 A lateral radiograph of a cervical spine, showing a needle in position for a C5 medial branch block. and Strichartz 1990). Concordant responses are the ideal. They have a sensitivity of 54% and specificity of 88% (Lord et al. 1995). excluded as the source of pain, and a new source con- Thehighspecificitymeansthatconcordantresponsesare sidered, such as a joint at another segmental level, or an very unlikely to be false. The low sensitivity, however, intervertebral disc. If pain is relieved, the response con- means that not all patients with zygapophysial joint pain stitutes prima facie evidence that the targeted nerves are will be detected. mediating the patient’s pain, and that it arises from the If discordant responses are accepted as positive, the joint that they supply. sensitivity rises to 100% but the specificity drops Inordertobepositive,theblocksmustproducecomplete to 65% (Lord et al. 1995). Thus, all patients with zy- reliefofpain.Partialreductionofpaindoesnotconstitute gapophysial joint pain will be detected, but some will a positive response. be false-positive. In some patients, however, their pain may arise from more than one joint. They may experience pain from Epidemiology both joints at the same segment, from consecutive The zygapophysial joints are the single-most common joints on the same side, or from joints at separate and source of chronic neck pain. They are the source of pain displaced segments. Typical patterns are: C5–6 on in at least 50% (Barnsley et al. 1995; Lord et al. 1996a), both sides, C5–6 and C6–7 ipsilaterally, and C5–6 and and up to 88% (Gibson et al. 2000), of patients with neck C2–3 on the same side. pain after whiplash. In 53% of patients with headache In such patients, anaesthetising one joint will not relieve after whiplash, the pain can be traced to the C2–3 joint all of their pain. However, blocking that joint will com- (Lord et al. 1994). pletely relieve pain in the particular region to which that joint refers its pain. Similarly, blocking the other joint Indications willrelievepainintheremainingarea.Thesubtletyofthe Neckpainforwhichadiagnosisisrequiredistheprimary diagnostic criterion is that the patient obtains complete indication for cervical MBBs. To date, they have been relief of pain in a particular topographical distribution. used only for the investigation of patients with chronic This is not the same as the patient obtaining partial relief neck pain, but their judiciousapplicationinpatientswith of their pain overall (International Spinal Intervention sub-acutepainwouldbeworthyofexploration.Isolating Society 2004). the source of pain and instituting appropriate treatment expeditiously could serve to prevent chronicity. Validity CervicalMBBsare target-specific, and the use ofminute Patient Selection volumes of local anaesthetic precludes other structures Studies in normal volunteers (Dwyer et al. 1990) and in being anaesthetised (Barnsley and Bogduk 1993). To patients (Fukui et al. 1996) have shown that the cervi- avoid false-positive responses, the blocks must be con- cal zygapophysial joints generate somatic referred pain Cervical Medial Branch Blocks 343

Blocks should not be performed when the patient’s pain is minimal, lest they be unable to distinguish the effects of a block from natural fluctuations in pain. Cervical MBBs are not recommended in patients whose typical pain is less than 40 on a 100 mm scale. C The response to diagnostic blocks should be evaluated immediately after the procedureandfor sometimeafter- wards, at the location at which the block was performed, and by an independent observer using validated and objective instruments and tools. Doing so avoids potential errors such as observer bias, patient or operator’s expectations, and recall bias. For a response to be judged positive, relief of pain should be accompanied by restoration of activities that are normally limited by pain. Utility Cervical MBBs have diagnostic utility, in that they can pinpoint the source of the patient’s pain. Establishing a firm diagnosis prevents the futile pursuit of a diagnosis Cervical Medial Branch Blocks, Figure 3 A map of the referred pain by other means. MBBs also have therapeutic utility. patterns from cervical zygapophysial joints at the segments indicated. A positive response to blocks predicts a favourable outcome from radiofrequency neurotomy (Lord et al. 1996b). in characteristic regions, specific to the segmental location of the joint stimulated (Fig. 3). These patterns can References be used to select the joints and nerves most likely to re- 1. Aprill C, Dwyer A, Bogduk N (1990) Cervical Zygapophyseal spond to blocks (International Spinal Intervention So- Joint Pain Patterns – II: A Clinical Evaluation. Spine 15:458–461 2. Barnsley L, Bogduk N (1993) Medial Branch Blocks are Specific ciety 2004; Aprill et al. 1990). for the Diagnosis of Cervical Zygapophyseal Joint Pain. Reg Tooptimise their efficiency, MBBs should beperformed Anaesth 18:343–350 in patients with discrete areas of neck pain, which cor- 3. Barnsley L, Lord S, Wallis B, Bogduk N (1993a) False- respond to one or more of these areas of referred pain. Positive Rates of Cervical Zygapophysial Joint Blocks. Clin J Pain 9:124–130 Patients with more diffuse patterns of pain are less likely 4. Barnsley L, Lord S, Bogduk N (1993b) Comparative Local to have identifiable joints as the source of pain. Anaesthetic Blocks in the Diagnosis of Cervical Zygapophyseal Joint. Pain 55:99–106 Contraindications 5. Barnsley L, Lord SM, Wallis BJ, Bogduk N (1995) The Preva- Absolute contraindications include localised or sys- lence of Chronic Cervical Zygapophyseal Joint Pain after Whiplash. Spine 20:20–26 temic infection, a bleeding diathesis, and possible 6. Bogduk N (1982) The Clinical Anatomy of the Cervical Dorsal pregnancy. Relative contraindications may include an Rami. Spine 7:319–330 allergy to contrast media or local anaesthetics, the con- 7. Butterworth JF, Strichartz GR (1990) Molecular Mechanisms of current treatment with non-steroidal anti-inflammatory Local Anesthesia: A Review. Anesthesiology 72:711–734 8. Dwyer A, Aprill C, Bogduk N (1990) Cervical Zygapophy- medication including aspirin and neurological signs. seal Joint Pain Patterns – I: A Study in Normal Volunteers. Radicular pain and chronic neck pain may co-exist. Spine 15:453–457 Whilst cervical medial branch blocks may alleviate 9. Fukui S, Ohseto K, Shiotani M et al. (1996) Referred Pain Dis- tribution of the Cervical Zygapophyseal Joints and the Cervical neck pain and any somatic referred pain, they will Dorsal Rami. Pain 68:79–83 not relieve radicular pain. 10. Gibson T, Bogduk N, MacPherson J, McIntosh A (2000) Crash Characteristics of Whiplash Associated Chronic Neck Pain. J Evaluation Musculoskeletal Pain 8:87–95 The value of diagnostic blocks lies in the information 11. International Spinal Intervention Society (2004) Cervical Medial Branch Blocks. In: Bogduk N (ed) Practice Guidelines for Spinal that they provide (International Spinal Intervention So- Diagnostic and Treatment Procedures. International Spinal In- ciety 2004). For the blocks to be valid, the patient must tervention Society, San Francisco be able to cooperate fully. They must understand that the 12. Lord SM, Barnsley L, Bogduk N (1995) The Utility of Compara- procedure is a diagnostic one, and it is neither designed tive Local Anaesthetic Blocks versus Placebo Controlled Blocks for the Diagnosis of Cervical Zygapophyseal Joint Pain. Clin J nor intended to be therapeutic. When multiple sources Pain 11:208–213 of pain are suspected, patientsshould understandthatre- 13. Lord S, Barnsley L, Wallis B, Bogduk N (1994) Third Occipital lief may occur in only a particular topographic area; and Nerve Headache: A Prevalent Study. J Neurol Neurosurg Psy- they must be able to determine if they obtain relief in a chiatry 57:1187–1190 14. Lord S, Barnsley L, Wallis BJ, Bogduk N (1996a) Chronic Cervi- discrete area. They should also understand the use of a cal Zygapophyseal Joint Pain after Whiplash: Placebo Controlled visual analogue scale or numerical pain rating scale. Prevalence Study. Spine 21:1737–1745 344 Cervical Medial Branch Neurotomy

15. Lord SM, Barnsley L, Wallis BJ, McDonald GJ, Bogduk N (1996b) Percutaneous Radiofrequency Neurotomy for Chronic Cervical Zygapophyseal Joint Pain. N Eng J Med 335:1721–1726

Cervical Medial Branch Neurotomy

JAYANTILAL GOVIND Department of Anaesthesia, Pain Clinic, Liverpool Hospital, University of New South Wales, Sydney, NSW, Australia [email protected]

Synonyms Cervical Facet Denervation; Cervical Radiofrequency Cervical Medial Branch Neurotomy, Figure 1 A sketch of a top view of Neurotomy the course of a cervical medial branch. As the nerve follows a curved path around the articular pillar, electrodes must be introduced along a sagittal plane and along a 30o oblique plane. Definition Cervical medial branch neurotomy is a treatment for neck pain or headache, stemming from one or more of thezygapophysialjointsofthecervicalspine. Itinvolves erate the lesions. Sedation should be avoided so that the coagulating the nerves that innervate the painful joint, patientcan bealertto any problemsthatmightoccurdur- or joints, with an electrode inserted onto the nerves ing the procedure, and which threaten their safety. The through the skin and muscles of the back of the neck. objective is to make a lesion as long as possible along the course of the target nerve. In order to capture the curved Characteristics courseofeachcervicalmedialbranch,theelectrodemust be introduced in both of two ways (Fig. 1). An oblique Mechanism pass, about 30o lateral from the sagittal plane is used to Medial branch neurotomy achieves relief of pain by reach the proximal part of the nerve, where it lays an- interrupting the transmission of nociceptive informa- terolaterally to the articular pillar (or anterolaterally to tion from a painful zygapophysial joint, by generating the C2/3 zygapophysialjoint, in the case of the third oc- a heat lesion in the nerves that mediate the pain (see cipital nerve). The second pass is along the sagittal plane Electrophysiological Principles of Radiofrequency to reach the nerve where it lies laterally to the articular Neurotomy). pillar. Along both the oblique pass and the sagittal pass, the Indications electrode is introduced through the skin and muscles of Cervical medial branch neurotomy is not a treatment the posterior neck, so that its tip lies parallel to the target for any form of neck pain. It is explicitly and solely nerve and against the articular pillar (or the C2–3 joint). designed to relieve pain from the zygapophysial joints. Attypicalcervicallevels,thisrequiresinsertingtheelec- Therefore, the singular indication for the procedure is trode upwards from below the target level, for the nerves complete, or near complete, relief of pain following course downwards as well as backwards (Fig. 2). The controlled, diagnostic blocks of the nerves from the third occipital nerve runs transversely and so, can be ap- painful joint or joints, i.e. cervical medial branch proached along a transverse plane instead of an inclined blocks. These blocks must be controlled, because the one (Fig. 3). false-positive rate of uncontrolled blocks is such that At each target point, two or three lesions need to be responses to single blocks will be false in up to 30% made, in order to accommodate possible variations in of patients, and those patients will not benefit from the the course of the nerve (International Spinal Interven- denervation procedure (Barnsley et al. 1993; Bogduk tion Society 2004; Lord et al. 1998). Each lesion is and Holmes 2000). made by increasing the heating current gradually by about 1˚C per second. Raising the temperature slowly Technique provides time for both the patient and the physician to A detailed protocol has been produced by the Interna- react if any untoward sensations arise, either because tional Spinal Injection Society (International Spinal In- the electrode has dislodged or because the target site has tervention Society 2004). In essence, the procedure is not been adequately anaesthetized; and for the physi- performed under local anaesthesia, in a room equipped cian to respond before any injury occurs to the patient. with a fluoroscope and the necessary equipment to gen- Once a temperature of 80˚–85˚C has been achieved, it Cervical Medial Branch Neurotomy 345

2004; Lord et al. 1998; Lord et al. 1996a; McDonald et al. 1999). Only this technique has been tested and shown to produce complete and lasting relief of pain. Variants are used by some operators, ostensibly in the belief that the procedure is faster or easier. These vari- C ants, however, have not been tested; and their efﬁcacy is not known (Bogduk 2002).

Efﬁcacy A controlled trial has shown that the effects of cervical medial branch neurotomy cannot be attributed to a placebo response (Lord et al. 1996a). When correctly performed, the efﬁcacy of cervical medial branch neurotomy is genuine. Provided that patients are correctly selected using controlled cervical medial branch blocks, and provided that the optimal technique is used, good outcome can be expected from cervical medial branch neurotomy. All patients should obtain relief of their pain, which should be evident as soon as the anaesthesia for the procedure Cervical Medial Branch Neurotomy, Figure 2 Lateral radiograph of an wears off, and any postoperative pain abates. If such im- electrode, inserted along a sagittal path, in position to coagulate a C5 medial mediate relief is not evident, an error will have occurred branch. The course of the nerve is depicted by a dotted line. either during the diagnostic blocks or in the conduct of the procedure; both of which should then be reviewed. When neck pain is the target complaint, and joints below C2/3 are treated, some 70% of patients obtain complete relief of their pain (Lord et al. 1998; Lord et al. 1996a; McDonaldetal.1999).Whenheadacheisthetargetcom- plaint,andthethirdoccipitalnerveistargeted,some85% of patients obtain complete relief (Govind et al. 2003). The cardinal reasons for initial failures are suboptimal placement of electrodes or failure, during the conduct of diagnostic blocks, to recognize a source of pain from an adjacent joint. If complete relief of pain is achieved, it is attended by restoration of activities of normal living, and no need for other health care for the pain (Lord et al. 1998; Lord et al. 1996a; McDonald et al. 1999; Govind et al. 2003). Furthermore, it is associated with complete resolution of psychological distress, without any need for psychological treatment (Wallis et al. 1997). The procedure is equally effective in patients who have Cervical Medial Branch Neurotomy, Figure 3 Lateral radiograph of an compensation claims as those who do not (McDonald electrode, inserted along a sagittal path, in position to coagulate the third et al. 1999; Bogduk 2002; Govind et al. 2003; Sapir and occipital nerve. The course of the nerve is depicted by a dotted line. Gorup 2001). Relief of pain is not permanent. In time, the coagulated is maintained for about 90 seconds to ensure adequate nerves regenerate and may again transmit nociceptive coagulation of the nerve. information from the painful joint or joints. The time The procedure is repeated for all nerves that were anaes- that it takes for this regeneration to occur, depends on thetized,inordertoproducereliefofpainduringtheprior how accurately and how thoroughly the nerves were conduct of diagnostic cervical medial branch blocks. coagulated. After medial branch neurotomy at typical cervical levels, patients can expect complete relief of Variants pain for at least 9 months, and up to 12 months or The optimal technique requires that the electrode be longer (Lord et al. 1998; Lord et al. 1996a; McDonald placed parallel to the target nerves, and that multiple le- et al. 1999). The duration of relief after third occipital sions be made to accommodate variations in the course neurotomy for headache is, on the average, slightly of the nerve (International Spinal Intervention Society shorter; some patients may maintain relief for only 346 Cervical Periradicular Epidural Steroid Injection

6 months, although durations longer than 12 months 3. Bogduk N (2002) Radiofrequency Treatment in Australia. Pain have been reported (Govind et al. 2003). Practice 2:180–182 4. Bogduk N, Holmes S (2000) Controlled Zygapophysial Joint Pain usually returns gradually; although it may not re- Blocks: The Travesty of Cost-Effectiveness. Pain Med 1:25–34 turn to its former intensity. If pain recurs and becomes 5. Gibson T, Bogduk N, Macpherson J, McIntosh A (2000) Crash sufﬁciently intense again as to warrant treatment, cervi- Characteristics of Whiplash Associated Chronic Neck Pain. J cal medial branch neurotomy can be repeated in order Musculoskeletal Pain 8:87–95 6. Govind J, King W, Bailey B, Bogduk N (2003) Radiofrequency to reinstate relief. Patients can have multiple repetitions Neurotomy for the Treatment of Third Occipital Headache. J withoutprejudicingtheirresponse(Lordetal.1998;Mc- Neurol Neurosurg Psychiatry 74:88–93 Donald et al. 1999; Govind et al. 2003). 7. International Spinal Intervention Society (2004) Cervical Me- dial Branch Neurotomy. In: Bogduk N (ed). Practice Guidelines Complications for Spinal Diagnostic and Treatment Procedures. International Provided that the correct technique is used, no compli- Spinal Intervention Society, San Francisco 8. Lord S, Barnsley L, Wallis B, Bogduk N (1994) Third Occip- cations are associated with this procedure. Side-effects ital Nerve Headache: A Prevalence Study. J Neurol Neurosurg are uncommon when the procedure is performed at typ- Psychiatry 57:1187–1190 ical cervical levels (Lord et al. 1998); but are more com- 9. Lord S, Barnsley L, Wallis BJ, Bogduk N (1996b) Chronic Cervical Zygapophysial Joint Pain after Whiplash: A Placebo- mon when the third occipital nerve is coagulated. They Controlled Prevalence Study. Spine 21:1737–1745 include dysaesthesiae when medial branches with cuta- 10. Lord SM, Barnsley L, Wallis B, McDonald GM, Bogduk N neous distributions are coagulated; and ataxia when the (1996a) Percutaneous Radio–Frequency Neurotomy for Chronic thirdoccipitalnerveiscoagulated.Thedysaesthesiaeare Cervical Zygapophyseal Joint Pain. N Eng J Med 335:1721–1726 11. Lord SM, Bogduk N (1997) Treatment of Chronic Cervical Zy- self-limiting and do not require treatment, as a rule. The gapophysial Joint Pain. N Engl J Med 336:1531 ataxia is accommodated by the patient relying on visual 12. Lord SM, McDonald GJ, Bogduk N (1998) Percutaneous Ra- cues for balance; and is readily tolerated in exchange for diofrequency Neurotomy of the Cervical Medial Branches: A the relief from headache. Validated Treatment for Cervical Zygapophyseal Joint Pain. Neu- rosurgery Quarterly 8:288–308 Whereas it may be believed by some that denervat- 13. McDonald GJ, Lord SM, Bogduk N (1999) Long Term Follow- ing a joint will create a neuropathic joint (Charcot’s Up of Patients Treated with Cervical Radiofrequency Neurotomy arthropathy), there is no evidence that this occurs, and for Chronic Neck Pain. Neurosurgery 45:61–68 no grounds for believing that it would occur (Lord 14. Sapir DA, Gorup JM (2001) Radiofrequency Medial Branch Neurotomy in Litigant and Non-Litigant Patients with Cervical and Bogduk 1997). Charcot’s arthropathy occurs in Whiplash. Spine 26:E268–E273 limbs that have been completely denervated, in which 15. Wallis BJ, Lord SM, Bogduk N (1997) Resolution of Psycho- potentially unstable joints are not protected by mus- logical Distress of Whiplash Patients following Treatment by Radiofrequency Neurotomy: A Randomised, Double-Blind, cle activity. In contrast, the zygapophysial joints are Placebo-Controlled Trial. Pain 73:15û22 intrinsically stable; they are stabilized further by the intervertebral disc, and most of the muscles that act on the affected segment remain functional. Utility Cervical Periradicular Epidural Steroid Cervicalmedialbranch neurotomy isthe singular means Injection by which pain from cervical zygapophysial joints can be eliminated. No other forms of treatment have been Cervical Transforaminal Injection of Steroids shown to be as effective for the treatment of proven cervical zygapophysial joint pain. No other form of treatment has been shown to consistently provide complete relief of neck pain or cervicogenic headache. Cervical Radiofrequency Neurotomy Given that the prevalence of cervical zygapophysial joint pain is in excess of 50% in patients with chronic neck pain after whiplash (Lord et al. 1994; Barnsley et Cervical Medial Branch Neurotomy al. 1995; Lord et al. 1996b; Gibson et al. 2000), and given that no other form of treatment has been shown to be effective for these patients, cervical medial branch neurotomy has a potentially enormous application in Cervical Root Avulsion practice. References Deﬁnition 1. Barnsley L, Lord S, Wallis B, Bogduk N (1993) False- Traumatic lesion of ventral and/or dorsal root, at the cer- Positive Rates of Cervical Zygapophysial Joint Blocks. Clin J vical level, consisting of detachment of the constituting Pain 9:124–130 rootlets of the root from the spinal cord; main mecha- 2. Barnsley L, Lord SM, Wallis BJ, Bogduk N (1995) The Preva- lence of Chronic Cervical Zygapophysial Joint Pain after nism is stretching. Whiplash. Spine 20:20–26 BrachialPlexusAvulsionandDorsalRootEntryZone Cervical Transforaminal Injection of Steroids 347

Rationale Cervical Selective Nerve Root Injection The rationale for injecting steroids is that they suppress inflammation of the nerve, which is believed to be the Cervical Transforaminal Injection of Steroids basis for radicular pain. The rationale for using a transforaminal route of injection, rather than an interlaminar C route, is that the injectate is delivered directly onto the Cervical Transforaminal Injection of target nerve. This ensures that the medication reaches Corticosteroids the target area in maximum concentration at the site of the suspected pathology. Definition Indications The directed deposition of corticosteroid into the cervical intervertebral neuroforamen. Cervical radicular pain is the only indication for cervi- Cervical Transforaminal Injection of Steroids cal transforaminal injection of steroids. Radicular pain is recognized by its dynatomal distribution, which is distinctly different from the dermatomes of the same Cervical Transforaminal Injection of nerve (Slipman et al. 1998). Confidence in the diagnosis is enhanced if the patient also has radiculopathy, Steroids although this may not always be evident. Paraesthesiae, TIMOTHY R. LAIR,JAMES P. R ATHMELL segmental numbness, weakness, and loss of reflexes Department of Anesthesiology, University of Vermont are reliable and valid signs of radiculopathy that allow College of Medicine, Burlington, VT, USA the diagnosis to be made clinically, without recourse to [email protected] investigations. Disc protrusion and foraminal stenosis are the most common causes, but diagnostic imaging is Synonyms required to exclude tumors and other infrequent causes such as infection, trauma, or inflammatory arthritides Cervical Periradicular Epidural Steroid Injection; Cer- (Boyce and Wang 2003). vical Selective Nerve Root Injection Definition Anatomy The C3-C8 spinal nerves lie in the lower half of their Cervical transforaminal injection of corticosteroids is respective intervertebralforamina. These foramina face a treatment for cervical radicular pain in which cor- anterolaterally. The vertebral artery lies just anterior to ticosteroids are delivered into a cervical intervertebral the exiting nerve (Fig. 1). Radicular branches from the neuroforamen. Characteristics Cervical radicular pain affects about one person per 1,000 of population, per year (Radhakrishnan et al. 1994), and is most often caused by a disc herniation or foraminal stenosis. Its natural history can be favorable (Bogduk et al. 1999), but not all patients recover naturally. For relieving cervical radicular pain, conservative therapy, typically including graduated exercise and oral analgesics, is supported only by observational studies, which have not controlled for natural history or non-specific effects of treatment. The controlled studies that have been conducted have shown no significant benefit for traction or exercises (British Association of Physical Medicine 1966; Goldie and Landquist 1970; Klaber et al. 1990). Surgery is the mainstay of treatment if conservative therapy fails (Chestnut et al. 1992; Ahlgren and Garfin 1996). Surgery, however, is not Cervical Transforaminal Injection of Steroids, Figure 1 A drawing of an without risks, and constitutes a major undertaking for axial view of the cervical intervertebral foramen and adjacent structures at patients. the level of C6, with a needle inserted parallel to the axis of the foramen along CTFIS constitutes an option for treatment, instead of its posterior wall. Note the proximity of adjacent structures, IJV, internal jugular vein; CA, common carotid artery; VA, vertebral artery; C6, vertebral surgery, when conservative therapy does not result in body of C6; ScA, anterior scalene muscle, ScM, middle scalene muscle; resolution of symptoms, and pain is the sole indication sap, superior articular process of C5–6 zygapophysial joint. (Reproduced for treatment. with permission from Rathmell et al. 2004). 348 Cervical Transforaminal Injection of Steroids

dle may encounter veins; below it, the needle may encounter the spinal nerve and its arteries. The needle must stay in contact with the posterior wall to avoid the vertebral artery. On anteroposterior view, the tip of the needle should not be advanced past the midpoint of thearticular pillar (Fig. 3b). Insertion beyond this depth risks punc- turing the dural sleeve or thecal sac. Under direct, real-time fluoroscopy, a small volume of non-ionic contrast medium (1.0 ml or less) is injected. The solution should outline the proximal end of the spinal nerve and spread centrally toward the epidural space (Fig. 4). Real-time fluoroscopy is essential to check for inadvertent intra-arterial injection, which Cervical Transforaminal Injection of Steroids, Figure 2 A sketch show- may occur even if the needle is correctly placed. Intra- ing patient position and fluoroscope orientation to obtain an oblique view arterial injection is manifested by very rapid clearance of the cervical intervertebral foramina. of the injected contrast material. In a vertebral artery, the contrast material will streak in a cephalized direction. In a radicular artery, it will blush briefly in a vertebral artery lie adjacent to the spinal nerve and its transverse direction medially towards the spinal cord. roots to the spinal cord. In either instance, the needle should be withdrawn and the procedure should be postponed until after a period Technique (Rathmell et al. 2004) long enough for the puncture to have healed. The patient lies supine, and a correct oblique view of the Sometimes the contrast medium may fill epiradicular target foramen is obtained with a fluoroscope (Fig. 2). veins. These are recognized by the slow clearance of the The correct oblique view is critical because, in less contrast medium, characteristic of venous flow. In that oblique views, the vertebral artery may lie along the event, the needle should be adjusted by either slightly course of the needle. withdrawing the needle, or redirecting it to a position Through a puncture point overlying the posterior half slightly lower on the posterior wall of the foramen. of the target foramen, a 25 gauge, 2½ – 3½ inch nee- Only a small volume of contrast medium (1.0 ml or less) dle is passed into the neck, and then carefully readjusted is required to outline the dural sleeve of the spinal nerve. to enter the foramen immediately in front of the ante- As it spreads onto the thecal sac, the contrast medium rior aspect of the superior articular process, at the mid- will assume a linear configuration (Fig. 4). Rapid di- point of the foramen (Fig. 3a). Above this level, the nee- lution of the contrast medium implies subarachnoid

Cervical Transforaminal Injection of Steroids, Figure 3 Right anterior oblique radiograph demonstrating a needle in position along the posterior aspect of the right C6–7 intervertebral foramen. Inset of mid portion of image with bony structures labeled: SAP, Superior Articular Process; La, Lamina; Ped, Pedicle; IAP, Inferior Articular Process; SpP, Spinous Process; C6, C6 vertebral body; C7, C7 vertebral body. (b) Anteroposterior radiograph demonstrating needle in ﬁnal position within the right C6–7 intervertebral foramen. The needle lies halfway between the medial and lateral borders of the articular pillars. Inset of mid portion of image with bony structures labeled: SpP, Spinous Processes of C5, C6, and C7; Facets, medial and lateral aspect of the facet column; TrP (T1), Transverse Process of T1. (Reproduced with permission from Rathmell et al. 2004). Cervical Transforaminal Injection of Steroids 349

Bush and Hillier (1996) treated patients with three different forms of injection therapy: cervical or brachial plexus block, CTFIS, and x-ray guided, interlaminar epidural steroid injection. They reported that 76% of patients achieved complete relief of arm pain, but it is C not possible from their report to derive what proportion responded to transforaminal injections. Slipman et al. (2000) reported good or excellent results, at 12–45 month follow-up, in 60% of 20 patients treated with an average of 2.2 injections. They did not, however, provide separate results for each category of outcome. Vallee et al. (2001) studied 34 patients with cervical radiculopathy with refractory symptoms after two months of medical management. Good or excellent results were reported in 53% of 32 patients at six months, after an average of 1.3 injections. At three months, 29% of patients had complete relief of pain. This proportion persisted at six months, but diminished to 20% at 12 months. Cervical Transforaminal Injection of Steroids, These studies appear to paint an encouraging picture of Figure 4 Anteroposterior radiograph demonstrating needle in fi- theroleforCTFIS.However,thissentimentmustbetem- nal position within the right C6–7 intervertebral foramen after injection peredbytherelativelylowlevelofevidencethesestudies of 1 ml of radiographic contrast medium (iohexol 180 mg/ml). Contrast provide. outlines the spinal nerve and extends along the lateral aspect of the epidural space above the foramen (arrows). (Reproduced with permission Caveats from Rathmell et al. 2004). CTFIS is an emerging therapy whose efficacy has not been corroborated by controlled studies. Yet it is asso- ciatedwithseriouscomplicationswhoseincidenceisnot spread, which may occur if the needle has punctured properly known. Although a possible option for cervical the thecal sac or a lateral dilatation of the dural root radicular pain, it should only be undertaken by operators sleeve into the intervertebral foramen. In that event, familiar with the relevant anatomy, with sufficient expe- the procedure should be abandoned and rescheduled rience and skill to maximize the safety of the procedure. to avoid potential subarachnoid deposition of local anesthetic or steroid. Once the target nerve has been References correctly outlined, a small volume of a short-acting 1. Ahlgren BR, Garfin SR (1996) Cervical Radiculopathy. Orthop local anesthetic (lidocaine 1%, 0.5 to 1.5 ml) is injected Clin North Am 27:253–263 in order to anaesthetize the target nerve. While ensur- 2. Baker R, Dreyfuss P, Mercer S, Bogduk N (2002) Cervical Trans- ing that the needle has not displaced, the procedure is foraminal Injection of Corticosteroids into a Radicular Artery: A completed by injecting a small dose of corticosteroid Possible Mechanism for Spinal Cord Injury. Pain 103:211–215 3. Bogduk N (1999) Medical Management of Acute Cervical Radic- (betamethasone,3–6mg,ortriamcinolone20–40mg). ular Pain. An Evidence-Based Approach. Newcastle Bone and Joint Institute, Newcastle Australia Complications 4. Boyce BH, Wang JC (2003) Evaluation of Neck Pain, Radicu- lopathy, and Myelopathy: Imaging, Conservative Treatment, and A case report has detailed fatal spinal cord infarction Surgical Indications. Instr Course Lect 52:489–95 following CTFIS (Brouwers et al. 2001). Another re- 5. British Association of Physical Medicine (1966) Pain in the Neck port referred to several unpublished cases in Australia, and Arm: A Multicentre Trial of the Effects of Physiotherapy. Brit Med J 1:253–258 Europe, and the USA in which patients suffered severe 6. Brouwers PJAM, Kottnik EJBL, Simon MAM, Prevo RL (2001) neurologic sequelae (Rathmell et al. 2004). Injection A Cervical Anterior Spinal Artery Syndrome after Diagnostic of corticosteroid into a radicular artery is one plausible Blockade of the Right C6-Nerve Root. Pain 91:397–399 mechanism for neurologic injury to occur (Baker R 7. Bush K, Hillier S (1996) Outcome of Cervical Radiculopathy Treated with Periradicular/Epidural Corticosteroid Injections: A et al. 2002). Meticulous attention to real-time fluoro- Prospective Study with Independent Clinical Review. Eur Spine scopic imaging is required to avoid such complications J 5:319–325 (Rathmell et al. 2004; Baker et al. 2002). 8. ChestnutRM, AbitholJJ, GarfinSR (1992)Surgical Management of Cervical Radiculopathy. Orthop Clin North Am 23:461–474 9. Goldie I, Landquist A (1970) Evaluation of the Effects of Dif- Outcomes ferent Forms of Physiotherapy in Cervical Pain. Scand J Rehab There are no randomized controlled trials comparing Med 2–3:117–121 10. Klaber Moffett JA, Hughes GI, Griffiths P (1990) An Investiga- CTFIS to placebo or other treatments. The literature is tion of the Effects of Cervical Traction. Part 1: Clinical Effec- limited to three small observational studies. tiveness. Clin Rehab 4:205–211 350 Cervical Zygapophysial Joint Blocks

11. Radhakrishnan K, Litchy WJ, O’Fallon WM, Kurland LT (1994) Freezing Model of Cutaneous Hyperalgesia Epidemiology of Cervical Radiculopathy. A Population-Based Nociceptive Processing in the Hippocampus and Study of Rochester, Minnesota, 1976 – 1990. Brain 117:325–335 12. Rathmell JP, Aprill C, Bogduk N (2004) Cervical Transforaminal Entorhinal Cortex, Neurophysiology and Pharma- Injection of Steroids. Anesthesiology 100:1595–1600 cology 13. Slipman CW, Lipetz JS, Jackson HB, Rogers DP, Vresilovic EJ Opioid Receptors at Postsynaptic Sites (2000). Therapeutic Selective Nerve Root Block in the Non- Spinothalamic Tract Neurons, Role of Nitric Oxide Surgical Treatment of Atraumatic Cervical Spondylotic Radic- ular Pain: A Retrospective Analysis with Independent Clinical Review. Arch Phys Med Rehabil 81:741–746 14. Slipman CW, Plastaras CT, Palmitier RA, Huston CW, Sterenfeld EB (1998) Symptom Provocation of Fluoroscopically Guided Cervical Nerve Root Stimulation. Are Dynatomal Maps Identical c-Fos Immediate-Early Gene Expression to Dermatomal Maps? Spine 23:2235–42 15. Vallee JN, Feydy A, Carlier RY, Mutschler C, Mompoint D, Vallee CA (2001) Chronic Cervical Radiculopathy: Lat- eral Approach Periradicular Corticosteroid Injection. Radiol- Definition ogy 218:886–892 c-Fos is one of a family of genes, called „immediate- early genes,“ which are expressed very soon after a salient environmental event (e.g. pain). The proteins Cervical Zygapophysial Joint Blocks encoded by immediate-early genes act as transcription factors to affect the expression of other genes. By using Cervical Medial Branch Blocks immunohistochemistry for Fos, the protein product of c-fos, one can identify with single cell resolution those neurons that „responded“ to the noxious stimulus, s. also c-Fos. CFA c-Fos Heritability of Inflammatory Nociception Synonyms Complete Freund’s Adjuvant Definition CFS Complete Freund’s Adjuvant is used in animal experiments to induce inflammation. Cutaneous Field Stimulation Complete Freund’s Adjuvant Substance P Regulation in Inflammation

CGRP C Fiber

C Afferent Axons/Fibers Calcitonin Gene Related Peptide Calcitonin Gene-Related Peptide and Migraine Headaches c-Fos CGRP and Spinal Cord Nociception

Deﬁnition A gene that codes for a transcription factor (Fos). c-fos CGRP and Spinal Cord Nociception can be switched on rapidly as a result of various stimuli, and its product regulates the expression of various other ANDREA EBERSBERGER genes in the cell. Fos protein, which can be detected by Department of Physiology, Friedrich Schiller immunocytochemistry, can be used to demonstrate that University of Jena, Jena, Germany a neuron has been activated, and, is therefore used as a [email protected] markertomapneuronalrecruitmenttostimuli,including noxious stimuli. In addition, c-Fos may play a role in Synonym activating ’late response’ genes. Alternative Medicine in Neuropathic Pain Calcitoningene-relatedpeptideandspinalcordnocicep- c-Fos Immediate-Early Gene Expression tion; Spinal Cord Nociception and CGRP CGRP and Spinal Cord Nociception 351

Definition by a sensitization of the afferents to mechanical stimuli. Calcitoningene-relatedpeptide(CGRP)isa37amino Additionally basal release is much higher in inflamed acid peptide of the calcitonin family with two isoforms, than in normal animals (Collin et al. 1993). This may α and βCGRP,with similar biologicalfunctions(Poyner result from an up-regulation of the synthesis of CGRP 1992). The neuropeptide is synthesized in up to 50% of that has been observed in the acute and chronic stage C the small- and medium-sized dorsal root ganglion neu- of inflammation. rons (DRGs) and is transported along the axon to the pe- CGRP Receptor Agonists and Antagonists ripheral endings (Donnerer et al. 1992) and to the central endings of the neuron in the dorsal horn of the spinal There are two CGRP receptor subtypes, namely CGRP1 and CRGP2, which both bind the endogenous ligands cord. In addition to its role in nociception, CGRP is in- α β volved in a number of other functions including vasodi- CGRP and CGRP . The subtypes are characterized by lation. the abilities of the fragment CGRP8–37to antagonize the effect of CGRP (CGRP1) and the linear agonistic Characteristics analog [Cys(ACN)2,7 ]hCGRPα to mimic the effect of Localization of Spinal CGRP CGRP (CGRP2). BIBN4096BS, the first potent non- peptide antagonist preferentially binds to the CGRP2 Fibers showing CGRP-immunoreactivity are located receptor (Watling 2001). in the dorsal horn of the spinal cord in laminae I and II at high density and in lamina V at lower density Effect of Spinal CGRP (Wiesenfeld-Hallin et al. 1984). CGRP-like immunore- Released CGRP can exert its action directly by binding activity and CGRP mRNA are also localized in mo- to CGRP receptors. However, it also interacts with the toneurons of the ventral horn. release and metabolism of substance P. CGRP can fa- Localization of CGRP Receptors cilitate release of substance P and, in addition, CGRP The density of CGRP receptors is highest in the superfi- controls the amount of substance P by inhibiting the en- cial and deep dorsal horn, but there are also receptors in zymaticdegradationofsubstanceP(Dugganetal.1992). the ventral horn. The distribution of CGRP binding sites Behavioral Experiments is thus similar to the distribution of CGRP positive fibers In behavioral experiments, intrathecally applied CGRP but they may even be located at sites where no CGRP- facilitated the responses to noxious stimulation (e.g. containing fibers are terminating. These receptors might Wiesenfeld-Hallin et al. 1984) and antagonization of be reached by the neuropeptide by diffusion within the endogenous CGRP with CGRP8-37, a CGRP1 recep- tissue. tor antagonist, was antinociceptive. CGRP was also Immunostaining of RCP, an essential component of the shown to support the generation and maintenance of CGRP receptor complex, corroborated the distribution mechanical allodynia and hyperalgesia in rats. of CGRP receptors in the spinal cord. The distribution CGRP8-37 alleviated mechanical and thermal allodynia in chronic central pain. Thus CGRP has a role in of the CGRP receptor subtypes, CGRP1-receptor (cor- normal nociception but it is also involved in pain states responding to CRLR/RAMP1) and CGRP2-receptor in the spinal cord has not been investigated. (reviewed by Schaible et al. 2004). Under pathophysiological conditions such as peripheral Effect on Neuronal Activity inflammation, increases and decreases in binding sites for CGRP have been observed (Galeazza et al. 1992). Application of CGRP in the vicinity of spinal cord Notonlythereceptorbutalsoitsaccessoryprotein(RCP) neurons caused no, or only weak, excitation of the can be regulated in inflammatory or neuropathic pain neurons (Ryu et al. 1988). But CGRP has a facilitatory states (Ma et al. 2003). effect on evoked activity in spinal cord neurons, e.g. activities evoked by innocuous or noxious mechanical Release of CGRP stimulation or substance P (Biella et al. 1991). CRGP There is a high basal release of CGRP from central is also involved in the development and maintenance endings of afferents in the spinal cord, which was of spinal hyperexcitability. This effect was shown in a shown with antibody-coated microprobes (Schaible et model of knee joint inflammation where CGRP or the al. 1994; Morton and Hutchison 1989). This release is antagonistCGRP8-37 had been ionophoretically applied not influenced by activating peripheral afferents with in the vicinity of spinal cord neurons that responded to innocuous stimuli or motor activity in the physiological mechanical stimulation of the leg (Fig. 1). range. Noxious mechanical stimuli, however, increase Since glutamate receptors are of major importance in this basal release (Morton and Hutchison 1989). The the excitation of spinal nociceptive neurons, a possible situation changes during peripheral inflammation. Dur- interaction between the responses of spinal cord neu- ing acute knee inflammation, mechanical stimuli of rons to CGRP and NMDA or AMPA was investi- innocuous intensity to the knee induce spinal CGRP gated.CoadministrationofCGRPandAMPAorNMDA release (Schaible et al. 1994). This is probably caused enhanced the responses to the excitatory amino acids 352 Channel Inactivation

development of acute inflammation in rat’s knee joint. Neuro- science 71: 1095–1109 9. Poyner DR (1992) Calcitonin gene related peptide: multiple actions, multiple receptors. Pharmac Ther 56:23–51 10. Ryu PD, Gerber G, Murase K, Randic M (1988) Actions of calcitonin gene-related peptid on rat spinal dorsal horn neurons. Brain Res. 441:357–361 11. Schaible H-G, Freudenberger U, Neugebauer V et al. (1994) In- traspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo – a study with antibody microprobes in cat and rat. Neuroscience 62:1293–1304 12. Schaible H-G et al. (2004) Involvement of CGRP in nociceptive processing and hyperalgesia: Effects of CGRP on spinal and dorsal root ganglion neurons. In: Brune K, Handwerker HO (eds) Hyperalgesia: Molecular Mechanisms and Clinical Implications. Progress in Brain Resarch and Management, vol 30. IASP Press, Seattle, pp 201–227 13. Watling KJ (2001) The Sigma-RBI handbook of receptor classification and signal transduction. Sigma-RBI, Natick, pp 82–83 14. Wiesenfeld-Hallin S, Hökfelt T, Lundberg JM et al. (1984) Im- munoreactive calcitonin-gene related peptide and substance P coexist in sensory neurons in the spinal cord and interact in spinal CGRP and Spinal Cord Nociception, Figure 1 The development of knee behavioral responses of the rat. Neurosci Lett 52:199–204 joint inflammation is paralleled by the development of spinal hyperexcitability measured as an increase in neuronal responses to repetitive noxious pressure applied to the knee joint (upper trace). When CGRP8−37was ionophoretically applied during and 90 min after induction of inflammation in the vicinity of the recorded neurons the development of spinal hyper- Channel Inactivation excitability was prevented (Neugebauer et al. 1996). Definition A period of silencing (due to the inability to re-open) (Ebersberger et al. 2000). Thus one explanation for the after an ion channel opens and then closes. spinaleffectofCGRPisitsinfluenceon glutamatergic Painful Channelopathies neuronal transmission.

References Channelopathies 1. Biella G, Panara C, Pecile A, Sotgiu ML (1991) Facilitatory role of calcitonin gene-related peptide (CGRP) on excitation induced Definition by substance P (SP) and noxious stimuli in rat spinal dorsal horn neurons. Brain Res 559:352–356 Channelopathies are disorders in which absence of ion 2. Donnerer J, Schuligoi R, Stein C (1992) Increased content and channels, abnormalfunction of ion channels, or deploy- transport of substance P and calcitonin gene-related peptide in ment of an aberrant of ensemble of ion channels produce sensory nerves innervatin inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo. Neuroscience clinical symptoms. 49:693–698 Migraine, Pathophysiology 3. Duggan AW, Schaible HG, Hope PJ, Lang CW (1992) Effect of Painful Channelopathies peptidase inhibition on the pattern of intraspinally released immunoreactive substance P detected with antibody microprobes. Brain Res. 579:261–269 4. Ebersberger A, Charbel Issa P, Venegas H, Schaible HG (2000) Charcot-Marie-Tooth Disease Differential effects of calcitonin gene-related peptide and calcitonin gene-related peptide8-37 responses to N-methyl-D- aspartate or (R,S)-α-amino-3-hydroxy-5-methylisoxazole-4- Synonyms propionate in spinal nociceptive neurons with knee joint input in the rat. Neuroscience 99:171–178 CMT 5. Galeazza MT, Stucky CL, Seybold VS (1992) Changes in 125IhCGRP binding sites in rat spinal cord in an experimental Definition model of acute, peripheral inflammation. Brain Res 591:198–208 6. Ma W, Chabot J-G, Powell KJ et al. (2003) Localization and CMT is any inherited neuropathy that is not part of a modulation of calcitonin gene-related peptide-receptor compo- syndrome. nent protein-immunoreactive cells in the rat central and periph- Hereditary Neuropathies eral nervous system. Neuroscience 120:677–694 7. Morton CR, Hutchison WD (1989) Release of sensory neuropeptides in the spinal cord: studies with calcitonin-gene related peptide and galanin. Neuroscience 31:807–815 C-Heat Receptor 8. Neugebauer V, Rümenapp P, Schaible H-G (1996) Calcitonin gene related peptide is involved in the generation and maintenance of hyperexcitability of dorsal horn neurons observed during Polymodal Nociceptors, Heat Transduction Chemotactic Cytokines 353

Definition Chemesthesis Chemokines are cytokines with chemoattractant prop- Definition erties, inducing cells with the appropriate receptors to migrate towards the source of the chemokines, which Sensitivitytoallchemicalsthatproducesensationsother includes the family of proinflammatory activation- C than (or in addition to) taste or smell. inducible cytokines. These proteins are mainly chemo- Nociception in Nose and Oral Mucosa tactic for different cell types. Based on chromoso- mal locations of individual genes, two different sub- families of chemokines are distinguished as CXC- Chemical Lesion chemokines (CXCL; also known as alpha-chemokines or 4q chemokine family) and CC-chemokines (CCL; Definition also known as beta-chemokinesor 17q chemokine family). In the earliest phases of inflammation, chemokines Selective lesion of neuronal cell bodies of the CNS. It are released and induce direct chemotaxis in nearby consists of injecting a concentrated solution of an exci- responsive cells. Together with intercellular adhesion tatory amino-acid that can normally excite the neurons molecules, chemokines and their receptors serve to at high concentration. At high concentration, the amino localize and enhance the inflammatory reaction at the acid (glutamic, kainic, quisqualic, ibotenic acids) can site of tissue damage. produce selective neuronal death (cell bodies only spar- Cytokines as Targets in the Treatment of Neuropathic ing nerve fibers) by excitotoxicity. Pain Thalamotomy, Pain Behavior in Animals Cytokines, Effects on Nociceptors Cytokine Modulation of Opioid Action Neutrophils in Inflammatory Pain Chemical Sympathectomy

Sympathetic Blocks Chemosensation

Deﬁnition Chemical Transmitter Sensations initiated through chemicals, e.g. gustatory or olfactory mediated sensations or sensations mediated Nociceptive Neurotransmission in the Thalamus through the intranasal trigeminal nerves. Nociception in Nose and Oral Mucosa

Chemoattractants Chemosensitive Sympathetic Afferent Definition Fibers Chemoattractants have been divided into two categories. One category is represented by the classical Definition chemoattractants like platelet activating factor (PAF), Afferentfibersthattransmitinformationresultingfroma leukotriene B4 (LTB4), formyl-methionyl-leucyl- variety of chemicals that are released during myocardial phenylalanine (FMLP), and complement protein C5a. ischemia. The second category consists of compounds belong- ing to the chemokine group. Both classical chemoattractants and chemokines act on target cells through Chemotactic seven-transmembrane domain receptors that are coupled to heteromeric G-proteins and elicit chemotactic Definition responses. Neutrophils in Inflammatory Pain Achemical(sodiummorrhuate)usedinprolotherapyso- lutions, which acts by attracting inflammatory cells. Prolotherapy Chemokines Chemotactic Cytokines Synonyms Chemotactic Cytokines Chemokines 354 Chemotherapy

Chemotherapy Childhood Sexual Abuse

Definition Definition Treatment with drugs that kill cancer cells that may be Any child below the age of consent may be deemed to givenbyoneormoreofthefollowingmethods:orally,by have been sexually abused when another sexually ma- venous or arterial injection (through a catheter or port), ture person has, by design or by neglect of their usual so- or topically. cietal or specific responsibilities in relation to that child, Cancer Pain Management, Chemotherapy engaged or permitted the engagement of that person in Cancer Pain Management, Treatment of Neuropathic any activity of a sexual nature that is intended to lead to Components the sexual gratification of the sexually mature person. This definition pertains whether or not it involves genital contact or physical contact, and whether or not there Chemotherapy-Induced Neuropathy is discernible harmful outcome in the short-term. Chronic Pelvic Pain, Physical and Sexual Abuse Definition A group of drugs used in chemotherapy are associated Chiropractic with a peripheral neuropathy. Vincristine was the first druginthisgroup.Themostcommonlyusedchemother- Definition apy agents that produce a painful neuropathy, which is also associated with a sensory loss, are Cisplatin (and Therapeutic manipulation of thespinetotreatawideva- Carboplatin) and Taxol. These two drugs bind to tubulin riety of conditions by correcting dysfunction in spinal intheaxoplasmandreducetheanterogradeslowcompo- alignment. nentof axoplasmictransport. Thismakesthenervessus- Alternative Medicine in Neuropathic Pain ceptible to chronic compression, whichcan be helped by Spinal Manipulation, Characteristics decompression of the involved nerves. The most recent Spinal Manipulation, Pain Management drug to be used for chemotherapy that has an associated neuropathy is Thalidomide. Ulceration, Prevention by Nerve Decompression Chloride Transporter

Synonyms Chest Pain Cl– Transporter

Deﬁnition Deﬁnition Chest pain is often caused by coronary artery disease, A chloride transporter is a membrane protein that assists but can originate from non-cardiac structures such as the in the movement of ions across the surface membrane esophagus. The most prominent feelings are pressure, of a neuron. The result can be a greater concentration of squeezing and/or crushing on the chest. chloride ions on one or the other side of the membrane. Visceral Pain Model, Angina Pain GABA Mechanisms and Descending Inhibitory Mechanisms

Chiari Type I Malformation Chloro-phenyl-2- Definition methylaminocyclohexanone- This is a protrusion of the cerebellar tonsils, below the hydrochloride foramen magnum, which can cause a valve-like obstruc- tiontotheflowofcerebrospinal fluid. Postoperative Pain, Ketamine Primary Cough Headache Cholecystokinin Childhood Migraine Synonyms Migraine, Childhood Syndromes CCK Chronic Back Pain and Spinal Instability 355

Definition Synonyms An eight amino acid peptide present in the gastroin- Dysfunctional Segmental Motion; Mechanical Low testinal tract and in the nervous system that modulates Back Pain; Lumbago; Back Pain; Myofacial pain syn- pain sensation as well as other neuronal processes. It drome; Muscle Spasm; Discogenic pain; Painful Disc was named for its effects on the gall bladder, but also Syndrome C thought to have pro-nociceptive effects in the spinal cord. Definition Alternative Medicine in Neuropathic Pain Chronic back pain is defined as pain in the dorsal aspect Pain Modulatory Systems, History of Discovery of the trunk (from the neck to the pelvis) that persists Peptides in Neuropathic Pain States for more than twelve weeks (Gatchel 1986). It may be Placebo Analgesia and Descending Opioid Modula- related to degenerative, neoplastic, traumatic or infection tious conditions. Chronic back pain may also be related to spinal instability. Spinal instability is defined as the inability of the spine to limit patterns of movement or displacement that may lead to deformity or pain. Other Chondrocytes entities that are particularly worthy of definition are mechanical back pain and myofacial pain syndrome, disco- Definition genic pain, pain of soft tissue injury origin and pain of Chondrocytes are cells that produce cartilage by secre- bony tissue injury origin: tion of the cartilaginous matrix. The secretion of the • Mechanical back pain – a deep and agonizing pain matrix by chondrocytes leads to their encapsulation in that increases with activity, such as the assumption this matrix where they eventually undergo programmed of the upright posture (loading) and decreases with cell death, or apoptosis. As a consequence, new chon- inactivity, such as assuming the supine position (un- drocytes constantly arise from their precursor cells. loading). Chondrocytes arise from chondroblasts, which arise • Myofacialpainsyndrome–synonymouswithmuscle from mesenchymal cells. spasm or strain. It isusually self-limiting. There often Arthritis Model, Osteoarthritis exists an underlying cause. • Discogenic low back pain – pain that originates from the intervertebral disc and the disc space. • Pain of soft tissue injury origin – such pain originates Chromosomes from the damage or destruction of richly innervated soft tissue. It may occur after surgery and is also seen Definition with muscle tear. • Pain of bony tissue destruction origin – pain that is Chromosomes contain the cell’s genetic information, associated with bony distortion. It is usually associ- and are structured as compact intertwined molecules of ated with weakened bone, as may be seen with tumor, DNA located in the nucleus of cells. infection, or trauma. NSAIDs, Pharmacogenetics Characteristics Chronic back pain is common. Eighty five percent of Chronic Abdominal Pain of Childhood cases are idiopathic. Potential anatomical sources of back pain include muscle, ligaments, tendons, bones, Recurrent Abdominal Pain in Children facet joints and discs. In many cases, it is difficult to determine the exact cause of back pain because of significant overlap in the nerve supply to the aforementioned structures. Approximately 80% of Americans Chronic Back Pain and Spinal Instability experience clinically-significant back pain. Eighty to ninety percent of the attacks resolve within 6 weeks 1 1 KENE UGOKWE ,AJIT KRISHNANEY , (Bigos 1994). It is the second most common reason for 1 1, 2 MICHAEL STEINMETZ ,EDWARD BENZEL which people seek medical attention (Cypress 1983). 1The Cleveland Clinic Foundation, Department of Back pain accounts for 15% of all sick leave and it is Neurosurgery, Cleveland, OH, USA the most common cause of disability for people less 2The Cleveland Clinic Foundation, Cleveland Clinic than 45 years of age (Cunningham 1984). Spine Institute, Cleveland, OH, USA Spinal instability is a common cause of back pain. Some [email protected] of the causes of spinal instability include age related 356 Chronic Back Pain and Spinal Instability degenerative changes, prior spinal surgery, physically Chronic Back Pain and Spinal Instability, Table 1 Quantitation of Acute dependent occupations, sedentary lifestyles, obesity, Instability for Subaxial Cervical, Thoracic, and Lumbar Injuries (The Point poor posture and certain sporting activities. In a pa- System) tient with chronic back pain, a diagnosis to consider is Condition Points Assigned spinal tumor. Pain at night that is relieved by aspirin Loss of integrity of anterior and middle column 2 may be suggestive of an osteoid osteoma or a benign osteoblastoma. Infections such as discitis (an infec- Loss of integrity of posterior columns 2 tion of the disc space between the vertebral bodies) Acute resting translational deformity 2 must also be ruled out. Spinal compression fractures may also be the source of severe back pain, particularly Acute resting angulation deformity 2 in the elderly. Other potential etiologies of chronic back Acute dynamic translation deformity 2 pain include: exaggeration Acute dynamic angulation deformity 2 Degenerative Conditions exaggeration • Degenerative spondylolisthesis: slippage of one ver- Neural element injury 3 tebral body over another (Pearcy 1983). Acute disc narrowing at the level of suspected 1 • Spinal stenosis pathology • Lateralrecesssyndrome:thelateralrecessisthechan- Dangerous loading anticipated 1 nel alongside the pedicle where the exiting nerve root resides. (Panjabi 1994; White 1990)

Spondyloarthropathies cluding the supraspinous and interspinous ligaments • Paget’s disease: this is a condition characterized by and the ligamentum flavum. areas of abnormal bone growth and an increased rate Many authors have used a point system approach to of bone resorption. quantify the extent of acute instability. White and Pan- • Ankylosing spondylitis: this is a connective tissue jabi described the accumulation of 5 or more points disease characterized by inflammation of the spine as being indicative of spinal instability (Panjabi 1994; and joints resulting in pain and stiffness. White 1990) (Table 1). They also described a stretch test It is important to note that all of the aforementioned con- in which the progressive addition of cervical traction ditions contribute to or cause spinal instability. Certain weight was accompanied by clinical assessments and patients,however,havenoorganicdiseaseandtheirback radiographs. The test was positive for instability when pain is psychogenic in nature. This may be as a result a disc interspace separation of greater than 1.7 mm, or of secondary gain, i.e. financial or emotional gain (Wad- a change in angle greater than 7.5 degrees between pre dell 1980). and post stretch measurements, was observed. Most clinicians do not employ this method due to the risks Spinal Instability involved and its cumbersome nature. Flexion and ex- There are two categories of spinal instability: (1) Acute tension radiographs or MRI (Dvorak 1991) may also spinal instability, and (2) Chronic spinal instability. be helpful in determining the degree of instability. Acute spinal instability may be further divided into Acute Instability overt and limited instability, while chronic instability is subcategorized into glacial instability and dysfunctional Overt Instability segmental motion (Benzel 2001). Denis described the Overt instability is defined as the inability of the spine to three-column concept of identifying criteria for insta- support the torso during normal activity. This is usually bility of the spine (Denis 1983). acute in nature, e.g. after a trauma. It also has a chronic component, and may also occur in the setting of tumor, The Three Column Concept of Spinal Integrity and Stability infection, or degenerative disease. It is characterized The spine is divided into three columns. by circumferential loss of spinal integrity. Treatment may involve surgical stabilization, with or without de- • Anterior column – composed of the ventral half of compression. The back pain experienced with overt the disc and the vertebral body, including the anterior instability is usually associated with soft tissue injury longitudinal ligament. and muscle spasms (Fig. 1a). • Middle column – composed of the dorsal half of the disc and vertebral body and the posterior longitudinal Limited Instability ligament Limited instability is characterized by loss of either ven- • Posterior column – the dorsal bony complex (poste- tral or dorsal spinal integrity. Posterior column disrup- rior arch) and the dorsal ligamentous complex, in- tion is not always associated with instability, unless the Chronic Back Pain and Spinal Instability 357

Chronic Back Pain and Spinal Instability, Figure 1 (a) Fracture dislocation in the thoracolumbar spine representative of overt instability. (b) Wedge compression fracture elucidating limited instability. posterior longitudinal ligament and the middle column Treatment are disrupted. Failure of the middle column represents When patients present with chronic low back pain, the an unstable injury (Denis 1983). Chronic forms of both initial management usually consists of non-surgical overt and limited instability exist, especially when overt therapy; except in the presence of cauda equina syn- and limited forms do not heal adequately (Fig. 1b). drome,progressiveneurologicdeficitorprofoundmotor weakness. Also, one may proceed directly to surgery Chronic Instability in the presence of severe pain that is not sufficiently Glacial Instability controlled with pain medications Glacial instability is defined as spinal instability that is neither overt nor limited. It does not pose a significant Non-Surgical Treatment risk for the rapid development of a spinal deformity. The • Bed rest helps reduce pressure on nerve roots and in- deformity progresses gradually; like a glacier moving tradiscal pressure, which is lowest in the supine semi- down a mountain. Glacial instability is associated with Fowler position (Nachemson 1992). This, however, pain that is mechanical in nature. In managing this type hasbeenshowninsubsequentstudiestobearelatively of instability, one must factor in the degree of progres- ineffective form of treatment (Malmivaara 1995). sion of deformity and the subjective complaint of pain. • Exercise, including physical therapy with low stress Causes include trauma, tumors and congenital defects aerobic exercise, may help relieve symptoms and (Fig. 2a). strengthen back muscles. Low stress aerobic exercise can minimize debility due to inactivity. Condition- Dysfunctional Segmental Motion ing exercises for trunk muscles are also helpful if Dysfunctional segmental motion is a type of instability symptoms persist. that is related to disc interspace or vertebral body de- • Analgesics (e.g. NSAIDS) in the initial short-term generative changes, tumor, or infection. A deep and ag- period may be helpful. Opioids may be required for onizing pain that is usually worsened by activity and im- more intense pain. proved by inactivity usually characterizes dysfunctional • Muscle relaxants, such as cyclobenzaprine and segmental motion. This type of pain is similar to that methocarbamol, may help with pain of muscle observed with glacial instability. This pain results from spasm origin (myofascial component of pain). the exaggeration of reflex muscle activity, which picks • Epidural steroid injections may be of assistance in up the slack from the inadequate intrinsic stability from some cases of chronic pain. the spine. The associated pain syndrome, as described • Modality (physical) treatments, including transcuta- here, is commonly known as mechanical low back pain neous electrical nerve stimulation (TENS) and trac- (Fig. 2b). tion, qualify as physical treatments but may only pro- 358 Chronic Central Pain Models

Chronic Back Pain and Spinal Instability, Figure 2 (a) Spondylolisthesis in the lumbar spine which is an example of glacial instability. (b) Lumbar canal stenosis and degenerative disc disease showing dysfunctional segmental motion.

vide minor relief for some patients. Biofeedback 3. Bush C, Ditto B, Feuerstein M (1985) A Controlled Evaluation has been advocated for chronic low back pain (Bush of Paraspinal EMG Biofeedback in the Treatment of Chronic Low Back Pain. Health Psychol 4:307–321 1985). 4. Cunningham LS, Kelsey JL (1984) Epidemiology of Muscu- • Injection therapy, including trigger point and liga- loskeletal Impairments and Associated Disability. Am J Public mentinjections,arecontroversialandareofequivocal Health 74:574–579 efficacy. Acupuncture has been studied in random- 5. Cypress BK (1983) Characteristics of Physician Visits for Back Symptoms: A National Perspective. Am Journal of Public Health ized clinical trials for chronic low back pain. The 73:389–395 studies have been mostly contradictory. This, how- 6. Denis F (1983) The Three Column Spine and its Significance in ever, should not discount the fact that they may be the Classification of Acute Thoracolumbar Spine Injuries. Spine effective for a subset of people. 8:817–831 7. Dvorak J, Panjabi MM (1991) Functional Radiographic Diagno- sis of the Lumbar Spine: Flexion-Extension and Lateral Bending. Spine 16:562–571 Surgical Treatment 8. Gatchel RJ, Mayer TG, Capra P et al. (1986) Quantification of In patients with compressive lesions, surgery (decom- Lumbar Function, VI: The Use of Psychological Measures in pression; e.g. laminectomy) is the next step when Guiding Physical Functional Restoration. Spine 11:36–42 9. Holdsworth FW (1963) Fractures, Dislocations, and Fracture- conservative therapy fails (Holdsworth 1963). Fusion Dislocations of the Spine. J Bone Joint Surg 45B:6–20 instrumentation is appropriate in the refractory patient 10. Lorenz M, Zindrick M (1991) A Comparison of Single Level with mechanical low back pain. The goal of surgical Fusion With and Without Hardware. Spine 16:455–458 intervention for mechanical low back pain is stabiliza- 11. Malmivaara A, Hakkinen U, Aro T (1995) The Treatment of Acute Low Back Pain – Bed Rest, Exercises, or Ordinary Ac- tion of unstable spinal segments. Spinal fusion is an tivity? N Engl J Med 322:351–355 accepted therapy for fracture/dislocation or acute in- 12. Nachemson AL (1992) Newest Knowledge of Low Back Pain. stability that may result from tumor or infection. It also A Critical Look. Clin Orthop 279:8–20 13. Panjabi MM, Lydon C (1994) On the Understanding of Clinical may be used in selected patients with glacial instability Instability. Spine 19:2642–2650 or dysfunctional segmental motion. It is important to 14. Pearcy M, Shepherd J (1983) Is there Instability in Spondylolis- note that the use of spinal instrumentation increases thesis? Spine10:461–473 the fusion rate (Lorenz 1991), but not necessarily the 15. Waddell G, McCulloch JA, Kummel E et al. (1980) Non-organic Physical Signs in Low Back Pain. Spine 5:117–25 clinical outcome. 16. White AA, Panjabi MM (1990) Clinical Biomechanics of the Spine, 2nd edn. Lippincott, Philadelphia, pp 30–342 References 1. Benzel EC (2001) Biomechanics of Spine Stabilization: Stability and Instability of the Spine. AANS Press, pp 29–43 2. Bigos S, Bowyer O, Braen G et al. (1994) Acute Low Back Prob- lems in Adults. Clinical Practice Guideline 14. AHCPR Publica- Chronic Central Pain Models tion No. 95-0642. Agency for Healthcare Policy and Research, Public Health Service, U.S. Department of Health and Human Services, Rockville, MD Spinal Cord Injury Pain Model, Hemisection Model Chronic Daily Headache in Children 359

children (45%) did not fit within the four types of CDH. Chronic Constriction Injury Model Instead, these children had a pattern of intermittent migraines with an underlying daily tension headache, Synonyms thus leading the authors to propose a fifth diagnostic CCI Model category of comorbid headache. C Definition Proposed Diagnostic Classification for Pediatric Chronic Daily Headache This is a nerve injury model of persistent pain. It consist Transformed Migraine of a partial nerve injury, mostly used in rodents, that is produced by tying several ligatures around a nerve, such A chronic daily (or near daily) headache that developed that these ligatures slightly constrict the nerve. This in- gradually over time from a pre-existing, well-defined duces an incomplete nerve injury that entails behavioral migraine headache. Headache is longer than 4 h per signs of hyperalgesia in the animals. day, can include a mixture of autonomic and tension- Neuropathic Pain Model, ChronicConstrictionInjury type symptoms and symptoms have progressed with Neuropathic Pain Model, Partial Sciatic Nerve Liga- increasing frequency and decreasing severity over at tion Model least 3 months. Nociceptive Processing in the Hippocampus and En- Chronic Tension-type torhinal Cortex, Neurophysiology and Pharmacology Very frequent headaches (>180 episodes per year) that Peptides in Neuropathic Pain States developed gradually over at least 3 months from pre- Purine Receptor Targets in the Treatment of Neuro- existing tension-type headache. Pain has pressing or pathic Pain squeezing quality, bilateral location and there is a relative absence of autonomic nervous system symptoms. Chronic Daily Headache New Daily Persistent Abruptonsetof head pain thatcontinueson adailybasis, New Daily Persistent Headache with no history of pre-existing migraine or tension-type headache. Pain episodes last longer than 4 h per day and have been present for greater than one month. Chronic Daily Headache in Children Hemicrania Continua

PATRICIA A. MCGRATH Daily unilateral headache for at least 1 month. Pain is The Hospital for Sick Children and University of continuous but fluctuating, moderately severe, lacks Toronto, Toronto, ON, Canada precipitating triggers and responds positively to in- [email protected] domethacin. Comorbid Headache Synonyms Daily tension-type headache, accompanied by intermit- Headache; CDH; Transformed Migraine tent and less frequent episodes of well-defined migraine headache. Definition Large descriptive studies should be conducted for chil- Chronic daily headache (CDH) is an almost continual dren to establish age and sex-related data on the clinical headache in the absence of organic pathology (Holden features of CDH in children. At present, our knowledge et al. 1994). This relatively new diagnostic category was of CDH in children is derived primarily from a few case created to characterize individuals who did not meet the series (Esposito and Gherpelli 2004; Gladstein et al. criteria for episodic tension or migraine headaches, but 1993; Hershey et al. 2001). Such studies indicate that instead presented with chronic daily pain. CDH typically has a bifrontal, rather than uni-lateral location. Children and adolescents often describe the Characteristics headache as diffuse, e.g. “All over, or around my head”, In 1994, Silberstein and colleagues proposed a new set instead of a specific region. Headache episodes vary of diagnostic criteria for chronic daily headache that widely in length from lasting only a few minutes to al- included 4 types seen in clinical practice, transformed most continuously. In my clinical experience, children migraine headache, chronic tension type headache, usually report that the headache “lasts all day”. They do new daily persistent headache and hemicrania not know exactly when they first notice the headache continua headache, as defined below (Silberstein et al. in the morning – some children describing noticing 1994). Gladstein and Holden (1996) evaluated whether it when they first open their eyes in bed, while other these new criteria were adequate for diagnosing a clin- children notice the headache when they are brushing ical sample of 37 children with CDH. Almost half the their teeth, eating breakfast, or dressing for school. 360 Chronic Daily Headache in Children

Children have similar difficulty in determining exactly and physical stimuli (e.g. foods, weather conditions and when the headache ends each day – often noting that it activities) can trigger recurrent headache attacks, the is present until they fall asleep. Children rarely report evidence base for these presumed triggers is negligible. that the headache disturbs their sleep at night. Heredity is important, but certain cognitive, behavioral Headache intensity also varies considerably among and emotional factors are critical for triggering attacks, children. Some children report a consistently mild pain, increasing pain, prolonging disability or maintaining a whileotherchildrendescribeasevereandincapacitating cycle of almost daily headache (McGrath and Hillier headache. Some children report that the pain intensity 2001). varies throughout the day, while other children report While CDH in children probably involves both central that the pain is constant, regardless of the time of day and peripheral nervous systems, the specific interplay or their activities. Some of the children, who rate their of systems is not known. Similarly, the extent to which headache as very strong, do not appear distressed by vascular and muscular components are involved is un- their continual pain – almost exhibiting “ la belle in- known and may differ according to the type of CDH. To difference”. They explain that the pain does not bother date, no studies have examined the pathophysiology of them because they have learned to adjust to it. CDH in children, so that our understanding is presumed rather than documented and based primarily on extrapo- Prevalence of CDH in Children lation from adult studies. For some cases with migraine Prevalence estimatesof headacheinchildrenrangefrom features, presumed mechanisms include a neurogenic 1.4–27% for migraine headache and from 6.3–49% inflammatory cascade, vascular reactivity and serotonin for other types of headache (McGrath 2001). These (5-HT), while for other cases, mechanisms may include estimates differ widely due to differences among epi- pericranial muscle tenderness or musculoskeletal ab- demiological studies in the sampling method used to normalities as noted recently for adults (Holden et al. identify children, the age and sex of children studied, 2001; Lipchik et al. 1996). Serotonergic dysregulation the diagnostic criteria used to classify headache, the has been postulated as a common point of neurotrans- country of origin and the presentation and analysis of mitter abnormality in anxiety, depression and migraine data. (Rossi et al. 1992). In view of the association between At present, we do not know the prevalence of CDH CDH and features of depression and anxiety in a subset for children and adolescents in the general population of children, serotonin dysfunction may also play a role according to age, gender and the diagnostic categories in CDH. listed above. The overall rate of CDH hasbeen estimated as low (<1%) in community samples (Abu-Arefeh and Risk Factors and Impact Russell 1994; Sillanpää et al. 1991), but this rate may Almost all studies of childhood headache evaluate underestimate the actual prevalence because most epi- demographic and psychosocial factors in an effort to demiological studies of childhood headache have not identify potential risk factors that may predispose chil- determined prevalence by headache frequency (Mc- dren to develop headache. However, only a few studies Grath 2001). The prevalence of CDH for children who have focused on CDH. Holden and colleagues (1994) seek treatment at specialized pediatric clinics is not compared 3 groups of children (CDH, migraine and known, although in my experience approximately 15% both CDH and migraine) with respect to the impact of of children with headache have CDH with half of these headache, children’s coping and headache disability. children experiencing an associated emotional prob- Children with CDH had higher rates of concurrent lem. Rossi and colleagues (1992) describe a prevalence psychiatric diagnoses, missed more school days and rate of 4.6% for children with daily headache and tended more to blame others as a coping mechanism in psychological problems in their clinical sample. comparison to children with migraine headache. Galli and colleagues (2004) noted psychiatric disorders Pathophysiology in approximately 64% of children with CDH, espe- Many questions remain about the pathophysiology cially sleep and anxiety disorders. From my clinical of recurrent headache in children, especially CDH experience, a subset of children with CDH also have (Holden et al. 2001). As noted previously in the sec- long-standing emotional problems suggestive of mood tion on diagnostic classification, CDH has different disorders, anxiety disorders and somatoform disorders. expressions in children and adults and the different Many of these children satisfy the existing IHS diagnos- expressions may reflect several different etiologies or a tic criteria outlined for chronic tension-type headache developmental continuum. Most childhood headaches, unassociated with disorder of pericranial muscles (pre- including CDH, are not caused by an underlying disease viously described as chronic psychogenic headache), or disorder. While a positive family history predisposes even though these children do not necessarily satisfy the children to develop headache, many environmental, criteria for a DSM-IV diagnosis (as required for coding biological and psychological processes are relevant. anxiety, etc. as a causative factor). At present, we do Despite widely held beliefs that many environmental not know whether this subset of CDH is associated with Chronic Daily Headache in Children 361 a particular one (or more) of the diagnostic categories such as attention and distraction, guided imagery and listed above. hypnosis to lessen their pain. Behavior therapy, often used in combination with cog- Management of CDS nitive therapy, is targeted either for children themselves Drug Therapy or for the adults who respond to them when they expe- C rience headache. At the initial consultation, health care Drug therapies for treating children’s headache include providers may assess whether children’s behaviors or analgesics, ergot derivatives, serotonin receptor ago- those of key adults (parents, teachers or coaches) are nists, antiemetics, β-blockers, serotonin antagonists, influencing the pattern and severity of headache attacks. tricyclic antidepressants, antihistamines, calcium chan- If so, they recommend how they should change their nel blockers and antiepileptics (Levin 2001). Yet their behaviors to improve pain control and lessen disability. efficacy has generally been accepted on the basis of Strong and consistent evidence supports the efficacy of studies with adults rather than demonstrated in con- most cognitive and behavioral therapies for relieving trolled trials with children and adolescents. At present, children’s headache. However, all studies have focused we lack data about which drugs are best for children on either migraine or general recurrent headache, so with CDH or its subtypes. that we lack definitive evidence about the efficacy of Dosing guidelines for prophylactic medication for chil- these cognitive-behavioral therapies specifically for dren with CDH are based on their use for children with CDH. Alternatively, psychologists and therapists coun- frequent migraine. Holden and colleagues (2001) rec- sel families about the impact of their behaviors and ommend that only those children with severe headache assist families to make required changes using operant who exhibited significant functional disability should conditioning programs. be considered for prophylaxis. Rothner (2001) recom- Many of these cognitive-behavioral therapies share a mends that if effective, children should use prophylactic common “child-centered” focus, addressing the unique medication for 4–6 months and then be weaned. If not causative and contributing factors for each child’s effective, the medication should be discontinued after headache. Although the evidence base supporting their 6–10 weeks and another medication tried. The dosing efficacy for relieving childhood headache is strong, guidelines for the common prophylactic medications there are no controlled trials evaluating their efficacy used for childhood headache are listed in Table 1. for children with CDH. Randomized controlled trials are needed to evaluate the efficacy of the varied drug therapies for treating Physical Techniques CDH in children and adolescents. In my clinical experi- Physical techniques include thermal stimulation, visual ence, many children benefit from a combined drug and modulation, transcutaneous nerve stimulation (TENS), non-drug protocol, including a low dose schedule of acupuncture, massage and chiropractic or osteopathic amitriptyline, a tricyclic antidepressant, combined with manipulation. Although eachtechnique hasbeenused to a cognitive-behavioral pain management program. treat headache in children, almost no studies have been conducted to evaluate their efficacy objectively. Instead, Nondrug Therapy physical techniques are recommended primarily on the A diverse array of nondrug therapies are used to treat basis of clinical experience and anecdotal information. children’s headache, including counseling, guided imagery, hypnosis, biofeedback, behavioral manage- Summary ment,acupuncture,massage,chiropracticmanipulation, CDH is a relatively new diagnostic category that de- homeopathic remedies, naturopathic approaches and scribes an almost continual headache in the absence herbal medicines (McGrath and Hillier 2001). of organic pathology. The management of CDH in children is exceptionally challenging. The current prin- Cognitive-behavioral Therapies ciples guiding our management of CDH in children and Cognitive therapy, designed to modify an individual’s adolescents are extrapolated from the existing literature beliefs, expectations and coping abilities, is an intrin- on childhood headache, CDH in adults and our clinical sic component of all headache treatment. Health care experience. providers educate families about the circumstances A child-centered focus is particularly important in the that cause headache, often counseling them about how treatment of CDH because it is not caused by an under- they can alter those circumstances (e.g., lifestyle man- lying disease or disorder. Optimal treatment of CDH agement, diet, sleep, exercise). In addition, children begins with the differential diagnosis and a compre- may learn specialized stress management techniques as hensive pain assessment to identify relevant causative part of a treatment program and families may receive and contributing factors. These factors may vary among guidance about how to minimize headache related dis- children, even children presenting with seemingly iden- ability. In some programs, therapists teach children tical headache symptoms. In our experience, children how to use individual cognitive pain control methods, benefit from a combined drug and nondrug regimen. 362 Chronic Daily Headache in Children

Chronic Daily Headache in Children, Table 1 Drugs used in the prophylaxis of childhood headache Drug Dosage _Comments

Beta-blockers Propranolol 1–3 mg kg−1 day−1 as b.i.d. Side effects: fatigue, bradycardia, hypotension, depression. Contraindications: asthma, heart block, bradyarrhythmias, diabetes, congestive heart failure. Avoid abrupt withdrawal.

Tricyclic antidepressants Amitriptyline 0.2–2.0 mg kg−1 day−1 as t.i.d. dose Side effects: weight gain, drowsiness, anticholinergic effects. Contraindication: cardiac disease.

Serotonin antagonists Pizotifen 0.5 mg t.i.d. (may use Side effects: sedation, weight gain. Start small dose at night and 0.5–1.5 mg kg−1 as t.i.d. dose) increase at weekly intervals to t.i.d. dose.

Methysergide 2–6 mg day−1 Side effects: retroperitoneal ﬁbrosis. Discontinue for 1 month every 3–6 months. Use in adolescents only.

Calcium channel blockers Flunarizine 5 mg day−1 Side effects: bradycardia, hypotension, weight gain, drowsiness. Contraindications: depression, extrapyramidal disorders.

Antihistamines Cyproheptadine Age 2–6 yr: 2 mg q8 –12 h Side effect: drowsiness (max 12 mg day−1) Age 7–14 yr: 4 mg q8–12 h (max 16 mg day−1)

Antiepileptics Valproate 10–50 mg kg−1 day−1 as b.i.d. dose Side effects: hepatoxicity, thrombocytopenia. Start at low dose and increase at weekly intervals.

Gabapentin 300–400 mg t.i.d. Start at 100 mg t.i.d. and increase daily by 100 mg t.i.d. to maximum dose.

Abbreviations: b.i.d., twice a day; t.i.d., three times a day; q 8–12 h, every 8–12 h (Levin 2001)

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10. Lipchik GL, Holroyd KA, France CR et al. (1996) Central and What Do Doctors Think About Women with Pelvic Pain? (Selfe peripheral mechanisms in chronic tension-type headache. Pain et al. 1998a) 64:467–475 11. McGrath PA, Hillier LM (2001) The Child with Headache: Di- agnosis and Treatment. IASP Press, Seattle Toobtain primary data on medical attitudes, focusgroup 12. Rossi LN, Cortinovis I, Bellettini G et al. (1992) Diagnostic crite- discussionswereconductedwithgroupsofgeneralprac- C ria for migraine and psychogenic headache in children. Dev.Med titioners, gynaecologists and patients. Themes common Child Neurol 34:516–523 13. Rothner AD (2001) Differential Diagnosis of Headaches in Chil- to all groups were expression of the need to find a patho- dren and Adolescents. In: McGrath PA, Hillier LM (eds) The logical cause for the pain, something that would provide Child with Headache: Diagnosis and Treatment. IASP Press, a diagnosis. Issues relating to time were discussed by Seattle, pp 57–76 all groups and this was particularly related by hospital 14. Silberstein SD, Lipton RB, Solomon S et al. (1994) Classifica- tion of daily and near-daily headaches in the headache clinic. gynaecologists and GPs to aspects of communication. Proposed revision to the International Headache Society crite- Both groups of doctors were aware of the possible stress ria. In: Olesen J (ed) Frontiers in Headache Research: Headache related and psychological influences of pain, although Classification and Epidemiology, vol 4. Raven Press, New York, patients seemed to avoid direct discussion of psycholog- pp 117–126 15. Sillanpää M, Piekkala P, Kero P (1991) Prevalence of headache ical factors which may have been related to their pain. at preschool age in an unselected child population. Cephalalgia Themes particular to general practitioners were diagno- 11:239–242 sis by exclusion, especially with respect to irritable bowel syndrome (IBS) and pelvic inflammatory disease (PID). They stated that the lack of a firm diagnosis meant that dealing with patients with CPP could be diffi- Chronic Gynaecological Pain, cult, particularly those patients who have experienced a Doctor-Patient Interaction ’negative’ laparoscopy. If no visible pathology was seen at laparoscopy to account for the pain, GPs found it dif- R. WILLIAM STONES ficult to know how to proceed with persistent patients. Princess Anne Hospital, University of Southampton, A provisional diagnosis, even if it was considered im- Southampton, UK precise, could provide a label by which to justify the [email protected] patient’s symptoms. This applied especially to IBS and “pelvic congestion” Synonyms GPs recognised the value of effective communication, Doctor-Patient Communication; Therapeutic Relation- but acknowledged that a good rapport with a patient was ships unlikely to develop after one short visit. GPs also com- mented on the complexity of a complaint in which it was Definition necessary to sort out “the emotional components of the problem” The proposition that patient outcomes in chronic Hospitalgynaecologistsimplied thatidentifyingpathol- pelvic pain are influenced by the quality of interaction ogy would somehow validate the pain as ’real’. When between patient and doctor. visible pathology had been excluded by previous referrals to other specialities such as gastroenterology, com- Characteristics mentsincluded “somepatientsaregoing to beafraid that While it is a truism that across the spectrum of illness you’re going to think it’s a psychological problem” and and disease, patients link their outcomes to experi- “they [the patients] come in and they say, I’m not mad ences in consultations with particular doctors, there you know” There was a clear awareness that an anxious are specific factors to consider in the case of chronic patientmaymakediagnosisdifficultandthatpatientsare gynaecological pain. The nature of the condition and alarmed by the suggestion of a psychologicaldiagnosis, associated symptoms mean that women are often dis- because they will be ’labelled’. Hospital gynaecologists tressed and anxious about associated issues such as were acutely aware of the time sometimes necessary to fertility and sexuality. Women frequently report unsat- dealeffectivelywithpatientssufferingfromCPP.Devel- isfactory and dismissive attitudes during consultations opment of rapport was found to be “difficult to establish for pain (Grace 1995) and this has been ascribed to in one outpatient session” If needed, consultation time inappropriately persistent mechanistic views of pain was extended, but doctors were concerned that “you’re causation (Grace 1998). Gynaecologists trained into a filling up the waiting room” and there wasanxietythat if, technical diagnostic and therapeutic role experience a for example, a patient starts to divulge adverse psycho- dissonance between patient expectations for explana- sexual experiences, it may well become a lengthy con- tion and support and their own approach of detecting sultation; the doctor thinks “Oh hell! I’ve got three pa- disease and disengaging once its apparent absence is tients in the waiting room” After a negative laparoscopy established, despite patients’ ongoing symptoms of hospital gynaecologists felt the need to look for other pain. causes, asking the question “Have I missed something"? 364 Chronic Gynaecological Pain, Doctor-Patient Interaction

They recognised thisasproblematic,asthepatientisdis- less impairment are more amenable to the therapeutic heartened by not having a diagnosis, a ’label’ by which effect of a good consultation. to define her problem. It was hypothesised that a propensity to inwardly di- Lasting Influences of Consultations rected hostility might underlie some of the difficulty The dimensions within which women recalled consul- experienced by some patients in establishing rapport tations 6 months later were examined. Lasting impres- (Fry and Stones 1996). However, further work high- sions of the doctor-patient interaction that had taken lighted the importance of the individual clinician and place could be characterised in terms of the constructs consultation in influencing outcomes. Disease factors “affect”, “expectation” and “cognition” (Stones et al. are of course also important; in statistical models the 2006). The first describes social interaction and the interaction between disease states and the consultation emotional response felt by the patient. It relates to setting was identified. In women referred to a hospi- whether the doctor is recalled as approachable and tal gynaecology department for symptoms present for expressing a friendly interest in and concern for the at least 6 months, continuing pain 6 months after an patient. Opposite recollections would not necessarily initial consultation was predicted by the presence of mean that the doctor had been unpleasant or rude to the endometriosis, but also by the patient’s initial report patient, but may simply reflect a businesslike manner, of pain interfering with exercise, her rating of the ini- a hurried consultation or the use of technical jargon. tial medical consultation as less satisfactory and the The construct “cognition” relates to memory and un- individual clinician undertaking the consultation. Inter- derstanding, a pre-requisite for adherence to treatment. estingly, the outcomes were not affected by the doctor’s Often patients do not understand what they have been grade or gender (Selfe et al. 1998b), although there has told, are afraid to ask questions and forget much of what been much attention in women’s health literature to has been said during a consultation. Under such circum- the gender imbalance among gynaecologists and the stances it is not unreasonable that patients who were mismatch with women’s preference to see a female given little information or could not remember much of doctor in many countries. In this study there was an the detail of the encounter would find it unsatisfactory. interaction between the impact of pain on exercise and The items loading to the subscale denoted “expectation” the extent to which the patient’s rating of the quality relate to the patient’s wish to understand her problem of the consultation was associated with probability of and what the implications may be for the future. Women pain resolution. For the group where exercise was not expected to be given a diagnosis and as a result a cure. impaired, there was a significant association, whereas If this expectation was not fulfilled, patients described this was not the case among those in whom exercise the situation as ‘disappointing’ or felt that they had been was impaired by pain (Fig. 1). It may be that those with ‘fobbed off’. In the present study, the item “I have re-

Chronic Gynaecological Pain, Doctor-Patient Interaction, Figure 1 Fitted probabilities of pain resolution and women’s rating of initial consultation, with and without exercise impairment. (Reproduced with permission from Selfe et al. 1998b). Chronic Low Back Pain, Definitions and Diagnosis 365 ceived enough information about my condition” loaded 6. Price JR, Blake F (1999) Chronic pelvic pain: The assessment to “expectation” rather than to “cognition”. This sug- as therapy. J Psychosom Res 46:7–14 7. Selfe SA, van Vugt M, Stones RW (1998a) Chronic gynaecolog- gests that, rather than the quantity, the appropriateness ical pain: an exploration of medical attitudes. Pain 77:215–225 of information given in relation to expectations is im- 8. Selfe SA, Matthews Z, Stones RW (1998b) Factors influenc- portant in determining satisfaction. ing outcome in consultations for chronic pelvic pain. J Womens C Lower current levels of pain at follow up were associ- Health 7:1041–1048 9. Stones RW, Lawrence WT, Selfe SA (2006) Lasting impressions: ated with highly significantly more favourable recall of influence ot the initial hospital consultation for chronic pelvic the original consultation in terms of the “expectation” pain on dimensions of patient satisfaction at follow-up. J Psy- subscale. However, the impact of an initial consultation chosom Res 60:163–167 rated positively by the patient on the subscales “affect” and “expectation”, but not “cognition”, was still evident after controlling for current pain intensity. Thus, the ex- Chronic Illness Problem Inventory perience of the initial consultation appeared to have an influence on the patient 6 months later irrespective of pain outcome. It is concluded that the doctor’saffect and Definition the extent to which expectations were met rather than The Chronic Illness Problem Inventory is a 65-item in- simple information provision are the elements of com- strumentdevelopedtomeasurepatientfunctioninginthe munication through which this influence is mediated. areas of physical limitations, psychosocial functioning, Reassurance health care behaviors, and marital adjustment. Pain Inventories Relief of symptoms by provision of reassurance is likely to be one of the doctor’s aims following negative investigations such as laparoscopy, but can also arise from explanation of normal findings at an initial consultation, Chronic Inflammatory Demyelinating for example where a careful history and physical exam- Polyneuropathy ination indicates a minimal likelihood of infection or endometriosis. However, there are mixed findings from re- Synonym search on the impact of assessment as therapy. In a randomised trial design, an ultrasound scan used as a basis CIDP; chronic relapsing polyneuropathy for counselling about normal findings was found to be helpful in relieving symptoms (Ghaly 1994). The reas- Definition suring effect of laparoscopy has been reviewed (Price Chronicinflammatorydemyelinatingpolyneuropathyis and Blake 1999). However, this approach can be coun- caused by demyelination due to an immune reaction. It terproductive, as shown in a study where women were is characterized by progressive weakness and impaired shown photographs of laparoscopic findings in order to sensoryfunctioninthearmsandlegs.ItisrelatedtoGuil- reinforce counselling, where no benefit was seen (On- laim Barré syndrome, and is sometimes considered to be wude et al. 2004). the chronic version of that disease. In conclusion, doctors need to be aware of the impor- Inflammatory Neuritis tance of establishing a therapeutic relationship through effective consulting behaviour that meets patients’ ex- pectationsand exploitsopportunitiesfor provision of reassurance and support. Chronic Low Back Pain, Definitions and References Diagnosis 1. Fry RPW, Stones RW (1996) Hostility and doctor-patient interac- CHRISTOPHER J. WINFREE tion in chronic pelvic pain. Psychother Psychosom 65:253–257 Deptartment of Neurological Surgery, Neurological 2. Ghaly AFF (1994) The psychological and physical benefits of pelvic ultrasonography in patients with chronic pelvic pain and Institute, Columbia University, New York, NY, USA negative laparoscopy. A random allocation trial. J Obstet Gy- [email protected] naecol 14:269–271 3. Grace VM (1995) Problems of communication, diagnosis, and treatment experienced by women using the New Zealand health Synonyms services for chronic pelvic pain: a quantitative analysis. Health Ankylosing spondylitis; Chronic pain; CT myelogra- Care Women Int 16:521–535 4. Grace VM (1998) Mind / body dualism in medicine: The case of phy; Diagnostic block; Discogenic pain; Facet joint; chronic pelvic pain without organic pathology –A critical review Fibromyalgia; Internal disc disruption; Intervertebral of the literature. Int J Health Serv 28:127–151 disc; Low back pain; Paget’s disease; Pathological 5. Onwude JL, Thornton JG, Morley S et al. (2004) A randomised fracture; Provocative discography; Reiter’s syndrome; trial of photographic reinforcement during postoperative counselling after diagnostic laparoscopy for pelvic pain. Eur J Obstet Sacroiliac joint; Spondyloarthropathy;Spondylolisthe- Gynecol Reprod Biol 112:89–94 sis; Zygapophyseal joint 366 Chronic Low Back Pain, Definitions and Diagnosis

Definition oblique (for inspection of the neural foraminae), and a Chronic low back pain is defined as pain localized to cone down lateral sacral view. Dynamic images to assist theregionborderedbyL1above,S1below,andtheerec- in the evaluation of spinal stability include lateral flex- tor spinae muscles laterally (Merskey 1994), which lasts ion and extension views. Magnetic resonance imaging for more than 3 months (Merskey 1986). Chronic low is the best modality available for evaluation of the soft back pain is often associated with pain radiating to the tissue structures of the spine. The intervertebral discs, buttock or legs; however, it is useful to distinguish be- ligaments, neural structures, and osseous structures are tweenthesedistinctpainsyndromes,astheyaretypically all well seen. Typically, non-contrast imaging is all treated differently. that is required; however, the use of contrast may be useful in the setting of tumor, malignancy, or previous Characteristics surgery. Caution must be exercised in the interpretation of positive findings on MRI, as over half of asymp- General tomatic subjects will have at least one abnormality Men and women are affected equally, most commonly on MR imaging (Jensen 1994). CT scanning is a vital th during the 4–6 decades (Deyo 2001). Chronic low part of provocative discography, providing detailed back pain is the most costly of the work-related disabil- anatomical data on the morphology of the interverte- ities (Andersson 1999). The lumbar spine is a complex bral discs in question. CT myelography provides the anatomical region, with a number of structures that may optimum contrast between neural and non-neural struc- serve as pain generators to be discussed below. tures. Subtle nerve root compression or spinal canal History encroachment invisible on MRI may be obvious on CT myelography. Bone scanning has limited but specific The initial assessment of the chronic low back pain pa- uses in the imaging of chronic back pain. It may be use- tientincludesacarefulmedicalhistory.Thedurationand ful in the evaluation of suspected pseudoarthrosis at a severity of symptoms, predisposing factors, exacerbat- previous fusion site, or also of malignancy or infection. ing factors, alleviating factors, and treatments may all be explored in the patient interview. Information regard- Discogenic Pain ingoccupationalhistory,disability,litigation,psychoso- Discogenic pain is defined as pain from the disc itself cial influences, and secondary gain may also be gleaned andnotsurroundingstructurescompressedbythedisc.It during the initial discussion. It is important to inquire is probably the most common cause of chronic low back about neurological function, such as weakness, bowel pain, with internal disc disruption present in approxi- and bladder function, and sexual function, to establish mately 40% of cases (Schwarzer 1995a). These patients whether neurological compromise is present, as treat- often describe pain localized to the low back, often ac- ment of these patients will likely proceed in a more ur- companied by pain referred to the hip, buttock, or groin. gent manner. It is also important to document a baseline Pain that radiates to the lower extremities may be patchy level of pain upon which to judge efficacy of interven- or “sclerotomal” in nature rather that dermatomal, as tions, if any. seen in herniated discs. These patients typically report Physical Exam that their pain is aggravated by standing or sitting and The physical exam is generally helpful but not typically relieved by lying down, presumably since this position sensitive or specific in the setting of chronic low back takes the pressure off the intervertebral discs. The inpain. The astute observer may discern peculiar move- tervertebral disc receives innervation along at least the ments or postures characteristic of the back pain patient. outer third of the annulus (Coppes 1997). The disc may For example, these patients sometimes sit bent forward become painful when it undergoes disruption; however, atthewaist,ashyperextensionoftenaggravateslowback nonspecific degenerative changes are not thought to symptoms. Some patients fail to get comfortable, and be specifically painful (Moneta 1994). These changes spend the time during the interview switching positions, may be obvious on conventional imaging studies, and or alternating standing and sitting. include loss of height, rupture, end plate changes, and dehydration. Other, subtler changes, such as internal Imaging disc disruption (IDD), may only be revealed as small Conventional roentgenography is rapid, inexpensive, radial fissures on CT imaging following discography and best suited for inspection of the osseous structures. (Vanharanta 1988). Provocative discography consists Vertebral fracture, osteoporosis, loss of disc height, end of both physiologic and radiographic assessment, and plate changes, facet hypertrophy, and alignment defor- is used to establish whether a degenerated disc is a mityareallreadilyseenonconventionalX-rays.Charac- pain generator in the chronic low back pain patient. It teristic bony changes of selected spondyloarthropathies involves the fluoroscopic placement of a needle into the are also readily identifiable with this modality. The intervertebral disc of the awake patient, and subsequent typical static images include anteroposterior and lateral injection of contrast dye. Intradiscal insertion and in- lumbar and sacral views, left and right lateral lumbar jection pressures are measured. A positive discogram Chronic Low Back Pain, Definitions and Diagnosis 367 occurs when the patient’s back pain is reproduced when 1996). Radiographic imaging is likewise unhelpful dye is injected into a particular disc at modest pressures. (Schwarzer 1995b). A negative discogram occurs when the pain on injection only occurs at extremely high pressures, or does not Spinal Instability match the patient’s normal pain. A complete discogram Spondylolisthesis consists of facet joint arthropathy C always includes the injection of a normal control disc, combined with disc degeneration, resulting in one ver- to exclude the possibility of non-specific patient pain tebral body subluxing over another (Mardjetko 1994). responses to injection. Once the procedure is complete, Common at L4-5 and L5-S1, such movement may be high resolution CT scanning is performed to illustrate duetotrauma,degenerativechanges,congenitaldefects, the morphology of the injected discs. Typically, positive or pathological fracture. X-rays readily demonstrate discs show some evidence of internal disruption, with spondylolisthesis, and may further show movement of extravasation of contrast beyond the inner confines of the vertebral bodies in relation to each other on dynamic the annulus. The key diagnostic criteria are the presence views. of concordant pain in a radiographically demonstrated degenerated disc. When careful technique is performed Other Causes using these rigid criteria, the false positive rate for Thespondyloarthropathiesareagroupofrheumatologic provocative discography approaches 0% (Walsh 1990). diseases that typically generate chronic low back pain thatisworstuponawakening,andimproveswithactivity Zygapophyseal Joint Pain (McCowin 1991). Ankylosing spondylitis commonly The lumbar facet joints,or zygapophyseal joints, affects young adult males, causes low back pain, de- are synovial joints that receive their segmental inner- creased spinal range of motion, and has characteristic vation from the medial facet branch of the posterior bony changes on spine imaging. Reiter’s syndrome, division of the respective spinal nerve (Bogduk 1979). another common cause of arthritis and low back pain The role of facet joint arthropathy in the pathogenesis in men, consists of the triad of arthritis, conjunctivitis, of low back pain was recognized early in the 20th Cen- and urethritis. Paget’s disease is a common cause of tury (Ghormley 1933). These patients typically have back pain in the elderly (Mazanec 1999). Characteristic low back pain that may radiate across the buttock or findings on history are deep, arthritic pain, and on imag- thigh. One estimate of its incidence in a low back pain ing are localized bony overgrowths. Fibromyalgia population was 15%, based upon diagnostic blockade is a common disorder causing back pain, associated (Schwarzer 1994). As in other forms of low back pain, with other conditions such as headache and irritable there are no reliable, reproducible diagnostic criteria bowel syndrome. Radiographic investigations are typi- (Jackson 1988; Schwarzer 1994). Injection of the joint cally normal. Diagnosis is based upon the symptoms of or its innervating fibers using a double block technique widespread pain and discreet trigger points (Mazanec to help reduce the influence of the placebo effect, and 1999). to increase the sensitivity and specificity, may represent Disability, Fear of Movements the most reliable diagnostic method (Schwarzer 1994). This technique involves the injection of facet joint (or References the medial facet branch) on one visit, followed by a 1. Andersson GBJ (1999) Epidemiologic Features of Chronic Low second confirmatory injection at a separate visit. A Back Pain. Lancet 354:581–585 positive response occurs when the patient reports >50% 2. Bogduk N, Long DM (1979) The Anatomy of the so-called “Ar- relief with both blocks. ticular Nerves” and their Relationship to Facet Denervation in the Treatment of Low-Back Pain. J Neurosurg 51:172–177 3. Coppes MH, Tamaki T, Hayashi N et al. (1997) Innervation of Sacroiliac Joint Pain “Painful” Lumbar Discs. Spine 22:2342–2350 4. Deyo RA, Weinstein JN (2001) Low Back Pain. N Engl J Med The sacroiliac joint is a diarthrodial joint with limited 344:363–370 mobility, receiving its innervation from the lumbosacral 5. Dreyfuss et al. (1996) The Value of Medical History and Phys- roots. Thought to be an important contributor to chronic ical Examination in Diagnosing Sacroiliac Joint Pain. Spine 21:2594–2602 low back pain, one estimate of its incidence in a se- 6. Ghormley RK (1933) Low Back Pain: With Special Reference to lected population of low back pain was 19% (Maigne the Articular Facets, with Presentation of an Operative Procedure. 1996). Pain may be located across the low back with JAMA 101:1773–1777 radiation to the buttock or groin, as in other forms of 7. Jackson RP, Jacobs RR, Montesano PX (1988) Facet Joint In- jection in Low-Back Pain: A Prospective Statistical Study. Spine low back pain. Some patients have tenderness over the 13:966–971 sacroiliac joint. Despite the myriad of specific physical 8. Jensen MC, Brant-Zawadzki MN, Obuchowski N et al. (1994) maneuvers designed to provoke a positive response in Magnetic Resonance Imaging of the Lumbar Spine in People patients with sacroiliac joint pain, no test alone or in without Back Pain. N Engl J Med 331:69–73 9. Maigne J-Y, Aivaliklis A, Pfefer F (1996) Results of Sacroiliac combination with others is reliable when compared Joint Double Block and Value of Sacroiliac Pain Provocation with diagnostic blockade of the joint itself (Dreyfuss Tests in 54 Patients with Low Back Pain. Spine 21:1889–1892 368 Chronic Migraine

10. Mardjetko SM, Connolly PJ, Shott S (1994) Degenerative Lumbar Spondylolisthesis: A Meta-Analysis of Literature Chronic Pain 1970–1993. Spine 19:2256–2265 11. Mazanec DJ (1999) Evaluating Back Pain in the Elderly. Clev Clin J Med 66:89–99 Definition 12. McCowin PR, Borenstein D, Wiesel SW (1991) The Current Approach to the Medical Diagnosis of Low Back Pain. Ortho Pain that persists on a constant basis for three months Clin North Am 22:315–325 or more. Some researchers and clinicians use a timeline 13. Merskey H (1986) Classification of Chronic Pain: Descriptions of six months or more. Chronic pain rarely has a known of Chronic Pain Syndromes and Definitions of Pain Terms. Pain 3:1–225 cause,andmaybehardtolocalizeinthebody. Treatment 14. Merskey H, Bogduk N (1994) Classification of Chronic Pain: is usually limited to general measures of pain control. Descriptions of Chronic Pain Syndromes and Definitions of Pain Emotive symptoms are commonly an important compo- Terms, 2nd edn. IASP Press, Seattle, pp 11–36 nent of the suffering associated with chronic pain. The 15. Moneta GB, Videman T, Kaivanto K et al. (1994) Reported Pain character of a chronic pain signal is often misinterpreted during Lumbar Discography as a Function of Annular Ruptures and Disc Degeneration: A Re-Analysis of 833 Discograms. Spine or grossly distorted. There is often a measurable imbal- 19:1968–1974 ance between pronociceptive and antinociceptive forces 16. Schwarzer AC, Aprill CN, Derby R et al. (1994) Clinical Features consistent with the perception of pain. No definition of of Patients with Pain Stemming from the Lumbar Zygapophysial chronic pain exists for newborns, but prolonged pain has Joints: Is the Lumbar Facet Syndrome a Clinical Entity? Spine 19:1132–1137 been defined as that lasting several hours or days. 17. Schwarzer AC et al. (1995a) The Prevalence and Clinical Features Acute Pain, Subacute Pain and Chronic Pain of Internal Disc Disruption in Patients with Chronic Low Back Amygdala, Pain Processing and Behavior in Animals Pain. Spine 20:1878–1883 18. Schwarzer AC, Aprill CN, Bogduk N (1995b) The Sacroiliac Assessment of Pain Behaviors Joint in Chronic Low Back Pain. Spine 20:31–37 Chronic Low Back Pain, Definitions and Diagnosis 19. Vanharanta H, Sachs BL, Spivey M et al. (1988) A Comparison of Depression and Pain CT/Discography, Pain Response and Radiographic Disc Height. ImpactofFamilialFactorsonChildren’sChronicPain Spine 13:321–324 20. Walsh TR, Weinstein JN, Spratt KF et al. (1990) Lumbar Discog- Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- raphy in Normal Subjects: A Controlled, Prospective Study. J ondary) Bone Joint Surg Am 72A:1081–1088 Pain Assessment in Neonates PainintheWorkplace,RiskfactorsforChronicity,Job Demands Pain Inventories Chronic Migraine Pain Treatment, Intracranial Ablative Procedures Pain Treatment, Motor Cortex Stimulation Definition Physical Exercise Migraine headache occurring more than 15 days per Postoperative Pain, Persistent Acute Pain month. Typically, a patient has a remote history of Prevalence of Chronic Pain Disorders in Children episodic migraine which slowly increases in frequency Psychiatric Aspects of Pain and Dentistry over time to a near daily headache with migraine Psychological Treatment of Chronic Pain, Prediction features. In many instances the patient is overusing of Outcome analgesics. Thalamus, Clinical Pain, Human Imaging New Daily Persistent Headache

Chronic Pain Disorder Prevalence in Chronic Neural Sensitization Children

Visceral Pain Model, Irritable Bowel Syndrome Prevalence of Chronic Pain Disorders in Children Model

Chronic Neuropathic Pain Chronic Pain in Children, Physical Medicine and Rehabilitation 1 2 Definition JOYCE M. ENGEL ,DEBORAH A. O’ROURKE 1 Chronic pain caused by dysfunction of or damage to the Department of Rehabilitation Medicine, University of nervous system. Washington, Seattle, WA, USA 2 Pain Treatment, Implantable Pumps for Drug Deliv- College of Nursing and Health Sciences, University ery of Vermont, Burlington, VT, USA Chronic Pain in Children, Physical Medicine and Rehabilitation 369 [email protected], The World Health Organization (WHO) International [email protected] Classification of Functioning, Disability, and Health (ICF; 2001) classification system uses a biopsychoso- Synonyms cial framework to describe functioning at three levels, the body, the individual and the individual within a Pediatric Physical Therapy; Occupational Therapy in C broad social context. Biological aspects include body Children; Pediatric Physiotherapy structures and body functions, while individual aspects Definition includeparticipatingindailyactivitiesandsocialaspects Physical medicine and rehabilitation are core compo- encompass overall functioning in society. Pain related nents of current multimodal and multidisciplinary ap- disability and optimal functioning are not simply linked proaches to chronic pain management and include the to particular pain conditions. Instead, they depend on disciplinesofphysicaltherapyandoccupationaltherapy. interactions among the specific child characteristics, Physical therapists apply a wide range of physical and the specific pain condition and the environmental or behavioral interventionsto reduce pain, prevent impair- contextual factors in which the child experiences pain. ment and disability as well as to promote function. Oc- According to this model, chronic pain impairs body cupational therapists are primarily concerned with the function due to various health conditions that often psychosocial and environmental factors that contribute result in additional impairments, activity limitations to pain and have an impact on an individual’s daily ac- and participation restrictions (i.e., secondary disabili- tivities and participation (Engel and Kartin 2004; Inter- ties). The child’s environment (family, physical, social, national Association for the Study of Pain ad hoc Sub- cultural) and their personal characteristics interact with committeeforOccupationalTherapy/PhysicalTherapy and determine functioning and disability in a dynamic Curriculum 1994). way. A comprehensive assessment of the child’s impairments, activities, participation and contextual factors Characteristics is needed to guide intervention. Clarity about the goals Physical therapists and occupational therapists are pri- of rehabilitation, the levels of intervention, the spe- marily, although not exclusively, involved in rehabilita- cific treatment techniques or modalities and expected tion programsfor childrenwithchronic musculoskeletal outcomes is essential. pain. Many diseases, injuries and disabling conditions Interventions are associated with chronic musculoskeletal pain (En- geland Kartin 2004).These includepainassociated with Interventions for children with chronic pain are typi- physical diseases (e.g. arthritis), pain that is secondary cally multimodal. Physical therapists and occupational to a physical disability (e.g. cerebral palsy (CP) and pain therapists follow the principles of family-centered that may occur without an identifiable cause (e.g. com- care when developing a treatment plan. In collaboration plex regional pain syndrome). with the child, family and other health care providers, they carefully identify all impairments, activity limi- Rehabilitation Conceptual Models tations and participation restrictions, pain frequency, Rehabilitation interventions are based on the biopsy- pain intensity and the child’s stage in development. chosocial model of health, functioning and pain. As Rehabilitation interventions reduce impairments at the an example, Loeser and Fordyce’s biopsychosocial body structure and function level, promote activity and model (1983) of pain is conceptualized into four do- participation level functioning, and address environ- mains, nociception, pain, suffering and pain behavior. mental or personal barriers to health and functioning. A child may experience some, but not all, domains. At the body structure and function level, interventions Some children with chronic pain may experience pain include electrotherapy modalities and physical agents. and suffering and demonstrate pain behaviors in the Electrotherapy modalities (e.g. transcutaneous elec- absence of nociception. Developmental aspects are trical nerve stimulation (TENS) and physical agents also critical to consider for the clinical assessment and (e.g. cryotherapy, hydrotherapy, manual therapy, management of chronic pain in children. The ability to massage, therapeutic exercise) are not widely used to describe and self-report pain and suffering is limited relieve chronic pain in children, but may have a place, in young children and in children with cognitive or especially in preparing the child for physical retraining. communication impairments, so that it is important to Possible clinical indications for TENS in children may evaluate and monitor a child’s overt pain behaviors. include chronic low back pain, arthritis, inflammatory For some children with physical disabilities (e.g. CP), disorders of soft tissues and procedural pain (McCarthy the range of potential pain behaviors may also be re- et al. 2003). Cryotherapy has been used successfully in duced secondary to paralysis, muscle contractures, reducing chronic muscle spasm and inflammation as- joint deformities and communication impairments. sociated with arthritis (Bell and Prentice 2002). Careful In this situation, family members and caregivers help monitoring of the child’s skin is necessary with both of to identify and interpret pain behaviors. these interventions. Hydrotherapy (e.g. whirlpool) 370 Chronic Pain in Children, Physical Medicine and Rehabilitation promotes muscle relaxation and can be a medium for problems walking and may benefit from rehabilitation exercise. Manual therapy techniques such as therapeutic interventions to correct gait deviations and increase massage and mobilization can induce muscle relax- walking capabilities. Chronic pain may also compro- ation, help lessen muscle spasm and increase range of mise the child’s usual level of participation in social motion. interactions, school participation and community recre- Therapeutic exercise is a primary component of re- ation and play or leisure activities. Physical therapists habilitation of adults and children with chronic pain and occupational therapists use a variety of develop- (Eccleston and Eccleston 2004). Children with chronic mentally appropriate strategies to promote the child’s pain do not move or exercise as much as their healthy capacity to resume their typical activities and participa- peers and this can result in decreased aerobic capacity, tion. For example, therapists often work in collaboration muscle strength, and flexibility. This pattern of inactiv- with school personnel to identify activities that are in- ity can result in a vicious cycle of additional inactivity, teresting and socially engaging for a child with chronic greater deconditioningand further reductions in muscle pain. strength and flexibility (Anthony and Schanberg 2003). Attention to contextual factors is also an essential com- Aerobic conditioning exercises can lessen chronic pain ponent of physical rehabilitation. An assessment of in children with arthritis (Klepper 1999) and in children the child’s environment may yield information about with complex regional pain syndrome (CRPS) (Sherry physical or social factors that can be modified to reduce et al. 1999). For children with CRPS, exercise and chronic pain in addition to impairment and associated other forms of physical activity play an important role disability. Interventions at this level include products in recovery of function (Lee et al. 2002). Research is and technology as well as social support systems. For needed to determine the frequency, type and duration of example, for children with limited mobility due to sig- exercise in combination with other forms of treatment nificant physical disability, modification of the physical required to achieve optimum outcomes in this group of environment is important and may include the pre- children (Berde 2005). Clearly, exercises for children scription of postural support systems, mobility devices with chronic pain must be developmentally appropriate and adaptive equipment to promote comfort and im- and as enjoyable as possible. prove access to and interaction with the environment. Exercises to improve muscle strength and flexibility are Assessment of the social environment is critical and another important component of therapeutic exercise. interventions may be warranted at home, at school and Muscle strengthening exercisesappear toincrease phys- in the community to address assumptions, attitudes ical functioning in children with and without disabilities and beliefs about chronic pain, its impact and its man- (Damiano et al. 2002). Research is needed to examine agement. Education and counseling are often required. whether muscle-strengthening exercises reduce pain. Finally, personal factors represent the second contex- Flexibility exercises such as passive range of motion tual factor and these characteristics are prominent in and stretching exercise must be individualized to each determining appropriate rehabilitation interventions. child to address potential biomechanical limitations and The child’s age, cognitive skills and communication other constraints. A recent study reported that children capabilities will determine whether physical therapists with significant physical disabilities demonstrated pain and occupational therapists can incorporate cogni- behaviors during passive stretching exercises (Hadden tive and behavioral strategies along with rehabilitative and von Baeyer 2002). In contrast, this particular form interventions. For young children and children with of therapeutic exercise has been advocated as a pain significant cognitive and communication impairments, reducing intervention in children with musculoskeletal this might not be possible. pain associated with other diagnoses. Meticulous at- The occupational therapist and physical therapist may tention to assessment findings and family knowledge use cognitive behavioral strategies as adjuncts to the of pain triggers is essential when therapists are work- above-described interventions. Personal factors treating with children who are nonverbal. For children who ments consist of relaxation training, distraction and have the ability to self-report, muscle strengthening and contingency management. Relaxation techniques may stretching exercises can be progressed in an incremental consist of diaphragmatic breathing, autogenic training, manner to tolerance. Other forms of therapeutic exer- progressive muscle relaxation or guided imagery. The cise include activities to improve posture and increase benefits of relaxation techniques include alleviation of balance and coordination. Often these exercises can be skeletal muscle tension, lessening of fatigue, distrac- addressed through games and age-appropriate physical tion and enhancement of other pain relief measures. activities. Numerous studies support the use of relaxation and Activity and participation level interventions are es- distraction in the treatment of arthritic pain, headache sential components in rehabilitation. Interventions at disorders and burn wound care (McGrath et al. 2003). this level include graded tasks, mobility training, self- An infrequent and mild side effect of relaxation train- care training and education. For example, children ing is a child feeling out of control when relaxation with chronic musculoskeletal pain often demonstrate occurs. Relaxation training may be done in conjunction Chronic Pain, Patient-Therapist Interaction 371 with biofeedback. Some research supports the use 15. Sherry DD, Wallace CA, Kelley C et al. (1999) Short and long- of biofeedback in children with arthritis and children term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain 15:218–223 with headaches (Engel and Kartin 2004). Distrac- 16. World Health Organization (2001) International Classification of tion has been effective in reducing pain and distress Functioning Disability and Health. World Health Organization, in youths with burn injuries (Hoffman et al. 2000). Geneva, pp 3–20 C Contingency management procedures for the treatment of children with recurrent abdominal pain, burn injuries or headaches have resulted in increased activity Chronic Pain, Patient-Therapist levels and participation, in addition to reduced pain frequency and pain behaviors (Engel and Kartin 2004). Interaction In summary, the roles of the physical therapist and oc- MARK P. J ENSEN cupational therapist on the pediatric pain management Department of Rehabilitation Medicine, University of team are emerging. Physicaltherapistsand occupational Washington, Seattle, WA, USA therapists use their knowledge of anatomy, physiology, [email protected] kinesiology, psychology and human development and function to develop and implementcomprehensive eval- Synonyms uationsand interventionsfor thechild with chronicpain. Relationship; Therapeutic Alliance A variety of activity-based and family-centered interventions are available. Evidence to support these inter- Definition ventions, however, is greatly needed. Patient-therapist interaction refers to the verbal and nonverbalinteractionsbetweenhealthcareprovidersand References their patients or clients. These interactions may include, 1. Ad Hoc Committee OT / PT Pain Curriculum (1994) Pain cur- but are not necessarily limited to, communication and riculum for students in occupational therapy or physical therapy. negotiations concerning the patient’s history, diagnosis, IASP Newsletter, International Association for the Study of Pain, Seattle and clinical care. 2. Anthony KK, Schanberg LE (2003) Pain in children with arthritis: a review of the current literature. Arthritis Rheum 49:272–279 Characteristics 3. Bell GW, Prentice WE. (2002) Therapeutic modalities for phys- Patient-Therapist Interaction and Pain Treatment Satisfaction ical therapists, 2nd edn. McGraw-Hill, New York 4. Berde CB, Lebel A (2005) Complex regional pain syndromes in Research shows that pain intensity has only a weak to children and adolescents. Anesthesiology 102:252–255 moderate association with pain treatment satisfaction, 5. Damiano DL, Dodd K, Taylor NF (2002) Should we be testing and training muscle strength in cerebral palsy? Dev Med Child due primarily to the fact that patients tend to report rela- Neurol 44:68–72 tively high levels of satisfaction with pain management 6. Eccleston Z, Eccleston C (2004) Interdisciplinary management care, regardless of pain severity levels (Miaskowski et of adolescent chronic pain: developing the role of physiotherapy. al. 1994; Ward and Gordon 1996; Dawson et al. 2002). Physiotherapy 90:77–81 7. Engel JM, Kartin D (2004) Pain in youth: a primer for current On the other hand, factors related to the interactions practice. Critical Reviews™ in Physical and Rehabilitation between patients and clinicians show consistent asso- Medicine 16:53–76 ciations with treatment satisfaction across measures 8. Hadden KL, von Baeyer CL (2002) Pain in children with and samples. For example, Sherwood and colleagues cerebral palsy: Common triggers and expressive behaviors. Pain (Sherwood et al. 2000) found that treatment satisfaction 99:281–288 9. Hoffman HG, Doctor JN, Patterson DR et al. (2000) Virtual re- with pain treatment was higher when patients felt that ality as an adjunctive pain control in wound care in adolescent their pain was addressed with the patient as an informed patients. Pain 85:305–309 partner, and was lower when the providers appeared 10. Klepper SE (1999) Effects of an eight-week physical conditioning program on disease signs and symptoms in children with uncaring, were slow to respond to pain complaints, or chronic arthritis. Arthritis Care Res 12:52–60 were perceived to lack knowledge and skills. Similarly, 11. Lee BH, Scharff L, Sethna NF et al. (2002) Physical therapy and Dawson and colleagues (Dawson et al. 2002) found cognitive-behavioral treatment for complex regional pain syn- that many patients who reported severe pain, and who dromes. J Pediatr 141:135–140 12. Loeser JD, Fordyce WE (1983) Chronic pain. In: Carr JE, Den- still reported that they were satisfied with pain care, gerink HA (eds) Behavioral science in the practice of medicine. attributed their satisfaction to their belief that their Elsevier, New York healthcare provider was making efforts to provide pain 13. McCarthy CF, Shea AM, Sullivan P (2003) Physical therapy man- relief. Riley and colleagues (Riley et al. 2001) found agement of pain in children. In: Schechter NL, Berde CB, Yaster M (eds) Pain in Infants, Children and Adolescents, 2nd edn. Lip- that patient-perceived quality of caregiver communi- pincott Williams and Wilkins, Philadelphia, pp 434–448 cation predicted satisfaction with individualized pain 14. McGrath PA, Hiller LM (2003) Modifying the psychological treatment plans in a sample of 107 patients seen in factors that intensify children’s pain and prolong disability. In: an orofacial pain clinic. McCracken and colleagues Schechter NL, Berde CB, Yaster M (eds) Pain in Infants, Chil- dren, andAdolescents2nd edn. Lippincott, Williamsand Wilkins, (McCracken et al. 1997) identified confidence and trust Philadelphia, pp 85–104 in the treatment provider, pain reduction, and time 372 Chronic Pain, Patient-Therapist Interaction spent waiting in the clinic as predictors of satisfaction statistically significant, there was also a trend for pa- with chronic pain treatment. In short, patients who are tients in the patient-centered condition to report greater satisfied with their pain care seem to be those who see decreases in pain intensity than patients who received themselves as having a collaborative relationship with usual care. a treatment provider who works collaboratively with the patient to address the pain problem. While pain Implications for Improving Pain Management Care reduction may be associated with treatment satisfaction The findings briefly reviewed abovesupport the conclu- in some instances, pain reduction does not appear to be sion that patient-therapist interaction factors play a role necessary for patients to be satisfied with their care. inpatienttreatmentsatisfactionandadherence,aswellas inlong-termtreatmentoutcome.Clinicianswouldthere- Patient-Therapist Interaction and Treatment Adherence and fore be wise to make any appropriate changes in the way Outcomes they interact with patients to maximize therapeutic al- Research also shows that treatment adherence is reliance. Attention to three specific areas may be partic- lated to patient-therapist interactions; in particular, the ularly useful: (1) communicate efforts to manage pain; existence of a collaborative relationship between the (2) make an effort to build and maintain rapport; (3) en- patient and clinician. While very little of this research courage a collaborative relationship. has been performed in samples of persons with chronic pain (for an exception, see discussion of Alamo et al. Communicate Efforts to Manage Pain 2002, below), this finding is consistent across a wide Most patients come to realize, by the time their pain be- variety of patient populations and treatments (Cruz and comes chronic, that there is no quick fix for their pain Pincus 2002). For example, Gavin et al. (2002) showed problem. However, these patients may still hope that a that a measure of treatment alliance (measuring the new treatment will be discovered that will provide pain extent to which patients and clinicians agree on treat- relief. Also, there exist many treatments for pain that ment goals and hold each other in positive regard) was subgroups of patients may find effective, even if these associated with medication adherence and treatment treatments are not necessarily effective for the major- outcome in a sample of adolescents with severe asthma. ity of patients (Engel et al. 2002). Clinicians could im- Weiss et al.(2002) similarly found that a measure of prove their relationships with patients, and increase pa- working alliance (which assessed patient-therapist tient treatment satisfaction, if they communicated that agreement of treatment goals and the tasks to be used to (1) they are vigilant in their efforts to identify effective work toward these goals, and the degree to which a bond pain treatments as these treatments are reported in the exists between the therapist and patient) was associated research literature and (2) they are willing to work with with future medication adherence and treatment out- the patient to find the specific combination of treatments come in a sample of patients with psychotic disorders. and approaches that are most effective for each individ- In a sample of patients with schizophrenia, Frank and ual patient. Gunderson (1990) found that patients who were able to form a good treatment alliance with their therapists Make an Effort to Build and Maintain Rapport within the first six months of treatment, adhered more to One of the most effective ways to build rapport is to intheir medication regimen and achieved better outcomes corporate reflective listening in interactions with pa- after two years (with less medication) than patients who tients. Reflective listening involves making statements did not form a good treatment alliance. that indicate that you understand what the patient is say- Alamo and colleagues (Alamo et al. 2002) found evi- ing.Suchstatementsdiffersubstantiallyfromusualclin- dence for the efficacy of a patient-centered approach ician responses, such as questions that call for or require in a sample of patients with chronic pain. In this study, a response or statements that merely provide informa- a group of family physicians were trained in the use of tion (Miller and Rollnick 2002; Rollnick et al. 1999). a patient-centered approach to pain treatment, which Examples of reflective responses to the statement, “I am included the following components, among others: sick and tired of this pain” would include, “You are frus- listening to the patient without interrupting in the first trated that it is taking so long for us to find an approach moments of the consultation, being supportive and that effectively reduces your pain” or “You are ready to empathic, allowing and encouraging patients to ask try something new to get this pain under better control.” questions, trying to reach an agreement about the na- The immediate concern of some clinicians, when they ture of the problem, and trying to find common ground consider using reflective listening during a patient en- about the management plan. Patients of the physicians counter, is that such statements might open a Pandora’s who were trained in and used the patient-centered ap- Box of patient talking, which may then use up the (lim- proach reported significantly greater improvements ited) time devoted to the encounter. However, clinicians after one year in psychological distress and number of need not make every statement a reflective one. More- tender points, than the patients of family physicians not over, encounters that include reflective listening can ac- trained in the patient-centered approach. Although not tually be more efficient than encounters that do not, be- Chronic Paroxysmal Hemicrania 373 cause once patients feel understood, they may feel less 2. Dawson R, Spross JA, Jablonski ES et al. (2002) Probing the compelled to interrupt and ask questions. In support of Paradox of Patients’ Satisfaction with Inadequate Pain Manage- ment. J Pain Symptom Manage 23:211–220 this, one study found that being responsive to patient 3. Engel JM, Kartin D, Jensen MP (2002) Pain Treatment and Health concerns (as opposed to ignoring patient concerns) was Care in Persons with Cerebral Palsy: Frequency and Helpfulness. associated with a decrease in the time of the encounter Am J Phys Med Rehabil 81:291–296 C (Levinson et al. 2000). 4. Frank AF, Gunderson JG (1990) The Role of the Therapeutic Alliance in the Treatment of Schizophrenia. Arch Gen Psychiatry 47:228–236 Encourage a Collaborative Relationship 5. Gavin LA, Wamboldt MZ, Sorokin N et al. (1999) Treatment For the most part, adequate management of chronic Alliance and its Association with Family Functioning, Adher- pain involves active patient participation and involve- ence, and Medical Outcome in Adolescents with Severe, Chronic Asthma. J Pediatr Psychol 24:355–365 ment, and good long-term adjustment depends much 6. Jensen MP, Nielson WR, Kerns RD (2003) Toward the Develop- more on what patients do, than on what is done to them ment of a Motivational Model of Pain Self-Management. J Pain (Jensen et al. 2003). As reviewed above, patients are 4:477–492 more likely to actively participate in treatment and 7. Levinson W, Gorawara-Bhat R, Lamb J (2000) A Study of Patient Clues and Physician Responses in Primary Care and Surgical adhere to treatment recommendations when there is a Settings. JAMA 284:1021–1027 good therapeutic alliance and when there is a collab- 8. McCracken LM, Klock PA, Mingay DJ et al. (1997) Assessment orative patient-therapist relationship. Developing and of Satisfaction with Treatment for Chronic Pain. J Pain Symptom Manage 14:292–299 maintaining a collaborative relationship with patients 9. Miaskowski C, Nichols R, Brody R et al. (1994) Assessment of does not have to involve any special skills, other than a Patient Satisfaction Utilizing the American Pain Society’s Qual- willingness to avoid lecturing patients or telling them ity Assurance Standards on Acute and Cancer-Related Pain. J what to do, and a willingness to provide the patient with Pain Symptom Manage 9:5–11 10. Miller W, Rollnick S (2002) Motivational Interviewing: Prepar- options and choices. nd ing People to Change, 2 edn. Guilford Press, New York Lecturing patients can create resentment and resis- 11. Riley JL, Meyers CD, Robinson ME, Bulcourf B et al. (2001) tance (Miller and Rollnick 2002). It is more effective to Factors Predicting Orofacial Pain Patient Satisfaction with Im- provide guidance, options, and advice, while at the same provement. J Orofac Pain 15:29–35 time communicating the expectation that the patient can 12. Rollnick S, Mason P, Butler C (1999) Health Behavior Change: A Guide for Practitioners. Churchill Livingstone, Edinburgh decide which parts of the recommended treatment plan 13. Sherwood G, Adams-McNeill J, Starck PL et al. (2000) Qualita- he or she will follow. As choice increases adherence, the tive Assessment of Hospitalized Patients’ Satisfaction with Pain collaborative clinician offers patients choices whenever Management. Res Nurs Health 23:486–495 possible (Miller and Rollnick 2002). For example, if 14. Ward SE, Gordon DB (1996) Patient Satisfaction and Pain Sever- ity as Outcomes in Pain Management: A Longitudinal View of both the clinician and patient decide that a graduated one Settings’ Experience. J Pain Symptom Manage 11:242–251 exercise program is worth trying, the patient should 15. Weiss KA, Smith TE, Hull JW et al. (2002) Predictors of Risk then be offered different methods for starting and main- of Non-Adherence in Outpatients with Schizophrenia and Other taining such a program. The patient could be offered Psychotic Disorders. Schizophr Bull 28:341–349 sessions with a physical therapist who could help them to develop a home program. Another option would be to allow the patient to develop a simple reactivation Chronic Pain, Thalamic Plasticity program at home, under the guidance of his or her physician, without the need to visit a physical therapist. The home program could be highly structured, with a Thalamic Plasticity and Chronic Pain series of specific exercises that the patient decides to engage in on a daily basis; or it could be less structured, with the patient setting goals to increase general activity levels by a certain percent every week. As there Chronic Paroxysmal Hemicrania are so many paths that may be taken to reach any one treatment goal, a treatment plan can, and should, be Synonyms developed that is tailored to the patient’s own situation, goals, and interests, and that is developed in close CPH collaboration with the patient. Such collaboration will Definition increase the chances that the patient will adhere to the treatment plan, and ultimately increase the chances of Chronic paroxysmal hemicrania is a trigemino-auto- a successful treatment outcome. nomic syndrome with frequent repeated facial pains, each lasting for 3 minutes or more. Attacks can re- References cur over >1 year without remission periods or with remission periods lasting <1 month. 1. Cruz M, Pincus HA (2002) Research on the Influence that Com- munication in Psychiatric Encounters has on Treatment. Psychi- Paroxysmal Hemicrania atr Serv 53:1253–1265 Primary Stabbing Headache 374 Chronic Pelvic Inflammatory Disease

Chronic Pelvic Inﬂammatory Disease

Chronic Pelvic Pain, Pelvic Inﬂammatory Disease and Adhesions

Chronic Pelvic Pain

Definition In woman, chronic pelvic pain isintermittent or constant pain in the lower abdomen or pelvis of at least 6 months’ duration,notoccurringexclusivelywithmenstruationor intercourse and not associated with pregnancy. Chronic Gynaecological Pain, Doctor-Patient Inter- action Chronic Pelvic Pain, Physical and Sexual Abuse Chronic Pelvic Pain, Endometriosis, Figure 1 Endometriosis of the Gynecological Pain and Sexual Functioning pelvic peritoneum. Gynecological Pain, Neural Mechanisms ChronicPelvicPain,Endometriosis, Table 1 Possible sites of endometriosis Chronic Pelvic Pain, Endometriosis Common sites Less common or rare sites Ovaries Umbilicus FRED M. HOWARD University of Rochester, Rochester, NY, USA Round ligaments Laparotomy scars [email protected] Broad ligaments Hernial sacs Uterosacral ligaments Small intestine Synonyms Rectovaginal septum Rectum Endometriosis Externa Appendix Sigmoid Definition Pelvic peritoneum Ureters Endometriosis is the presence of ectopic endometrial Bladder Vulva glands and stroma, that is endometrium located outside Pelvic lymph nodes Extremities the endometrial cavity (Fig. 1). Occasionally only endometrial glands are present in cases of endometriosis. Cervix Pleural cavity Hemosiderin-laden macrophages may be present also, Vagina Lung but their solitary presence without endometrial glands Fallopian tubes Nasal mucosa or stroma does not confirm endometriosis. Sampson first applied the name “endometriosis” to ectopic endometrium in 1921 (Sampson 1921). or chocolate cysts. Endometriosis is primarily a disease of women of reproductive age. Characteristics Endometriosis is most often found within the peritoneal Prevalence cavity in the pelvis, but may also occur in numerous As endometriosis is accurately diagnosed only by sur- other, even remote, locations (Table 1). There is still a gical biopsy with histological confirmation, accurate great deal about it that is unclear and controversial and prevalence is difficult to determine, but is estimated to it remains an enigmatic disorder in that the etiology, the be about 7% (Barbieri 1990). In women who undergo natural history and the precise mechanisms by which a laparoscopy to evaluate chronic pelvic pain (CPP) it causes pain are not completely understood. In some the prevalence of endometriosis is about 33% (Howard patients it behaves almost like a malignancy, spreading 1993). In patients undergoing laparoscopy for infertility rapidly and widely, yet in others it is a seemingly irrel- the prevalence is about 40%. Additionally it appears that evant, insignificant, incidental histological diagnosis. about 70% of women with endometriosis have some Grossly, endometriosis has a variety of appearances; it type of pelvic pain symptoms. It has been observed that may be red, purple, blue, white, yellow, brown, clear or the severity of pain frequently does not correlate with black lesions, peritoneal pockets or windows, adhesions the severity of endometriosis (Vercellini 1991). Chronic Pelvic Pain, Endometriosis 375

Etiology menstrual debris into surrounding tissues, with production of prostaglandins as possible chemical mediators None of several theories of etiology alone explain of pain and inflammation. It is also hypothesized that the protean manifestations of endometriosis or the lesions produce prostaglandins and cause functional predilection of some women but not others to develop pain symptoms, like dysmenorrhea, via direct produc- C symptomatic endometriosis. Sampson’s theory is that tion of prostaglandins (Vernon 1985). Finally, it has endometriosis is due to retrograde flow of menstrual been suggested that lesions cause pain via nociceptor effluent through the fallopian tubes into the peritoneal stimulation by mechanical pressure or by stretching cavity. However, most women experience some de- tissue. Such a mechanism would predict that larger gree of retrograde menstruation, so there is more to lesions and more deeply infiltrating lesions would the development of endometriosis than just retrograde cause more frequent or more severe pain (Cornillie flow. Metaplasia of coelomic epithelium, the epithelium 1990). from which the mullerian duct is derived, can result in endometrium. Metaplasia needs an induction phenomenon or factor, which might be menstrual debris, Symptoms and Signs estrogen or progesterone. The theory of lymphatic and Classically the woman with endometriosis presents vascular metastases is invoked to explain the occur- with one or more of the following, an adnexal mass rence of endometriosis in remote locations such as the (endometrioma), infertility, pelvic pain or dysmen- pleura, nose and spinal column. It has been reported orrhea. Estimates are that up to 40% of women with that endometriosis is present in pelvic lymph nodes in endometriosis have chronic pelvic pain. Pelvic pain 30% of women with pelvic endometriosis, which sup- most often starts as dysmenorrhea and at least 75% of ports this theory. A defect of the immunological system women with endometriosis-associated pelvic pain have is supported by a good deal of research and helps to dysmenorrhea as an initial component of their pain. explain why not all women develop endometriosis sec- Dyspareunia with deep penetration is also a frequent ondary to retrograde menstruation. It also ties into the component of endometriosis-associated pain, occur- theory of genetic predisposition, as an immunologic ring in about 33% of cases. Although CPP, dyspareunia disorder may be inherited. Finally, recent research has and dysmenorrhea are significantly more common focused on the endometrial cells that are present in in women with endometriosis than in women with a endometriosis and found a number of abnormalities normal pelvis, these pain symptoms are not as spe- that may contribute either to initiation or development cific nor diagnostic for endometriosis as is commonly of endometriosis. For example, endometriosis cells thought and by themselves do not justify a diagnosis of have been found to have abnormal production of aro- endometriosis. matase cytochrome P450, an enzyme that is not present Intestinal involvement, usually of the appendix, rec- in normal endometriumand is integral to the conversion tosigmoid or anterior rectum, may cause abdominal of androstenedione and testosterone to estrogen. This pain, dyspareunia, tenesmus, dyschezia, constipation, ability to produce estrogen locally may directly stim- diarrhea, low back pain and, rarely, hematochezia or ulate the growth of endometrial cells of endometriotic symptoms of bowel obstruction. Urinary tract involve- lesions. Endometriosis cells have also been observed to ment, most often at the bladder peritoneum and anterior have increased amounts of vascular endothelial growth cul-de-sac, may cause frequency, pressure, dysuria or factor and interleukin-6. hematuria. Involvement of the distal one-third of the Itisworthwhile to especially note the role of estrogen, as ureter may lead in rare cases to symptoms of ureteral there are several clinical observations that suggest that obstruction. With lung involvement, endometriosis the development and persistence of endometriosis are may rarely cause dyspnea on exertion, pleural effusion estrogen dependent. First, endometriosis is rare before and lung collapse. Catamenial hemothorax has been re- puberty or after menopause unless the woman is on es- ported. A cyclically bleeding or a cyclically tender mass trogenreplacementtherapy.Second,bilateraloophorec- in an incisional scar may also occur with endometriosis. tomy typically results in regression of endometriotic le- The physical examination is often normal, but there sions. Third, decreased levels of estradiol via GnRH ag- is tenderness, especially during the menses, in many onist treatment results in regression of endometriosis. women with endometriosis-associated pelvic pain. A Fourth, endometriosis can develop in the prostatic utri- fixed retroverted uterus with posterior tenderness is par- cle of a male with DES treatment for prostatic cancer. ticularly suggestiveof endometriosis. Tendernodularity Finally,immunohistochemicalstudiesshowvirtuallyall of the uterosacral ligaments and cul-de-sac is a classi- endometriosis lesions contain estrogen receptors. cally described finding with endometriosis. Narrowing The etiology of symptoms in some women but not in of the posterior vaginal fornix or lateral deviation of the others is also not understood. Endometriosis might position of the cervix may rarely be present. In patients produce symptoms due to swelling of the tissue with with endometriomas a tender adnexal mass may be hormonal stimulation, plus extravasation of blood and noted. 376 Chronic Pelvic Pain, Endometriosis

Diagnostic Studies FSH levels in premenopausal women, but lowers es- At the present time an accurate diagnosis can only be trogen levels by directly inhibiting steroidogenesis at made by surgical and histological confirmation. Before the ovarian and adrenal levels. Sixty to 83% of patients the introduction of diagnostic laparoscopy, this required obtain significant relief of pelvic pain with danazol an exploratory laparotomy. Laparoscopy is a much less therapy and the number needed to treat is 1.7 (Barbieri invasiveprocedureandiscurrentlytherecommendeddi- et al. 1982). Danazol is contraindicated in patients with agnostic procedure for any patient suspected of having abnormal uterine bleeding, pregnancy, breastfeeding or endometriosis. impaired renal, cardiac or hepatic function. A preoperative ultrasound is worthwhile as 15–20% of Gonadotropin releasing hormone (GnRH) agonists women with endometriosis have endometriomas. These are analogues of naturally occurring gonadotropin- generally range from 3 to 8 cm in size and are not al- releasing hormone and are the most commonly pre- ways palpable by physical examination. Measurement scribed medical treatment for endometriosis in the of serum Ca-125 levels has a low sensitivity and speci- U.S.A. Examples of GnRH agonists are nafarelin, ficity, although it is more reliable for advanced stage dis- leuprolide and goserelin. They all work at the hypo- ease (Lanzone 1991). Ca-125 levels are also elevated thalamic-pituitary level to shut down LH and FSH with cancersof the ovary, endometrium,gastrointestinal production and release, resulting in a dramatic decline tract, fallopian tube and breast as well as pelvic inflam- in estradiol levels. Pain relief with GnRH agonists is matory disease, pregnancy, menses and leiomyomata. about the same as with danazol. Side effects of the Adolescents with endometriosis should be evaluated for GnRH agonists are loss of bone density, hot flashes, obstructive anomalies of the reproductive system using vaginal dryness, decreased libido, headaches, emo- magnetic resonance imaging, ultrasound and hysterog- tional lability, acne and reduced breast size (Bergqvist raphy. About 10% will have such an anomaly. et al. 1998; Kennedy et al. 1990; Wheeler et al. 1992). In patients in whom intestinal endometriosis is sus- Because of concerns about loss of bone density, add- pected, evaluation of the intestinal tract is usually back therapy with 5 mg day-1 of norethindrone acetate, normal, as most patients have involvement of the serosa with or without 0.625 conjugated equine estrogen, is or muscularis, not the mucosa. Sigmoidoscopy may recommended for up to 1 year of treatment (Hornstein show a bluish submucosal mass in some of these cases. et al. 1998). After discontinuation of treatment, symp- Mucosal lesions may be diagnosed by sigmoidoscopy, toms tend to recur in most patients, with mean time to colonoscopy or barium enema studies, but these evalu- recurrence between 8 to 11 months. ations are certainly not necessary on a routine basis. A number of progestagens, particularly medroxypro- In patients with suspected urinary tract involvement, gesterone acetate and norethindroneacetate, are used to cystoscopy and intravenous pyelography or comput- treat endometriosis. Breakthrough bleeding, prolonged erized tomography of the kidney, ureters and bladder amenorrhea, mood changes, depression, weight gain may be indicated. and irritability are common side effects. Gestrinone, a 19-nortestosterone derivative with mostly progesta- Medical Treatment genic and low androgenic activity, has also been used There are many options for medical and surgical treat- to treat endometriosis (not available in the US) (The ment of endometriosis-associated pelvic pain (see list Gestrinone Italian Study Group 1996). below). Oral contraceptives are commonly used to treat endometriosis. They appear to be less effective than GnRH General treatment options for women with endometri- agonists in relieving dysmenorrhea and dyspareunia, osis-associated pelvic pain but comparable in relief of non-menstrual pelvic pain (Vercellini et al. 1993). Side effects are weight gain, • Observation with palliative treatment breast tenderness, nausea, chloasma, abnormal uterine • Conservative surgery bleeding, enlargement of myomas, thrombophlebitis • Hormonal suppression and thromboembolism, increased appetite, irritabil- • Combined medical and surgical treatments ity, depression, edema, hypertension and increased • Definitive extirpative surgery (radical surgery) vaginal discharge. They are contraindicated in women Danazol, a 17-ethinyl-testosterone derivative, was ap- with a history of or high risk of thrombosis or a his- proved by the FDA for treatment of endometriosis in tory of breast cancer and relatively contraindicated 1976 (Greenblatt et al. 1971). It is mildly androgenic with diabetes, collagen vascular disease or hyperten- and anabolic, properties that account for many of its sion. side effects. Side effects include acne, edema, weight gain, hirsutism, voice changes, hot flushes, abnormal Surgical Treatment uterine bleeding, decreased breast size, decreased li- Surgical treatment of endometriosis may be conser- bido, vaginal dryness, nausea, weakness and muscle vative (i.e. without extirpation of the uterus, tubes or cramps. Danazol does not significantly affect LH and ovaries) or radical (i.e. with extirpation of the uterus Chronic Pelvic Pain, Endometriosis 377 or one or both ovaries). Radical surgery appears to be References more effective in achieving pain relief, but conservative surgery is more appropriate in younger women, 1. Barbieri RL (1990) Etiology and epidemiology of endometriosis. especially if preservation of reproductive potential is Am J Obstet Gynecol 162:565–567 important. Also, conservative surgery can be done at 2. Barbieri RL, Evans S, Kistner RW (1982) Danazol in the treatment of endometriosis: analysis of 100 cases with 4-year follow- C the time of laparoscopic diagnosis (Howard 1994). The up. Fertil Steril 37:737–746 core of either conservative or radical surgical treat- 3. Bergqvist A, Bergh T, Hogstrom L et al. (1998) Effects of trip- ment is the removal or destruction of all endometriotic torelin versus placebo on the symptoms of endometriosis. Fertil lesions. A randomized clinical trial of conservative Steril 69:702–708 4. Candiani GB, Fedele L, Vercellini P et al. (1992) Presacral surgery for endometriosis shows that on average there neurectomy for the treatment of pelvic pain associated with is a 50% decrease of pain 6 months postoperatively endometriosis: a controlled study. Am J Obstet Gynecol and the number needed to treat is 2.5 (Sutton et al. 167:100–103 1994). 5. Cornillie FJ, Oosterlynck D, Lauweryns JM et al. (1990) Deeply infiltrating pelvic endometriosis: Histology and clinical signifi- Both presacral neurectomy (resection of the supe- cance. Fertil Steril 53:978–983 rior hypogastric plexus) and uterosacral neurectomy 6. Greenblatt RB, Dmowski WP, Mahesh VB et al. (1971) Clin- (transection of the uterosacral ligament) have been ical studies with an antigonadotropin – danazol. Fertil Steril recommended for relief of CPP associated with en- 22:102–112 7. Hornstein MD, Hemmings R, Yuzpe AA et al. (1997) Use of dometriosis, but results of randomized clinical trials nafarelin versus placebo after reductive laparoscopic surgery for show efficacy only for presacral neurectomy, (Candiani endometriosis. Fertil Steril 68:860–864 etal. 1992;Zullo etal. 2003) notuterosacralneurectomy 8. Hornstein MD, Surrey ES, Weisberg GW et al. for the Lupron (Sutton et al. 2001; Vercellini et al. 2003). Presacral Add-Back Study Group (1998) Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gy- neurectomy is most effective for the treatment specif- necol 91:16–24 ically of midline dysmenorrhea. There appears to be 9. Howard FM (1993) The role of laparoscopy in chronic pelvic a small effect, if any, on non-menstrual pelvic pain or pain: promise and pitfalls. Obstet Gynecol Survey 48:357–387 10. Howard FM (1994) Laparoscopic evaluation and treatment of dyspareunia. womenwithchronicpelvicpain. JAmer Assoc Gynecol Laparosc If fertility is not desired, then hysterectomy, with or 1:325–331 without bilateral salpingo-oophorectomy, is often rec- 11. Kennedy SH, Williams IA, Brodribb et al. (1990) A comparison ommended for endometriosis-associated pelvic pain. of nafarelin acetate and danazol in the treatment of endometriosis. Fertil Steril 53:998–1003 There is no consensus as to the advisability of removal 12. Lanzone A, Marane R, Muscatello R et al. (1991) Serum Ca- of both ovaries if one or both are not directly involved by 125 levels in the diagnosis and management of endometriosis. endometriosis, but recurrence of pain when one or both J Reprod Med 36:603 ovaries are preserved has been reported to be increased 13. Namnoum AB, Hickman TN, Goodman SB et al. (1995) Inci- dence of symptom recurrence after hysterectomy for endometrio- (relative risk for pain recurrence of 6.1, confidence sis. Fertil Steril 64:898–902 interval 2.5 to 14.6) (Namnoum et al. 1995). Although 14. Parazzini F, Fedele L, Busacca M et al. (1994) Postsurgical medi- uncommon, endometriosishasbeenreportedto recuraf- cal treatment of advanced endometriosis: results of a randomized ter hysterectomy and bilateral salpingo-oophorectomy, clinical trial. Am J Obstet Gynecol 171:1205–1207 15. Sampson JA (1921) Perforating hemorrhagic (chocolate) cysts with and without estrogen replacement therapy. Finally, of the ovary. Arch Surg 3:245 currently available data do not allow a conclusion as 16. Sutton CJG, Ewen SP, Whitelaw N et al. (1994) Prospective, to whether medical or conservative surgical treatment randomized, double-blind trial of laser laparoscopy in the treat- is more effective in the treatment of endometriosis ment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 62:696–700 associated pelvic pain. 17. Sutton C, Pooley AS, Jones KD et al. (2001) A prospective, randomized, double-blind controlled trial of laparoscopic uterine Combined Medical and Surgical Treatment nerve ablation in the treatment of pelvic pain associated with endometriosis. Gynaecol Endoscopy 10:217–222 There are no clinical trials of preoperative medical 18. Telimaa S, Ronnberg L, Kauppila A (1987) Placebo-controlled treatment. There are however, at least three random- comparison of danazol and high-dose medroxyprogesterone ac- ized, placebo-controlled clinical trials of postoperative etate in the treatment of endometriosis after conservative surgery. medical treatment (Hornstein et al. 1997; Parazzini Gynecol Endocrinol 1:363–371 19. The Gestrinone Italian Study Group (1996) Gestrinone versus et al. 1994; Telimaa et al. 1987). These trials suggest a gonadotropin-releasing hormone agonist for the treatment of that pain is decreased with postoperative medical treat- pelvic pain associated with endometriosis: a multicenter, ran- ment while patients are on the medications, but within domized, double-blind study. Fertil Steril 66:911–919 6–12 months after discontinuation of medications pain 20. Vercellini P, Bocciolone L, Vendola N et al. (1991) Peritoneal endometriosis: morphologic appearance in women with chronic levels are similar in postoperative patients whether or pelvic pain. J Reprod Med 36:533 not they received medical treatment. A reasonable way 21. VercelliniP,TrespidiL, ColomboAetal. (1993) Agonadotrophin- to apply these data is to initiate medical treatment after releasing hormone agonist versus a low-dose oral contraceptive conservative surgical debulking therapy if patients have for pelvic pain associated with endometriosis. Fertil Steril 60:75–79 persistent or recurrent pain, rather than treat all patients 22. Vercellini P, Aimi G, Busacca M et al. (2003) Laparoscopic postoperatively. uterosacral ligament resection for dysmenorrhea associated 378 Chronic Pelvic Pain, Epidemiology

with endometriosis: results of a randomized, controlled trial. Chronic Pelvic Pain, Laparoscopic Pain Mapping, Table 1 Visual ana- Fertil Steril 80:310–319 logue scores (VAS) of various anatomic structures at the time of laparoscopic 23. Vernon MW, Beard JS, Graves K et al. (1985) Classiﬁcation of pain mapping endometriotic implants by morphological appearance and capac- Anatomic Structure Median VAS When Median VAS When ity to synthesize prostaglandin F. Fertil Steril 46:801–806 Structure is Not StructureisSiteof 24. Wheeler JM, Knittle JD, Miller JD (1992) Depot leuprolide Site of Pain Pain versus danazol in treatment of women with symptomatic endometriosis. I. Efﬁcacy results. Am J Obstet Gynecol Uterus 2 9 167:1367–1371 25. Zullo F, Palomba S, Zupi E et al. (2003) Effectiveness of pre- Ovaries 3 8 sacral neurectomy in women with severe dysmenorrhea caused by endometriosis who were treated with laparoscopic conserva- Fallopian Tubes 2 - tive surgery: A 1-year prospective randomized double-blind trial. Am J Obstet Gynecol 189:5–10 Round Ligaments 1 - Uterosacral 19 Ligaments & Chronic Pelvic Pain, Epidemiology Cul-de-sac Intestines 1 - Epidemiology of Chronic Pelvic Pain Unpublished data courtesy of P. Reginald

Chronic Pelvic Pain, Interstitial Cystis of whom were found to have diffuse visceroperitoneal tenderness (Palter and Olive 1996). It has also been Interstitial Cystitis and Chronic Pelvic Pain used to evaluate women with endometriosis-associated pelvic pain (Demco 1998). The technique used to map the pelvis is a gentle probing or tractioning of tissues and organs with a blunt probe or Chronic Pelvic Pain, Laparoscopic Pain forcepspassed through a secondary cannula site. During Mapping a systematic evaluation of the entire pelvis, the patient is asked to note the presence or absence of tenderness and FRED M. HOWARD pain and to rate its severity when present. In particular, Department of Obstetrics and Gynecology, University the patient is to note if there is replication of her usual of Rochester, Rochester, NY, USA [email protected] or presenting pain. Diagnosis of an etiologic lesion or organ should be based on the severity and quality of pain elicited, especially reproduction of the patient’s Synonyms presenting pain. It has been suggested that applying or Conscious Laparoscopic Pain Mapping; Pain Map- injecting local anesthetic to sites of focal tenderness ping; Conscious Pain Mapping; Patient Assisted La- may block the pain response and possibly improve the paroscopy; Laparoscopy (for Pain) under Local Anes- predictability that surgical excision will be therapeutic. thesia; Laparoscopic Pain Mapping Also, superior hypogastric plexus block can be done at the time of laparoscopic pain mapping and may help Definition to predict the efficacy of presacral neurectomy (Steege Laparoscopic pain mapping is a diagnostic laparoscopy 1998). under local anesthesia, with or without conscious seda- It has been shown that when laparoscopy is done under tion, performed with the goal of identifying sources or local anesthesia in women without pelvic pain, there is generators of pain in women with chronic pelvic pain. It no significantpain or tendernessto probing of theuterus, has been suggested that laparoscopic pain mapping can ovaries, omentum or bowel (Zupi et al. 1999). Table 1 lead to the treatment of subtle or atypical areas of dis- summarizes the pain levels of viscera in women with ease that might have been overlooked if the procedure chronic pelvic pain in one unpublished series of laparo- had been done under general anesthesia (Almeida and scopies under local anesthesia. Val-Gallas 1997). Also, it may help to avoid surgical interventions when there are no surgically treatable pain Characteristics generators present. However, there are limited data con- Not all women with chronic pelvic pain are candidates firming these potential benefits (Demco 1997). for laparoscopic pain mapping. Patients who are mor- Laparoscopy under local anesthesia is not new, but its bidly obese (BMI greater than 30), have significant use as a diagnostic modality to localize areas of ten- anesthesia risk, have anxiety disorders or psychiatric derness potentially responsible for chronic pelvic pain disease or are known or suspected to have severe adhe- is a relatively new technique. It was first described in sive disease are not ideal candidates for the procedure. 1996 in a series of eleven patients with pelvic pain, ten Counseling and preparation of the patient is also cru- Chronic Pelvic Pain, Laparoscopic Pain Mapping 379 cial, because chronic pelvic pain patients experience stimulation can reproduce a patient’s pain. This strongly greater pain with laparoscopy under local anesthesia supports the hypothesis that some adhesions cause ab- than non-pain patients. Intolerable pain is the most dominopelvic pain. As appears to be the case with en- common reason for failures with laparoscopic pain dometriosis, these data also suggest that adhesions are mapping. Other reasons for failures may include adhe- notalwaysasourceofpaininwomenwithchronicpelvic C sions that obliterate the visual field, inability to access pain and adhesions. the peritoneal cavity and inability to visualize the entire pelvis. Published success rates range from 70–100%. Chronic Visceral Pain As with traditional diagnostic laparoscopy, endometrio- Laparoscopicpainmappingnotinfrequentlyshowsgen- sis and adhesions are the most common diagnoses made eralized pelvic visceral and peritoneal hypersensitivity, with laparoscopic pain mapping; i.e. they are the lesions suggesting such patients may have chronic visceral pain thatmostfrequentlyelicitpainandtendernessatthetime syndrome of visceral neuropathic etiology. We believe of pain mapping. However, even in patients with tender that our finding of patients with diffuse pelvic visceral endometriosis or adhesions, other endometriotic lesions and peritoneal tenderness may represent a way to con- or adhesions may not be tender to probing at the time of firm the diagnosis of chronic visceral pain syndrome, laparoscopic pain mapping. a diagnosis that has been suggested for chronic pain Other less common lesions found to map pain at the time syndromes believed to be of visceral origin (Wesselman of laparoscopic pain mapping include sciatic hernia, 1999). Unpublished data suggest that reproductive vis- leiomyoma, hernia repair site, postoperative peritoneal cera tend to be tenderer than peritoneum or intestines cyst, colon carcinoma, chronic ileal disease, staple at the at the time of laparoscopic pain mapping. It may be ureter, pseudo stone secondary to gallbladder spillage, that many of the patients with no apparent diagnosis peritoneal puckering, two with ovary, herniorrhaphy at the time of diagnostic laparoscopy under general site and peritoneal scarring. Individual pelvic viscera anesthesia may have chronic visceral pain syndrome. have also been mapped as painful, including the uterus, Clearly further evaluations are needed to confirm these ovary, fallopian tube, round ligament, appendix, bladder proposals. and vaginal apex.

Endometriosis Summary In one published series there were 15 cases with suc- Chronic pelvic pain is a multifactorial and complicated cessful conscious pain mapping and a visual diagnosis disorder. It is premature to assume that the findings with of endometriosis and in these cases endometriotic laparoscopic pain mapping translate directly into cause lesions were mapped as painful sites in seven. In all andcure.Forexample,comparingseriesofpatientsfrom seven of these cases there was histological confirmation our center who were evaluated with traditional diagnos- of the diagnosis. In the remaining eight successfully ticlaparoscopytothoseevaluatedwithlaparoscopicpain mapped cases in which endometriotic lesions did not mapping showed similar prevalences of endometrio- map positively, there was histological confirmation of sis and adhesions in both groups (endometriosis in the diagnosis in only two cases. Thus seven of nine cases 38% versus 40% and adhesions in 34% versus 54%, with histologically confirmed endometriosis mapped respectively) (Howard 1994). Treatment based on the pain to endometriotic lesions, versus none of six cases findings at the time of laparoscopic pain mapping did in which the visual diagnosis of endometriosis was not change the outcomes however, compared to the not histologically confirmed (P = 0.007, Fischer’s ex- outcomes based on traditional diagnostic laparoscopy. act test). These findings emphasize the importance of With laparoscopic evaluation and treatment without the histologically confirmed presence of endometrial pain mapping, 78% of patients had decreased pain and glands and stroma to generation of pain by suspected 45% were pain-free. With laparoscopic pain mapping, endometriotic lesions. Another published series cor- 44% had decreased pain and 16% were pain-free. The relating the appearance of endometriotic lesions with patients in the two groups were not identical, as only tenderness showed that 84% of red lesions, 76% of clear one-half of the patients in the traditional diagnostic lesions, 44% of white scar lesions and 22% of black laparoscopy series had undergone prior evaluations and lesions are painful (Demco 1998). Findings at laparo- treatments for chronic pelvic pain, compared to all of scopic pain mapping have also suggested that up to as the patients evaluated by laparoscopic pain mapping. much as a 3 cm area of normal-appearing peritoneum The clinical value of conscious pain mapping both surrounding endometriotic lesions may be tender. diagnostically and therapeutically cannot be stated yet, as only observational studies are available. Current data Adhesions suggest it does help to avoid unnecessary operative Whether adhesions can produce pain is controversial. laparoscopies in some cases. Whether it improves out- All of the published series of conscious pain mapping comes in women with chronic pelvic pain by leading to have shown that adhesions can be tender and that their more specific medical and surgical treatments requires 380 Chronic Pelvic Pain Model more study and probably a prospective, randomized however, can be somatic pain, such as lower abdom- trial. inal wall pain in irritable bowel syndrome, celiac disease or colitis, flank pain in renal colic and pelvic floor References or pelvic region myofascial pain syndromes in inter- 1. Almeida Jr OD, Val-Gallas JM (1997) Conscious pain mapping. stitial cystitis or endometriosis. The visceral component J Am Assoc Gynecol Laparosc 4:587–590 can be difficult to identify or can be overlooked, because 2. Demco LA (1997) Effect on negative laparoscopy rate in chronic visceral pain is diffuse and poorly localized. One must pelvic pain patients using patient assisted laparoscopy. J Soc La- paroendosc Surg 1:319–321 have a high degree of suspicion in order to identify the 3. Demco LA (1998) Mapping the source and character of pain due visceral component of pain when the complaint is so- to endometriosis by patient-assisted laparoscopy. J Am Assoc matic pain like a myofascial pelvic floor muscle pain Gynecol Laparosc 5:241–245 syndrome. The visceral syndromes that are common in 4. Howard FM (1994) Laparoscopic evaluation and treatment of womenwithchronicpelvic pain. J AmerAssoc Gynecol Laparosc women include endometriosisandinterstitialcystitis, ir- 1:325–31 ritable bowel syndrome and irritable bladder syndrome, 5. Metha PV (1989) A total of 250,136 laparoscopic sterilizations whereas prostatitis or prostadynia, interstitial cystitis by a single operator. Br J Obstet Gynaecol 96:1024–1034 6. Palter SF, Olive DL (1996) Office microlaparoscopy under local and irritable bowel syndrome are common in men (Vec- anesthesia for chronic pelvic pain. J Am Assoc Gynecol Laparosc chiet et al. 1992; Wesselmann 1999; Lukban et al. 2001; 3:359–364 Verne et al. 2001; Nadler 2002). 7. Steege JF (1998) Superior hypogastric block during microlaparo- Myofascial pain syndromes can also refer pain to a re- scopic pain mapping. J Am Assoc Gynecol Laparosc 5:265–267 8. Wesselman U (1999) A call for recognizing, legitimizing, gion where visceral pain is common, either as local or and treating chronic visceral pain syndromes. Pain Forum as referred pain. The attendant trigger point formation 8:146–150 and the referred pain can cause or aggravate visceral or- 9. Zupi E, Sbracia M, Marconi D et al. (1999) Pain mapping during gan dysfunction. This is readily seen in bladder or bowel minilaparoscopy in infertile patients without pathology. J Am Assoc Gynecol Laparosc 6:51–54 dysfunction in the presence of trigger points in the levator ani and other pelvic floor muscles. Abdominal wall and pelvic floor trigger points can persist long after an initiating visceral insult has passed. This is seen very Chronic Pelvic Pain Model strikinglywhenabdominalwall triggerpointsform(in the abdominal oblique muscles) in response to ureteral Visceral Pain Models, Female Reproductive Organ colic and persist for weeks after the stone has passed, Pain or recur weeks or months later like renal colic, when in fact there is only somatic trigger point pain. Treatment of the trigger points eliminates the local and the referred pain. Chronic Pelvic Pain, Musculoskeletal Syndromes Visceral Pain Visceral Nociception and Pain can result from such ROBERT D. GERWIN non-tissue injuring mechanisms as distention or in- Department of Neurology, Johns Hopkins University, creased capsular pressure or from inflammation, is- Bethesda, MD, USA chemia or obstruction. Thus, visceral pain can arise [email protected] from conditions that produce or threaten tissue destruction or from conditions that are benign. Interstitial Synonyms cystitis, irritable bowel syndrome, chronic prostatitis Viscerosomatic pain syndromes; myofascial pain syn- and endometriosis are common causes of pelvic pain dromes; myofascial trigger points. with pelvic region muscular pain representation. As many as 20–30% of cases of chronic prostatic related Definition painconditionsarenotduetoinflammatoryorinfectious causes (Krieger et al. 2002; Schaeffer et al. 2002) and Chronic pelvic pain syndromes (CPPS) and even acute could be called prostadynia, a condition largely related pelvic pain syndromes (APPS) can have both visceral to pelvic floor myofascial pain syndromes. Vulvadynia and a body wall (somatic) representations, referred to as and vulvar vestibulitis are not visceral pain syndromes, viscerosomatic and musculoskeletal or myofascial pain in the strict sense that they do not arise from hollow syndromes respectively. viscera, but they are non-muscular sources of chronic pelvic pain that are associated with musculoskeletal Characteristics pain syndromes. Pain can arise from a disorder of a visceral organ, as in Pain from pelvic region visceral and genital structures inflammatory bowel disease or endometriosis, ureteral is transmitted to the central nervous system through calculusor interstitial cystitis. The presenting complaint the visceral afferent sensory fibers of both sympathetic Chronic Pelvic Pain, Musculoskeletal Syndromes 381 nerves (the splanchnic nerves) and parasympathetic (muscular) pain syndromes need to be treated in order nerves (the pelvic nerve), involving both the parasym- to produce a positive outcome. pathetic and sympathetic nerves in the superior and The mechanisms of visceral induced hypersensitiza- inferior hypogastric plexuses. Transmission of pelvic tion include both peripheral nerve and central nervous region pain is by both the dorsal spinal column to the system activation. Sensitization lowers the pain thresh- C thalamus, and via the lateral columns to the medullary old, magnifies pain and results in a larger area of the lateral reticular nucleus (Ness 2000). Pseudoaffective body being perceived to be painful. An example of a responses associated with heart rate and blood pressure mechanism resulting in peripheral sensitization is the changes are mediated via the lateral column. increase in rectal nerve fibers that are immunoreactive In addition to direct nociceptive pathways from vis- to the heat and capsaicin receptor vanilloid receptor 1 ceralorgansaswellasfrommuscle tothespinalcordand (Chan et al. 2003). Central sensitization results in part brain, there are psychophysiological responses as well. through activation of the dorsal horn neuron by such These responses are associated with central and perhaps means as N-methyl D-aspartate receptor activation or peripheral sensitization. They are not uniformly found by the convergence of two afferent nociceptive nerve in all hollow viscera. Rectal distention does not result fibers on one dorsal horn neuron. A recently discovered in an accelerated response with repeated stimulation as mechanism of central hypersensitization is the increase is found in the colon or in the urinary bladder. Repeated in the number of spinal lamina 1 neurons that express stimulation of the urinary bladder by a distending stim- substance P receptor, seen in both non-inflamed dis- ulus results in lowering of the pressure threshold needed tended rat colon and in the inflamed rat colon (Honoré to evoke sensory responses and an acceleration of auto- et al. 2002). Visceral inflammation markedly increased nomic responses (Ness et al. 1998). The same effect has the number and the rostro-caudal extent of lamina 1 been noted following repeated distention of the colon. substance P receptor neurons that were activated by Moreover, the area of sensitization or the region of the normally non-noxious and noxious distention of the body where discomfort is experienced widens with suc- colon. Neuroplastic changes in the central nervous sys- cessive stimulation. tem take place very rapidly in response to nociceptive afferent input from viscera and from muscle, resulting Referred Pain from Viscera in hypersensitivity, allodynia and an increase in Studiesofsubjectsexposedtorepeateddistentionofhol- the receptive fields of individual dorsal horn neurons. loworgans(colon,urinarybladder)haveshownthatpain Tenderness develops in response to non-nociceptive from visceralorgansisexperienced inthebodywall. Re- stimulation, increased perceived pain in response to ferred pain from the gall bladder to the right shoulder nociceptive stimulation and this is perhaps part of the area, esophageal pain to the chest and cardiac pain to basis for referred pain. the neck and arm are well known, as are prostatic and Another phenomenonthat is important for pain referred labor pains referred to the perineum. Visceral organs in from viscera to somatic tissues and from abdominaland general have both a somatic representation and a cuta- pelvic myofascial trigger points to viscera is the extent neous representation. These representations are related of spread of afferent input in the spinal cord. Spinal cord to the local spread of incoming nociceptive stimulation spread of non-nociceptive sensory afferent fibers in the to the spinal cord. Thus, referred pain from genitouri- classical sensory system is over about 4 segments, 2 seg- nary structures is felt in pelvic region musculoskeletal ments upwards and 2 segments downward. Spinal cord structures rather than thoracic or lower extremity struc- spread of nociceptivesensory afferentfibersis7–10seg- tures. ments in extent. The more extensive spread of nocicep- The mechanisms underlying central sensitization have tive sensory afferent fibers increases the possibility of been well studied over the past quarter century. Cuta- referred pain at a greater distance from the source of the neous pain and somatic referred pain are both clinically nociceptivestimulus.Nociceptiveneuronalactivationin experienced. Pelvic floor pain, lower abdominal and the dorsal horn spreads from neuron to neuron through flank pain and proximal thigh pain are all examples of the excitation of cell surface receptors and the unmask- myofascialreferred pain syndromes. There isan interac- ing and activation of inactive or non-functional affer- tion between primary visceral pain, primary myofascial ent connections from normally non-functionalreceptive pain and referred pain to and from these regions. Pain fields. Activating these quiescent afferent connections that originates as a myofascial pain syndrome from results in a given dorsal horn neuron responding to stim- non-visceral causes can be experienced as visceral pain ulation of receptive fields that normally belong to other with symptoms characteristic of interstitial cystitis, dorsal horn neurons. Thus, chronic painful stimulation irritable bowel syndrome or genital dysfunction. As from either pelvic region viscera or from abdominal and discussed above, visceral pain can result in muscular pelvic region myofascialtrigger pointsresultsin pain re- pain. In other words, the symptoms of referred pain go ferral either to the somatic muscles or to visceral struc- in both directions, visceral to somatic and somatic to tures or regions respectively. Viscerosomatic pain refer- visceral (Gerwin 2002). Both the visceral and somatic ral is segmental and is most common locally. Thus, pain 382 Chronic Pelvic Pain, Musculoskeletal Syndromes from interstitial cystitis is most often felt in the pubic re- posterior or dorsal portion with colon and rectal/anal gion and in the ventral portion of the pelvic floor mus- dysfunction.Thebulbospongiosus,ischiocavernosus cles, like the levator ani muscle. Pain from endometrio- and transverse perinei muscles develop trigger points sis is often felt in the suprapubic and pubic region and in in association with genital dysfunction and give rise the low back. Pain in irritable bowel syndrome is often to dyspareunia in women and penile, scrotal and felt in the dorsal or posterior portion of the levator ani prostatic pain in men. and other pelvic floor muscles like the piriformis mus- 4. Obturator internus trigger points often accompany cles. Trophic changes can also be seen in the region of chronicpelvicpain conditionsinvolving bowel, blad- referred pain from visceral trigger points. Neurogenic der and genital organs, but are particularly associated plasmaextravasationcausingcutaneousedemawasseen with rectal pain. in the region of referred pain in the rat in which uter- 5. The gluteal muscles, including the gluteus maximus, ine inflammation was produced (Wesselmann and Lai gluteus medius, gluteus minimis and the piriformis 1997). muscle, give rise to trigger points in association with pain from any of the pelvic organs. Abdominal and Pelvic Floor Myofascial Pain Syndromes 6. Adductor magnus medial thigh muscle trigger points referpaindeepwithinthepelvisandcansimulategen- Myofascial trigger points are painful areas within mus- ital, bladder or rectal pain. cle that are composed of tender regions or zones on tight or taut bands of muscle that can be palpated in Diagnosis of these myofascial pain syndromes is made accessible muscles (Simons et al. 1999). The trigger by palpation of the appropriate muscles for hardened or zones within the muscle can be quiescent and not taut bands within the muscle. These bands generally run painful until the muscle is activated by use or they can from one tendinis insertion to the other, will be tender to be spontaneously painful even at rest. A property of palpation and may refer pain to areas commonly experi- myofascial trigger points that arises from central sensi- enced as painful by the patient. Referred pain phenom- tization of dorsal horn neurons in the spinal cord is the ena usually take about 5–10 seconds of firm pressure to development of referred pain zones in a predominantly develop. localized, segmental manner, similar to the segmental spread of referred pain from viscera. Trigger points in Treatment the muscles discussed below are relevant to chronic Treatment is directed towards inactivating the myofas- pelvic pain syndromes when stimulation of the trigger cial trigger points and preventing their return. Inactiva- points reproduces symptoms commonly experienced tionoftriggerpointsrequiresreducingoreliminatingthe by the patient. Visceral dysfunction, such as bladder or pain from the trigger point and restoring normal length bowel irritability or dyspareunia, can occur as a result of to the shortened, contracted, taut or hard band of mus- myofascial trigger points. The classical chronic pelvic cle that harbors the trigger point. This can be done man- pain triad of endometriosis or prostadynia together with ually through the use of trigger point compression, lo- interstitial cystitis and irritable bowel syndrome is usu- cal stretching and then stretching the entire muscle. In ally accompanied by abdominal and pelvic floor muscle chronic pelvic pain conditions, this may involve work- trigger points that serve to perpetuate and aggravate the ing within the pelvis through the vagina or the rectum, pelvic visceral syndromes. even though the majority of manual work can be done The following muscle trigger point referred patterns are externally. of importance in pelvic visceral pain syndromes. Trigger points can be reduced and pain relieved by phys- 1. Lateral abdominal wall myofascial trigger points ical therapy modalities such as electrical stimulation, refer pain to the lower abdominal quadrant and to the including percutaneous electrical stimulation. Ultra- groin. These muscles are affected by chronic colitis, sound may release superficial trigger points, but does Crohn’s disease and renal and ureteral chronic pain not penetrate far enough to be effective in most deep conditions and can be associated with abdominal trigger points. Trigger point injection with local anes- cramping pain, diarrhea or constipation. thetic or needling the trigger zone with an acupuncture 2. Thoracolumbar paraspinal muscle trigger points, needle without instilling local anesthetic is a highly especially the lower thoracic, lumbar and multi- effective way of inactivating trigger points. A local fidi muscle trigger points, refer pain to the buttock, twitch response elicited from the trigger zone (which sacral and coccygeal region and are associated with is followed by partial or complete relaxation of the both rectal-colonic dysfunction and genitourinary taut or hardened band and a reduction in trigger point dysfunction. tenderness) is the confirmatory sign that the trigger 3. Pelvic floor muscles, including the pubococcygeous zone has actually been entered and injected. There is and iliococcygeousmuscles of the levator ani, are as- no evidence to support the injection of substances other sociated with pelvic organ dysfunction, the anterior than local anesthetics, such as steroids, cyanocobal- or ventralportion with genitourinary dysfunction,the amin or ketorolac. Injection or dry needling can be Chronic Pelvic Pain, Pelvic Inflammatory Disease and Adhesions 383 done diagnostically to see if a trigger point is indeed causing a problem, to treat acute pain and to facilitate Chronic Pelvic Pain, Pelvic Inflammatory physical therapy. Trigger point injections in the pelvic Disease and Adhesions region can almost always be done externally, including FRED M. HOWARD injections of the levator ani, piriformis and obturator Department of Obstetrics and Gynecology, University C internus muscles. Only rarely is it actually necessary to of Rochester, Rochester, NY, USA inject vaginally. [email protected] Conditions that create or perpetuate pelvic pain and pelvic region myofascial trigger points must be ad- Synonyms dressed and corrected. Thus, vulvar vestibulitis, interstitial cystitis and structural factors such as pelvic Acute Salpingitis; Salpingitis-Oophoritis-Peritonitis; torsion, pubic symphysis shear and sacroiliac joint dys- Chronic Pelvic Inflammatory Disease; Tubo-Ovarian function must be treated and corrected. Muscle energy Complex; pelvic inflammatory disease techniques are often adequate for the correction of the Definition structural perpetuating factors. Treatment of trigger points in the muscles that refer pain to the pelvis will Pelvic inflammatory disease (PID) comprises a spec- often result in dramatic improvement of chronic pelvic trum of inflammatory disorders of the upper female pain states and of pelvic organ dysfunction. genital tract, including any combination of endometritis, salpingitis, tuboovarian abscess and pelvic peritonitis (Centers for Disease Control 1998). Chronic References abdominopelvic pain (CPP) and adhesive disease are significant sequelae of pelvic inflammatory disease 1. Chan CHL, Facer P, Davis JB et al. (2003) Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hy- (Safrin et al. 1992). persensitivity and faecal urgency. Lancet 361:385–391 PID is most often due to ascent of organisms from the 2. Gerwin RD (2002) Myofascial and visceral pain syndromes: vagina and cervix, but it may also be from contiguous visceral-somatic pain representations. J Musculoskel Pain 10:165–175 spread of organisms (e.g. from appendicitis) or from 3. Honoré P,Kamp EH, Rogers SD, Gebhart GF, Mantyh PW (2002) lymphatic or hematogenous spread (e.g. tuberculo- Activation of lamina 1 spinal cord neurons that express the sub- sis). PID may be iatrogenic after invasive diagnostic stance P receptor in visceral nociception and hyperalgesia. J Pain or therapeutic procedures, but more often it is sponta- 3:3–11 4. Krieger JN, Ross SO, Deutsch L et al. (2002) The NIH Consen- neously associate with sexual activity. Infection with sus concept of chronic prostatitis/chronic pelvic pain syndrome gonococcus or chlamydia increases the risk of PID. compared with traditional concepts of nonbacterial prostatitis and In the United States there are an estimated 1.2 million prostatodynia. Curr Urol Rep 3:301–306 visits per year to physicians’ offices (Curran 1980) and 5. Lukban JC, Parkin JV, Holzberg AS et al. (2001) Interstitial cystitis and pelvic floor dysfunction: a comprehensive review. Pain about 280,000 women per year are hospitalized for Medicine 2:60–71 PID (Jones 1980; Washington 1984). In addition, an 6. Nadler RB (2002) Bladder training biofeedback and pelvic floor estimated 150,000 surgical procedures are performed myalgia. Urology 60 (S6):42–43 annually for complications of salpingitis. The estimated 7. Ness TJ (2000) Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord. Pain incidence of PID is 14.2 per 100 women. 87:83–88 8. Ness TJ, Richter HE, Varner RE et al. (1998) A psychophysio- Characteristics logical study of discomfort produced by repeated filling of the Etiology urinary bladder. Pain 76:61–69 9. Schaeffer AJ, Knauss JS, Landis JR et al. (2002) Chronic Pro- PID is a polymicrobial infection. Microorganisms that statitis Collaborative Research Network Study Group. Leukocyte have been recovered from the upper genital tracts of and bacterial counts do not correlate with severity of symptoms in men with chronic prostatitis: the National Institutes of Health women with PID include N. gonorrhoeae, C. trachoma- Chronic Prostatitis Cohort Study. J Urology 168:1048–1053 tis, mycoplasmas, anaerobic and aerobic bacteria from 10. Simons DG, Travell JG, Simons LS (1999) Myofascial Pain and the endogenous vaginal floor such as Bacteroides, Pep- Dysfunction: The trigger point manual, 2nd edn. Williams and tostreptococcus, Gardnerella vaginalis, Escherichia Wilkins, Baltimore, pp 11–93 11. Vecchiet L, Giamberardino MA, de Bigontina (1992) Referred coli, Haemophilus influenza and aerobic Streptocci Pain from Viscera. In: Sicuteri F, Tenenius L, Vecchiet L et al. (Eschenbach et al. 1975; Monif et al. 1976). PID is of- (eds) Pain versus Man, Advances in Pain Research and Therapy, ten precipitated by gonococcal or chlamydial infections vol 20. Raven Press, New York, pp 101–110 of the cervix. 12. Verne GN, Robinson ME, Price DD (2001) Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome. Pain Chronic pelvic pain develops in 18–36% of women sub- 93:7–14 sequent to PID and may occur in up to 67% after three or 13. Wesselmann U (1999) Pain - the neglected aspect of visceral more episodes of PID (Haggerty 2003; Westrom 1980). disease. Eur J Pain 3:189–191 (The etiology of CPP after PID is not known, but is gen- 14. Wesselmann U, Lai J (1997) Mechanisms of referred visceral pain: uterine inflammation in the adult virgin rat results in neu- erally thought to be due to adhesive disease and to in- rogenic plasma extravasation in the skin. Pain 73:309–317 jury of the fallopian tubes and ovaries by the infection 384 Chronic Pelvic Pain, Pelvic Inflammatory Disease and Adhesions

Chronic Pelvic Pain, Pelvic Inflammatory Disease and Adhesions, filled tubes with or without pelvic fluid or tubo-ovarian Table 1 Peritubal adhesions and distal tubal pathology among PID patient complex (Cacciatore et al. 1992). with chronic pain CPP associated with prior PID is generally thought to be Women with Total women Number Rate ( % ) duetoadhesionsortubaldisease,butusuallythereareno chronic pain specific findings on examination that allow a diagnosis ADHESIONS of adhesions or tubal damage. Occasionally with dense None 57 5 9 uterine adhesions the uterus is found in a fixed, immo- bile retroverted position. With hydrosalpinges or tubo- Slight 23 3 13 ovarian complexes, a tender adnexalmassmay be palpa- Moderate 40 25 63 ble. Laparoscopy for CPP may show fallopian tubes that are tortuous, clubbed or phimotic and may show tubo- Extensive 32 29 91 ovarian adhesions in women with prior PID. In many FIMBRIATED ENDS patients laparoscopic findings may be normal. Normal 74 23 31 Treatment Phimotic 18 8 44 Acute PID should be treated empirically with broad- Clubbed 41 23 56 spectrumantibioticstocoverthevarietyoflikelyaerobic and anaerobic pathogens. Oral versus parenteral treatment does not appear to alter outcomes nor change the likelihood of developing CPP. Hospitalization should (Westrom1988)).OnepossiblemechanismforCPPmay occur if the diagnosis is uncertain and the patient seems be related to chronic inflammation due to host immuno- ill, the patient is pregnant, the patient does not respond logical responses to the acute infection. Another may clinically to oral antimicrobial therapy, the patient is be recurrent infections due to repeated infectious expo- unable to follow or tolerate an outpatient oral regimen, sures and weakened host defenses secondary to previ- the patient has severe illness, nausea and vomiting or ous damage (Moller et al. 1995; Patton et al. 1983). At high fever, the patient has a tubo-ovarian abscess or the second-look laparoscopy, 88% of post-PID women with patient is immunodeficient. CPP had morphological changes in the fallopian tubes The ideal treatment of women with CPP secondary to or ovaries or both and the severity of chronic pelvic pain PID is not known. Empirical antibiotic therapy is often was highly correlated with the extensiveness of pelvic tried in women with CPP in whom prior, chronic or adhesions (Table 1) (Westrom 1992). recurrent PID is suspected. Unfortunately there are no studies supporting efficacy for this approach. Surgical Signs and Symptoms treatment by adhesiolysis or even removal of severely PID is difficult to diagnosis because of wide variation damaged organs, such as hydrosalpinges, is utilized for in symptoms and signs. Overall, the clinical diagnosis conservative management, but only observational and of symptomatic PID has a positive predictive value of anecdotal data are available to support this approach. 65 to 90%, yet many patients with mild symptoms may Hysterectomy with bilateral salpingo-oophorectomy go unrecognized. Even though PID is an infectious dis- is commonly performed for CPP with pelvic findings ease, 30–50% of patients are afebrile. Lower abdomi- suggestive of prior PID, although there is not much nal and pelvic pain are usually present and of less than published information documenting efficacy for relief 2 weeks duration. Physical examination usually shows of CPP. bilateral lower abdominal tenderness, bilateral adnexal References tenderness and cervical motion tenderness. Abnormal 1. Cacciatore B, Leminen A, Ingman-Friberg S et al. (1992) cervical or vaginal discharge is characteristic. Labora- Transvaginal sonographic findings in ambulatory patients with tory testing may show elevated erythrocyte sedimenta- suspected PID. Obstet Gynecol 80:912–916 tion rate, elevated C-reactive protein, leukocytosis and 2. Centers for Disease Control (1997) 1998 guidelines for treat- positive cultures for N. gonorrhoeae or C. trachomatis. ment of sexually transmitted diseases. MMWR Recomm Rep 47:79–86 There is a strong correlation between exposure to sex- 3. Curran JW (1980) Economic consequences of pelvic inflam- ually transmitted organisms and PID. matory disease in the United States. Am J Obstet Gynecol Laparoscopy is the current gold standard for the di- 1080:138–905 agnosis of acute PID. However, routine laparoscopy 4. Eschenbach DA, Buchanan T, Pollock HM et al. (1975) Polymi- crobial etiology of acute pelvic inflammatory disease. N Engl J is logistically and economically impractical for all Med 293:166 patients suspected of having acute PID. Other useful 5. Haggerty CL, Schulz R, Ness RB (2003) Lower Quality of Life studies for diagnosing acute PID include histopatho- Among Women With Chronic Pelvic Pain After Pelvic Inflam- logical evidence of endometritis on endometrial biopsy matory Disease. Obstet Gynecol 102:934–939 6. Jones OG, Saida AA, St John RK (1980) Frequency and distribu- (Paavonen et al. 1985) and transvaginal sonography tion of salpingitis and pelvic inflammatory disease in short stay or other imaging techniques showing thickened fluid in hospitals in the United States. Am J Obstet Gynecol 138–905 Chronic Pelvic Pain, Physical and Sexual Abuse 385

7. Moller BR, Krostiansen FV, Thorsen P et al. (1995) Sterility of childhood and adulthood, in patients presenting with a the uterine cavity. Acta Obstet Gynecol Scand 74:216–219 variety of chronic medical conditions including chronic 8. Monif GRG, Welkos SL, Baer H et al. (1976) Cul-de-sac isolates from patients with endometritis, salpingitis, peritonitis and pelvic pain. Much of the published research comes from gonococcal endocervicitis. Am J Obstet Gynecol 126:158 North America, and how well these findings generalise 9. Paavonen J, Aine R, Teisala K et al. (1985) Comparison of to other countries is not clear. C endometrial biopsy and peritoneal fluid cytology with la- More attention has been given to sexual abuse than paroscopy in the diagnosis of acute PID. Am J Obstet Gynecol 151:645–650 physical abuse in the literature. Reported prevalence 10. Patton DL, Halbert SA, Kuo CC et al. (1983) Host response to rates for sexual abuse in patients with chronic pelvic Chlamydia trachomatis infection of the fallopian tube in pig- pain range from 26% to 64% (Collett et al. 1998; Reiter tailed monkeys. Fertil Steril 40:829–840 and Gambone 1990; Toomey et al. 1993; Walker et 11. Safrin S, Schachter J, Dahrouge D et al. (1992) Long-term sequelae of acute PID. Am J Obstet Gynecol 166:1300–1305 al. 1988; Walling et al. 1994), and from 11% to 50% 12. Washington AE, Cates W, Sadi AA (1984) Hospitalizations for for physical abuse (Rapkin et al. 1990; Toomey et al. pelvic inflammatory disease. Epidemiology and trends in the 1993). This wide range is a reflection of the significant United States 1975 and 1981. JAMA 251:2529–2533 methodological problems characterising this area of 13. Westrom L (1980) Incidence, prevalence and trends of acute pelvic inflammatory disease and its consequences in industri- research. One of the main problems is with definitions. alized countries. Am J Obstet Gynecol 138:880–892 Sexual abuse is defined in various ways by different 14. Westrom L (1988) Chronic pain after acute PID. In: Belfort P, investigators. Some studies have only included con- Piatti JA, Eskes TKAB, (eds) Advances in gynecology and obstet- tact sexual abuse, whereas others have used a wider rics. Proc XIIth World Congress Gynecol Obstet. Rio de Janeiro, October 1988, vol 6, pp 265–272 definition of sexual abuse and have included episodes 15. Westrom LV,Berger GS (1992) In: Berger GS, Westrom LV (eds) of threatened or attempted abuse without any direct Consequences of pelvic inflammatory disease. Raven Press, New genital contact. Other studies have excluded isolated York, pp 101–114 incidents of abuse. Some have distinguished between childhood abuse (usually below the age of 14 years) and abuse in adulthood, whereas others have not made Chronic Pelvic Pain, Physical and Sexual this distinction. Similar problems exist with definitions of physical Abuse abuse. Some studies only include life threatening abuse, BEVERLY J. COLLETT,CHRISTINE CORDLE where there is intent to seriously harm or kill, whereas University Hospitals of Leicester, Leicester, UK others have defined it as any pattern of physical dis- [email protected] cipline or punishment, performed by a more powerful other individual to a person aged under 18 years, re- Definition sulting in physical injury such as marks, bruises and welts. Physical Abuse It is clearly important for investigators to define sexual Hitting, shaking, throwing, poisoning, burning or scald- and physical abuse in a more uniform way, taking into ing, drowning, suffocating, or otherwise causing phys- account the age at the time of abuse, the nature, the range ical harm to another person (DoH 2000a). and duration of the abuse, and the relationship of the perpetrator to the abused person. There are also prob- Sexual Abuse lemswith defining chronicpelvicpain,which represents Forcing or enticing another person to take part in sexual a very heterogeneous group of patients. It has been sug- activities, whether or not they are aware of what is gested that certain subgroups of patients with chronic happening. The activities may involve physical con- pelvic pain have a higher prevalence of sexual trauma tact, including penetrative (e.g. rape or buggery) and (Reiter et al. 1991). non-penetrative acts. They may include non-contact The other factor known to influence reported prevalence activities, such as involving another person in look- rates is the method of data collection. Most data is col- ing at, or in the production of, pornographic material lectedusingface-to-faceinterviewsorself-administered or watching sexual activities or encouraging another questionnaires. It has been suggested that lengthy inter- person to behave in sexually inappropriate ways (DoH views carried out in a certain style are more likely to re- 2000a). sult in abuse disclosure (Wyatt and Peters 1986). The issue of defining sexual abuse in practice is both Many of the early studies did not include control groups, complex and problematical. and although this has been addressed in more recent research, there is still lack of agreement over what Characteristics constitutes an appropriate control group. Groups are The role of abusive experiences in chronic pelvic pain rarely matched for such factors as chronicity of pain began to be the focus of investigation in the early 1980’s. and age. Age may have a role in abuse reporting. Briere Since then, there has been growing documentation of found that older women reported less sexual abuse prevalence rates for sexual and physical abuse during than younger women, and this was attributed to the 386 Chronic Pelvic Pain, Physical and Sexual Abuse older woman’s discomfort with speaking about sexu- A recent prospective investigation of childhood sexual ality (Briere 1992). Many studies are limited by small andphysicalabuseandneglectfoundnoassociationwith sample sizes and are based on a population of patients adultpain symptoms. However,unexplained painsymp- referred to speciality pain clinics. The findings from tomswere found to be associatedwithretrospectiveself- such clinics may not be generalisable to patients seen reports of all types of childhood victimisation. Perhaps in routine gynaecology clinics or in the primary care patientswhorecallchildhoodabuseandneglectperceive setting. There is a need for prospective studies with themselves to be trapped by a history that they cannot larger sample groups, although these are very difficult undo, and this in turn leads to helplessness and passivity to carry out. The methodological problems in this area (Raphael 2001). of research make it difficult to draw conclusions from In view of the high prevalence of lifetime abuse in thedatapresented. women with chronic pelvic pain, it has been argued A number of controlled studies, comparing women with that such women should be routinely asked about any chronic pelvic pain with women with pain in a different abuse history as part of their assessment. A number of site and women with no pain, have demonstrated an studies have shown that women with chronic pelvic increased prevalence of lifetime sexual abuse in the pain are rarely asked about assault, and only a small chronic pelvic pain group (Collett et al. 1998). In one minority of women volunteer this information to a study, this association only held for women who had gynaecologist or physician. When women were asked been abused as an adult, whether or not they had also whether they thought they should be asked, 90 per cent been abused as a child (Jamieson 1997). She also found answered in the affirmative (Robohm and Buttenheim that recent abuse was more likely to be associated with 1996). In addition to asking about any past abuse his- pain syndromes. tory, it is important to ensure that the women are not There ismuch lessinformation aboutphysicalabuse and involved in any ongoing abuse. Interpersonal sensitiv- chronic pelvic pain. One often quoted study by Rapkin ity in treating these women is particularly important. (1990), found that women with chronic pelvic pain were Concerns about trust in the doctor-patient relationship significantly more likely to report a history of childhood are common, and women with a history of childhood physical abuse than women receiving routine gynaecol- sexual abuse report more anxiety, embarrassment and ogy care or women with pain in another site. This find- vulnerability associated with a gynaecological exam- ing has not been replicated, although other workers have ination than other women (Robohm and Buttenheim suggested that a history of physical abuse may be more 1996). relevant than a history of sexual abuse in women with Linton found that more than 85 percent of the women chronic pelvic pain (Walling et al. 1994). in his sample did not believe that their history of abuse There has been considerable speculation in the literature affected their pain or their sex lives. Interventions, there- astothepossiblemechanismslinkingabusewithchronic fore, oriented directly towards abuse may be difficult to pelvic pain. It has been suggested by several workers incorporate into general pain treatment. Specific ther- that any type of childhood trauma, including violence, apy for the abuse may be the best way to deal with the separations, illnesses and neglect, would be a predictor problem if the patient has unresolved issues around the for pain proneness in adulthood. It is argued that trau- abuse, which are affecting her current functioning. matised individuals are more likely to feel vulnerable In summary, there are complex interactions between about their body and their health. Some psychologists child and adult abuse, depression, stressful life events conceptualise the pain amongst victims of sexual abuse and the occurrence of chronic pelvic pain, and clinicians as a defence against the overwhelming emotions con- need to take these psychosocial factors into considera- nected to the traumatic experience. Linton (1996) sug- tion when assessing and treating women with chronic gested an indirect relationship in that abuse may affect pelvic pain. pain by altering perception and ones ability to cope with Little research into physical and sexual abuse amongst pain. Support for this model comes from the knowledge patientswith chronicvulvar painsyndromesor vulvo- that abused patients have higher levels of depression and dynia has been undertaken. However, studies that have affective distress, and lower levels of perceived control, been undertaken show that there is a significantly higher compared to non abused patients. It may be that women incidence of sexual abuse and psychological distress with an abuse history have a tendency to report more in chronic pelvic pain patients, compared to women symptomsofanykindasafunctionofpsychologicaldis- with chronic vulvar pain and to gynaecologicalcontrols turbance. Although the data are consistent with the idea (Bodden-Heidrich et al. 1999, Reed et al 2000). that abuse may be instrumental in the development of chronic pain problems, we do not understand the mech- References anisms involved with this. It has been pointed out that abuse may be a correlate rather than a causal variable, 1. Bodden-Heidrich R, Kuppers V, Beckmann MW, Rechenberger I, Bender HG (1999) Chronic Pelvic Pain Syndrome (CPPS) and since abuse may be related to many lifestyle risk factors Chronic Vulvar Pain Syndrome (CVPS): Evaluation of Psycho- (Fry 1993). somatic Aspects. J Psychosom Obstet Gynecol 20:145–151 Chronic Pelvic Pain, Physical Therapy Approaches and Myofascial Abnormalities 387

2. Briere J (1992) Child Abuse Trauma. Theory and Treatment of Definition the Lasting Effects. SAGE Publications, London 3. Collett BJ, Cordle CJ, Stewart CR, Jagger C (1998) A Compar- A myofascial trigger point is a hyper-irritable spot ative Study of Women with Chronic Pelvic Pain, Chronic Non- within a taut band of skeletal muscle or muscle fas- Pelvic Pain and Those with no History of Pain Attending General cia which is painful on compression and gives rise to Practitioners. Br J Obstetrics Gynaecology 105:87–92 4. Department of Health (2000a) Working Together to Safeguard characteristic referral pain patterns, tenderness and C Children in Need and Their Families. The Stationary Office, Lon- autonomic phenomena. (Travell and Simons 1983) don, p 5 Myofascial pain syndrome has had various defini- 5. Fry RP, Crisp AH, Beard RW, McGuigan S (1993) Psychosocial tions over the years. An early definition identifies it as Aspects of Chronic Pelvic Pain with Special Reference to Sexual Abuse. A study of 164 women. Postgrad Med J 69:566–574 a regional muscle pain disorder that is characterized 6. Glaser D & Frosch S (1988) Child Sexual Abuse. Macmillan, by tender spots in taut bands of muscle that refer pain London, p 5 to areas overlying or distant to the tenderness. (Travell 7. Jamieson DJ, Steege JF (1997) The Association of Sexual Abuse 1990) The sensory, motor and autonomic phenomenon with Pelvic Pain Complaints in a Primary Care Population. Am J Obstet Gynecol 177:1408–1412 caused by myofascial trigger points is the currently 8. Linton SJ, Larden M, Gillow AM (1996) Sexual Abuse and acceptable definition. (Simons et al. 1999) In diagnos- Chronic Musculoskeletal Pain: Prevalence and Psychological ing a myofascial pain syndrome, the specific muscle or Factors. Clinical Journal of Pain 12:215–221 muscle group must be specified. 9. Raphael KG, Widom CS, Lange G (2001) Childhood Victimiza- tion and Pain in Adulthood: A Prospective Investigation. Pain 92:283–293 Characteristics 10. Rapkin AJ, Kames LD, Darke LL, Stampler FM, Nabiloff BD (1990) History of Physical and Sexual Abuse in Women with Chronic pelvic pain has many definitions. At this time, Chronic Pelvic Pain. Obstet Gynecol 76:92–95 there is not a universally accepted definition of chronic 11. Reed BD, Haefner HK, Punch MR, Roth RS, Gorenflo DW, Gillespie BW (2000) Psychosocial and Sexual Functioning in pelvic pain, which mirrors the problems with defin- Women with Vulvodynia and Chronic Pelvic Pain. J Reprod Med ing myofascial pain syndrome. In 1989, the American 45:624–632 College of Obstetricians and Gynecologists defined 12. Reiter RC, Gambone JC (1990) Demographic and Historic Vari- chronic pelvic pain as pain that had persisted for six ables in Women with Idiopathic Chronic Pelvic Pain. Obstet Gy- necol 75:428–432 months or longer and of such severity that it signifi- 13. Reiter RC, Shakerin LR, Gambone JC, Milburn AR (1991) Cor- cantly impacted the ability to function and relationships. relation Between Sexual Abuse and Somatisation in Women with (Steege 1989) Six common characteristics associated Somatic and Nonsomatic Chronic Pelvic Pain. Am J Obstet Gy- with chronic pelvic pain were: duration of 6 months or necol 165:104–109 14. Robohm JS, Buttenheim M (1996) The Gynaecological Care Ex- longer, incomplete relief by most previous treatments, periences of Adult Survivors of Childhood Sexual Abuse: A Pre- significantly impaired function at home or work, signs liminary Investigation. Women Health 24:59–75 of depression, pain out of proportion to pathology and 15. Toomey TC, Hernandez JT, Gittelman DF, Hulka JF (1993) Rela- altered family roles” (Steege 1989). Over time, defining tionship of Sexual and Physical Abuse to Pain and Psychological Assessment Variables in Chronic Pelvic Pain. Pain 53:105–109 chronic pelvic pain evolved to be based on the duration, 16. Walker E, Katon W, Harrop-Griffiths J, Holm L, Russo J, Hickok the anatomical and physical basis or psychological LR (1988) Relationship of Chronic Pelvic Pain to Psychiatric characteristics of the pain. (Steege et al. 1993) Chronic Diagnoses and Childhood Sexual Abuse. Am J Psychiatry 145:75–80 pelvic pain in the absence of obvious pathology is de- 17. Walling MK, Reiter RC, O’Hara MW, Milburn AK, Lilly G, fined by the International Association for the Study of Vincent SD (1994) Abuse History and Chronic Pain in Women: Pain as chronic or recurrent pelvic pain that appears Prevalence of Sexual Abuse and Physical Abuse. Obstet Gy- to have a gynecologic origin but without a definitive naecol 84:193–199 18. Wyatt GE, Peters SD (1986) Methodological Considerations in lesion or cause (Mersky and Bogduk 1994). Research on the Prevalence of Child Sexual Abuse. Child Abuse Many pain syndromes are included within the domain Negl 10:241–251 of chronic pelvic pain. Vulvodynia, vulvar vestibulitis, urethral syndrome, interstitial cystitis, penile pain, or- chialgia, perineal pain, chronic prostatitis, prostadynia, proctalgia fugax, are a few of the pain syndromes asso- Chronic Pelvic Pain, Physical Therapy ciated with chronic pelvic pain. Approaches and Myofascial Confusion in defining chronic pelvic pain has not been limited to medical management of the female. In 1995, Abnormalities the National Institutes of Health (NIH) proposed that RHONDA K. KOTARINOS the definition of Chronic Pelvic Pain Syndrome in men Long Grove, IL, USA would be based on “the presence of genito urinary pain [email protected] and the absence of uropathogenic bacteria by standard microbiological methodology.” (Kreiger et al. 1999) ChronicAbacterialProstatitis/ChronicPelvicPainSyn- Synonyms drome is a new category (Category III) established by Myofascial trigger point; myofascial pain syndrome NIH. The specific definition being discomfort of pain 388 Chronic Pelvic Pain, Physical Therapy Approaches and Myofascial Abnormalities in the pelvic region (for at least three months, variable ders and skeletal malalignment, have been described. voiding and sexual symptoms with no demonstrable in- (Punch et al. 1994) Within each category the specific fection). diagnostic criteria, typical muscle groups implicated Chronic pelvic pain in both sexes continues to be a diag- for each category and the therapeutic treatment plan for nostic and therapeutic challenge. Musculoskeletal dys- the dysfunction was delineated. (Table 1) function is emerging as a common denominator in the Punch et al. found that 35 women of 160 that were re- manifestation of chronic pelvic pain in both men and ferred to their university hospital clinic had a muscu- women. loskeletal cause for their chronic pelvic pain. Physical Two major categories of musculoskeletal dysfunction therapy management as described (Table 1) and trigger associated with chronic pelvic pain are myofascial point injections, being determined on an individual ba- dysfunction and somatic dysfunction (Grunman sis, was administered to the subjects. Sixty-nine percent 1989). Several studies have investigated the most com- reported total or significant pain relief. mon components of the somatic dysfunction. Somatic Pelvic floor dysfunction is well established as being a dysfunction describes dysfunction within the mus- factor in many of the syndromes associated with chronic culoskeletal system that is characterized by skeletal pelvic pain. Weiss performed a retrospective study of asymmetry, altered articular mobility and tissue texture 52 patients that presented to him with a diagnosis of ei- abnormality. In a retrospective study performed at the ther interstitial cystitis or urgency-frequency syndrome. University of Tennessee, 75 % of 132 patients were (Weiss2001) Manualphysicaltherapytothe pelvic floor found to have a “typical pelvic pain posture.” (King et includes trigger point release techniques with and with- al. 1991) A lordosis of the lumbar spine with an anterior out injections, active and passive stretching, and neuro- pelvic tilt were the common components of the typical muscular reeducation. Eighty-three percent of the pa- pelvic pain posture. Other common musculoskeletal tients with urgency-frequency syndrome had moderate dysfunctions identified in the typical pelvic pain posture tocompleteresolutionoftheirsymptoms.Ofthepatients patients included decreased iliopsoas length, decreased with a diagnosis of interstitial cystitis, 70 % had marked range of motion of lumbar spine flexion, decreased or moderate improvement. range of motion of hip rotation and increased pelvic Another retrospective study investigated musculoskele- floor muscle tone. tal pelvic pain in a pediatric and adolescent gynecology Individualized physical therapy treatment plans were setting. (Schroeder et al. 2000) To be included in the developed and executed for each patient. Physical ther- study, the subject had to have a diagnosis of pelvic pain apy treatment included active and passive stretching, not explained by a standard gynecologic work up or no active and passive lumbar flexion exercises, abdominal response to standard treatments for known endometrio- muscle strengthening, and joint mobilization. Other sis. Of the sixty three patients who met the inclusion cri- physical therapy modalities included massage, external teria, 50 % had a final diagnosis of musculoskeletal pain supports, moist heat and electrotherapy. Education as to with 10 % having trigger points as a causative factor. proper posturing for lifestyle factors was included in the Physical therapy management resulted in complete res- physical therapy management. Complete or significant olution in 20 / 21 (95.24 %) who completed treatment. relief was achieved in 70 % of the chronic pelvic pain Fivesubjectsunderwenttriggerpointinjectionswith4/5 patients that received physical therapy treatment. Adler (80 %) responding positively. investigated musculoskeletal structure as sources of Inthepast,pelvicpaincomplaintsinmostmenhavebeen undiagnosed pelvic and / or abdominal pain. (Adler attributed to prostate pathology, even when no pathol- 2003) Twenty women that had continued pain after ogy could be demonstrated. More recent studies are now hysterectomy for pelvic / abdominal pain were referred demonstrating that there is a high incidence of muscu- to physical therapy, primarily for concomittent low loskeletal dysfunction in men who present with chronic back pain. During the comprehensive orthopedic phys- pain syndrome type III A and III B. (Hetrick et al. 2003) ical therapy evaluation, the subjects were to inform the This study compared pelvic muscle function in 62 men therapist if their chief complaint could be reproduced with chronic pelvic pain syndrome III to 89 healthy men by palpation of various musculoskeletal structures. A withoutpelvicpain.Increasedpelvicmuscletenderness, positive result was documented when their pain was increased pelvic floor muscle tone, greater incidence of reproduced to a level of 80 % or higher. pelvicfloormusclespasmandagreaterincidenceofsub- Seventeen of the twenty subjects (85 %) reported that stitution of other muscles when an isolated pelvic floor their pain was reproduced during the physical therapy contractionwasattemptedwasfoundinthesubjectswith evaluation. Mechanical dysfunctions, poor postural a diagnosis of chronic pelvic pain syndrome III A & III habits and myofascial trigger points were musculoske- B. tal factors that were determined to be elements of pelvic Musculoskeletal dysfunction is slowly, but surely, be- and / or abdominal pain. ing established as one of many contributing factors as- Two major categories of musculoskeletal dysfunction sociated with chronic pelvic pain in men and women. Si- associated with chronic pelvic pain, myofascial disor- multaneously, health care professionalsare learningthat Chronic Pelvic Pain, Physical Therapy Approaches and Myofascial Abnormalities 389

Chronic Pelvic Pain, Physical Therapy Approaches and Myofascial Abnormalities, Table 1 Assessment of Musculoskeletal Dysfunction (Punch et al 1994).

1. Typical Muscle Groups Affecting Pelvic Function (most common muscles emphasized) Pelvic Floor Levator Ani C Coccygeous Anterior Action Abdominal Wall Iliopsoas Rectus Fermoris Sartorius Quadratus Femoris Gracilis Posterior Action Gluteus Maximus Hamstrings Quadratus Lumborum Piriformis Lateral Rotators Medial Action Adductor Magnus Adductor Longus Adductor Brevis Pectineus Lateral Action Tensor Fascia Latae Gluteus Medius Gluteus Minimus 2. Articular Dysfunctions Relevant to Pelvic Pain Pubic Symphysis Sacroiliac Joints Lumbosacral Junction Lumbar Spine 3. Screening for Musculoskeletal Dysfunctions Clinical Picture Exacerbated by Movement, Postures or Positioning Stiffness Poorly Localized Deep Ache, Tightness or Burning May become more Diffuse Over Time 4. Treatment of Musculoskeletal Dysfunction Restore ROM for involved muscles with Stretching protocol emphasizing Twice Daily Home Exercises and Duration of Stretch (15–30 Seconds)

Modalities to facilitate ROM Ice Heat Fluorimethane Spray Ultrasound Trigger Point Injections Post Re-education Progressive Strengthening Program 390 Chronic Postoperative Pain a multidisciplinary approach is more likely to be effec- 7. Mersky H, Bogduk N (1994) Classification of Chronic Pain. IASP tive in managing chronicpelvic pain. (Wesselman 1998) Press 8. Punch MR, Roth RS, Pominville L (1994) Musculoskeletal Ori- A comprehensive multidisciplinary pain clinic should gins of Chronic Pelvic Pain in Women. American Society for include representation from gynecologists, urogynecol- Psychosomatic Obstetrics and Gynecology, 22nd Annual Meet- ogists, urologists, anesthesiologists, gastroenterologist, ing. San Diego, California. Poster Presentation colorectal surgeons, physical therapists and various al- 9. Shroeder B, Sanfilippo J, Hertweck S (2000) Musculoskeletal ternative medicine disciplines. Pelvic Pain in a Pediatric and Adolescent Gynecology Practice. Journal of Pediatric and Adolescent Gynecology 13:90 Physical therapy is developing into an essential service 10. Simons D, Travell J, Simons L (1999) Myofascial Pain and Dys- in treating chronic pelvic pain. All patients should be function: The Trigger Point Manual, vol 1, 2nd edn evaluated for musculoskeletal dysfunction and then 11. Steege J (1989) Chronic Pelvic Pain. ACOG Technical Bulletin managed with an individualized treatment plan that ad- 129:1–6 12. Steege J, Stout A, Somkuti S (1993) Chronic Pelvic Pain in dresses the skeletal and myofascial dysfunctions noted. Women: Toward and Integrated Model. Obstetric and Gynecol- A comprehensive physical therapy evaluation would ogy Survey 48:95–110 include a postural evaluation, gait analysis, muscle 13. Travell J, Simons D (1983) Myofascial Pain and Dysfunction: strength assessment, articular range of motion of the The Trigger Point Manual, vol 1, 1st edn trunk and extremities, and muscle length. 14. Travell JG (1990) Chronic Myofascial Pain Syndromes Advances in Pain Research and Therapy 17:129–137 A soft tissue evaluation should also be done. The tissues 15. Weiss J (2001) Pelvic Floor Myofascial Trigger Points: Man- to be assessed with this evaluation are the connective, ual Therapy for Interstitial Cystitis and the Urgency-Frequency muscle and neural tissues. Neural tissue assessment Syndrome. J Urol 166: 2226–2231 would be looking for adverse neural tension.Pain 16. Wesselmann U (1998) Management of Chronic Pelvic Pain. In: Arnoff G (ed) Evaluation and Treatment of Chronic Pain. symptoms can develop from neural tissue that has Williams & Wilkens, Baltimore, pp 269–279 impaired movement and elasticity. (Butler 1991) The physical therapist should also perform athorough pelvic floor exam. An internal exam would include a localized soft tissue assessment, as well as assessment of the Chronic Postoperative Pain pelvic floor strength and range of motion. An instru- mented evaluation of the pelvic floor with EMG or pressure biofeedback can be useful, but is not required. Iatrogenic Causes of Neuropathy The individualized treatment plan would address all dysfunctions noted. Treatment could include postural corrective exercise, active and passive stretching, neuromuscular reeducation, progressive strengthening, and Chronic Post-Surgical Neuralgia joint mobilization. Manual therapy techniques would be employed to address the soft tissue dysfunctions. They couldinclude myofascialmanipulation, connective Iatrogenic Causes of Neuropathy tissue manipulation, neural mobilization / stretching, muscle energy techniques, and myofascial release. Adjunctive management with modalities of physical therapy could include ice, heat, ultrasound, diathermy, Chronic Post-Surgical Pain Syndromes electrical stimulation (TENS, high volt pulsed gal- vanic, interferential, etc.), biofeedback, and trigger point injections. Definition A pain lasting more than three months, persisting after References healing from a surgical procedure. Chronic post surgi- 1. Adler T, Personius W, Lamb R et al. (2003) Abstract Presentation. cal pain syndromes are most often the consequence of a Musculoskeletal Symptoms Mimicking Pathological Pelvic Pain peripheral nerve injury directly or indirectly caused by in Women. The International Pelvic Pain Society 10th Scientific Meeting on Chronic Pelvic Pain the surgical intervention. Proper identification of the in- 2. Butler D (1991) Mobilization of the Nervous System. Churchill jured nerve is crucial for adequate pain management. Livingstone, Melbourne, p vii Iatrogenic Causes of Neuropathy 3. Greenman P (1989) Principles of Manual Medicine. Williams & Wilkins, Baltimore 4. Hetrick D, Ciol M, Rothman I et al. (2003) Musculoskeletal Dys- function in Men with Chronic Pelvic Pain Syndrome Type III: A Case Control Study. J Urol 170:828–831 5. King P, Myers L, Ling F et al. (1991) Journal of Psychosomatics, Chronic Relapsing Polyneuropathy Obstetrics and Gynecology 12:87–98 6. Kreiger JN, Nyberg L, Nickel J (1999) NIH Consensus Definition and Classification of Prostatitis. Journal of American Medical Chronic Inflammatory Demyelinating Polyneuropa- Association thy Chronicity, Prevention 391

Reference Chronic Tension-Type Headache Wolfe F, Smythe H, Yunus M, et al. (1990) The Ameri- canCollegeofRheumatology.CriteriafortheClassifica- Definition tion of Fibromyalgia. Report of the Multicenter Criteria Classification of International Headache Society de- Committee. Arthritis Rheum 33:160-172 C scribing a subtype of chronic daily headache as very frequent headaches (≥ 15 days per month for at least 3 months, ≥ 180 days per year). Pain has 2 of the following characteristics: pressing or tightening quality, Chronicity, Prevention mild or moderate intensity, bilateral location, and not MICHAEL K. NICHOLAS aggravated by routine physical activity. Headache has University of Sydney, Royal North Shore Hospital, St. only one of the following: photophobia, phonophobia Leonards, NSW, Australia or nausea and does not have moderate or severe nausea [email protected] and no vomiting. Headache is not attributed to another disorder, an individual’s use of analgesics or other acute medication, and is ≤ 10 days per month. Synonyms Chronic Daily Headache in Children Secondary Prevention New Daily Persistent Headache Definition Interventionsaimed at reducing the risk of a recently in- Chronic Vulvar Pain jured person developing chronic pain and disability. Characteristics Gynecological Pain and Sexual Functioning The natural history of pain following injury, especially non-specific injuries like low back pain, is that such pain typically eases to minimal levels within 1–12 weeks. If Chronic Widespread Allodynia pain persists beyond 12 weeks it has been reclassified as ‘chronic’ (Merskey and Bogduk 1994) and may last for prolonged periods. However, recurrences of low back Definition pain, once it has settled, are common. A systematic re- The fibromyalgia syndrome can now be viewed phys- viewof published evidencebyPengeletal.(2003) found iologically as the classical human model for chronic, that recurrences of low back pain in the first year after widespread allodynia. initial onset were in the region of 70%. Epidemiologi- Allodynia cal findings of chronic pain, using the 3–month defini- Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- tion, indicate that around 20% of adults in western in- ondary) dustrialisedcountriesreportexperiencingsuchpain(e.g. Blyth et al. 2001). Importantly, however, at least half of this group report that persisting pain was having little impact on their lives, indicating that having persisting pain does not, by itself, mean that the person will be dis- Chronic Widespread Pain abled by it. In contrast, the remaining half of those with persisting pain reported that it was interfering in their Synonyms lives to some degree, a proportion reporting substantial impact on their lifestyles due to pain. CWP Given the evidence that the transition from acute to chronic pain, and the concurrent development of dis- Definition ability, can be modulated by psychological and envi- Chronic widespread pain refers to pain in the left side of ronmental (or social) factors, a number of studies have thebody, pain in therightsideof thebody,pain abovethe described attempts to modify these psychosocial fac- waist, and pain below the waist. In addition, axial pain tors to prevent the development of secondary disability. (cervical, thoracic or low back) must be present and pain Some interventions have addressed psychological risk must have persisted for at least three months (Wolfe F, factors, such as beliefs, fears, coping strategies, and Smythe H, Yunus M, et al. 1990). avoidance and escape behaviours. Other interventions Physical Exercise have addressed environmental or social risk factors, Fibromyalgia such as workplace arrangements, or compensation 392 Chronicity, Prevention factors. A number of controlled treatment studies, ad- scribed by Bendix et al. 1998). Patients were followed dressing these risk factors in people with acute and up 14–months post-treatment. sub-acute musculoskeletal pain conditions, have now The results reported by Haldorsen et al. indicated that been reported. injured workers assessed to have a good prognosis of WaddellandBurton(2000),intheirsystematicreviewof return to work achieved good outcomes, regardless of the treatment literature for acute and sub-acute low back whichever level of intervention they received. While pain, concluded that there is strong evidence that advice those with only medium prognostic profiles benefited tocontinueordinaryactivitiesofdailylivingasnormally equally from the light and intensive multidisciplinary as possible despite the pain, can give equivalent or faster programs,butnotfrom‘standardorordinary’care.How- symptomatic recovery from acute symptoms, and leads ever, those assessed to have a poor prognosis responded to shorter periods of work loss, fewer recurrences and best to the intensive multidisciplinary treatment, with lesswork lossthe following year than “traditional” med- significantly better return to work rates up to 14–months ical treatment. Specifically, they reported that interven- post-treatment than light mobilisation (55 vs. 37%). tions containing education (aimed at managing pain and Recently, Schonstein et al. (2003) reported the results disability, as opposed to simply anatomy/physiology), of a systematic review of randomised and controlled reassurance and advice (to stay active), progressive fit- physiotherapy exercise programs for injured workers. ness exercises, and pain management advice (using be- This review concluded that there is evidence that the havioural principles) were likely to reduce the risks of programs “that include a cognitive-behavioural ap- developing chronic, disabling pain. Waddell and Burton proach can reduce the number of sick days lost for also found that there was moderate evidence that such workers with chronic back pain” (p. 5). They also con- approaches were more effective, if they were combined cluded that “there is no evidence for or against specific with organisational (workplace) arrangements aimed at exercises which are not accompanied by a cognitive- facilitating return to work. behavioural approach being effective” (p. 5) (in terms Since that review, a number of randomised controlled of sick days lost, for both acute and chronic back pain studies have provided further evidence that interven- cases). Thus, there is strong evidence that encourage- tions aimed at psychosocial risk factors were effective ment to resume normal activities or exercises, using at preventing the development of chronic disability. For cognitive-behavioural methods, such as goal setting, example, Linton and Anderson (2001) demonstrated consistent reinforcement for progress, and graduated in- that a brief (six 2–hour group sessions) cognitive- crements in activities and exercises can limit secondary behavioural pain management (conducted by a clinical disability due to persisting musculoskeletal pain. psychologist) intervention, for workers (who were still working but increasingly missing days at work due to References back pain) with sub-acute low back pain (defined by 1. Bendix BT, Bendix A, Labriola M, Boekgaard P (1998) Func- them as 6–8 months), was more effective than standard tional Restoration for Chronic Low Back Pain. Two Year Follow- rehabilitation and information provision (via booklets) Up of Two Randomized Clinical Trials. Spine 23:717–725 2. Blyth FM, March LM, Brnabic AJM, Jorm LR, Williamson M, in terms of lost sick days and reduced use of healthcare. Cousins MJ (2001) Chronic Pain in Australia: A Prevalence These effects were still present a year later, and there Study. Pain 89:127–134 was a 9–fold advantage for the cognitive-behavioural 3. Haldorsen EM, Grasdal AL, Skouen JS, Risa AE, Kronholm K, approach over the alternative interventions in terms of Ursin H (2002) Is There a Right Treatment for a Particular Pa- tient Group? Comparison of Ordinary Treatment, Light Multi- lost work days. disciplinary Treatment, and Extensive Multidisciplinary Treat- Haldorsen et al. (2002) compared three different treatment for Long-Term Sick-Listed Employees with Musculoskele- ment modalities with a large sample of injured workers tal Pain. Pain 95:49–63 with a range of musculoskeletal conditions who still 4. Indahl A, Velund L, Reikeraas O (1995) Good Prognosis for Low Back Pain when Left Untampered: A Randomized Clinical Trial. had jobs, but had been sick-listed for at least 8–weeks in Spine 20:473–477 the previous 2–years. The patients were first classified 5. Linton SJ, Andersson T (2000) Can Chronic Disability be Pre- according to three prognostic categories for likely re- vented? A Randomized Trial of a Cognitive-Behavioral Inter- turn to work (based on a combination of questionnaire vention and Two Forms of Information for Spinal Pain Patients. Spine 25:2825–2831 evaluation of psychosocial factors and physiotherapy 6. Merskey H, Bogduk N (1994) Classification of Chronic Pain. assessment). Patients in each category were then ran- Descriptions of Chronic pain Syndromes and Definitions of Pain domly assigned to one of the different treatments. The Terms, 2nd edn. IASP Press, Seattle treatments consisted of ‘ordinary treatment’ (referral 7. Pengel LH, Herbert R, Maher CG, Refshauge KM (2003) Acute Low Back Pain: Systematic Review of its Prognosis. to a general practitioner combined with some phys- BMJ 327:323–327 iotherapy); ‘light multidisciplinary treatment’ (like a 8. Schonstein E, Kenny DT, Keating J, Koes BW (2003) Work Con- light mobilisation program or encouragement to resume ditioning, Work Hardening and Functional Restoration for Work- normal activities, similar to that reported by Indahl et ers with Back and Neck Pain. Meta-Analysis. Cochrane Database of Systematic Reviews (1) al. 1995); and ‘extensive multidisciplinary treatment’ 9. Waddell G, Burton K (2000) Evidence Review. In: Carter JT, Bir- (4–weeks of an intensive program similar to that de- rell LN (eds) Occupational Health Guidelines for the Manage- Cingulate Cortex, Functional Imaging 393

ment of Low Back Pain at Work – Principal Recommendations. Faculty of Occupational Medicine, London

Chung Model C Animal Models and Experimental Tests to Study No- ciception and Pain Neuropathic Pain Model, Spinal Nerve Ligation Model Retrograde Cellular Changes after Nerve Injury Spinal Nerve Ligation Model

Cingulate Cortex, Functional Imaging, Figure 1 Anatomy of the human cingulate cortex. The cingulate cortex is delimited ventrally by the corpus CIDP callosum. The full line corresponds to its approximate anterior, posterior and dorsal borders. The sub-regions of the cingulate cortex are delimited Chronic Inflammatory Demyelinating Polyneuropa- by dotted lines according to the corresponding Brodmann areas identified thy by numbers. Regions of the cingulate cortex can also be divided based on their location relative to the body of the corpus callosum (dorsal = supracallosal; ventral = subcallosal) and to the anterior (rost = rostrum and genu) or posterior (spl = splenium) parts of the corpus callosum. The subgenual area corresponds to BA25, the perigenual area corresponds to Cingulate Cortex BA33 and to the anterior part of BA24 and BA32 and the retrosplenial area corresponds to BA26, BA29 and BA30. Definition Cortical tissue also referred to as Limbic Cortex or Cin- (ACC) comprises Brodmann area 25 (BA25) below gulate Gyrus that encircles the hippocampus and other the rostrum of the corpus callosum and BA24, BA32 structures of the limbic region. It is sometimes inter- and BA33 above the body and curving around the genu rupted as treatment for obsessive compulsive disorder of the corpus callosum. The posterior region of the cin- or pain. gulate gyrus corresponds to BA23, BA31, BA30, BA29 Cingulate Cortex, Nociceptive Processing, Behav- and BA26. Traditionally, the cingulate cortex is consid- ioral Studies in Animals ered part of the limbic system, which is associated Pain Treatment, Intracranial Ablative Procedures with emotions. Furthermore, functional brain imaging studies have shown that sub-regions of the cingulate cortex, in particular within the anterior cingulate cortex Cingulate Cortex, Effect on Pain-Related (ACC), are activated in response to painful stimuli and Behavior in Humans therefore may be involved in pain related functions. Seeking to explain these findings, several theoretical Pain Processing in the Cingulate Cortex, Behavioral models have placed the cingulate cortex at the interface Studies in Humans of the sensory, affective, cognitive, skeletomotor and visceromotor systems (e.g. Vogt 2005). Characteristics Cingulate Cortex, Functional Imaging Nociceptive Activation of the Cingulate Cortex PIERRE RAINVILLE Almost all functional brain-imaging studies of pain Department of Stomatology, Faculty of Dental using positron emission tomography (PET) or Medicine, University of Montreal, Montreal, QC, functional magnetic resonance imaging (fMRI) have Canada found pain related activation of the ACC (Apkarian et [email protected] al. 2005). In these studies, experimental pain is produced using noxious thermal, mechanical, electrical or Definition chemical stimuli applied to the skin or viscera of normal The cingulate cortex is a part of the medial frontal human volunteers. Peaks of activation are found most and parietal cerebral cortices situated immediately reliably in the caudal part of the supracallosal ACC and above the corpus callosum and curving around its occasionally in the perigenual area. This activation is most anterior part. The human cingulate cortex can consistent with the projection of nociceptive neurons be subdivided into several sub-regions as shown in from the medial and intralaminar nuclei of the thalamus Fig. 1. Histologically, the anterior cingulate cortex to BA24 (Vogt 2005). 394 Cingulate Cortex, Functional Imaging

Functional Role of the ACC in Pain and Pain Modulation A role for the ACC in pain modulation is also supported by studiesinvestigating theopioid system. Theμ-opioid Painisacomplexexperiencedescribedalong sensory- receptorisfoundinmanybrainareasincludingtheACC. discriminativeand affective-motivationaldimensions In a PET study, the systemic administration of the μ- influenced by cognitive processes and associated with opioidagonistfentanylincreasedactivityintheACCina somato-motor and viscero-motor responses. The ACC control condition without pain and reduced pain evoked may contribute to each of these aspects. Levels of activitywithinthethalamusandcorticalareas,including activation in the supracallosal ACC have been corre- theACC(Caseyetal.2000).Thisdecreaseinpainrelated lated with the subjective reports of pain (Coghill et ACC activity was associated with a decrease in reported al. 2003). More specifically, activity in certain regions pain intensity and pain unpleasantness, as well as with of the ACC may reflect the affective-motivational pain related heart rate responses. Endogenous activation dimension of pain, as the modulation of pain unpleas- of the μ-opioid system in the ACC and other areas has antness, independently of pain intensity, changes ACC also been associated with decreased affective ratings of activity (Rainville 2002). Furthermore, the affective- pain(Zubietaetal.2001)andsuggestedasanunderlying motivational dimension of pain is strongly influenced mechanism of placebo analgesia (Petrovic et al. 2002). by cognitive-evaluative processes shown to be highly Beyond Nociception: the ACC and the Mental Representation dependent upon the function of the ACC (Price 2000). of Pain The supracallosal ACC is part of higher order systems involved in the voluntary regulation of behavioral and In addition to its roles in the experience of pain and in the motor responses. Therefore, pain related activation in modulation of pain, the ACCmay also be activated inthe this area probably reflects motivational aspects of pain contextofpain,intheabsenceofanoxiousstimulus.This behaviors and conscious processes involved in pain re- has been suggested by studies showing that ACC activa- lated responses. Similarly, the perigenual region of the tion may occur during the anticipation of pain, prior to ACCisinvolved in physiologicalarousal, afundamental the presentation of a painful stimulus (Rainville 2002). aspect of emotion and a critical component of pain re- However, pain related activation of the ACC may also be lated affective responses. Changes in activity within the observed when the subject is merely thinking about, but perigenual area have been associated with physiological not expecting or anticipating, an actual painful stimulus arousal during emotional experiences, the performance to the self. For example, ACC activity has been reported of motor and cognitive tasks and the anticipation of pain in response to visual stimuli depicting a hand or foot re- (see Rainville 2002). However, the precise nature of the ceivingapainfulstimulus(Morrisonetal.2004;Jackson relationshipbetweenpainrelatedactivityintheACCand etal. 2005), videosshowing apatientdisplayingpain be- physiological arousal remains to be demonstrated. Fi- haviors (Botvinick et al. 2005) or cues indicating that a nally,posteriorregionsofthecingulatecortexmaybein- loved one is receiving a painful stimulus (Singer et al. volved in the representation of viscerosomatic changes, 2004). ACC activation during both pain experiences and but the functional role of this area in pain is unclear. in response to cues signaling impending pain in the self The ACC is also critically involved in cognitive pro- or pain in others may reflect a general involvement of cesses, as demonstrated by innumerable brain imaging this structure in the mental representation of pain. studies showing activation in this area during the perfor- A Multifunctional and Integrative Role for the ACC in Pain mance of cognitive tasks (see Rainville 2002). However, From this brief overview of brain imaging studies, it is this activation is typically observed in a more dorsal clear that the role of the ACC in pain is multifaceted. region, within BA32, whereas pain related activation The ACC receives ascending nociceptive input and is in is more ventral, in BA24. Nonetheless, regions of the an excellent position to integrate this information with ACC involved in cognitive processes may be involved signals related to the motivational, emotional and under- in the modulation of pain. Studies investigating the lying viscerosomatic state of the organism. The ACC is modulation of pain by hypnosis (Rainville et al. 1999), also well positioned to modify cognitive and behavioral placebo analgesia (Petrovic et al. 2002; Wager et al. prioritiesbasedonthebiologicalsignificanceofpainsig- 2004) and distraction (Valet et al. 2004) have in fact nals.Inaddition,theACCmaycontributetohigherorder shown some activation in the dorsal anterior region of processesinvolved in pain modulation. Finally,theACC the ACC (typically in BA32). This activation is associ- may play a critical role in the mental representation of ated with a decrease in the response to painful stimuli pain in self and in others. This may provide a fundamen- in other pain related areas such as the somatosensory tal neurobiological basis for social interactions and pain cortices and is consistent with a reduction in the pain empathy. reported by subjects. In some of these studies, activation of the ACC has also been found to correlate with References activity in the brain stem, consistent with the activation 1. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Hu- of the periaqueductal grey area (PAG), a key structure man brain mechanisms of pain perception and regulation in health of descending pain inhibitory mechanisms. and disease. Eur J Pain 9(4):463–484 Cingulate Cortex, Nociceptive Processing, Behavioral Studies in Animals 395

2. Botvinick M, Jha AP, Bylsma LM et al. (2005) Viewing facial natureoftheneuroanatomicalandneurochemicalmech- expressions of pain engages cortical areas involved in the direct anisms underlying the processing of higher order pain experience of pain. Neuroimage 25:312–319 3. Casey KL, Svensson P, Morrow TJ et al. (2000) Selective opi- processing in rodents is beginning to be understood. ate modulation of nociceptive processing in the human brain. J Characteristics Neurophysiol 84:525–533 C 4. Coghill RC, McHaffie JG, Yen YF (2003) Neural correlates of The experience of pain consists of affective and sensory interindividual differences in the subjective experience of pain. Proc Natl Acad Sci USA 100:8538–8542 components. It is the affective component that under- 5. Jackson PL, Meltzoff, AN, Decety J (2005) How do we perceive lies the suffering that accompanies many persistent pain the pain of others? A window into the neural processes involved states. An understanding of the neural substrates medi- in empathy. Neuroimage 24:771–779 ating the affective processing of nociceptive stimulation 6. Morrison I, Lloyd D, di Pellegrino G et al. (2004) Vicarious responses to pain in anterior cingulate cortex: is empathy a mul- is essential for the development of successful pain thera- tisensory issue? Cogn Affect Behav Neurosci 4:270–278 pies. The anterior cingulate cortex (ACC) is one brain 7. Petrovic P, Kalso E, Petersson KM et al. (2002) Placebo region that has been implicated in the affective compo- and opioid analgesia– imaging a shared neuronal network. nent of pain with relatively little involvement in sensory Science 295:1737–1740 8. Price DD (2000) Psychological and neural mechanisms of the processing (Vogt1985). For instance, ACC neuronal ac- affective dimension of pain. Science 288:1769–1772 tivity increases in direct response to and / or anticipa- 9. Rainville P (2002) Brain mechanisms of pain affect and pain tion of noxious, but not nonnoxious chemical, mechan- modulation. Curr Opin Neurobiol 12:195–204 ical and thermal stimuli (Hutchison et al. 1999; Koyama 10. Rainville P, Hofbauer RK, Paus T et al. (1999) Cerebral mechanisms of hypnotic induction and suggestion. J Cogn et al. 2001). Surgical cingulotomy and cingulectomy, or Neurosci 11:110–125 transection of the cingulum bundle and cingulate cortex 11. Singer T, Seymour B, O’Doherty J et al. (2004) Empathy for respectively, decrease the affective response to noxious pain involves the affective but not sensory components of pain. Science 303:1157–1162 stimuli but do not alter ability to localize the unpleas- 12. Valet M, Sprenger T, Boecker H et al. (2004) Distraction modu- ant stimulus. Brain imaging studies consistently report lates connectivity of the cingulo-frontal cortex and the midbrain increased ACC neuronal activity preceding and during during pain–an fMRI analysis. Pain 109:399–408 the presentation of an acute noxious stimulus or during 13. Vogt BA (2005) Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci 6:533–544 persistent pain conditions. Hypnotic suggestions to se- 14. Wager TD, Rilling JK, Smith EE et al. (2004) Placebo-induced lectivelydecreasepainaffectpriortoandduringnoxious changes in FMRI in the anticipation and experience of pain. Sci- stimulationresultedindecreasedratingsofpainunpleas- ence 303:1162–1167 antnessbutnotpain intensity (Rainville etal. 1997). Ma- 15. Zubieta JK, Smith YR, Bueller JA et al. (2001) Regional mu opioid receptor regulation of sensory and affective dimensions nipulating pain unpleasantness by hypnotic suggestion of pain. Science 293:311–315 also changed the regional cerebral blood flow (rCBF) in the ACC but not in the somatosensory cortex, providing evidence that the ACC is involved in the processing of Cingulate Cortex, Nociceptive pain-related affect but not in the sensory processing of noxious stimulation (Rainville et al. 1997). Processing, Behavioral Studies in Animals Most of the studies that have examined supraspinal PERRY N. FUCHS,VERNE C. COX focal brain stimulation or microinjection of drugs Department of Psychology, University of Texas at into discrete nuclei have measured reflexive behav- Arlington, Arlington, TX, USA ioral response to acute noxious stimulation. Indeed, [email protected] activation of various subcortical, brainstem and spinal cord systems produces antinociception, as revealed Synonyms by an increase in the threshold or latency to respond to noxious stimulation. In most studies, it is assumed Anterior cingulate cortex; pain affect; Nociceptive Pro- that manipulations of limbic system structures alter cessing in the Cingulate Cortex, Behavioral Studies in pain processing through selective modulation of pain Animals affect (Donahue et al. 2001). However, the majority of past and current behavioral paradigms cannot provide Definition definitive information about the aversive and unpleas- Nociceptive processing in the cingulate cortex is be- ant qualities of a persistent pain condition. Thus, it has lieved to reflect the affective component of pain and is been difficult to examine the affective / motivational and probably a critical structure in the neural network that sensory / discriminative components of pain processing contributes to the suffering that accompanies persistent in animal models. In addition, any study that attempts pain states. Behavioral studies in animals have utilized to examine higher order processing of noxious input in paradigms that measure escape and / or avoidance of a animals must address the exact nature of pain affect. For noxious stimulus. It is assumed that escape / avoidance instance, the affective (i.e. worrisome, cruel, fearful, behaviorisevidencethatanimalsfindthenoxiousstimu- terrifying, etc.) nature of chronic pain in humans is lusaversive. With the use of these paradigms, the precise dissociable from the sensory (i.e. shooting, stabbing, 396 Cingulate Cortex, Nociceptive Processing, Behavioral Studies in Animals pinching, cramping, etc.) nature of the condition by the value of the mechanical stimulus. Morphine has been descriptors that patients select on the McGill Pain found to impair performancein various tests of memory Questionnaire. In animal studies, the precise nature of such as the Morris water maze and the radial arm pain affect is more difficult to define. Affect, as it relates maze. However, the effect of morphine on the radial arm to noxious input, is most certainly a negative hedonic maze requires chronic high dose administration (up to state that can be identified in one way as aversion to a 40 mg / kg) that almost certainly is associated with se- noxious stimulus. dation and impairment in task performance rather than With this in mind, a number of investigators have devel- with interference in memory. Other investigators report oped new behavioral methodologies to study the com- biphasicresultsinratssuchthatlowerdosesofmorphine plexity of nociceptiveprocessing in theACC of animals. enhance, while higher doses impair, memory. Anatom- Theunderlyingfeatureofthesemethodologiesisthates- ically, impairment of learning and memory function is capeand/oravoidanceofanoxiousstimulusareclearin- typically associated with manipulationsto the more pos- dications that animals find the stimulus aversive (Fuchs terior regions of the cingulate cortex. 2000). For instance, Johansen et al. (2001) utilized the It is inappropriate to examine the role of the ACC formalin test with the place-conditioning paradigm. in nociceptive processing in animals with the use of In this paradigm, formalin injection elicits an acute no- reflexive behaviors to examine the aversive nature of ciceptive response and induces conditioned place avoid- persistent pain conditions. Experiments using only ance (F-CPA) to the compartment of the apparatus that quantified mechanical thresholds or acute formalin in- is associated with the formalin injection. Another recent jection behaviors can lead to the erroneous conclusion paradigm utilizes place escape / avoidance in which an- that the ACC does not effect supraspinal pain process- imals must associate the application of the mechanical ing. Clearly, functional alterations of the ACC by lesion stimulus to the hyperalgesic paw with the preferred dark and neurochemical methods reduce the avoidance of area of the test chamber (LaBuda and Fuchs 2000). Es- noxious mechanical hind paw stimulation as measured cape / avoidance behavior is measured as a shift from using the place escape / avoidance paradigm and the for- the preferred dark area of the chamber to increased time malin conditioned place avoidance paradigm. Sensory spent within the non-preferred light area of the chamber. mechanisms of pain processing are clearly important In both instances, damage to the ACC, by either neu- but fail to highlight the mechanisms underlying the rotoxic or electrolytic procedures, decreases behavioral affect that accompanies many persistent pain condi- evidence that the noxious stimulus is aversive (Johansen tions. Clinically, the sensation of pain can be treated by et al. 2001; LaGraize et al. 2004). At this time, the most reducing the sensory input as well as by manipulating parsimoniousexplanationofthebehavioralstudiesinro- affective-motivational and cognitive factors (Melzack dents is that the ACC is involved in the modulation and and Casey 1968). Therefore, an understanding of the processing of pain affect and that manipulations of the neural substrates mediating the affective processing of ACC decrease the affective component of pain process- nociceptive stimulation should advance our knowledge ing. of pain processing and contribute to advances in thera- Behavioral paradigms that permit the separate assess- peutic interventions to reduce the affective component ment of affective and sensory components of the pain of pain that accounts for the suffering so frequently experience have led to examination of the underlying seen in clinical conditions. neurochemicalprocessesthatmightbe involvedin modulating pain affect. One possible mechanism of action by which the ACC selectively modulates pain affect is References via the mu-opioid receptor system. The ACC has a high 1. Donahue RR, LaGraize SC, Fuchs PN (2001) Electrolytic lesion density of opioid receptors and activation of the ACC of the anterior cingulate cortex decreases inflammatory, but not neuropathic pain in rats. Brain Res 897:131–138 mu-opioid receptor system during sustained pain is neg- 2. Erel U, Arborelius L, Brodin E (2004) Increased cholecystokinin ativelycorrelatedwithMcGillPainQuestionnaireaffec- release in the rat anterior cingulate cortex during carrageenan- tive scores (Zubieta et al. 2001). In animals, morphine induced arthritis. Brain Res 1022:39–46 microinjection into the ACC produces a selective de- 3. Fuchs PN (2000) Beyond reflexive measures to examine higher order pain processing in rats. Pain Res Manag 5:215–219 creaseinescape/avoidancetomechanicalstimulationof 4. Hutchinson WD, Davis KD, Lozano AM et al. (1999) Pain- the hyperalgesic paw (LaGraize et al., 2006). Additional related neurons in human cingulate cortex. Nat Neurosci contributions of the NMDA (Lei et al. 2004), cholecys- 2:403–405 tokinin (Erel et al. 2004), and glutamatergic (Johansen 5. Johansen JP, Fields HL (2004) Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat et al. 2004) systems have been reported. Neurosci 7:398–403 It is unlikely that the above findings can be attributed to 6. Johansen JP, Fields HL, Manning BH (2001) The affective com- the role of the ACC in learning and memory processes, ponent of pain in rodents: direct evidence for a contribution of the that is the possibility that ACC manipulation interferes anterior cingulate cortex. Proc Natl Acad Sci USA 98:8077–8082 7. Koyama T, Kato K, Tanaka YZ et al. (2001) Anterior cingu- with acquisition and retention of an escape / avoidance late activity during pain-avoidance and reward tasks in monkeys. response rather than a change in the negative hedonic Neurosci Res 39:421–430 Classification 397

8. LaBuda CJ, Fuchs PN (2000) A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain Circumventricular Brain Structures in rats. Exp Neurol 163:490–494 9. LaGraize SC, LaBuda CJ, Rutledge MA et al. (2004) Differential effect of anterior cingulate cortex lesion on mechanical hyper- Definition sensitivity and escape / avoidance behavior in an animal model Specific regions within the brain where the blood brain of neuropathic pain. Exp Neurol 188:139–148 C 10. LaGraize SC, Borzan J, Peng YB et al. (2006) Selective regulation barrier is weak or absent. of pain affect following activation of the opioid anterior cingulate Proinflammatory Cytokines cortex system. Exp Neurol 197:22–30 11. Lei L-G, Sun S, Gao Y-J et al. (2004) NMDA receptors in the anterior cingulate cortex mediate pain-related aversion. Exp Neurol 189:413–421 – 12. Melzack R, Casey KL (1968) Sensory, motivational, and central Cl Transporter control determinants of pain. In: Kenshalo DR (ed) The Skin Senses. CC Thomas, Springfield, pp 423–439 Chloride Transporter 13. Rainville P, Duncan GH, Price DD et al. (1997) Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277:968–971 14. Vogt BA (1985) Cingulate cortex, In: Peters A, Johns EG (eds) Cerebral Cortex. Plenum Publishing Corporation, New York, Classical Conditioning pp 80–149 15. Zubieta J-K, Smith YR, Bueller JA et al. (2001) Regional mu opioid receptor regulation of sensory and affective dimensions Synonyms of pain. Science 293:311–315 Pavlovian conditioning; respondent conditioning

Definition Also called “Pavlovian conditioning” or “respondent Cingulotomy conditioning” it is a type of learning that results from the association of stimuli with reflex responses, whereby a Definition neutral stimulus (usually called the conditioned stimulus, CS) acquires the response eliciting properties of a The creation of lesions in the cingulate gyrus, usually previously potent stimulus (the unconditioned stimulus, for the relief of intractable pain and in the treatment of US). Through repeated pairings of the CS (e.g. tone) psychiatric disorders and addiction. with the US (e.g. shock) stimulus, the CS can be used Pain Processing in the Cingulate Cortex, Behavioral to elicit the same or similar response, the conditioned Studies in Humans response (CR, e.g. withdrawal) as the US. Pain Treatment, Intracranial Ablative Procedures Amygdala, Functional Imaging Amygdala, Pain Processing and Behavior in Animals Behavioral Therapies to Reduce Disability Muscle Pain, Fear-Avoidance Model CIPA Pavlovian Conditioning Psychology of Pain and Psychological Treatment Congenital Insensitivity to Pain with Anhidrosis Respondent Conditioning of Chronic Pain

Classical Massage Circadian Rhythms/Variations Massage and Pain Relief Prospects Deﬁnition Rhythms of parameters with a frequency close to, but not exactly, 24–hr. Classical Migraine Diurnal Variations of Pain in Humans Clinical Migraine with Aura

Circadian Variations in Pain Level Classiﬁcation

Diurnal Variations of Pain in Humans Taxonomy 398 Claudication

sound sensitivity or neck stiffness or affective symp- Claudication toms namely depression, euphoria and concentration difficulties. Definition Characteristics Claudication is characterized by leg pain and weakness brought on by walking, with the disappearance of the General Characteristics symptoms following a brief rest. It has been estimated that migraine with aura occurs Vascular Neuropathies in about 4% of the general population each year (Ras- mussen and Stewart 2000) suggesting that it occurs in up to one third of migraine sufferers. Many patients who have attacks of migraine with aura also have attacks Clearance of migraine without aura. Aura symptoms are clinically localizable to the cerebral cortex or brainstem Definition and resolve fully in between attacks. In addition, no static changes in conventional anatomical neuroimag- The clearance describesthe hypotheticalvolume of fluid ing occur as a result of the migraine aura. Although that is cleared from the unchanged drug per unit of time the duration of a single migraine aura is limited to byanyeliminationpathway.Theclearancecanbefurther 60 minutes, an individual patient may within a single categorized as the total clearance (CL) (all elimination attack have more than one type of aura. When the auras pathways) or the organic clearance (e.g. renal clearance occur in sequence, their total time may extend beyond (CL ), hepatic clearance (CL ), etc.). R H 60 minutes up to as much as 60 minutes for each aura NSAIDs, Pharmacokinetics type and still be considered aura. When the aura types occur in sequence, the most common order is visual, then sensory followed by language or motor symptoms Clinical Migraine With Aura although the order may vary. There are two general characteristics of the aura that seem to distinguish it F. MICHAEL CUTRER from ischemia. 1. There is a tendency for the symptoms Department of Neurology, Mayo Clinic, Rochester, to spread or migrate slowly with time and 2. there is MN, USA bimodal progression in which positive symptoms (tin- [email protected] gling or visual shimmering) are followed by negative symptoms (numbness or visual scotoma). Synonyms Aura Types Classical Migraine; classic migraine; Complex Mi- Traditionally, four types of migraine aura have been graine; Complicated Migraine; Migraine Accompa- recognized. These include visual, sensory,language and gnee; Migraine Ophthalmic; Migraine With Aura; motor.However,themostrecentInternationalHeadache Migraine Optical; Migraine Hemiparesthetic; Migraine Society (IHS 2004) diagnostic criteria consider motor Aphasic; Migraine Hemiplegic aura a separate migraine subtype, as recent genetic data Definition suggest the possibility of a distinct pathophysiology in motor aura. The three remaining aura types, visual, Migraine aura is a disorder during which episodes of sensory and language auras are collectively termed transient focal neurological symptoms develop over a “typical aura”. period of 5–20 minutes and resolve within 60 minutes (IHS 2004). Most commonly, these symptoms occur Visual Aura within 60 minutes of the onset of a migraine headache Visual aura consists of episodes of visual disturbance, (i.e. unilateral throbbing headache of moderate to se- which although frequently stereotypical within a given vere intensity, lasting 4–72 hours and associated with individual, may differ from on individual to another. In nausea, vomiting, photophobia, phonophobia and the classical progression, the aura begins as a small area worsening with routine exertion). Less commonly, the of visual disturbance often just lateral to central fixation. aura may occur during the course of a headache, in This visual phenomenon, generally described as either association with a headache which does not have all of a shimmering or sparkling light or as a crawling geo- the features of a migraine headache or in the absence metric or zigzagging pattern, is very characteristic of the of headache altogether. The aura is distinct from the aura of migraine. Within a few minutes of onset, the area term “prodrome” which refers to often vague symptoms of visual dysfunction begins to expand from its original that occur hours to a day prior to the onset of headache central location slowly outward often in a crescent-like and which include both vegetative symptoms such as patterntoinvolveasmuchasaquarterorhalfofthevisual fatigue, pallor, yawning, anorexia, nausea, light or field in both eyes. The expanding shimmering margin of Clinical Migraine With Aura 399 the aura leaves in its wake an area in which there is no fers from other typical aura types in that it is sometimes image. This area is termed a scotoma. The scotoma is longer than 1 hour and may actually persist after reso- usually not a particular color but has been likened to the lution of the headache. This would argue for a distinct blind spot left in the visual field after having looked at a pathophysiology. However, most patients who experi- flashing light. The rate of the shimmering or flickering ence hemiplegic migraine also report other aura types C observed by the patient during aura seems to increase as that may occur within the same attack. the aura spreads toward the periphery. Gradually vision is restored, first centrally and then in areas of peripheral Pathophysiology vision as the aura moves out of the visual field. The slow spreading nature of the scintillating distur- The spread is usually quite slow taking from 40–60 min- bance in migraine visual aura led to early speculation utes, but may be much more rapid, sometimes being that aura may be caused by the phenomenon of corti- completed in less than 15 minutes. Fragments of the cal spreading depression (CSD) (Lashley 1941). CSD aura (scotoma with shimmering or vice versa) maybe is an electrically measurable wave of neuro-glial ex- recalled as well as differences in the direction of expan- citation that causes a brief disruption in local ionic sion implying variability from one patient to another or homeostasis and is followed by a resultant depres- within the same patient from one attack to another. The sion of activity (Leao 1944). The wave appears and shimmering component of the aura is usually seen when then migrates over the cortex in experimental animals the eyes are closed and passive movement of the eyeball at a slow rate of 3–4 mm per minute after mechanical through the eyelid does not change the position of the or chemical perturbation. Functional magnetic reso- aura, implying that the abnormality occurs outside the nance imaging (fMRI) techniques including perfusion eyeball itself. The visual aura is by far the most common weighted (Cutrer et al. 1998) and blood oxygen level form of migraine aura. dependent (BOLD) imaging (Hadjikhani et al. 2001) applied during spontaneous migraine visual auras in hu- Sensory Aura mans have shown that CSD and visual aura share many Sensory aura is the second most common aura type and characteristics. 1. Both CSD and the migraine visual generally first manifests as a tingling sensation or pares- aura are characterized by an initial hyperemia lasting thesiaononesideofthefaceorinanarmorleg.Justasthe 3–4.5 minutes. 2. The hyperemia signal spreads across visual aura expands or migrates, thesensory disturbance the affected cortex at a slow rate (2–5 mm/min) 3. The may march along the arm or leg only to jump upward to hyperemiainbothCSDandmigraineauraisfollowedby affecttheface,graduallymovingacrossitandtheninside mild hypoperfusion lasting 1–2 hours. 4. Evoked visual the mouth to affect the gums and/or tongue on one side. responses during CSD and during aura are suppressed The involvement of half the tongue is quite suggestive and take about 15 minutes to recover. 5. The BOLD of migraine and not typical for ischemia. Also indica- signal complexes during both aura and induced CSD in tive of migraine is the sensory aura’s bimodal wave of animals halt at major sulci.6.InCSDandmigraine paresthesias, which leavesin itswake a mild to moderate aura, the first affected area is the first to recover normal numbness that persists for up to an hour. response to standard visual stimuli. Thus far, factors that render over 25% of migraineurs vulnerable to a Language Aura CSD-like phenomenon are poorly understood and may Language aura is the least common of the typical aura be genetically determined. One recent report found that forms but can be quite disturbing to patients when they prolonged visual symptoms associated with migraine first experience it. This aura type is actually a dysfunc- headaches are not associated with the perfusion defects tion of language, which makes it difficult for the patient seen in typical migraine visual aura. (Jager et al. 2005) to choose the correct words or speak them in a coher- At this point, the relationship between the aura and mi- ent fashion. The language aura may also disrupt reading graine headache is incompletely understood. There is or writing. It is clearly distinct from slurring of speech, experimental evidence that events intrinsic to the cere- which may occur with sensory aura if half the tongue bral cortex such as CSD are capable of exerting effects is numb. Because thought is generally in conducted in on trigeminal perivascular nociceptive neurons, thereby a given language, patients are often distressed by an inactivating headache. Immunohistochemical studies in ability to think clearly. rodents have shown that CSD is capable of activating the expression of the immediate early gene c-fos, a non- Motor Aura specific marker of neuronal activation within the nuclei Motor aura is now considered as a separate entity by the of neurons of the superficial laminae of the trigeminal InternationalHeadacheSocietybecausesinglegenemu- nucleus caudalis (second order nociceptive neurons) tations have been identified as the cause of hemiplegic (Moskowitz et al. 1993). In addition, laser speckle migraine in several families. Patients with hemiplegic imaging studies (Bolay et al. 2002) recently demon- migraine report unilateral weakness involving the face strated that CSD could initiate long lasting dilation and/or an extremity. The duration of the motor aura dif- within pain sensitive middle meningeal artery branches 400 Clinical Migraine Without Aura by a brainstem reflex dependent on intact trigeminal primary afferent and parasympathetic efferent neurons. Clinical Trial It may well be that the aura represents one of several mechanisms by which the headache is activated, as it is Definition clear that migraine headache may occur without aura A clinical trial is a research study designed to test the and the aura may occasionally occur with activation of safetyand/oreffectivenessofdrugs,devices,treatments, headache. or preventive measures in humans. Clinical trials can References usually be divided into four categories or “phases” Central Pain, Outcome Measures in Clinical Trials 1. Bolay H, Reuter U, Dunn AK et al. (2002) Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8:136–142 2. Cutrer FM, Sorensen AG, Weisskoff RM et al. (1998) Perfusion- Clitoral Pain Weighted Imaging Defects During Spontaneous Migrainous Aura. Ann Neurol 43:25–31 ALLAN GORDON 3. Hadjikhani N, Sanchez Del Rio M, Wu O et al. (2001) Mech- anisms of migraine aura revealed by functional MRI in human Wasser Pain Management Centre, Mount Sinai visual cortex. Proc Natl Acad Sci USA 10;98:4687–4692 Hospital, University of Toronto, Toronto, ON, Canada 4. Headache Classification Subcommittee of the International [email protected] Headache Society (2004) The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24:24–30 5. Jager HR, Taylor MN, Theodossy T et al. (2005) MR imaging- Characteristics guided interstitial photodynamic laser therapy for advanced head Introduction and neck tumors. Am J Neuroradiol 26:1193–200 6. Lashley KS (1941) Patterns of cerebral integration indicated by “Why is it that the very places in my body that should the scotomas of migraine. Archives of Neurology and Psychiatry give me pleasure give me pain” (Chicago) 46:331 7. Leao AAP (1944) Spreading depression of activity in the cerebral Quote from a woman with a painful clitoris and painful cortex. J Neurophysiol 7:359–390 nipples (The PNPC Syndrome). 8. Moskowitz MA, Nozaki K, Kraig RP (1993) Neocortical spreading depression provokes the expression of c-fos protein-like im- Description of the Clitoris munoreactivity within trigeminal nucleus caudalis via trigemi- The best place to find out about the clitoris is the web- novascular mechanisms. J Neurosci 13:1167–1177 9. Rasmussen BK and Stewart WF (2000) Epidemiology of Mi- site www.the-clitoris.com. Here the clitoris is described graine. In: Olesen J, Tfelt-Hansen P, Welch KMA (eds) The in clear terms with excellent graphics. The major parts Headaches, 2nd edn. Lippincott Williams & Wilkins, Philadel- are the prepuce or hood, the glans, the body and phia, pp 231–232 the crura (O’Connell et al. 1998; www.the-clitoris.com) (see Fig. 1). The major function is sexual pleasure and orgasm. The clitoris has up to 8000 nerve endings mak- Clinical Migraine Without Aura ing it extremely sensitive (www.the-clitoris.com).

Migraine Without Aura

Clinical Pain

Deﬁnition „Physiological”painispainfeltintheintact,non-injured organism. „Clinical“ pain is pain felt after a tissue injury has induced sensitization of the peripheral and central nervous system. Postoperative Pain, Pre-Emptive or Preventive Anal- gesia

Clinical Signs

Deﬁnition Clinical signs are abnormal responses elicited by clinicians during the physical examination. Hypoalgesia, Assessment Clitoral Pain, Figure 1 The Clitoris. Clitoral Pain 401

The clitoris is innervated by the dorsal nerve of the cli- roma (Fernandes-Aguilar and Noel 2003), hair tourni- toris off the pudendal nerve. That transmits somatic sen- quet (Kuo et al. 2002), and phimosis (Munarriz et al. sation including pain, temperature, vibration, and pro- 2002) as well as various tumors. The author’s paper in prioception. The clitoris also receives sympathetic and 2002 represents the only significant collection of cases parasympathetic fibers for sexual function. (Gordon 2002), which reports the clinical features of 21 C women with clitoral pain. What is Clitoral Pain? An Internetsearch, however, willpick upinformationon Clitoral pain is pain either present at rest and/or induced chat line discussions, sex information sites and/or sites by touch or pressure on the glans, body of the clitoris that appear pornographic. or crura of the clitoris. Occasionally pain is felt in or next to the clitoral hood or just posterior to the glans and My Patient Population body. Itmay bethereon itsownor morecommonly asso- In our paper (Gordon 2002) we reported on 21 individ- ciated with vulvar pain or urethral pain and also deeper uals, 7 from my own practice and 14 who had contacted muscular pain. The pain may be referred into the urethra the author online through various sources. We have from other sites e.g. the urethra. added to the numbers and are in the process of reporting One definition is a “specific subset of vulvodynia pro- a larger group of 26 patients, and more than 40 who duced by neuralgia of the anterior division of the puden- sought and supplied information via the internet. Some dal nerve” (Perry 2004). However, that may be too ex- patients were followed for up to 4 years. The National clusive a definition since there is such a variety of causes Vulvodynia Association also referred women patients. possible. Thefollowingrepresentsinformationfromthepaperand Many women with genital pain including vulvodynia personal observations and communication. and vulvar vestibulitis, may not mention their clitoral pain unless they have been so involved with the Clinical Points healthcare system that they lose their reserve. More • The rest pain is often described as mild to severe and importantly, many practitioners do not ask or examine to be burning, stinging or aching. All our examined for it. For instance, many women with fibromyalgia or clinic patients have rest pain. irritable bowel may also have vulvar pain and/or clitoral • There is pain on touching or contacting the clitoris, pain, but do not volunteer it or are not asked about it. and the pain is moderate to severe in intensity. The This is certainly the case in our pain clinic where such women examined may have allodynia, hyperalge- pain is described mainly upon direct questioning. sia or pain on firmer touch or pressure. The allodynia Some women have a ‘sensitive’ clitoris that is uncom- andhyperalgesiasuggestsaneuropathicpainprocess. fortable at rest or to touch but it does not interfere with • Allodynia of the clitoris and introitus often coexist as sexual activity. Others may have a true pain in the cli- well as periurethral touch induced pain. toris, enough so that they do not like it touched. These • Intercourse is almost always painfulevenwith the use terms need to be better defined in further population of techniques to avoid touching the clitoris. This in- health studies. terferes greatly with intimate relations. Inaninternetsurveyof423womenwithvulvarpainonly • Primary anorgasmia is relatively uncommon (Gor- 3.3% had clitoral pain, and none had it alone (Gordon don 2002), and secondary anorgasmia may occur be- et al. 2003). cause of the pain and unwillingness to try because of pain.Mostcontinuetobeorgasmic,somealsoachiev- Literature and Internet Search ing orgasm through a vaginal approach. Wesselman and Burnett (Wesselmann and Burnett • Many women avoid intercourse or sexual activity be- 1999) refer to very few cases and talk mainly about pain cause of the pain. Sexual desire may not be decreased post- ritualistic clitoral excision. It is not mentioned in despite the pain but more commonly desire is sup- “Chronic Pelvic Pain: An Integrated approach” (Steege pressed. Non-penetrative sex may also be painful. et al. 1998). • The pain may be part of established diseases includ- The International Pelvic Pain Society website http:// ing Lichen Sclerosus. Our article describes 5 such www.pelvicpain.org (Perry 2004) contains an article patients (Gordon 2002). on Clitoral Pain that was also published in a text- • Some patients have had it for 10 or more years, up to book (Perry 2000) and in the Fall 2000 edition of the 18 years in practice and 25 years online. National Vulvodynia Association Newsletter. Perry • In others it was much shorter in duration, sometimes mentions metabolic (e.g. diabetes), violent stimulation, just months. tight clothing, or laser vaporization as known causes of • Relapse and remissions may occur and spontaneous clitoral pain recovery may also occur. A Pub Med search for key words “Clitoris Pain” yields • Weknow of at least 4 women who had remission with articleson FGM (female genital mutilation) (Okonofyet pregnancy, with the remission persisting in four post al. 2002), painful priapism (Medina 2002), clitoral neu- partum. Another one worsened after pregnancy. 402 Clitoral Pain

• Wehad at least 10 women who complained of painful Common Mechanism or very highly sensitive nipples associated with the While yeast or other infections might suggest an acute clitoralpain (Gordon 2000, 2002). The reason for this nociceptive mechanism, most patients have evidence of association is unclear. a chronic neuropathic pain. There is clitoral allodynia • Clitoral pain may be associated with vulvar pain, and at times hyperalgesia. While documented or un- vaginismus, urethral pain, and occasionally anal documented pudendal nerve entrapment may present pain as well as interstitial cystitis, painful urethral in some in Alcock’s canal, this would not explain syndromes and urethral dyssynergia. pain seen in direct trauma. Clitoral pain seems to be an • There is often a fruitless search for infections. example of neuropathic pain and seen in central pain • Other c-morbidities include endometriosis, ﬁ- (MS), polyneuropathy or Lichen Sclerosis. Ultimately, bromyalgia, anorexia, and back pain including whatever the insult, there must be peripheraland central spondylolisthesis. Depression was common in at sensitization. Clitoral pain deserves more study as an least 14 of our own patients. example of neuropathic pain derived from many basic • Painful clitoral priapism was seen in 2 of our patients. causes, be it post-infectious, post-traumatic, iatrogenic, • Clitoral pain may rarely be associated with a constant direct injury, or chronic nerve entrapment state of arousal. • Clitoral pain may be the presenting feature in some, Clinical Evaluation andthemostdisconcerting,butmorecommonlythere This must include: are other genital pain issues. • Women with clitoral pain can be desperate for ex- • Clinical history planations and relief, are concerned about being • Sexual History labeled as psychogenic, and look back in regret to • Psychosocial history and evaluation events, particularly traumatic or surgical events that • Alcohol, addiction and abuse history may have precipitated or aggravated their condi- • Treatments tried tion. • Neurological, musculoskeletal and gynecological exam • Detailed vulvar exam including Q tip and pain and Causes of Clitoral Pain in our Groups temperature and retraction of prepuce 1. Direct ‘sexual’ trauma (e.g. vigorous masturbation; • Pelvic and rectal exam checking for deeper pain and vigorous cunnilingus; a slipped’ vibrator; vigorous anal pain sexual intercourse were all reported to us) • Pelvic and spinal imaging when clinically appropri- 2. Direct ‘non sexual’ trauma (e.g. doing the splits on a ate with ultrasound, CT scan or magnetic resonance beam while doing gymnastics; injury during car ac- scan cident from direct trauma) • Pudendal nerve latencies if available 3. Injury to lumbar spine and/or coccyx and possible • Quantitative sensory testing of genital area lower sacral root irritation • Cultures of vulva, vagina and urine 4. Pelvic fracture and indirect trauma • Urogynecological evaluation if urinary symptoms 5. Multiple Sclerosis with other urogenital complaints of pain, altered libido and voiding dysfunction due to Treatment central plaques 6. Post-hysterectomy especially with vascular misad- The treatment depends upon clinical diagnosis and venture (2 with recurrent engorgement) co-morbidity. There are no published clinical trials 7. Post spinal fusion procedure with insertion of a cage and even very few anecdotal reports on clitoral pain. 8. Peripheral polyneuropathy Awareness of the condition, asking the right questions 9. Part of a unilateral or bilateral pudendal neuralgia in the right way, and validating the patients pain are syndrome key, and a detailed multidisciplinary or transdisciplinary 10.Associated with Lichen Sclerosis with deforming tis- examination is necessary: Management is best in a mul- sue destruction tidisciplinary pain clinic where chronic pelvic region 11.Following explained or unexplained infection, such pain is regularly treated. as yeast, vaginosis, or herpes 12.Primary clitoral pain of unknown cause Treatments to Try and Comments 13.Part of unexplained genital pain syndrome involving 1. Oral tricyclic antidepressants such as amitriptyline. clitoris, urethra, vulva, and anus Occasionally effective 14.Part of a severe chronic pelvic pain disorder with dif- 2. Oral anticonvulsants such as gabapentin. Variable refuse muscle and genital pain sults 15.Related to sexual abuse 3. Topical medications such as amitriptyline, gabapen- 16.A feature of vulvodynia tin, ketamine and even capsaicin (which burns). More Cluster Analysis 403

studies needed with these agents. Clinical trials are 5. Kuo JH, Smith LM, Berkowitz CD (2002) A Hair Tourniquet needed Resulting in Strangulation and Amputation of the Clitoris. Obstet Gynecol 99:939–941 4. Opiates. They are often tried because of other co- 6. Medina CA (2002) Clitoral Priapism: A Rare Condition Present- morbid pain conditions, and experience suggests ing as a Cause of Vulvar Pain. Obstet Gynecol 100:1089–1091 that they are not particularly effective in clitoral pain 7. Munarriz R, Talakoub L, Kuohung W et al. (2002) The Prevalence C 5. Topical cocaine. Usually associated with addictive of Phimosis of the Clitoris in Women Presenting to the Sexual Dysfunction Clinic: Lack of Correlation to Disorders of Desire, behavior Arousal and Orgasm. J Sex Marital Ther 28:181–185 6. Anesthetic block of dorsal nerve of clitoris. No liter- 8. O’Connell HM, Hutson JM, Anderson CR et al. (1998) ature studies (Perry 2004) Anatomical Relationship between Urethra and Clitoris. J 7. Pudendal nerve block. Of diagnostic value in puden- Urol 159:1892–1897 9. Okonofy FE, Larsen U, Oronsaye F et al. (2002) The Associ- dal neuralgia and no specific studies for clitoral pain. ation between Female Genital Cutting and Correlates of Sex- 8. Pudendal nerve decompression. Must be well docu- ual and Gynecological Morbidity in Edo State, Nigeria. BJOG mented and in experienced hands only. 109:1089–1096 9. Physical therapy May have through therapy of spine, 10. Perry CP (2000) Vulvodynia. In: Howard FM, Perry CP,Carter JE et al. (eds) Pelvic Pain: Diagnosis and Management. Lippincott internal and external muscle. Williams & Wilkins, Philadelphia, pp 204–210 10.Specific treatment of underlying, associated or co- 11. Perry CP (2004) Clitoral Pain. http://www.pelvicpain.org/ morbid conditions such as vulvodynia, Lichen Scle- 12. Steege JF, Metzger DA, Levy BS (eds) (1998) Chronic Pelvic rosis and depression. Pain: An Integrated Approach. WB Saunders Company, Philadel- phia 11.Psychological therapies including cognitive behav- 13. Wesselmann U, Burnett AL (1999) Genitourinary Pain. In: Wall ioral therapy. P, Melzack R (eds) Textbook of Pain, 4th edn. Churchill Living- 12.Pelvic floor surface EMG. Only if evidence of pelvic stone, Edinburgh, pp 689–709 floor disturbance and probe does not hurt. 14. www.the-clitoris.com, Copyright 1998–2004 Fox Internet Ser- 13.Sexualtherapies.Assistsindevelopingalternatetech- vices niques and exploring attitudes, preferences and experiences. 14.Cannabis: No trials but anecdotal reports from pa- Clofazimine tients does suggest some benefit Definition

Conclusion Clofazimine is a substituted iminophenazine dye with antibacterial properties, which is used in the treatment Clinical trials will clearly be necessary in order to un- of leprosy; it is administered orally. derstand what really works. In the meantime, conserva- Hansen’s Disease tive multimodal treatments should be considered. The relative rarity of clitoral pain, the many associated conditions, and the fact that most practitioners are not prepared to evaluate these patients has meant that trials are Clonidine not carried out. However, it is also clear that we need to know more about the clinical and natural history of Deﬁnition clitoralpain,aswellasunderstandmoreaboutthepatho- Clonidineisaprototypicalα -adrenoceptoragonistwith physiology and the various associated and/or co-morbid 2 potent sympatholytic effects. It activates neuronal cell features. That can be achieved by detailed study includ- membrane potassium channels causing hyperpolariza- ing the use of neurophysiologic techniques and the cre- tion, reducing the rate of neuronal ﬁring. It also inhibits ation of an observational database. neurotransmitter release by inhibiting calcium conduc- Clitoral pain is reframed as an example of neuropathic tancethroughN-typecalciumchannels.Clinically,ithas pain, and studied in the same way as other forms of neu- antihypertensive, sedative, anxiolytic and analgesic ac- ropathic pain. tions, which may also be useful in the management of complex pain states. References Acute Pain in Children, Post-Operative Alpha(α) 2-Adrenergic Agonists in Pain Treatment 1. Fernandes-Aguilar S, Noel JC (2003) Neuroma of the Clitoris after Female Genital Cutting Obstet Gynecol 101:1053–1054 Postoperative Pain, Appropriate Management 2. Gordon AS (2000) The PNPC Syndrome. Platform presentation at PUGO Special Interest Group meeting (Sept 23, 2000) Ham- burg, Germany 3. Gordon AS (2002) Clitoral Pain: The Great Unexplored Pain in Cluster Analysis Women. J Sex Marital Ther 28:181–185 4. Gordon AS, Panahian-Jand M, McComb F et al. (2003) Char- acteristics of Women with Vulvar Pain Disorders: Response to Multidimensional Scaling and Cluster Analysis Ap- a Web Based Survey. J Sex Marital Ther 29:25.58 plication for Assessment of Pain 404 Cluster Headache

Pain Measurement by Questionnaires, Psychophysi- cal Procedures and Multivariate Analysis CNS Changes after Peripheral Nerve Injury

Central Changes after Peripheral Nerve Injury Cluster Headache

Deﬁnition CNS Stimulation in Treatment of An uncommon headache disorder with a striking male Neuropathic Pain predilection. They are called cluster headaches because attacks occur in a group or “cluster” during which time Central Nervous System Stimulation for Pain patients suffer from 1–8 headaches daily. Individual headaches last between 20–180 minutes each, are ex- cruciatingly severe, and are associated with one or more autonomic features such as conjuntival injection, CNV lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, eyelid edema. Cluster Contingent Negative Variation cycles last 2–8 weeks each and are followed by remission periods of 6–12 months, during which time patients are pain-free. Attacks are strictly unilateral orbitally, CO Staining supraorbitally and/or temporally. Hemicrania Continua Cytochrome Oxidase Staining Human Thalamic Response to Experimental Pain (Neuroimaging) Paroxysmal Hemicrania CO2 Laser

Definition Clustering CO2 laser is frequently used as a pain (heat) stimulator. Since it is a heat beam, tactile receptors are not excited, Trafficking and Localization of Ion Channels and the time-lock is extremely good. Magnetoencephalography in Assessment of Pain in Humans C-Mechanoheat Receptor Cochlea Polymodal Nociceptors, Heat Transduction Definition The cochlea is the coiled structure within the inner ear C-Mechanoreceptor where vibrations caused by sound are transduced into neural impulses by the Organ of Corti. Perireceptor Elements Mechanonociceptors

Cognition CM-PF Complex Deﬁnition Parafascicular Nucleus, Pain Modulation Cognition is the mental act or process by which knowledge may be acquired or analyzed. A distinction is typically made between the content of cognition such as beliefs,attitudes,ormemories;andtheprocessofcognition CMT involving acts such as perception, interpretation, infer- ence, retrieval, or problem solving. Charcot-Marie-Tooth Disease Pain Assessment in the Elderly Cognitive-Behavioral Perspective of Pain 405

Psychology of Pain, Assessment of Cognitive Vari- ables Cognitive-Behavioral Model

Deﬁnition In the context of bodily sensations, this model states that C Cognitive (mis)interpretations (cognitions) of bodily sensations have a profound impact upon how patients perceive their body, cope and behave. Often a vicious circle is Deﬁnition assumed between bodily sensations, cognitions and behavior. Pertaining to the internal thoughts, images and con- Muscle Pain, Fear-Avoidance Model structs of the individual. Pain as a Cause of Psychiatric Illness Psychological Treatment in Acute Pain Cognitive-Behavioral Model of Chronic Low Back Pain

Definition Cognitive Appraisal Cognitive behavioral models of chronic low back pain state that catastrophic misinterpretations in response to Definition acute pain lead to fear of movement/(re)injury. As a consequence, a vicious cycle develops in which subsequent Cognitive appraisal is an evaluation of environmental avoidance of activities and hypervigilance lead to an in- stimuli. Resources available to cope with a potential crease of functional disability, pain, depression and a stressor, and their ability to offset the threatening stim- decrease of physical fitness, thereby further advancing uli, determines the degree and intensity of the stress chronicity. response. Disability, Fear of Movement Stress and Pain Fear and Pain

Cognitive-Behavioral Perspective of Pain Cognitive Aspect of Pain DENNIS C. TURK Department of Anesthesiology, University of Definition Washington, Seattle, WA, USA [email protected] Perceptual component of pain perception including pain-related learning and memory and the recognition Synonyms of the painful nature of the stimulus. Primary Somatosensory Cortex (S1), Effect on Pain- Cognitive Model of Pain; Behavioral/Cognitive Per- Related Behavior in Humans spective Definition The Cognitive-Behavioral (CB) model of pain incorporates pain sufferers’ fear avoidance and contingencies Cognitive Assessment of reinforcement, but suggests that cognitive factors, in particular, and expectations rather than conditioning factors are of central importance. Thus, the model is a Psychology of Pain, Assessment of Cognitive Vari- hyphenated one – CB. It does not ignore the important ables role of contextual factors and principles of learning theory, but rather incorporates them within an integrated perspective on pain sufferers and pain management. The CB model proposes that so-called conditioned reactions Cognitive-Behavior Modification are largely self-activated on the basisof learnedexpecta- tions rather than automatically evoked. The critical factor for the CB model, therefore, is not that events oc- Cognitive-Behavioral Treatment of Pain cur together in time or are operantly reinforced, but that 406 Cognitive-Behavioral Perspective of Pain people learn to predict them based on experiences and decides the symptom requires attention from a health information processing. They filter information though care provider, initiates a set of circumstances different their preexisting knowledge, and organized representa- from the person with the same symptom who chooses tions of knowledge (Turk and Salovey 1985), and react to self–manage ( self-management). accordingly. Their responses, consequently, are based A fourth assumption is that if people have learned mal- not on objective reality but their idiosyncratic interpre- adaptive ways of thinking, feeling, and responding, tations of reality. As interaction with the environment then successful interventions designed to alter behavior is not a static process, attention is given to the ongoing should focus on maladaptive thoughts, feelings, physi- reciprocal relationships among physical, cognitive, af- ology, and behaviors, and not one to the exclusion of the fective, social, and behavioral factors. others. There is no expectancy that changing thoughts, feelings, or behaviors will necessarily result in the other Characteristic two following suit. According to the CB model then, it is the pain sufferer’s The final assumption of the CB perspective is that in perspective, based on their idiosyncratic attitudes, be- the same way as people are instrumental in develop- liefs, appraisals, and expectations that filter and interact ing and maintaining maladaptive thoughts, feelings, reciprocally with emotional factors, social influences, and behaviors, they can, are, and should be considered behavioral responses, as well as sensory phenomena. active agents of change of their maladaptive modes of Moreover, patients’ behaviors elicit responses from responding. People with chronic pain, no matter how significant others (including health care professionals) severe, despite their common beliefs to the contrary, that can reinforce both adaptive and maladaptive modes are not helpless pawns of fate. They can and should of thinking, feeling, and behaving. become instrumental in learning and carrying out more There are five central assumptions that characterize the effective modes of responding to their environment and CB perspective on pain (Turk and Okifuji 1999). The their plight. firstassumption isthatallpeople are active processorsof From the CBperspective, people with pain are viewed as information rather than passive reactors to environmen- having negative expectations about their own ability to tal contingencies. People attempt to make sense of stim- controlcertainmotorskillswithoutpain.Moreover,pain uli from the external environment by filtering informa- patients tend to believe they have limited ability to ex- tion through organized schema derived from their prior ert any control over their pain. Such negative, maladap- learning histories, and by general strategies that guide tive appraisals about the situation and personal efficacy theprocessing of information. People’sresponses(overt may reinforce the experience of demoralization,inactiv- aswellascovert) are based on appraisalsand subsequent ity, and overreaction to nociceptive stimulation. These expectations and are not totally dependent on the actual cognitive appraisals and expectations are postulated as consequences of their behaviors (i.e. positive and nega- having an effect on behavior, leading to reduced efforts tive reinforcements and punishments). Thus, from this and activity that may contribute to increased psycholog- perspective, anticipated consequences are as important ical distress ( helplessness) and subsequently physical in guiding behavior as actual consequences. limitations. If we accept that pain is a complex, subjec- A second assumption is that one’s thoughts (e.g. ap- tive phenomenon that is uniquely experienced by each praisals, attributions, expectancies) can elicit or mod- person, then knowledge about idiosyncratiCBeliefs, ap- ulate affect and physiological arousal, both of which praisals, and coping repertoire s become critical for may serve as impetuses for behavior. Conversely, af- optimal treatment planning, and for accurately evaluat- fect, physiology,and behavior can instigate or influence ing treatment outcome (Turk et al. 1983). one’s thinking processes. Thus, the causal priority is Biomedical factors that may have initiated the original dependent upon where in the cycleone chooses to begin. report of pain play lessand lessof arolein disability over Causal priority may be less of a concern than the view time, although secondary problems associated with de- of an interactive process that extends over time. conditioning may exacerbate and serve to maintain the Unlike orthodox behavioral models (operant and re- problem. Inactivity leads to increased focus on and pre- spondent conditioning) that emphasize the influence occupation with the body and pain, and these cognitive- of the environment on behavior, the CB perspective attentional changes increase the likelihood of misinter- focuses on the reciprocal effects of the person on the preting symptoms, overemphasis on symptoms, and the environment, as well as the influence of environment perception of oneself asbeingdisabled.Reductionof ac- on behavior. The third assumption of the CB perspec- tivity, fear of re-injury, pain, loss of compensation, and tive, therefore, is that both the environment and the an environment that, perhaps, unwittingly supports the individual reciprocally determine behavior. People not pain-patient role can each impede alleviation of pain, only passively respond to their environment but elicit successfulrehabilitation,reductionofdisability,andim- environmental responses by their behavior. In a very provement in adjustment. As has been noted, cognitive real sense, people create their environments. The person factors may not only affect the patient’s behavior and in- who becomes aware of physical events (symptoms) and directly their pain, but may actually have a direct effect Cognitive-Behavioral Perspective of Pain 407 of physiological factors believed to be associated with any control over their pain, and they avoid activities that the experience of pain (e.g. Flor et al. 1985). they believe will exacerbate their pain or contribute to People respond to medical conditions in part based on additional injury (Vlaeyen et al. 1995). Moreover, they their subjective representations of illness and symp- often view themselves as helpless. Such negative, mal- toms ( cognitive schemata). When confronted with adaptive appraisals about their condition, situation, and C new stimuli, the person engages in a meaning anal- their personal efficacy in controlling their pain andprob- ysis that is guided by the schemata that best match lems associated with pain serve to reinforce their over- the attributes of the stimulus. It is on the basis of the reaction to nociceptive stimulation, inactivity, and expe- person’s idiosyncratic schema that incoming stimuli rience of demoralization. These cognitive appraisals are are interpreted, labeled, and acted on. posedashavinganeffectonbehavior;leadingtoreduced People build fairly elaborate representations of their effort, reduced perseverance in the face of difficulty and physical state, and these representations provide the activities and increased psychological distress. basis for action plans and coping. Beliefs about the The specific thoughts and feelings that patients experi- meaning of pain and one’s ability to function de- ence prior to exacerbations of pain, during an exacerba- spite discomfort are important aspects of the cogni- tionorintenseepisodeofpain,aswellasfollowingapain tive schemata of pain. These representations are used episode can greatly influence the experience of pain and to construct causal, co-variational, and consequential subsequent pain episodes (e.g. Jensen et al. 1994; Turk information from their symptoms. For example, a cog- and Okifuji 2002). Moreover, the methods patients use nitive schema that one has a very serious, debilitating, to control their emotional arousal and symptoms are im- condition, that disability is a necessary aspect of pain, portant predictors of both cognitive and behavioral re- that activity is dangerous, and that pain is an accept- sponses. able excuse for neglecting responsibilities will likely TheCBperspectiveonpainmanagementfocusesonpro- result in maladaptive responses. Similarly, if patients viding patients with a repertoire of techniques to help believe they have a serious condition that is quite fragile them gain a sense of control over the effects of pain on and a high risk for re-injury, they may fear engaging their lives, as well as actually modifying the affective, in physical activities. Through a process of stimulus behavioral, cognitive, and sensory facets of the experi- generalization, patients may avoid more and more ac- ence. Behavioral experiences help to show patients that tivities, become more physically deconditioned, and they are capable of more than they assumed, increas- more disabled. ing their sense of personal competence. Cognitive tech- People’s beliefs, appraisals, and expectations about niques (e.g. problem solving and coping skills training) pain, their ability to cope, social supports, their disor- help to place affective, behavioral, cognitive, and sen- der, the medicolegal system, the health care system, sory responses under the patient’s control. The assump- and their employers are all important as they may facil- tionisthatlong-termmaintenanceofbehavioralchanges itate or disrupt the patient’s sense of control.These will only occur if the patient has learned to attribute suc- factors also influence patients’ investment in treatment, cess to his or her own efforts. There are suggestions that acceptance of responsibility, perceptions of disability, these treatments can result in changes of beliefs about support from significant others, expectancies for treat- pain, coping style, and reported pain severity, as well as ment, acceptance of treatment rationale, and adherence direct behavior changes. Further, treatment that results to treatment. inincreasesinperceivedcontroloverpainanddecreased Cognitive interpretations will also affect how patients catastrophizing also are associated with decreases in present symptoms to significant others, including health pain severity ratings and functional disability (Sullivan care providers and employers. Overt communication of etal. 2001;Turner and Aaron 2001). Themostimportant pain, suffering, and distress will enlist responses that factor in poor coping may be the presence of catastro- may reinforce pain behaviors and impressions about the phizing, rather than differences in the nature of specific seriousness, severity, and uncontrollability of the pain. adaptive coping strategies (Jensen et al. 1999; Jensen et That is, reports of pain may lead physicians to prescribe al. 1994). more potent medications, order additional diagnostic In summary, people have prior learning histories that tests, and, in some cases perform surgery. Family mem- precede the development of their current pain. Based bers may express sympathy, excuse the patient from on these experiences, they have developed cognitive usual responsibilities, and encourage passivity thereby schema that consist of all information acquired over fostering further physical deconditioning. It should their lifetime. These cognitive schemata serve as the be obvious that the CB perspective integrates the op- filters through which all subsequent experiences are erant conditioning emphasis on external reinforcement perceived and to which they are responded. Thus, it and the respondent’s view of learned avoidance within is essential that people with chronic pain be viewed the framework of information processing. as integrated wholes, not body parts that are damaged People with persistent pain often have negative expecta- and requiring repair. Failure to attend to cognitive tions about their own ability and responsibility to exert and affective influences either by a narrow focus on 408 Cognitive-Behavioral Programs physiology and anatomy, as is the case in the tradi- negative cognitive appraisals of pain may contribute to tional medical model, or exclusively on environmental the development of depression. influences, as is emphasized in operant models, will Depression and Pain prove to be inadequate. People are more than physical parameters or pawns of reinforcement contingences. Rather, they observe, anticipate, and interpret internal and external stimuli. Moreover, people exist in a so- Cognitive-Behavioral Therapy cial environment and contextual factors also play an important role in the pain experience. Since chronic pain is by virtue of its sole defining characteristic Synonyms chronic, and since there is no cure, it is essential that CBT treatment focuses on their adaptation to the symptoms and accompanying problems and not just the symp- Definition toms. Cognitive behavioral therapy refers to a class of psy- References chotherapy incorporating a wide range of techniques, and which is capable of addressing a range of psycho- 1. Flor H, Turk DC, Birbaumer N (1985) Assessment of Stress- logical problems including chronic pain e.g. anxiety, de- Related Psychophysiological Responses in Chronic Back Pain Patients. J Consult Clin Psychology 54:354–364 pression, specific symptoms of psychosis. A central as- 2. Jensen MP, Romano JM, Turner JA et al. (1999). Patient Beliefs sumption of CBT is that a person’s emotional and be- Predict Patient Functioning: Further Support for a Cognitive- havioral reactions to adverse circumstances are deter- Behavioral Model of Chronic Pain. Pain 81:95–104 3. Jensen MP, Turner JA, Romano RM et al. (1994) Relationship mined by their cognitive representation of the circum- of Pain-Specific Beliefs to Chronic Pain Adjustment. Pain stances, and their appraisal of them, thus being able to 57:301–309 influenceaperson’smoodorbehaviour.Themain aimof 4. Sullivan MJL, Thorn B, Haythornthwaite JA et al. (2001) The- therapy is therefore to change the way in which the indi- oretical Perspectives on the Relation between Catastrophizing and Pain. Clin J Pain 17:52–64 vidual represents the circumstance and their appraisals. 5. Turk DC, Meichenbaum D, Genest M (1983) Pain and Behav- This is achieved through active elicitation of a person’s ioral Medicine: A Cognitive-Behavioral Perspective. New York, thoughts and beliefs, and active behavioral and cogni- Guilford, 1983 tive tasks that are designed to enable the person to re- 6. Turk DC, Okifuji A (1999) A Cognitive-Behavioral Approach to Pain Management. In: Wall PD, and Melzack R (eds) evaluate their circumstances in a manner that is likely Textbook of Pain, 4th edn. Churchill-Livingstone, London, to be beneficial for them. pp 1431–1444 Cognitive-Behavioral Perspective of Pain 7. Turk DC, Okifuji A (2002) Psychological Factors in Chronic Cognitive-Behavioral Treatment of Pain Pain: Evolution and Revolution. J Consult Clin Psychol 70:678–690 Coping and Pain 8. Turk DC, Salovey P (1985) Cognitive Structures, Cognitive Pro- Dyspareunia and Vaginismus cesses, and Cognitive-Behavioral Modification: I. Client Issues. ImpactofFamilialFactorsonChildren’sChronicPain Cogn Ther Res 9:1–17 Premenstrual Syndrome 9. Turner JA, Aaron LA (2001) Pain-Related Catastrophizing: What Is It? Clin J Pain 17:65–71 Psychiatric Aspects of Visceral Pain 10. Vlaeyen JWS, Kole-Snijders A, Boeren R et al. (1995) Fear of Psychological Treatment in Acute Pain Movement/(Re) Injury in Chronic Low Back Pain and its Relation Psychological Treatment of Headache to Behavioral Performance. Pain 62:363–372 Psychological Treatment of Pain in Children Psychology of Pain, Efficacy Recurrent Abdominal Pain in Children Relaxation in the Treatment of Pain Cognitive-Behavioral Programs

Interdisciplinary Pain Rehabilitation Cognitive-Behavioral Transactional Model of Family Functioning

Cognitive-Behavioral Theories Deﬁnition Cognitive-behavioral transactional model of family functioning emphasizes the role of cognitions and be- Deﬁnition liefs in the appraisal of pain and pain-related behavioral Cognitive-behavioral theories of the relationship be- interactions. tween pain and depression suggest that a persons’ Spouse, Role in Chronic Pain Cognitive-Behavioral Treatment of Pain 409

psychological variables such as the perception of con- Cognitive-Behavioral Treatment of Pain trol, the meaning of pain to the patient, and dysphoric DENNIS C. TURK affect (Turk and Flor 1999). Department of Anesthesiology, University of It is important to differentiate the CB perspective from Washington, Seattle, WA, USA CB treatments. The CB perspective is based on five C [email protected] central assumptions, and can be superimposed upon any treatment approach used with chronic pain patients: Synonyms • People are active processors of information and not passive reactors Cognitive-Behavioral Therapy (CBT); Cognitive-Be- • Thoughts (e.g. appraisals, expectancies, beliefs) can havior Modification; Cognitive Therapy elicit and influence mood, affect physiological processes, have social consequences and can also serve Definition as an impetus for behavior; conversely, mood, physi- Cognitive-Behavioral Therapy (CBT) or cognitive- ology, environmental factors, and behavior can influ- behavior modification (CBM) are generic terms that ence the nature and content of thought processes incorporate a wide-range of treatment modalities (e.g. • Behavior is reciprocally determined by both the in- stress management, distraction, relaxation, problem- dividual and environmental factors solving, cognitive restructuring), all of which are de- • Peoplecanlearnmoreadaptivewaysofthinking,feel- signed to enhance coping, facilitate self-management, ing, and behaving and improve emotional and physical functioning. The • Peopleshouldbeactivecollaborativeagentsinchang- primary goals are to help patients understand the effects ing their maladaptive thoughts, feelings, and behav- that thoughts, feelings, and behaviors have on pain, the iors potential of patients to exert some control over their In many cases, the perspective is as important as the con- symptoms, and education and practice in the use of tent of the therapeutic modalities employed, somatic as cognitive and behavioral coping skills. well as psychological (Turk 1997). The application of the CB perspective to the treatment Characteristics of chronic pain involves a complex clinical interaction The cognitive-behavioral (CB) approach to pain man- and makes use of a wide range of tactics and techniques. agement evolved from research on a number of mental Despite the specific techniques used, all CB treatment health problems (e.g. anxiety, depression and pho- approaches are characterized by being present, focused, bias). Following the initial empirical research on CB active, time limited, and structured. Therapists are not techniques in the early 1970s, there have been a large simply conveyers of information acting on passive pa- number of research and clinical applications. The com- tients,butserveaseducators,coaches,andtrainers.They mon denominators across different CB approaches work in concert with the patient (and sometimes family include: members) to achieve mutually agreed upon goals. A growing body of research has demonstrated the im- 1. Interest in the nature and modification of a patient’s portant roles that cognitive factors (appraisals, beliefs, thoughts, feelings and beliefs, as well as behaviors; expectancies) play in exacerbating pain and suffering, 2. Some commitment to behavior therapy procedures in contributing to disability and influencing response to promoting change (such as graded practice, home- treatment (Turk and Rudy 1992). Thus, CB interven- work assignments, relaxation, relapse prevention tions are designed to help patients identify maladaptive training, social skills training) (Turk et al. 1983). patterns and acquire, develop and practice more adap- In general, the CB therapist is concerned with using tive ways of responding. Patients are encouraged to environmental manipulations, as are behavior (operant become aware of, and monitor, the impact that negative conditioning) therapists, but for the CB therapist such pain-engendering thoughts and feelings play in the manipulations represent informational feedback trials maintenance of maladaptive overt and covert behav- that provide an opportunity for the patient to question, iors. Additionally, patients are taught to recognize the reappraise, and acquire self-control over maladaptive connections linking cognitions, affective, behavioral, thoughts, feelings, behaviors and physiological re- and physiological responses together with their joint sponses. Although the CB approach was originally consequences. Finally, patients are encouraged to un- developed for the treatment of mental health disorders, dertake ‘personal experiments’, and to test the effects the perspective has much in common with the multidi- of their appraisals, expectations, and beliefs by means mensional conceptualizations of pain, which emphasize of selected homework assignments. the contributions of cognitive and affective, as well as The CB therapist is concerned not only with the role that sensory phenomena (Melzack and Wall 1965). The CB patients’ thoughts play in contributing to their disorders perspective emphasizes the important contribution of but, equally important, with the nature and adequacy 410 Cognitive-Behavioral Treatment of Pain of the patients’ behavioral repertoire, since this affects lives, despite the presence of varying levels of discom- resultant intrapersonal and interpersonal situations. A fort that may persist. Other goals include the reduction CB treatment program for pain patients is multifaceted. of excessive reliance on the healthcare system, reduced Treatment may be conducted for individuals or groups dependence on analgesic medications, increased func- on an inpatient or outpatient basis. tionalcapacityand,wheneverfeasible,returntoemploy- The CB perspective should be considered not merely ment or usual household activities. The primary objec- as a set of methods designed to address the psycho- tives of CB treatment are: logical components of pain and disability, but as an • To combat demoralization by assisting patients to organizing strategy for more comprehensive rehabili- change their view of their pain and suffering from tation (Turk 1997). For example, patients’ difficulties overwhelming to manageable arising during physical therapy may be associated not • To teach patients that there are coping techniques and only with physical limitations, but also with the fear skills that can be used to help them to adapt and re- engendered by anticipation of increased pain or con- spond to pain and the resultant problems cern about injury. Therefore, from a CB perspective, • To assist patients to reconceptualize their view of physical therapists need to address not only the pa- themselves from being passive, reactive and helpless tient’s performance of physical therapy exercises and to being active, resourceful and competent the accompanying attention to body mechanics, but • To help patients learn the associations between also the patient’s expectancies and fears as they will thoughts, feelings and their behavior, and subse- affect the amount of effort, perseverance in the face quently to identify and alter automatic, maladaptive of difficulties and adherence with the treatment plan patterns (Meichenbaum and Turk 1987). These cognitive and • To teach patients specific coping skills and, more- affective processes, including self-management con- over, when and how to utilize these more adaptive cerns, may be impediments to rehabilitation and thus responses need to be considered and addressed, along with tradi- • To bolster self-confidence and to encourage patients tional instructions regarding the proper performance of to attribute successful outcomes to their own efforts exercise. The attention paid to the individual’s thoughts • To help patients anticipate problems proactively and and expectancies by a psychologist should be adopted generate solutions, thereby facilitating maintenance by all members of the interdisciplinary treatment team. and generalization In short, CB treatment should not be viewed as totally scripted. Therapists must realize that flexibility and The over-riding message of the CB approach is that peo- clinical skills have to be brought to bear throughout the ple are not helpless in dealing with their pain, nor need treatment program. they view pain as an all-encompassing determinant of The CB treatment consists of five overlapping phases: their lives. Rather, a variety of resources are available for confronting pain, and pain will come to be viewed 1. Initial assessment by patients in a more differentiated manner. The treat- 2. Collaborative reconceptualization of the patient’s mentencouragespatientsto maintain aproblem-solving views of pain orientation and to develop asenseof resourcefulness, in- 3. Skills acquisition and skills consolidation, including stead of the feelings of helplessness and withdrawal that cognitive and behavioral rehearsal revolve around bed, physicians, and pharmacists. 4. Generalization, maintenance, and relapse prevention The CB approach offers promise for use with a variety 5. Booster sessions and follow-up of chronic pain syndromes across all developmental lev- Although the five treatment phases are listed separately, els (Turk and Okifuji 1999). CB approaches have been it is important to appreciate that they overlap. The dis- evaluated in a number of clinical pain studies. The re- tinction between phases is designed to highlight the dif- sults tend to support the effectiveness of CB therapy in ferent components of the multidimensional treatment. reducing pain and improving functional activities (Mor- Moreover,although the treatment, as presented, follows ley et al. 1999). The American Psychological Associa- a logical sequence, it should be implemented in a flex- tion Task Force on Treatment Efficacy designated CBT ible, individually tailored fashion. Patients proceed at for chronic pain as one of 20 applications of psycholog- varying pacesand the therapistmustbe sensitive to these ical treatments for which there was significant empiri- individual differences. cal support. CBT is frequently used as a complement to The CB treatment is not designed to eliminate patients’ other treatment modalities including information, exer- pain per se, although the intensity and frequency of their cise, and medication in the treatment of FMS patients, pain may be reduced as a result of increased activity, and is incorporated within interdisciplinary and multi- physical reconditioning achieved during physical ther- disciplinary programs (Flor et al. 1992). apy, and the acquisition of various cognitive and behav- Taken as an aggregate, the available evidence suggests ioral coping skills. Rather, the treatment is designed to that the CB approach has a good deal of potential as a help patients learn to live more effective and satisfying treatment approach by itself and in conjunction with Cognitive Schemata 411 other treatments. The CB perspective is a reasonable wayforhealthcareproviderstothinkaboutanddealwith Cognitive Factors their patients, regardless of the therapeutic modalities utilized. Definition References Cognitive factors are the beliefs, appraisals, expecta- C tions, and meaning through which individuals filter 1. Flor H, Fydrich T, Turk DC 1992 Efficacy of Multidisci- plinary Pain Treatment Centers: A Meta-Analytic Review. Pain information. These cognitive factors will have an in- 49:221–230 fluence on emotional and physiological arousal and 2. Meichenbaum D, Turk DC (1987) Facilitating Treatment Adher- behavior. ence: A Practitioner’s Guidebook. Plenum Press, New York Cognitive-Behavioral Perspective of Pain 3. Melzack R, Wall PD (1965) Pain Mechanisms: A New Theory. Science 150:971–979 Psychological Assessment of Pain 4. Morley S, Eccleston C, Williams AC de (1999) Systematic Re- view and Meta-Analysis of Randomized Controlled Trials of Cognitive Behavior Therapy and Behavior Therapy for Chronic Pain in Adults, Excluding Headache. Pain 80:1–13 Cognitive Impairment 5. Turk DC (1997) Psychological Aspects of Pain. In: Bakule P (ed) Expert Pain Management. Springhouse, pp 124–178 Cancer Pain, Assessment in the Cognitively Impaired 6. Turk DC, Rudy TE (1992) Cognitive Factors and Persistent Pain: A Glimpse into Pandora’s Box. Cognitive Therapy and Research 16:99–122 7. Turk DC, Flor H (1999) Chronic Pain: A Biobehavioral Perspec- tive. In: Gatchel RJ, Turk DC (eds) Psychosocial Factors in Pain. Cognitive Model of Pain Guilford Press, New York, pp 18–34 8. Turk DC, Okifuji (1999) A Cognitive-Behavioral Approach to Cognitive-Behavioral Perspective of Pain Pain Management. In: Wall PD, Melzack R (eds). Textbook of Pain, 4th edn. Churchill Livingstone, London, pp 1431–1444 9. Turk DC, Meichenbaum D, Genest M (1983) Pain and Behavioral Medicine: A Cognitive-Behavioral Perspective. Guilford Press, Cognitive Modulation of Pain New York Descending Circuits in the Forebrain, Imaging Cognitive Coping Training

Definition Cognitive Restructuring CognitiveCopingTrainingincludes,butisnotlimitedto, Definition attention diversion strategies, reinterpreting pain sensations, calming self-statements, and imagery techniques. Cognitiverestructuringisaprocesswherebypatientsare Psychological Treatment of Headache taughttomonitortheirthoughtsandfeelings,andtoeval- uate whether these are appropriate in light of the circumstances and evidence available. Patients are encouraged tobecomeawareoftheirautomaticresponsesandtocon- Cognitive Dysfunction sider the accuracy of the assumptions on which these responses are based. They are instructed to evaluate the Definition assumptions that result in specific behaviors and to con- Changes in consciousness, higher cortical functions, sider alternatives that may be more adaptive. mood, or perception that may be induced by any of Catastrophizing numerous neurological or systemic diseases, or by in- Multidisciplinary Pain Centers, Rehabilitation gestion of substances, including drugs, that have the Psychological Treatment of Headache potential for central nervous system toxicity. Cancer Pain Management, Opioid Side Effects, Cog- nitive Dysfunction Cognitive Schemata

Definition Cognitive Error Cognitive schemata are models that people create to assist them to structure and make sense of life circum- Definition stances, constructs, and categories. These are efficient A discrepancy between actual and perceived aspects of templatesthathelppeoplenavigateintheirworldandfil- a particular situation. ter new information. Newly acquired information must Catastrophizing be assimilated into these existing cognitive structures 412 Cognitive Tasks or will contribute to a modification (accommodation)of the schemata to incorporate the new data of experience. Cold Allodynia Test Cognitive-Behavioral Perspective of Pain Definition One or two drops of acetone are thrown on the plantar Cognitive Tasks aspect of the leg. In rats, this procedure does not produce a significant reaction (score <0.5), however, in rats with mononeuropathya vigorous reaction is induced by Definition acetone-drops for a period up to 20 s. Procedures used to engage participants in a particular Allodynia Test, Mechanical and Cold Allodynia cognitive activity. These include (but are not restricted Thalamotomy, Pain Behavior in Animals to) tasks such as the retrieval of words or memories, reaction times to identify specific stimulus features or to complete different mental operations, or the interpreta- Cold Hyperalgesia tionofambiguousstimuli.Theoperationofspecificcog- nitive processes is typically inferred on the basis of dif- Definition ferent patterns of cognitive task performance. Psychology of Pain, Assessment of Cognitive Vari- Pain induced abnormally, or exacerbated, by low tem- ables perature.Acommonsymptominmanyneuropathicpain patients. Nociceptors, Cold Thermotransduction Cognitive Therapy

Cognitive-Behavioral Treatment of Pain Cold Nociception

Nociceptors, Cold Thermotransduction Cohort

Deﬁnition Cold Nociceptors Cohort refers to a group, band, or body of people who DONALD A. SIMONE are followed over time. Department of Diagnostic and Biological Sciences, Prevalence of Chronic Pain Disorders in Children University of Minnesota, School of Dentistry, Minneapolis, MN, USA [email protected]

Cohort Study Deﬁnition

Longitudinal Study Nociceptors are sensory receptors located on peripheral Longitudinal Study nerveendingsthatareexcitedbynoxiousorpainfulstim- uli. Subgroups of nociceptors are excited by cold and encode the intensity of cold stimuli. Coital Pain Characteristics In humans, reduction of skin temperature to approxi- Dyspareunia and Vaginismus mately 15˚C or less evokes a sensation of pain. Interest- ingly, pain from noxious cold can have different qualities, including cold, burning, pricking and aching, de- Cold Allodynia pendingontheintensity,duration,rateofstimulationand location of the cold stimulus (Chery-Croz 1983; Davis and Pope 2002; Kunkle 1949). This suggests that differ- Deﬁnition ent classes of nociceptors are excited by noxious cold Pain produced by a normally non-painfulcold stimulus. stimuli. Neuropathic Pain Model, Partial Sciatic Nerve Liga- Early studies documented that a portion of cutaneous tion Model Aδ and C nociceptors that are responsive to mechanical Neuropathic Pain Model, Tail Nerve Transection stimuli are excited by noxious cold (Bessou and Perl Model 1969; Burgess and Perl 1967; Georgopoulos 1976; Cold Pressor Test 413

LaMotte and Thalhammer 1982; Saumet et al. 1985). References Many of the nociceptors excited by cold are also ex- 1. Bessou P, Perl ER (1969) Response of cutaneous sensory units cited by heat, and are considered to be polymodal with unmyelinated fibers to noxious stimuli. J Neurophys- nociceptors. However, the exact proportion of Aδ and iol 32:1025–1043 2. Burgess PR, Perl ER (1967) Myelinated afferent fibres re- C nociceptors excited by cold varied among the studies sponding specifically to noxious stimulation of the skin. J C because stimulus temperatures and species used varied. Physiol 190:541–562 For example, nociceptors in monkeys were not excited 3. Cain DM, Khasabov SG, Simone DA (2001) Response properties by stimuli to 15˚C (Perl 1968), whereas 78% of Aδ of mechanoreceptors and nociceptors in mouse glabrous skin: an in vivo study. J Neurophysiol 85:1561–1574 and C nociceptors were excited by the application of 4. Campero M, Serra J, Ochoa JL (1996) C-polymodal nociceptors ice to the skin (LaMotte and Thalhammer 1982). In activated by noxious low temperature in human skin. J Phys- an extensive study of the response properties of the iol 497:565–572 various subtypes of nociceptors in rats, Leem et al. 5. Chéry-Croze S (1983) Painful sensation induced by a thermal δ cutaneous stimulus. Pain 17:109–137 (1993) found that approximately 10% or less of A 6. Davis KD, Pope GE (2002) Noxious cold evokes multiple sen- and C nociceptors were excited by cold. Using stim- sations with distinct time courses. Pain 98:179–185 ulus temperatures between 27 and 12˚C, they found 7. Georgopoulos A (1977) Stimulus-response relations in high- response thresholds of nociceptors were between 22 threshold mechanothermal fibers innervating primate glabrous skin. Brain Res 128:547–552 and 12˚C. However, when a wider range of stimulus 8. Kunkle EC (1949) Phasic pains induced by cold. J App Phys- temperatures was used, it was found that nearly all iol 1:811–824 mechanosensitive nociceptors in rat hairy skin were 9. LaMotte RH, Thalhammer JG (1982) Response properties of high-threshold cutaneous cold receptors in the primate. Brain excited by noxious cold (Simone and Kajander 1996; Research 244:279–287 Simone and Kajander 1997). Response thresholds for 10. Leem JW, Willis WD, Chung JM (1993) Cutaneous sensory re- Aδ nociceptors ranged from 14 to -18˚C; 79% of Aδ ceptors in the rat foot. J Neurophysiol 69:1684–1699 nociceptors had cold response thresholds at or below 11. Perl ER (1968) Myelinated afferent fibers innervating the primate skin and their response to noxious stimuli. J Physiol 0˚C. Most C nociceptors exhibited response thresh- (Lond) 197:593–615 olds above 0˚C and thresholds ranged from 12 to -6˚C. 12. Saumet J-L, Chéry-Croze S, Duclaux R (1985) Response of cat A wide range of cold response thresholds was also skin mechanothermal nociceptors to cold stimulation. Brain Res observed for nociceptors in mouse skin (Cain et al. Bull 15:529–532 13. Simone DA, Kajander KC (1996) Excitation of rat cutaneous 2001). nociceptors by noxious cold. Neurosci Lett 213:53–56 Sensitivityofnociceptorstocoldhasalsobeendescribed 14. Simone DA, Kajander KC (1997) Responses of cutaneous A-fiber in humans (Campero et al. 1996; Torebjrk 1974). Using nociceptors in noxious cold. J Neurophysiol 77:2049–2060 stimulus intensities between 19 and 0˚C, it was found 15. Torebjrk HE (1974) Afferent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. Acta that 40% of Cnociceptorsthat were sensitive to mechan- Physiol Scand 92:374–390 ical and heat stimuli were also excited by noxious cold stimuli. A few studies have examined the intensity encoding Cold Pressor Test propertiesofnociceptorsfornoxiouscoldstimuli(Geor- gopoulos 1977; Simone and Kajander 1996; Simone and Kajander 1997). Using a range of stimulus temper- Definition atures from 20 to -12˚C (or sometimes to -12˚C), each The cold pressor test is a widely used experimental pain for a duration of 10 seconds, it was found that responses procedure to determine a person’s pain threshold and of Aδ and C nociceptors in rats increased as stimulus pain tolerance. Subjects are asked to immerse their right temperature decreased (Simone and Kajander 1996; or left lower arm (up to the elbow) or foot into a basin Simone and Kajander 1997). The number of evoked of water, which is kept at a constant given temperature impulses, the average discharge rate and the peak dis- between 0˚C and 10˚C. Pain threshold is defined as charge rate each increased as stimulus temperature the elapsed time between arm immersion and the first decreased. Discharge rates evoked by stimulus temper- report of a pain sensation. Pain tolerance is defined as atures greater than 0˚C were typically low (less than 1 the elapsed time until voluntary withdrawal of the hand. impulse per second) and increased with colder temper- Since the cold pressor test induces pronounced sym- atures. Power functions were generated to determine pathetic activation and vasoconstriction, the maximum the stimulus-response relationship for Aδ nociceptors duration of limb immersion is typically restricted by and the slopes of the power functions ranged from 0.12 the experimenter in order to prevent vascular problems. to 2.28. Experimental Pain in Children In summary, the majority of cutaneous nociceptors that Modeling, Social Learning in Pain are excited by mechanical stimuli, including polymodal Pain in Humans, Thermal Stimulation (Skin, Muscle, nociceptors, are excited by noxious cold stimuli. Cuta- Viscera), Laser, Peltier, Cold (Cold Pressure), Radi- neous nociceptors exhibit a wide range of cold response ant, Contact thresholds and encode stimulus intensity. Pain in Humans, Thresholds 414 Cold Therapy

Psychological Aspects of Pain in Women Psychology of Pain, Self-Efﬁcacy Collateral Sprouting

Definition Induction of new axonal sprouts from an intact nerve by Cold Therapy nerve growth factor. The sprouts grow into an area of an adjacent, injured, degenerating, peripheral nerve. Corti- cal sensations related to this phenomenon can be related Therapeutic Heat, Microwaves and Cold to either the injury itself, or the response to dividing the injured peripheral nerve to treat a painful neuroma. Col- lateral sprouting pain can be misinterpreted as failure of the original treatment for the painful scar or painful neu- Cold Thermoreceptor roma. Painful Scars Definition In biophysical terms, a cold thermoreceptor is a nerve Colorectal Distension ending excited only, or preferentially,bya coldtempera- turestimulus.Theyshouldbedistinguishedfrom„spuri- Synonyms ous“ thermoreceptors like slowly adapting mechanoreceptors that also respond to thermal stimulation. CRD Cold Nociceptors Nociceptors, Cold Thermotransduction Definition Controlled innocuous or noxious visceral stimulus applied by distension of a balloon placed in the lumen of the descending colon and rectum. In humans under nor- Cold Thermotransduction mal conditions, distension pressures below 40 mmHg are felt as non-painful, whereas distension pressures greater than 40 mmHg are felt as painful. Cold Nociceptors Descending Modulation of Visceral Pain Nociceptors, Cold Thermotransduction Postsynaptic Dorsal Column Neurons, Responses to Visceral Input Spinal Dorsal Horn Pathways, Dorsal Column (Vis- ceral) Cold-Induced Hyperalgesia Visceral Pain Model, Lower Gastrointestinal Tract Pain Freezing Model of Cutaneous Hyperalgesia Colposcopy

Colitis Definition Colposcopy is a diagnostic tool aimed at verifying the cause of abnormalities found in Pap smears. It involves a Definition visual examination of the cervix, genitals, and vagina as Inflammation of the large intestine, or colon, often wellastheapplicationofaceticacidtoidentifyabnormal caused by a primary disease, irritation of the bowel, an- cells. tibiotic use, or ulceration. Acute colitis can be produced Dyspareunia and Vaginismus experimentally by the introduction of an irritant, such as mustard oi1, zymosan or capsaicin into the lumen of the colon. Symptoms may include abdominal pain or Combined Spinal Epidural (CSE) bloating, diarrhea, dehydration, and increased intestinal gas. Technique Amygdala, Pain Processing and Behavior in Animals Definition Animal Models of Inflammatory Bowel Disease Visceral Pain Model, Lower Gastrointestinal Tract An anesthetic technique where both spinal and epidu- Pain ral anesthesia is administered to the same patient as one Complete Freund’s Adjuvant 415 technique. It offers the advantages of a spinal anesthetic (intense analgesia) with the advantages of an epidural Comorbidity anesthetic (flexibility and long duration of action). Analgesia During Labor and Delivery Definition Comorbiditydefinesanassociationbetweentwoormore C disorders or diagnoses at one time that are more than Common Fears coincidental. Migraine, Preventive Therapy Psychiatric Aspects of the Epidemiology of Pain Definition More specific fears directed at an apparent object (such as spider phobia, agoraphobia, fear of pain). They arise Compartmental Syndrome as the result of an interaction between the fundamental fears and learning experiences, and can thus be logically Postoperative Pain, Compartment Syndrome derived from these three fundamental fears. Fear and Pain Competitive Agonist or Antagonist Common Migraine Definition Migraine Without Aura Compound that interacts with the endogenous ligand- binding site of the receptor. NociceptiveProcessingintheAmygdala,Neurophys- iology and Neuropharmacology Common Toxicity Criteria Spinal Cord Nociception, Glutamate Receptor (Metabotropic) Definition WHOandNationalCancerInstitutemethodofassessing the morbidity associated with cancer and cancer treat- Complement ment by organ system. Cancer Pain Management, Chemotherapy Definition Non-specific mediator of humoral immunity. Many agents (antigens) trigger the complement cascade, Communication Limitations or which may ultimately result in the generation of mem- Neurological Impairment brane attack complex and lysis of cells presenting the triggering agent. Inflammatory Neuritis Pain in Children with Disabilities

Complementary Medicine Comorbid Headache Alternative Medicine in Neuropathic Pain Definition Classification proposed by Gladstein and Holden (1996), describing a subtype of chronic daily headache Complementary Therapies in children as a daily tension-type headache, accompanied by intermittent and less frequent episodes of Alternative Medicine in Neuropathic Pain well-defined migraine headache. Chronic Daily Headache in Children

Reference Complete Freund’s Adjuvant Gladstein J, Holden EW (1996) Chronic daily headache in children and adolescents: a 2-year prospective study. Synonyms Headache 36:349-351 CFA 416 Compensation, Disability, and Pain in the Workplace

sequence, decisions regarding the presence and im- Compensation, Disability, and Pain in pact of pain are based on inferences derived from prior the Workplace experience and assumptions related to the amount of pain that might be expected given objective indica- JAMES P. ROBINSON,DENNIS C. TURK tions of pathology or disease. At a clinical level, con- Department of Anesthesiology, University of flicts and distrust frequently develop between disabil- Washington School of Medicine, Seattle, WA, USA ity applicants and the health care provider and disabil- [email protected], ity adjudicators who are involved in their claims. In- [email protected] dependent medical examiners and attorneys often be- Introduction come participants in these conflicts. People experiencing pain often feel that physicians and others discount Pain is the epitome of a private experience. Only the their reports; physicians and adjudicators may experi- person with pain has direct access to the experience. ence doubt or outright skepticism about reports of pain At the same time however, pain has a public face, be- in the absence of corroborating physical findings. The cause people in pain communicate their suffering to essay Ethics of Pain-Related Disability Evaluations others either verbally or by non-verbal behavior and explores ethical and conceptual issues related to the often request assistance. Observers of someone in pain taskofmakinginferencesaboutthepainofanotherper- are challenged because they are not able to experience son. the other’s pain directly. Thus, they are forced to make inferencesandmaywellhavedifficultyinterpretingthe Disability Systems communications of the pain sufferer. Social interactions related to pain occur in both for- Communities frequently provide assistance to people mal and informal settings. As an example of the latter, who are incapacitated. This type of helping behavior a person with pain will communicate his or her suffer- can be seen not only in modern societies, but also in ingtofamilymembers.Researchhasdemonstratedthat primitive ones and even in communities of infrahuman the family members, in turn, respond to the pain suf- primates (Fabrega 1997). Tolerance toward and care ferer in fairly predictable ways (Romano et al. 1995). of the sick, infirm, injured and disabled appears to be But not only family members respond to the behavior a fundamental feature of society dating back to pre- of those who experience pain. Co-workers and super- historic times (Ranavaya and Rondinelli 2000). For- visors and health care providers are also asked to re- mal disability compensation systems were recorded as spond by making work place accommodations in the many as 4000 years ago by the Babylonians, who pro- case of the former and prescribing treatment in the lat- vided compensation for loss of life or a body part inter. Health care providers are also frequently asked to curred in the service of the state. During the time of the make recommendations regarding the impairments of ancient Egyptians and Greeks, the state provided com- individuals who report incapacitation because of pain. pensation for injuries caused by a wrongful act or oc- These may serve as the basis for financial compen- curring in the context of military service, respectively. sation and accommodations on the job. The present Contemporary approachestothe issue of assistance for field of this volume addresses social interactions re- incapacitated people can be traced back to social insur- lated to pain that occur in a formal context – in partic- ance programs instituted in Germany in the late 19th ular, it addresses interactions between pain sufferers century (Ritter 1983). and 1) health care providers who offer treatment and The social insurance programs that are most relevant make decisions about disability and 2) societal agen- to the present field of this volume are those that pro- ciesthat provide benefitsfor work disability.Examples vide income maintenance benefits (also referred to as of such societal agencies include workers’ compensa- “wage replacement” or “time loss” benefits) for per- tion programs (which compensate individuals only if sons who are incapacitated from work. As noted in a their medical problems were caused by work) and pro- comprehensive survey of social insurance programs in gramssuchastheUnitedStatesSocialSecurityAdmin- 138 countries and territories, programs to assist citi- istration (which compensate disabled people regard- zens who are incapacitated exist in most countries (So- less of the cause of their disability). cialSecurityAdministration,OfficeofResearch,Eval- The problems of impairment and disability (these 2 uation and Statistics 1999). Several of these are dis- inter-related concepts are defined and differentiated cussed as illustrations in the essays impairment rat- below) secondary to pain are elusive and yield con- ing, ambiguity; impairment rating, ambiguity, IA- flicts and contradictions at multiple levels of analy- IABC system; disability evaluation in the social se- sis. The central problem relates to the fact that there curity administration and rating impairment due to is currently no objective measure of pain. As a con- pain in a workers’ compensation system. Compensation, Disability, and Pain in the Workplace 417

Among income maintenance programs, a basic dis- reflect an ethical commitment to support citizens who tinction can be made between work injury (or work- areincapableofworking.Ifaprogramistoorestrictive, ers’ compensation)programs and disability programs. it may consign needy andworthyapplicantstopoverty; Workers’ compensation programs provide benefits for if it is too lax, it may encourage disability applications individuals who are disabled because they have sus- frompeoplewhoareactuallycapableofworking.Even C tained injuries or developed diseases “out of and in the if a program is meeting its ethical mandate quite well, course of employment” (p. 10) (Williams 1991). Dis- it may strain the financial resources of the payer to the ability programs in contrast provide benefits for peo- breakingpoint.Thisispreciselytheconcernthatisnow ple who are incapable of working for any reason. Thus, being voiced about many of the programs run by the both workers’ compensation programs and disability Social Security Administration in the United States. programs provide income maintenance only if an indi- At a scientific level, issues related to disability are vidual is judged to be unable to work because of a med- usually unanswerable, because the research underpin- ical condition, but workers’ compensation programs nings for “disability evaluation science” are so mea- impose an additional criterion – that the medical con- ger. Moreover, the search for scientifically valid condition was caused by the person’s work activities. clusions about disability may be compromised by the A central thesis of this field in the Encyclopedic Ref- adversarial settings in which disability evaluations are erence of Pain is that important problems and signif- conducted, and the enormous financial stakes involved icant ambiguities emerge as individuals with painful (see independent medical examinations). disordersinteractwithagenciesthatadministerincome Finally, ataphilosophicallevel, theproblemof disabil- maintenance programs. A corollary of thisthesisisthat ity evaluation in chronic pain rests on an epistemolog- the problems that emerge in these interactions will de- ical dilemma – the information available to an individ- pend on specific features of disability programs. It is ual suffering pain is fundamentally different from the beyond the scope of this essay to discuss the complexi- information available to any external observer who at- tiesof disability programs, but evena cursoryreview of tempts to assess the pain. Scarry succinctly captured themrevealsenormousvariationfromcountrytocoun- this dilemma when she asserted: “To have great pain try in the manner in which programs are financed and is to have certainty; to hear that another person has pain integrated into a network of social security programs, is to have doubt.”(p. 7) (Scarry 1985). and in the eligibility criteria and procedures they use In clinical situations, patients frequently communicate toevaluateapplicants(SocialSecurityAdministration, the sense that they are severely incapacitated by pain Office of Research, Evaluation and Statistics 1999). and ask health care providers to support their claims. Some of the essays (e.g. the ones on patient credibility Typically, the health care providers who evaluate these and pain behavior; see credibility, assessment and patients cannot identify tissue damage or organ pathol- nonorganicsymptoms and signs) are relevant to any ogy that makes the limitations communicated by the system of income maintenance for persons who allege patient seem inevitable, proportional or even plausible. work incapacity because of pain. However, many of The health care provider then has the dilemma of inte- the other essays discuss attempts by specific disabil- gratingthepatient’ssubjectivereportwiththeobjective ity agencies to address problems presented by pain re- evidence of tissue damage and organ pathology to es- lated incapacitation. These essays should be viewed as tablish some final judgment about the extent to which providing examples of ways in which specific disabil- the patient really is incapacitated. At one extreme, a ity agencies have addressed problems associated with health care provider might simply ignore a patient’s pain, rather than as comprehensive discussions of the self-assessments and make a disability determination ways in which these problems might be addressed. based strictly on objective findings of tissue damage or At an administrative level, bureaucracies that have organ pathology. At the opposite extreme, the health specific imperatives operate disability programs. For care provider might accept the patient’s description example, the Social Security Administration in the of the situation, and provide a disability rating that is United States, which operates the 2 largest disabil- congruent with the patient’s self-assessment. Adjudi- ity programs, strives for uniformity, objectivity and cators at disability agencies face the same dilemma costcontainmentinitsdisabilityevaluationprocedures when they decide whether or not to award benefits (Derthick1990).Oneoftheessays, impairment,pain to disability applicants. It has proved extremely diffi- related, pointsoutthathoweversensiblethesegoalsare cult to find some intermediate position in which both from a bureaucratic standpoint, they are often at odds objective evidence and self-assessments by patients with the clinical realities of patients with chronic pain can be incorporated into disability evaluations (see (Osterweis et al. 1987; Robinson et al. 2004). impairment rating, ambiguity; impairment rat- At a societal level, additional concerns and perspec- ing, ambiguity, IAIABC system; impairment, pain- tives emerge. As noted previously, disability programs related and independent medical examinations). 418 Compensation, Disability, and Pain in the Workplace

The issues discussed in this field are particularly (AMA Guides) defines disability as “an alteration of relevant to 5 groups of professionals: 1) clinicians an individual’s capacity to meet personal, social or oc- who treat patients with chronic pain, 2) physicians cupational demands or statutory or regulatory require- who conduct independent medical examinations (see ments because of an impairment” (p. 8) (Cocchiarella independent medical examinations), 3) allied pro- and Andersson 2001). This very broad definition re- fessionals who participate in disability mitigation pro- flects the fact that the AMA Guides describe an evalu- grams (e.g. vocational rehabilitation counselors) 4) ation system that is relevant to many kinds of disability individuals involved in disability policy and 5) psy- (rather than just work disability) and that permits gra- chologists interested in the study of interpersonal per- dations in disability to be identified (rather than just the ception and the ways in which social interactions in- 2 categories of totally disabled vs. non-disabled.) fluence pain. An impairment can best be understood as a deficiency in the functioningof an organ or body part that leads to Definitions: Disability and Impairment incapacitation or disadvantage in various arenas (such “Disability” and “impairment” are fundamental con- as inability to work or inability to do routine activities cepts that provide the conceptual cornerstones for dis- at home). “Impairment” is defined in a similar way by ability programs. Disability can be informally defined different disability agencies and expert panels. As an as the inability to carry out certain activities because example, the formal definition of impairment given in of a medical problem (an abnormality in the structure the AMA Guides is: “a loss, loss of use or derange- or function of an organ or body part). There are differ- mentof any body part, organ system ororgan function” ent kinds of disability, since there are different types of (p. 2) (Cocchiarella and Andersson 2001). Thus, one activities that might be affected by a physical disorder. might say: “Mr. Jones’ heart has been impaired since For example, a person might be disabled in the sense he suffered a myocardial infarction” or “Mrs. Brown’s of being unable to work, in the sense of being unable right hand is impaired because of her carpal tunnel to manage his or her personal finances or in the sense syndrome.” The essay impairment, pain-related ad- of being unable to perform activities of daily living in- dressesproblemsthatarisewhentheAMAGuidescon- dependently. The current field focuses specifically on struct of impairment is applied to individuals who re- work disability – the inability to engage in substantial, port incapacitation because of pain. Additional discus- gainful employment. sions of the definitions and the relationships among Unfortunately, there is no unique formal definition of body function and structures, activities and participa- work disability, since various agencies that adminis- tion as conceptualized by the World Health Organiza- ter disability programs define the term slightly differ- tion are included in the essays disability and impair- ently. These differences reflect a fundamental reality ment definitions and WHO system on impairment about disability agencies and the criteria used for mak- and disability. ing decisions. For a disability agency, definitions serve Disability agencies assume significant linkages be- the practical function of identifying the criteria that ap- tween impairment and disability. First, they construe plicants must meet in order to be eligible for benefits. impairment as a necessary condition for disability. The Thus, agencies have different definitions, because they logic underlying this requirementis simple. Disability have different mandates and different eligibility crite- programs are designed to assist people who are inca- ria. pable of competing in the workplace because of a med- The United States Social Security Administration de- ical condition. In essence, disability programs attempt fines disability as: “the inability to engage in any sub- to partition persons who fail in the workplace into 2 stantialgainfulactivity...byreasonofanymedicallyde- large groups, ones who fail because of a medical con- terminable physical or mental impairment that can be dition and ones who fail for other reasons (e.g. lack expected to result in death or that has lasted or can be of demand for their skills). Therefore, disability pro- expected to last for a continuous period of not less than grams require evidence that an applicant actually has a 12 months” (p. 2) (SSA Publication 1994). This def- medical problem underlying his or her workplace fail- inition reflects 3 facts about eligibility criteria for the ure.Impairmentprovidesthenecessaryevidence,since SocialSecurityDisabilityInsuranceandSupplemental it can be viewed as a marker that an individual has a Security Income programs: 1) applicants must be to- medical problem that diminishes his or her capability. tally disabled from work; 2) the work disability must Conversely, if a person has no apparent impairment, be “permanent” (or at least long-term); 3) causation is this means that he or she does not have limitations due irrelevant – that is, an individual is eligible for benefits to a medical condition. regardless of how or why he or she became disabled. In Disability agencies typically assume that the severity contrast, the American Medical Association’s Guides of a person’s impairment is highly correlated with the totheEvaluationofPermanentImpairment,5thedition severity (or probability) of his or her being disabled Compensation, Disability, and Pain in the Workplace 419 from work. Thus, even when an agency grants awards quently to warrant a thorough discussion of pain in the only on the basis of work disability, the agency will workplace. often seek information about a person’s impairment in order to rationalize its decision about whether or Basic Problems Involving the Interface between Dis- not to award disability benefits. Studies have shown, ability Systems and Injured Workers with Chronic Pain C however, that the association between physical impair- Objective Factors ments and work disability is far from perfect (Waddell 1987). As the above discussion suggests, the practi- Disability agencies strive to use disability evaluation cal question facing a disability agency is to determine procedures that are based on objective findings of in- whetherornotanapplicantissufficientlyincapacitated capacitation. This administrative objective seems in- to be eligible for disability benefits. Impairment evalu- nocuous enough; however, it has profound implica- ation should be viewed as an intermediatestep in mak- tions. In essence, disability agencies must make signif- ing this determination. Many of the essays in the field icant simplifying assumptions about disability in order of compensation, disability and pain in the workplace to achieve their administrative goal. The most funda- focus on disability and disability determination. mental simplifying assumption is that impairment and disability should be “transparent” to an experienced physician,namelythatactivitylimitationsasdescribed When Should a Disorder Be Construed as a Pain Prob- ordemonstratedbypatientsshouldbehighlycorrelated lem? with evidence of tissue damage or organ dysfunction Pain occurs in a wide range of medical disorders. It is thatcanbeobjectivelyassessedbyaphysician.Thisas- usually conceptualized as a “component” of a disor- sumption underlies the routine demand that disability der that is typically inextricably interwoven with other adjudicators make for physicians to rely on “objective manifestations of disease or injury. From this perspec- findings” when they proffer conclusions about activity tive, it issomewhat arbitrary to abstract painfrom other limitations of claimants. manifestationsofdisorders,justasitwouldbearbitrary The assumption that impairment and disability can be to isolate fevers from malaria or shortness of breath objectively assessed is so pervasive that most physi- from myocardial infarction. cians – and essentially all disability adjudicators – ac- A related point is that many painful disorders are cept it without question. The assumption is valid for treated by specialistsof an affectedorgansystem rather certain medical conditions. For example, physicians than by pain specialists. For example, chest pain is a have tools to quantify impairment stemming from am- cardinal symptom of cardiac ischemia, but a patient putations or complete spinal cord injuries. However, with chest pain of cardiac origin is much more likely to in many medical conditions – including most chronic be treated by a cardiologist or a thoracic surgeon rather pain syndromes – physicians cannot objectively iden- than by a pain specialist. Specialists in organ pathol- tifyimpairmentsthatrationalizetheactivitylimitations ogy typically view pain as a symptom of a biological that patients report. In a monograph on the disability abnormality that is important as a guide to appropri- programs administered by the Social Security Admin- ate diagnosis and treatment. In this model, symptoms istration in the United States, Osterweis et al. (1987) and signs are used to diagnose disorders and treatment summarize the problem as follows. is directed toward the abnormal pathophysiology that The notion that all impairments should be verifiable by comprises a disorder, rather than toward the symptoms objective evidence is administratively necessary for an of the disorder per se. The assumption is that once the entitlement program. Yet this notion is fundamentally underlying biological abnormality has been corrected, at odds with a realistic understanding of how disease the symptoms – including pain – will abate. and injury operate to incapacitate people. Except for a The discussion in the previous paragraph raises a prac- very few conditions, such as the loss of a limb, blind- tical question. When should disorders that occur in the ness, deafness, paralysis or coma, most diseases and workplace be construed as pain problems? Two related injuries do not prevent people from working by me- criteria are suggested. A disorder is appropriately con- chanical failure. Rather, people are incapacitated by a strued as a pain problem when either 1) patients report variety of unbearable sensations when they try to work pain, but do not demonstrate structural or functional (p. 28). abnormalities that unequivocally explain their pain or In essence, this statement indicates that in many medi- 2) patients demonstrate limitations in activities that are cal disorders disability is related to subjective factors – not inevitable consequences of biological abnormali- especially pain – rather than to objectively measurable ties, but rather appear to be consequences of pain that “mechanical failure” of body parts or organs. As dis- thepatientsexperienceastheyengageinactivities.One cussed in several essays ( impairment rating, ambi- or both of these circumstances occur sufficiently fre- guity impairmentrating,ambiguity,IAIABCsystem 420 Compensation, Disability, and Pain in the Workplace

disability evaluation in the social security adminis- how much weight to place on the claimant’s subjec- tration disability,effectofphysiciancommunication tivereports,asopposedtoobjectivefindingsoforganor rating impairment due to pain in a workers’ com- body part dysfunction (see impairment, pain-related pensation system), disability agencies have developed and disability evaluation in the social security ad- differentsolutionstotheproblemofreconcilingthead- ministration for discussions of attempts to integrated ministrative imperative of basing disability determina- subjective reports with objective evidence in impair- tions on objective findings with the reality that subjec- ment / disability determination). tive factors are the proximate cause of work incapac- A comparison between rheumatoid arthritis (RA) and itation for many patients. fibromyalgia syndrome (FMS) provides a dramatic example of the difficulty of assessing severity of Credibility impairment-disability in a person with chronic pain. Many disability agencies have at least implicitly ac- People with RA and FMS typically report compara- cepted the premise that determinations about eligibil- bly severe activity limitations. However, the former ity for disability benefits should rely, at least in part, typically have observable evidence of joint inflamma- on claimants’ reports about pain and other subjective tion or destruction, whereas physical and laboratory experiences. To the extent that disability determina- examinations for the latter are often completely nor- tion relies on subjective reports by claimants about the mal (except for tenderness to palpation). The question difficulties they have when working, agencies must be for a disability agency is should the activity limitations concerned about how to assess the integrity of these re- reported by people diagnosed with FMS be given as ports. In the extreme case, it is possible for malingerers much weight as those reported by people with RA for to simulate incapacitation and receive disability bene- purposes of awarding disability benefits? This type of fitswhentheyhaveessentiallynoworklimitations.The dilemma occurs routinely when claimants allege in- problem of malingeringisaddressedin malingering, capacitation secondary to pain. Three essays in this primary and secondary gain. field cover specific examples of syndromes in which A more common scenario is that claimants report dra- patients complain of severe pain, but have little or no matic activity restrictions because of pain, and demon- evidence of tissue pathology that rationalizes the com- strate severe functional limitations during physical ex- plaints – low back pain ( epidemiology of work dis- amination. Examining physicians and disability agen- ability, back pain), FMS ( disability in fibromyalgia cies face a quandary when evaluating these patients, patients), and upper extremity injuries ( disability, since, as noted above, it is often not possible to iden- upper extremity). tify evidence of organ damage that makes the alleged activity restrictions seem inevitable, proportional or Causation even plausible. The essay credibility, assessmentad- dresses general problems in the assessment of credibil- Causation is important when a person is seeking dis- ity and veracity among patients with chronic pain. In ability benefits from an agency that is responsible only nonorganic symptoms and signs, the assessment of for medical conditions that arise in certain circum- “non-organic signs” on physicalexaminationisspecif- stances. In particular, workers’ compensation carriers ically addressed, namely the assessment of examina- are responsible only for conditions that arise out of tion findings that indicate something other than well- employment. The assessment of causation is thorny at described organic pathology. both the conceptual (Kramer and Lane 1992; Lakoff and Johnson 1999) and practical levels. The difficulty Severity of Impairment and Disability in determining whether a medical condition has been As discussed, disability agencies attempt to base de- caused by work is by no means limited to painful con- cisions on objective evidence of organ or body part ditions. For example, controversy rages about whether dysfunction. The assessment of disability secondary to and when hearing loss should be construed as work pain is in conflict with this administrative imperative. related (Dembe 1996). However, issues of causation People with chronic pain typically attribute their pain are often particularly vexing for painful conditions and activity limitations to dysfunction of an organ or that are commonly attributed to work. The difficulty body part. But these subjective reports are difficult to stems in part from the fact that many disorders that are assess precisely because examination of the involved commonly attributed to work (e.g. non-radicular low organorbodypartoftendoesnotidentifyabnormalities back pain) often reflect a combination of degenerative that make the pain reports inevitable (Robinson et al. changes and inciting physical loads. As a result, it is 2004). It often appears to an examiner that the affected difficult to weigh the influence of work exposures with organ or body part is capable of functioning, but that non-work exposures. But another reason for the dif- the claimant does not use it normally because of pain. ficulty is that an examiner typically has no objective Thus, the examiner has the challenge of determining method for determining the severity of incapacitation Compensation, Disability, and Pain in the Workplace 421 in a patient with LBP.The claimant may allege that his toapproachreturntoworkwithconfidence.Inaddition, LBP started or became worse during the course of ac- workers may develop resentment toward the disability tivitiesatwork,buttheexaminerwillnotbeabletocon- agency with which they interact and thereby become firm or deny such a statement on the basis of objective more resistant to rehabilitation. medical information. Thus, the problem of determin- The disability syndrome construct is difficult to prove C ing causation in people with chronic pain overlapswith empirically. For example, it is possible that injured the problem of determining severity of disability – in workerswhofailtorecoverinatimelywayhadmedical both instances, the examiner must decide how much or psychosocial risk factors that existed at the time of weight to assign to claimants’ reports. their injury, but were recognized only after the workers Disability agencies differ significantly in the standard showed a delayed recovery (Mustard and Hertzmann they set for establishing causation. Some agencies fol- 2001). However, the construct provides a plausible ex- low the principle that in order for an index injury to planation for the common observation that an injured be accepted as the cause of a claimant’s impairment, worker, who seems straightforward and highly moti- the injury must be the significant factor contributing vated just after an injury, often becomes more resistant to the impairment. Others adopt a much lower stan- to rehabilitation at a later point. dard of causation that has been described as “lighting The possibility that disability policies and agencies in- up”. When this standard applies, an index injury may advertently promote disability is a cause for great con- be viewed as the cause of an impairment even when the cern. The concern is similar to that expressed by crit- injury is minor and impairment is severe. For example, ics of welfare programs in the United States during the consider a person with a multiply operated knee who 1990s.Thecriticismofthoseprogramswasthatbypro- falls at work, develops an effusion in the knee and is viding long-term financialsupportfor unemployed, in- toldbyanorthopedistthatheneedsatotalkneereplace- digent members of the society, welfare programs ac- ment. If the individual’s workers’ compensation car- tually promoted continued indigence and unemploy- rier operated under the “lighting up” standard of cau- ment. sation,thisperson’skneesymptomsandneedforatotal kneereplacementwouldbeviewedascausedbyhisslip Epidemiology of Pain in the Workplace and fall. The differences between disability agencies in the criteria required for establishing causation high- As discussed above, there is ambiguity about the cir- light the general point that the rules and regulations of cumstances in which it is appropriate to label a medical different disability agencies vary greatly. disorder as a pain disorder. This ambiguity clouds the interpretation of data on the epidemiology of pain in Iatrogenesis the workplace. The ambiguity is increased further by Most clinicians who treat injured workers believe that the fact that the databases of workers’ compensation some of them report symptoms that are not explained systems and disability agencies generally do not pro- biologically, but rather reflect influences of the dis- vide data in a manner that highlights the role that pain ability system as filtered by psychological tendencies. plays in various injuries. The term “disability syndrome” is often used to de- However, a few simplifying assumptions make it pos- scribe these people. A disability syndrome is concep- sible to obtain at least approximate data regarding the tualized as a set of dysfunctional attitudes and beliefs frequency of work related disorders in which pain is a that evolvesover time following an injury (Robinson et major problem, butobjective evidence of biologicalin- al. 1997). One probable contributor to a disability syn- jury is either minimal or bears an equivocal relation to drome is the injured worker’s adaptation to non-work thepainthatinjuredworkersreport.First,manymuscu- roles; for example, an injured worker might take over loskeletal disorders meet these criteria. The discussion childcare duties, while hiswife entersthe work force to below will focus on these disorders, and in particular make up for family income losses. Another likely con- on 2 types of musculoskeletal problems – LBP and up- tributoristhedysfunctionalinteractionsthatmayoccur per extremity disorders associated with repetitive mo- between an injured worker and a disability agency. tion (see epidemiology of work disability, back pain AsHadler (1996) haspointed out, injured workerswho and disability, upper extremity). Second, although claim ongoing work disability must run a gauntlet of sprainscan be associated with unequivocalevidence of challengesbytheirclaimsmanager,threatstotheirben- a structurallesion(e.g.acompletetearoftheanterior efits and independent medical examinations. In these cruciate ligament would be coded as a sprain), work- situations, they must convincingly portray themselves ers’ compensation carriers routinely use the designa- as incapacitated in order to maintain their benefits. tion sprain / strain to describe musculoskeletal com- Hadler argues that after trying so hard to convince oth- plaints in the absence of definite evidence of a signif- ersoftheirincapacity,injuredworkersarelikelytohave icant structural lesion. Thus, the designation “sprain difficulty conceptualizing themselves as fit for work or or strain” in a workers’ compensation database can be 422 Compensation, Disability, and Pain in the Workplace

taken as a proxy for a disorder characterized primar- group consisted of sprainsandstrains. Table2provides ily by musculoskeletal pain in the absence of a definite a breakdown of conditions (injuries and illnesses com- structural lesion. Third, many of the disorders coded as bined) according to the body part affected. The most upper extremity repetitive motion disorders meet the commonly affected body part is the hand or fingers. above criteria, since they are not associated with defi- However, over 27,000 injuries involved the back, with nite evidence of structural lesions (Miller and Topliss an additional 8,427 involving the back and neck. Ap- 1988). proximately 90% of the back injuries were diagnosed as sprains or strains. Data from the Bureau of Labor Statistics in the United Common Work Injuries and Illness States (U.S. Department of Labor 1995) indicate that Workers’ compensation carriers generally distinguish approximately 7% of all claims filed during 1992 were between work injuries and occupational illnesses for occupational illnesses rather than injuries. Approx- (Blessmann 1991). Conceptually, an injury involves imately 60% of the claims for illnesses involved repet- a single event, whereas an illness arises gradually as itive trauma, usually of the upper extremity. (Carpal a consequence of repeated work exposures. The dis- tunnel syndrome is a subset of upper extremity ill- tinction between a work injury and an occupational nesses caused by repetitive trauma.) The second and illness is obvious if a logger who is crushed by a tree third largest groups are skin disorders (14%) and resis compared to a carpenter who develops a mesothe- piratory conditionsdue to toxic agents (5%). The most lioma after years of exposure to asbestos. However, the frequent types of repetitive activities associated with distinction becomes opaque when it is applied to mus- occupational illnesses are repetitive grasping or mov- culoskeletal disorders. For example, episodes of LBP ing of objects (other than tools) and repetitive use of are coded as injuries, whereas carpal tunnel syndrome tools. As one would expect from the types of repeti- and other upper extremity disorders associated with tive activities that produce occupational illnesses, the repetitive motion are coded as occupational illnesses. overwhelming majority of them occur in manufactur- Tables 1 and 2 provideunpublished data about injuries ing jobs. In fact, the 25 industries with the highest rates that occurred among workers covered by the Depart- of repetitive trauma occupational illnesses are all in mentofLaborandIndustriesinWashingtonStateofthe themanufacturingsector,withmeatpackingplantsand United States in 1988. Table 1 provides a break down manufacturers of motor vehicles leading the way. The of injuries according to the mechanism of injury. Col- Bureau of Labor Statistics also identifies keyboarding umn 1 indicates that the largest proportion of injuries as a significant cause of repetitive trauma induced oc- wereclassifiedascontusions,bruises,cuts,lacerations, cupational illnesses, but it is much less important than punctures, scratches or abrasions. The second largest repetitive grasping or repetitive use of tools.

Compensation, Disability, and Pain in the Workplace, Table 1 1988 Washington State injury proﬁle by nature of injury Nature of injury I II III All Claims (% of total claims) % of Claims in Column 1 that # of Claims with time loss lead to time loss > 120 days > 120 days (% of total claims with time loss > 120 days)

Contusions, Bruises, Cuts, 75,713 (47.6%) 0.8% 644 (9.6%) Lacerations, Punctures, Scratches, Abrasions

Sprains, Strains 59,729 (37.6%) 7.5% 4456 (66.1%)

Fractures 7,424 (4.7%) 11.9% 882 (13.1%)

Burns 5,777 (3.6%) 0.6% 38 (0.6%)

Multiple Injuries 2,689 (1.7%) 10.2% 273 (4.0%)

Dislocations 1,483 (0.9%) 19.0% 282 (4.2%)

Amputations 237 (0.1%) 18.1% 43 (0.6%)

Other 5,918 (3.7%) 2.1% 123 (1.8%

Totals 158,970 (100%) – 6,741 (100%)

Washington State Department of Labor and Industries (unpublished) Compensation, Disability, and Pain in the Workplace 423

Compensation, Disability, and Pain in the Workplace, Table 2 1988 Washinton State injury and illness proﬁle by body part Body part I II III All Claims (% of total claims) % of Claims in Column 1 that # of Claims with time loss lead to time loss > 120 days > 120 days (% of total claims with time loss > 120 days) C Finger 29,721 (17.7%) 0.7% 207 (2.8%)

Back 27,196 (16.2%) 9.6% 2598 (34.6%)

Eyes 17,981 (10.7%) 0.1% 19 (0.2%)

Hand / Wrist 17,444 (10.4%) 3.7% 643 (8.5%)

Back &Neck 8427 (5.0%) 8.7% 734 (9.8%)

Knee 7478 (4.4%) 8.1% 609 (8.1%)

Foot 6611 (3.9%) 2.6% 173 (2.3%)

Multiple 5583 (3.3%) 10.2% 571 (7.6%)

Other 47,616 (28.3%) 4.1% 1945 (25.9%)

Totals 168,057 (100%) – 7499 (100%)

Washington State Department of Labor and Industries (unpublished)

The Effect of Work Place Factors that are associated with work disability, it is important to distinguish ones associated with short periods off An enormous amount of research has been conducted work vs. ones associated with prolonged time loss. Al- todetermineworkplacefactorsthataffecttheprobabil- though any injured worker who reports that he or she ity that workers will become injured. The essay pain is unable to work must be viewed with concern, most in the workplace, risk factors for chronicity, workplace injuries involving time off work end uneventfullywith factorsreviewsmanyoftheworkplacefactorsthathave the worker returning to his or her job after a short time been investigated. The essay ergonomicsprovides a period. For example, amongworkersin1992whowent historicaloverviewof thefield of ergonomicsandsum- off work because of a back injury, the median time off marizes research on risk factors for upper extremity work was 7 days (U.S. Department of Labor 1995). work related musculoskeletal disorders and LBP. This As far as long term work disability is concerned, Col- research has supported the conclusion that the risk of umn 1 of Table 1 shows that contusions, bruises, cuts, upper extremity musculoskeletaldisordersisincreases lacerations, punctures, scratches and abrasions rep- when jobs require forceful, repetitive motions, espe- resented the largest category of industrial injuries in cially when workers are also subjected to vibration and Washington State during 1988, but Column 2 indicates have to maintain awkward positions. Research hasalso that only 0.8% of patients with these conditions lost found 4 factors associated with an increased risk of more than 120 days from work. As a result, these pa- LBP, 1) lifting and forceful movements, 2) awkward tients represented only 9.6% of the total of patients postures, 3) heavy physical work and 4) whole body with time loss of more than 120 days (column 3). Fur- vibration. ther examination of Columns 2 and 3 reveals that the The essay Pain in the workplace, risk factors for probability of protracted time loss is high for disloca- chronicity, job demands also addresses work place fac- tions, amputations, fractures and multiple injuries. It tors that influence the frequency of work injuries. It is moderately high for sprains and strains. However, considers ergonomic factors briefly and also reviews since sprains and strains are relatively common to be- several psychosocial work place factors that influence gin with, patients with these conditions represent 66% injury rates, including monotonous work, lack of per- of the total number of patients with time loss greater sonal control and job dissatisfaction. than 120 days. Columns 2 and 3 of Table 2 provide similar informa- Conditions Associated with Prolonged Time Off Work tion for industrial conditions in Washington State as a Bureau of Labor Statistics data (U.S. Department of functionofaffectedbodypart(injuriesandillnessesare Labor1995)intheUnitedStatesindicatethat66%ofall combined in this table). Inspection reveals that 9.6% workers who filed injury or occupational illness claims of patients with back disorders remain off work more in 1992 did not miss time from work. Among claims than 120 days. Since back problems occur frequently, 424 Compensation, Disability, and Pain in the Workplace

fully 34.6% of the group who miss more than 120 days factors that permitted predictions to be made about from work do so because of back problems. which workers are most likely to become chronically disabled. Research directed toward several of the fac- Skewed Recovery Curves tors that have been investigated is briefly summarized A major problem is that the recovery curves for some here. Specifically, the essays Pain in the workplace, of the most important industrial conditions are highly risk factors for chronicity, demographics Pain in skewed.Forexample,althoughmostworkerswithLBP the workplace, risk factors for chronicity, psychoso- returntoworkwithinseveraldays(iftheygooffworkat cial factors Pain in the workplace, risk factors for all), a small proportion go on to very extended or even chronicity, workplace factors,and Pain in the Work- permanent work incapacity. In a representative study, place, Compensation and Disability Management dis- Cheadle et al. (1994) examined 28,473 claims among cuss the roles of demographic, sychosocial, and work- Washington Stateworkersbetween 1987 and 1989.All placefactorsinpredictingprolongeddisability.Amore workers with claims involving more than 3 days off extended discussion can be found a recent review by work were included. Approximately 86% of the back Krause et al. (2001a). pain claimants returned to work within 4 months of injury. After that, however, the recovery curve flattened Severity of Injury out, so that only about 5% of patients returned to work At the extremes, the expected relation between injury during months 5–8 following injury. Similar results severity and duration of disability has been demon- have been reported by Spitzer et al. (1987) and others strated. For example, Cheadle et al. found that injured (Clinical Standards Advisory Group (1994). workers with “catastrophic injuries” (i.e., ones hospi- A few points about the skewed recovery curve deserve talized within 28 days of injury) were off work about emphasis. First, the curve is by no means descriptive 2.5 times as long as ones without catastrophic injuries only of LBP. In fact, Cheadle et al. (1994) found simi- (Cheadleetal. 1994). However,only6%oftheworkers larly skewed curves for carpal tunnel syndrome, frac- intheirsamplehadcatastrophicinjuries.Thus,thefind- tures and unspecified other industrial injuries. Second, ing that patients with catastrophic injuries are disabled the costs of claims with delayed recoveries are stagger- for prolonged time periods does little to help the physi- ing. In Washington State, almost 80% of work injuries cian make predictions among the much larger group of do not lead to any time off work. Of people who go people who do not sustain catastrophic injuries. off work because of injuries, more than three-fourths return to their jobs within 120 days. Thus, injuries as- Diagnosis sociated with the loss of more than 120 days from work Statisticsclearlydemonstratethattheriskofprotracted represent less than 5% of the total number of injuries. disability is much greater for some types of injuries However, fully 84% of the total payments made to in- than for others. For example, workers with lacera- jured workers are paid to this small group (Washington tionsorabrasionsonlyrarelyhaveprotracteddisability, StateDepartmentofLaborandIndustries1994).Third, whereas ones with sprains or strains account for fully the flattening of the recovery curve demonstrated by 66% of claims with more than 120 days of time loss Cheadle et al. and other investigators (Waddell 1987) (Table 1). In particular, since back strains have a high indicates that a worker who has been on disability for a incidence rate and a moderately high associated proba- prolonged time is at great risk of continuing on disabil- bility of protracted time loss, they account for approxi- ityindefinitely.Inarecentliteraturesynthesis,theClin- mately 35% of all protracted time loss claims (Cheadle ical Standards Advisory Group (1994) constructed an et al. 1994). estimatedlong-termrecoverycurveforLBPpatients.It indicates that the probability of ever returning to work Specific Diagnosis Within an Injury Category is about 25% for a person who has been off work 1 year It is a difficult task to predict the duration of disabil- and about 10% for a person who has been off work ity among patients with a common problem such as 2 years. LBP. Making predictions within LBP patients is important for an obvious reason. Since the outcomes of Predictors of Delayed Recovery injuriesarehighlyvariable,aphysicianwhocanpredict Data provided above indicate that prevalent muscu- which patients are likely to become chronic can focus loskeletal conditions, particularly LBP and carpal tun- on rehabilitating them (see epidemiology of work nel syndrome, are sometimes associated with the pro- disability,backpain).Unfortunately,predictionsbased tracted disability. But the data are onlyoflimitedvalue, on detailed medical information have been only mod- because of the enormousvariation in outcomes among estly successful. Several studies have shown that pa- injured workers with these conditions. The clinician’s tientswithsciaticahavemoreprolongeddisabilitythan job would be much easier if he or she could identify ones only with low back pain (Andersson et al. 1983). Compensation, Disability, and Pain in the Workplace 425

Also,thereisevidencethatinjuredworkersgivenaspe- contribute to disability. All of them need to be included cific diagnosis within 1 week of injury (such as sciat- inacomprehensivereviewofpainintheworkplaceand ica, disc injury or facet joint syndrome) are more likely in a comprehensiveevaluation of an individual injured to demonstrate prolonged disability than ones given a worker. non-specific diagnosis such as lumbar strain (Aben- C haim et al. 1995). This suggests that physicians can Medical Factors identifysomehigh-riskpatientsonthebasisofahistory These, of course, vary with the specific disorder un- and physical examination. However, since only 8.9% der consideration. Several essays ( disability assess- ofthepatientsinAbenhaimetal.’sstudyreceivedaspe- ment, psychological/psychiatric evaluation; yellow cific diagnosis, the study is not helpful in identifying flags; ethics of pain-related disability evaluations) predictors among the remaining 91% of patients who state (or imply) that medical factors are not as im- were given non-specific diagnoses. In a similar vein, portant as psychosocial factors in determining which Franklin et al. (1994) studied injured workers who un- workers become disabled by musculoskeletal injuries derwentlumbarspinalfusions.Althoughthesepatients A few general observations on this issue are worth- ended up having very protracted disability, most of while. First, the role of medical factors in the outcome them were initially given non-specific diagnoses such of a musculoskeletal injury depends on the severity as lumbar strain. of the injury. Severe musculoskeletal injuries (frac- Age tures, amputations and any injuries requiring immedi- Data from the Bureau of Labor Statistics indicate that ate hospitalization) are associated with a high risk of older workers are less likely than younger ones to sus- protracted work disability. However, the bulk of low tain work related injuries, but are at greater risk for back injuries and upper extremity disorders that lead protracted disability if they do sustain an injury. Sev- to disability are not associated with obvious markers eral studies have confirmed the fact that among pa- of severe biological dysfunction. As a consequence, an tients who sustain disabling injuries, older ones are analysis that attempts to predict length of disability on more likely to experience prolonged disability (Chea- the basis of severity of biological injury is hampered dle et al. 1994; Rossignol et al. 1988). See the essay by restriction in the range of the independent variable. Pain in the workplace, risk factors for chronicity, de- Second, most of the painful disorders that occur in the mographics for a more extended discussion of age as workplace can be construed as making it more diffi- well as other demographic factors in predicting pro- cultfor an individualto continueworking,butnotcom- longed disability. pletely precluding work. The relation between pain severity and strength of mo- The Effect of Work Place Factors tivation to avoid or discontinue activity limitation is illustrated in Fig. 1. As the figure indicates, people with Multiple factors associated with the work place affect no or minimal pain are described as being in an unre- the duration of work injuries, which is considered in stricted zone as far as activities are concerned, whereas the essay Pain in the Workplace, Compensation and as ones with extremely severe pain are described as be- Disability Management. At the level of the physical inginacompulsoryzone,suchthatitisvirtuallyimpos- demands of work, there is good evidence that work- sible for them to continue with normal activities. But ers who do physically demanding work are more likely most people with musculoskeletal pain are in what is to demonstrate protracted disability after a back injury described as a discretionary zone – they can continue thanoneswithlighterwork(Krauseetal.2001b).How- ever, as pointed out in Pain in the Workplace, Com- pensation and Disability Management, psychosocial aspects of the work environment – including the extent to which employers invest resources to encourage return to work – also affect the duration of work injuries.

Disability Evaluation –General The Biopsychosocial Model Virtually all experts agree that one must use a biopsychosocial model (Waddell 1987; Waddell 1998) to evaluate disabling musculoskeletal disorders in the workplace. Within this model, it is appropriate to dis- Compensation, Disability, and Pain in the Workplace, tinguish among 3 broad groups of factors that might Figure 1 Motivational consequences of activity-related pain. 426 Compensation, Disability, and Pain in the Workplace

to engage in important activities, but only with signif- claimants, claimants’ current symptoms and reported icant effort. The behavior of patients with pain in the activity limitations, their physical findings on a single discretionary zone will depend on psychological fac- physical examination, the consistency of their findings tors such as their resourcefulness in finding alternative over repeated examinations, the presence or absence ways to accomplish tasks and their ability to manage of acute or chronic psychiatric conditions, their appar- emotional distress provoked by pain. ent motivation to return to productivity and various incentives or disincentives for continued disability. As a Psychological Factors metaphor, we can visualize very high claimant credi- As discussed in the essays on disability assessment, bilityasanalogoustoamountaintop,withvariouspath- psychological / psychiatric evaluation yellow flags, ways leading “downward” to questionable credibility. and Psychological assessment of pain, individuals An assumption in discussions of credibility is that, in a with psychological vulnerabilities are relatively likely highly credible patient, there is a relatively direct path to succumb to disability following musculoskeletal in- from injury through tissue damage to present signs, jury. In particular, the risk of disability has been found symptoms and reported activity limitations. Another to be elevated among individuals with anxiety dis- way to state the assumption is that the presentation of orders, depressive disorders, personality disorders or a highly credible patient is determined almost exclu- problems with chemical dependency. In addition, per- sively by abnormal biology. In contrast, the factors that sons who are somatically focused (as manifested, for compromise patient credibility are usually construed example, by elevated scores on the hypochondriasis as being in the psychosocial sphere. The question then scale of the Minnesota multiphasic personality inven- becomes what are the psychological processes that un- tory [MMPI]) are at risk, even if they do not warrant a derlie the behavior of claimants whose credibility is psychiatric diagnosis. suspect? Some investigators have emphasized the role of somatic anxiety as a factor underlying claimants’ Situational and Social Factors verbal statements about their abilities and their behav- Another theme that emerges from several of the es- iorduringaphysicalexamination(see disability,fear says in this field (e.g. Pain in the workplace, risk of movement). For example, if claimantsare extremely factors for chronicity, psychosocial factors and Pain anxiousabouthurting themselvesduringaphysicalex- in the Workplace, Compensation and Disability Man- amination, they might well demonstrate exaggerated agement) is that the likelihood of prolonged disability pain behaviors such as guarding and pain-inhibited among injured workers is affected by their satisfaction weakness. withtheirjobsandtheeffortsthattheiremployersmake Another possibility is that claimants exaggerate their to reintegrate them into the work force. reports about their incapacity and demonstrate limitations on examination as a deliberate strategy to max- Assessing Credibility imize the disability payments they are awarded. That As indicated, disability assessment in painful condi- is, they are malingerers. A more subtle analysis posits tions poses a challenge because an examiner must rely “secondary gain” as a determinantof a patient’s behav- ontheverbalandnonverbalpainbehaviorsofaninjured ior. In effect, thisanalysisindicatesthatmoneyactsasa workerinordertoassesstheextenttowhichpainaffects reinforcer that influences a claimant’s behavior. How- the worker’s ability to function. Some disability agen- ever, it allows for the possibility that the influence oc- cies attempt to finesse this dilemma by mandating that cursatanunconsciouslevel,namelythattheclaimantis decisions about disability should rely almost entirely not necessarily maliciously and deliberately mislead- on objective findings. However, if an agency permits ing an examiner (as occurs in the case of malingering). subjective data from injured workers to be considered The essay malingering, primary and secondary gain in disability evaluations, it must immediately confront deals specifically with the issues of secondary gain and the issue of assessing the credibility of patients with malingering and adds an important concept to the lexi- pain problems. Issues related to patient credibility are conrelatedtopatientcredibilitywhenitdiscusses“sec- often poorly formulated and emotionally tinged. ondary losses” (i.e., the types of reinforcers that a per- As a point of departure in clarifying these issues, it is sonislesslikelytoreceiveifheisseverelydisabled).As worth considering the type of presentation by a patient pointed out in malingering, primary and secondary that an examiner would find highly credible. The table gain,formostinjuredworkersthefinanciallossesasso- listed below lists a set of findings that would convince ciated with protracted disability far outweigh the gains most examiners that an examinee was highly credible associated with disability payments (Reno et al. 1997; (see Characteristics associated with high patient cred- Reville et al. 2000). ibility). The areas mentioned cover a wide range – in- In principle, information bearing on the credibility of cludingthenatureoftheinjury,thebiologicresponseof claimants can be gleaned from several sources, includ- Compensation, Disability, and Pain in the Workplace 427

Compensation, Disability, and Pain in the Workplace, Table 3 Characteristics Associated with High Patient Credibility (Robinson JP “Psycho- logical Aspects of Disability.” Presented to Employer Advisory Group, Valley Medical Center, Renton WA, June, 1997) Characteristics Associated with High Patient Credibility No pre-existing condition C No medical co-morbidities Definite stimulus – e.g. crushed by a tree Definite tissue damage – e.g. fracture Symptoms, signs, activity limitations – fit expectations for the medical problem Consistent findings over repeated examinations No exaggerated pain behavior No inconsistencies between symptoms / signs noted in MD’s office and behavior outside the office No chronic psychiatric disorders or long-term psychosocial risk factors No reactive psychiatric problems – e.g. anxiety disorder, depression Patient motivated to return to productivity Job opportunities exist No incentives for disability ing information abouttheindividual’sinjury,examina- be performed to manage the worker’s disability (i.e. tion of records of health practitioners who have seen to foster return to work). If the worker’s disability be- him in the past, statements by the patient about his cur- comes protracted, the focus of evaluations subtly shifts rent symptoms and activity restrictions and observa- toward issues related to the extent of permanent im- tion of claimants’ behavior during a physical exami- pairment and disability and the financial liability of an nation. The essay credibility, assessment discusses insurer or disability agency in the event of permanent the significance of these types of data. work disability. Sometimes an evaluation can serve a The essay nonorganic symptoms and signs deals dual purpose, namely, it can be used either to facilitate withaspecificissuerelatedtocredibility–thebehavior return to work or to establish the severity of disability of a patient during a physical examination. In particu- forpurposesoflong-termcompensation.The Painin lar, a set of “non-organic” signs have been developed the Workplace, Compensation and Disability Manage- that can sometimes be observed by an examiner during ment; ethics of pain-related disability evaluations the physical examination of a patient with LBP.Exten- and impairment, pain-related essays deal with eval- sive research on the “Waddell signs” suggests that they uations and interventions that are often used to manage are primarily indicators of somatic anxiety on the part disability by facilitating return to work. One crucial el- of patients with LBP. ement in disability management is the assessment of The interpretation of Waddell signs is far from obvious a worker’s risk for long-term disability. The essay on (see malingering, primary and secondary gain). Al- yellow flags addresses this important issue. thoughWaddelldescribedthemas“non-organic”signs Another crucial issue for a worker who is unlikely to in his initial publication on them, recent research sug- return fully to his pre-injury status is the assessment gests that they could be manifestations of altered ner- of his residual physical capacities. Although disabil- vous system functioning in response to pain (Banic et ity agencies routinely ask treating physicians to pro- al. 2004; Curatolo et al. 2004). That is, they might be vide detailed information about a patient’s activity tol- construed as manifestations of a genuine medical dis- erances and activity restrictions, the examinations that order rather than solely as indicators of psychological a physician conducts in an office setting generally do dysfunction (see dysfunctional pain and the interna- not provide relevant data to make such judgments. As tional classification of function.) discussed in the essay disability, functional capacity evaluations, physical capacities evaluations can provide detailed data about the ability of a patient to per- Rehabilitation of Pain Related Disability formarangeofphysicaltasksoverperiodsoftimerang- During the interval shortly after a worker sustains a ing from a few hours to a few days. disabling injury, the focus of attention is typically on Anothercrucialinputfordisabilitymanagementisare- medical or surgical treatment of his injury. If disabil- alistic assessment of the workers’ vocational options, ity persists, variousevaluationsandinterventionsmay- especially if the probability is high that they will not 428 Compensation, Disability, and Pain in the Workplace

be able to return to the job they had when they were ities. The essay disability management in managed injured. As discussed in vocational assessment in care system describes the interaction between man- chronic Pain, the role of the vocational rehabilitation aged care organizations and injured workers. counselor isto identify vocationaloptionsand tofacili- Finally, as discussed Pain in the Workplace, Com- tate communication among physicians, employers and pensation and Disability Management, there is persua- the worker to maximize the probability that the worker sive evidence that initiatives by employers can reduce will be able to return to gainful employment. the incidence of work injury claims and the duration As far as treatment of disability is concerned, the of disability for claims that are filed. These initiatives disability, effect of physician communication essay include programs for rotating activity schedules for highlights the importance of communication between workers and promoting early return to modified work physiciansand injured workers. Effective communica- following a work injury. The essay Pain in the Work- tion that enables patients to cope with their injuries is place, Compensation and Disability Management also notusuallythoughtofasatreatment,butexpertopinion cites data supporting the importance of programs to and at least some empirical evidence (Catchlove and promote a positive psychosocial environment in the Cohen 1982; Hall et al. 1994) support the conclusion workplace. In particular, it describes research demon- that such communication can substantially influence strating that workers are relatively likely to return to the outcome of work injuries. workquicklyfollowinginjuryiftheyhavegoodrapport Manyworkersreceivephysicaltherapyasacomponent with their supervisors and if their supervisors express of the treatmentthey receive for their workinjuries. Al- concern about them following an injury. though such treatment is often helpful, workers who are sliding into protracted disability often report lack Assessing Permanent Impairment / Disability Associ- of benefit from physical therapy. Ineffective physical therapycanoccurforavarietyofreasons.Onecommon ated with Pain problem is that physical therapists sometimes focus As noted previously, if a worker fails to recover fully excessively on passive treatments such as diathermy from an injury, the agencies involved with his claim or massage, rather than on active functional restora- need to make some determination regarding his per- tion. Even when progressive exercise is emphasized in manent impairment and his ability to work. Decisions physical therapy, patients may fail to benefit because regarding these issues determine the agencies’ finan- they are fearful that physical activity will cause rein- cial obligations to the worker. Logically, the starting jury or will delay their recovery (see disability, fear point for a system to evaluate impairment and disabil- of movement). As discussed in physical condition- ity in an injured worker is a set of concepts that links ingprograms,structuredphysicalconditioningorwork the many interacting factors that contribute to disabil- hardening programs may be helpful in this situation. ity following a work injury. The essays disability These programs are structured in the sense that they and impairmentdefinitionsand WHO system on im- emphasize progressive exercise and that they require pairment and disability describethecurrentWHOcon- patients to attend treatment sessions several times per ceptual system. Key concepts in it are body functions, week. body structures, impairments, activity-activity limita- It is noteworthy that a recent extensive review of litera- tions, participation-participation limitations and dis- ture on structured physical conditioning programs re- ability.Theessay dysfunctionalpainandtheinterna- vealed that such programs were reliably effective only tional classification of function describes how sensory when they were combined with psychosocial support changesthatarepostulatedtooccurinchronicpainsyn- (Schonstein et al. 2002) (see physical conditioning dromes can be conceptualized within the WHO frame- programs and multidisciplinary pain centers). This work. finding supports the logic underlying the most aggres- At a practical level, the essay impairmentrating, am- sive rehabilitation programs for workers with chronic, biguitydescribesseveralissuesthatmakeitdifficultfor disabling pain – multidisciplinary pain center or func- agencies to evaluate impairment and disability in an tional restoration treatments. As discussed by Turk in efficient, equitable manner. The essays are not limited his essay multidisciplinary pain centers, these pro- to the evaluation of painful conditions, but emphasize grams have demonstrated efficacy in the treatment of thedifficultyofdeterminingimpairmentordisabilityin selected injured workers. However, there is often re- such conditions. The companion essay impairment luctance by third party payers to provide coverage and rating, ambiguity, IAIABC system describes the re- reimbursement for these treatments. centlydevelopedimpairmentratingsystemoftheInter- Managed care organizations in the United States have nationalAssociationofIndustrialAccidentBoardsand particular difficulties when it comes to treatment of Commissions. For the most part, this system does not people they cover that experience work related disabil- specifically address impairment secondary to chronic Compensation, Disability, and Pain in the Workplace 429 pain, butdoesdo so in selected disorders(suchasphan- abilityfollowingnon-traumaticworkinjuries.Itmakes tom limb pain). a convincing case that we have sufficient data to craft Essays on disability evaluation in the social secu- programsthatfocusondisabilitypreventionratherthan rity administration rating impairment due to pain in treatment and long-term wage replacement following a workers’ compensation system and impairment, the development of disability. Disability prevention C pain-related describe the approaches to the assessment addresses protracted disability in general rather than of impairment-disability associated with chronic pain chronic pain specifically. However, it is highly relevant taken by the Social Security Administration, the Wash- to an understanding of work related chronic pain, since ington State workers’ compensation system, the Cal- chronic pain is a major cause of protracted disability ifornia workers’ compensation system and the AMA following a work injury. Guides. The Social Security Administration system The essay back pain in the workplace describes a emphasizes the potential importance of pain to disabil- monograph about work related low back pain. The ity and provides fairly specific guidelines for adjudi- monograph, entitled Back Pain in the Workplace cators to follow as they gather information from ap- (Fordyce 1995) focuses on problems associated with plicants regarding their pain. The California system our current concepts regarding low back pain and work alsoemphasizesthepotentialimportanceofpaintodis- disability. In essence, the authors argue that impair- ability, but does not give specific guidelines regarding ment cannot be assessed validly in nonspecific LBP, its assessment. The AMA Guides devote a chapter to because 1) an examiner’s assessment of impairment the assessment of pain-related impairment, but fail to from LBP depends on the performance of a patient integrate the concepts elaborated in the chapter into during an examination and 2) a back pain patient’s the overall impairmentassessment system and contain performance during an examination is determined not multiple inconsistencies related to the assessment of only by the severity of the anatomic and physiolog- impairment secondary to pain. The Washington State ical functional loss he or she has sustained, but also system specifically excludes chronic pain as a basis for by a variety of psychosocial factors. In the authors’ impairment. These essays are presented as representa- words: “Not all potential impairments can be con- tive; however, there are wide variations in compensa- firmed by verifiable measures of their presence in- tion systems within and between countries. The only dependent of performance by the person purported conclusion one can reach with confidence from read- to be impaired. Because performance is also “effort- ing the essays disability evaluation in the social se- related” as well as related to anatomical or physiolog- curity administration rating impairment due to pain icalcapabilities,itisinevitablylinkedtoandinfluenced in a workers’ compensation system and impairment, by such factors as attitudes, motivation and personal- pain-related is that there is a striking lack of consen- ity”(p. 28). sus about how to incorporatepain into impairmentand The authors of the Back Pain in the Workplace report disability evaluations. go on to promote the idea that people with nonspecific LBP should be classified as “unemployed” rather than disabled if they “persist... in activity intolerance be- Paradigm Shifts; Systemic Changes yond the allotted time for medical treatment and tem- It is safe to say that no system has solved the problems porary disability status” (p. 59). Thus, people with per- of how to assess, rehabilitate and compensate people sistent nonspecific LBP would, for benefits purposes, whoreportchronicpainfollowingworkinjuries.Inthis be classified with healthy people who are unable to find unsatisfactory situation, it is appropriate to consider work. strategies for improving the ways in which disability It is important to note that Back Pain in the Workplace agencies conceptualize and evaluate chronic pain and makes recommendations for disability policy only in disability. Two essays in this field discuss concepts relation to nonspecific LBP; they do not consider any that need to be considered in any systemic change in other chronic pain conditions. Also, although their rec- workers’ compensation systems or disability systems ommendationsaboutdisability policyrestontheir pes- in general. Disability incentives addresses the influ- simistic view of the ability of physicians to determine ences of incentives and “moral hazards” on the behav- impairment in patients with nonspecific LBP, they do ior of both injured workersand thehealth professionals not provide any data to buttress this view. In essence, who treat them. It does not propose specific changes in their monograph is a consensus document rather than a current disability systems, but it strongly suggests that presentation of empirical data. However, in view of the a successful disability system needs to be based on a eminence of its authors, Back Pain in the Workplace carefulconsideration of incentives and disincentives to is a provocative work that has been read widely and, disability. The essay disability prevention reviews a as documented in back pain in the workplace,has wealthofdataonfactorsassociatedwithlong-termdis- generated a heated debate. 430 Compensation, Disability, and Pain in the Workplace

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Definition of pain and disability develops. Furthermore, many Anoilemulsionthatcontainsadeadmycobacteriumthat factors such the how the child thinks, feels and behaves elicitsaninflammatoryandimmuneresponseinvivo.In- in response to the pain can intensify the pain and dis- jection of CFAinto the skin of the hind paw is frequently tress and prolong the disability. Some of the common used as an experimental model of peripheral inflamma- situational and child factors that intensify pain and C tion in mice or rats. prolong disability are outlined in Fig. 1 (McGrath and CFA Hillier 2003). These children also tend to have compo- IB4-Positive Neurons, Role in Inflammatory Pain nents of nociceptive (normal pain) and neuropathic NerveGrowthFactorOverexpressingMiceasModels (nerve pain), which make them more difficult to treat. of Inflammatory Pain Therefore, interdisciplinary chronic pain teams are necessary to treat complex chronic pain conditions adequately in order to ensure that assessments and interventions are child-centred (e.g. tailored to the needs Complex Adaptive System of the individual child) rather than just focused on the underlying disease or condition. Definition Characteristics A complex adaptive system is a large set of units that interact with each other, and with an external environ- Given that these complex chronic pain conditions have ment, to produce overall patterns that are significantly multiple causes, children must be treated from an inter- more complex than the behaviors of the individual en- disciplinary, multimodal, rehabilitation perspective. tities comprising the system. Drug, physical and psychological therapies should be Consciousness and Pain incorporated into a flexible, child-friendly program with particular attention to the cognitive, behavioural and emotional factors contributing to the underlying Complex Chronic Pain in Children, problem. Because of the complexity of chronic pain, no single discipline has the expertise to assess and Interdisciplinary Treatment manage it independently. Therefore, specialised inter- JENNIFER N. STINSON disciplinary chronic pain teams are now considered the The Hospital for Sick Children and The University of standard of care for children with complex chronic pain Toronto, Toronto, ON, Canada conditions. [email protected] Composition of Interdisciplinary Pain Teams Synonyms Chronic pain teams for children generally include specialised physicians (e.g. anaesthesiologists, neu- Multidisciplinary treatment; Paediatric Chronic Pain rologists, psychiatrists), nurses, psychologists and Management; Pain-Related Disability physical therapists. More recently, teams may also include complementary and alternative therapists (e.g. Definition acupuncturists, massage therapists). The specific team Chronic pain in children is defined as any recurring (e.g. members involved in any one case depend on the indi- headaches, abdominal and limb pain) or persistent pain vidual needs of the child and family. A child’s initial (e.g. back pain, cancer pain, complex regional pain consultation includes either a joint team interview and syndrome) that lasts a minimum of 3 months (McGrath physical examination or separate interviews with each 1999). While most children with chronic pain function healthcare professional. Comprehensive physical and quite well, some develop more complex chronic pain psychosocial assessment may typically last a few hours conditions with associated distress and disability (Mc- to a full day, depending on the child’s previous diag- GrathandFinley1999).Thesechildrentypicallypresent nostic tests and the team’s core assessment battery (i.e. with subjective ratings of pain out of proportion to the standardised sensory testing, questionnaires). The team objective physical findings and are more disabled than then meets to formulate the child’s pain diagnosis and one would expect. treatment plan. The treatment plan should include: the The pain adversely affects all aspects of children’s diagnosis (underlying causes and contributing factors), lives. They stop going to school, refrain from exercis- rationale for a rehabilitative approach with a clear ing or playing sports for fear of increasing the pain and description of the specific treatment options and an withdraw from their peers. These children often have opportunity for the family to help fine-tune the plan. It impaired sleep, suffer from anxiety and or depression is essential to educate children and their families about and have disrupted family relationships (Bursch et al the nature of chronic pain (e.g. different from acute pain 1998; Dahlquist and Switkin 2003). The pain becomes where there is a single cause and a single treatment) and the focus of the children’s lives and a vicious cycle the factors that intensify it, as well as the drug and non- 432 Complex Chronic Pain in Children, Interdisciplinary Treatment

Complex Chronic Pain in Children, Interdisciplinary Treatment, Figure 1 Model of situational and child factors that modify pain and disability. drug strategies they can use to control the pain. Some • The treatment plan typically including pharmaco- children’s clinics also offer inpatient, day or residential logical, psychological and physical therapies and in treatment programs (Berde and Solodiuk 2003). some cases medical (e.g. nerve blocks) intervention. • The specific goals of the treatment plan including: (a) Goals of Interdisciplinary Chronic Pain Treatment increasing independent function in terms of activities Interdisciplinary chronic pain programs use a rehabili- of daily living, school, social and physical activity; tative approach where children’s pain is treated with the (b) facilitating adaptive problem solving, communi- mostappropriatedrugtherapyandwheretheteamassists cation and coping skills; (c) treating specific prob- children and their parentsto improve children’sfunction lems identified from the comprehensive assessment despite their pain. In some instances, teams work with (e.g.depression,anxiety)and(d)helpingchildrenand families to help them understand that their child’s pain theirfamiliestounderstandthenatureofpain,thepain might not be eradicated fully, so that efforts are directed condition and its treatment from a holistic perspec- towards improving function and quality of life. Interdis- tive. ciplinary treatment goals include: • Ongoing assessment and re-evaluation of the treat- • Comprehensive physical and psychosocial assessment plan. One way to monitor children with chronic mentofthechildwithpainandtheirfamilytoevaluate pain isthrough the use of electronic pain diaries. Stin- aetiology and contributing factors. son and colleagues (2005; 2006) have developed and • Design and implementation of a flexible child- are testing a new electronic (PDA-based) multidi- centredtreatmentapproachthataddressesallcausative mensional chronic pain measure for children called factors. the e-Ouch. Complex Chronic Pain in Children, Interdisciplinary Treatment 433

Pharmacological Therapies treatment program for children with chronic pain. These Pharmacologic methods are an important componentof types of programs might help to overcome some of the an integrated, flexible approach that combines psycho- traditional barriers to treatment (e.g. stigma associated logicalandphysicalstrategies.Thechoiceofmedication with these therapies, acceptability and accessibility). depends in part on the source of pain (e.g. nociceptive, Physical Therapies C neuropathic or mixed). Pain medications are tailored to the individual needs of each child based on the results of Chronic pain often leads a child to avoid physical activ- theirassessment.Drugtherapiesaredividedbroadlyinto ity due to fear of re-injury or because it exacerbates the analgesics and adjuvant medication. Analgesics are ad- pain. Lack of muscle use leadstolossofmuscle strength, ministeredinastepwiseapproachandarerecommended flexibility and endurance and overall deconditioning. for pain conditions with characteristics of nociceptive or Therefore,physicaltherapiesareanintegralcomponent, mixed pain. Simple analgesics, such as acetaminophen and in certain instances the cornerstone, of treatment for and non-steroidal anti-inflammatory drugs (e.g. ibupro- children with complex chronic pain problems. Exercise fen) in adequate doses, are effective for some children. therapy, physiotherapy, thermal (heat and cold) and Opioids may be added to the analgesics regimen when sensory ( desensitization, transcutaneous electrical these mild analgesics do not alleviate the pain. In con- nerve stimulation or TENS) stimulation and massage trast, pain conditions with characteristics of neuropathic are the most commonly used physical modalities. They painareoftenresistanttodrugtherapiesthattypicallyre- are frequently used in combination. Regular exercise lievenociceptivepain(e.g.opioids).Therefore,adjuvant (e.g. 20 min 3 × per week) should help improve sleep, pain medications such as anti-convulsants and tricyclic mood, self-esteem and energy levels. However, main- anti-depressants are used. Gabapentin is the most com- taining normal daily activities such as school, sports monly used anti-convulsant, as it is safe and well toler- and play are often as effective as a formal exercise ated. Amitriptyline is the most commonly used tricyclic program. Some children will benefit from intensive anti-depressant and is often recommended for children physiotherapy. Physiotherapy is usually administered whose sleep is disturbed. Antidepressants are also help- on an outpatient basis with the ultimate goal of teaching ful for children who have chronic pain and who are de- the child to execute the program at home. A program the pressed (Sethna 1999) (see Analgesic guidelines for child enjoys (e.g. swimming) and one where the amount infants and children). of time spent in the activity is gradually increased is one the child is more likely to continue with (McCarthy Psychological Therapies et al. 2003). Many psychological therapies are available to treat chronic pain in children. These treatments include Summary counselling, relaxation therapy, biofeedback, In summary, children with complex chronic pain con- behavioural modification and cognitive strategies ditions experience prolonged suffering and disability. including hypnosis and psychotherapy (McGrath The pain adversely impacts all aspects of children’s et al. 2003). Often these therapies are integrated into lives in terms of physical, psychological, social and a comprehensive cognitive-behavioural therapy (CBT) role functioning. Many sensory, cognitive, behavioural program that is directed at identifying and ameliorating and emotional factors may intensify the pain and pro- the thinking, behaving and feeling factors that affect a long pain related disability. Moreover, these complex child’s pain and disability. A recent systematic review pain conditions tend to have components of nociceptive documented the efficacy of CBT for chronic headache and neuropathic pain, which makes them more difficult and abdominal pain in children (Eccleston et al. 2002). to treat. Given this complexity, unidisciplinary and CBT is often organized into a program of therapy that is unimodal treatments are rarely successful. Therefore, delivered by various members of the chronic pain team. children with complex chronic pain conditions must be The content of the programs varies across clinics but treated from an interdisciplinary, multi-modal, reha- usually includes teaching children specific pain and life bilitation perspective. Pharmacological, physical and coping skills, encouraging positive family responses for psychological therapies should be incorporated into a resuming typical activities, reframing or changing the flexible, child-centred program. family’s beliefs that may impede rehabilitation, exercise therapy, education and self-management strategies. The References goal of these psychological therapies is to help children 1. Berde CB, Solodiuk J (2003) Multidisciplinary programs for regain their lives and take back control from the pain. management of acute and chronic pain in children. In: Schechter Finally, there is strong evidence that these psychologi- NL, Berde CB, Yaster M (eds) Pain in Infants, Children and cal treatments can be effective without a therapist being Adolescents. Lippincott Williams and Wilkens, Philadelphia, physically present, using alternative models of service pp 471–486 2. Bursch B, Walco GA, Zeltzer L (1998) Clinical assessment and delivery such as the Internet (Elgar and McGrath 2003). management of chronic pain and pain-associated disability syn- We are currently developing a web-enabled distance drome. Dev Behav Pediatr 19:45–53 434 Complex Migraine

3. Dahlquist LM, Switkin MC (2003) Chronic and recurrent pain. as causalgia. Whether it exists in the facial region is still In: Schechter NL, Berde CB, Yaster M (eds) Pain in Infants, a matter of debate. Children and Adolescents. Lippincott Williams and Wilkens, Philadelphia, pp 198–215 Adrenergic Agonist 4. Eccleston C, Morley S, Williams A et al. (2002) Systematic re- Atypical Facial Pain, Etiology, Pathogenesis and view of randomised controlled trials of psychological therapy Management for chronic pain in children and adolescents, with a subset meta- Causalgia, Assessment analysis of pain relief. Pain 99:157–165 5. Elgar FJ, McGrath PJ (2003) Self-administered psychosocial Central Nervous System Stimulation for Pain treatments for children and families. J Clin Psychol 59:321–339 Complex Chronic Pain In Children, Interdisciplinary 6. McGrath PA (1999) Chronic pain in children. In: Crombie IK Treatment (ed) Epidemiology of Pain. IASP Press, Seattle, pp 81–101 Complex Regional Pain Syndrome and the Sympa- 7. McGrath PJ, Finley GA (1999) Chronic and recurrent pain in children and adolescents. In: McGrath PJ, Finley GA (eds) Chronic thetic Nervous System and recurrent pain in children and adolescents. Progress in Pain Complex Regional Pain Syndromes, General Aspects Research and Management, vol 13. IASP Press, Seattle, pp 1–4 CRPS-1 in Children 8. McGrath PA, Hillier LM (2003) Modifying the psychological Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- factors that intensify children’s pain and prolong disability. In: Schechter NL, Berde CB, Yaster M (eds) Pain in Infants, Children ondary) and Adolescents. Lippincott Williams and Wilkens, Philadelphia, Sympathetically maintained Pain and Inflammation, pp 85–104 Human Experimentation 9. McGrath PJ, Dick B, Unruh AM (2003) Psychologic and Sympathetically Maintained Pain, Clinical Pharma- behavioural treatment in pain in children and adolescents. In: Schechter NL, Berde CB, Yaster M (eds) Pain in Infants, cological Tests Children and Adolescents. Lippincott Williams and Wilkens, Sympathetically Maintained Pain in CRPS I, Human Philadelphia, pp 303–328 Experimentation 10. McCarthy CF, Shea AM, Sullivan P (2003) Physical therapy management of pain in children. In: Schechter NL, Berde CB, Yaster Sympathetically Maintained Pain in CRPS II, Human M (eds) Pain in Infants, Children and Adolescents. Lippincott Experimentation Williams and Wilkens, Philadelphia, pp 434–448 11. Sethna NF (1999) Pharmacotherapy in long-term pain: Current experience and future direction. In: McGrath PJ, Finley GA (eds) Chronic and Recurrent Pain in Children and Adolescents. Complex Regional Pain Syndrome and the Progress in Pain Research and Management, vol 13. IASP Press, Seattle, pp 243–264 Sympathetic Nervous System 12. Stinson J Petroz G, Stevens B et al. (2005) e-Ouch electronic pain diary for adolescents with arthritis: A pilot test. International JAMES N. CAMPBELL Association for the Study of Pain 11th World Congress, Sydney Johns Hopkins University School of Medicine, Australia, August 21–26 Baltimore, MD, USA 13. Stinson J, Petroz G, Tait G et al. (2006) e-Ouch: Usability testing [email protected] of an electronic chronic pain diary for adolescents with arthritis. Clin J Pain 22:295–305 Synonyms Reflex Sympathetic Dystrophy; Sympathetically- Complex Migraine maintained pain; Causalgia Definition Clinical Migraine with Aura Sympathetically maintained pain (SMP) refers to pain that is dependent on neural activity in the sympa- Complex Regional Pain Syndrome thetic nervous system and is present in some patients with complex regional pain syndrome (CRPS). Synonymss Characteristics CRPS; Complex Regional Pain Syndrome Type I Activity in nociceptors induces an increase in sympa- (CRPS I) thetic discharge. It is in this way, in part, that noxious (painful)stimuliinduceariseinbloodpressure.Usually, Definition theconverseisnottrue:sympatheticactivitydoesnotim- CRPS is a medical syndrome characterized by chronic pact the discharge of nociceptive neurons. In certain pa- regionalized STP,edema, blood flow changes, sudomo- tients with pain, however, nociceptors acquire sensitiv- tor changes, dysfunction, and bone turnover dispropor- ity to norepinephrinereleased by sympathetic efferents. tionate in response to what is often a recognized nox- Pain dependent on activity in the sympathetic nervous iousincitingevent. TheCRPSdesignationisanewname system is referred to as sympathetically maintained pain for this kind of disorder. The name applies to CRPS–1, (SMP). which was formerly known as sympathetic dystrophy This linkage with the sympathetic nervous system may, without nerve injury, and to CRPS–2, formerly known in some patients, be a dominant mechanism for pain. Complex Regional Pain Syndrome and the Sympathetic Nervous System 435

SMP, in particular, is noted in many cases of complex sensitization of intact nociceptors after nerve injury regional pain syndrome (CRPS). CRPS typically occurs of companion fibers (Sato and Perl 1991). C-fibers after trauma that may or may not result in nerve injury. ending in a neuroma also display adrenergic sensitivity The distal extremities, areas rich in sympathetic inner- (Devor and Jänig 1981; Häbler et al. 1987; Wall and vation, are usually affected. The patients present with Gutnick 1974; Scadding 1981). These data indicate that C edema (at least in the early stages) and striking hyper- SMP is likely to arise from expression of α1-adrenergic algesia. Patients with CRPS often have motor disability receptors on the terminals of nociceptors. with difficulty moving the affected painful body parts, regardless of an intact sensory/motor pathway. The skin Phentolamine Infusion as a Test for SMP may be very cool and sweaty, or sometimes very warm The gold standard for diagnosing SMP has been deter- compared to the opposite normal side. The disorder ap- mination of the response to blockade of the appropriate pears to spread in some patients from distal to proximal level of the sympathetic chain with local anesthetic. parts of the extremity, and may in fact spread to other Phentolamine, given systemically, has proven to be extremities as well. safe and is now considered (by some at least) to be a more specific way to diagnose SMP. After infusion of SMP is a Receptor Disorder saline to hydrate the patient, and after administration The dramatic relief of pain that occurs with selective of 1–2 mg of propranalol to block the development of blockage of the sympathetic nervous system defines reflex tachycardia, phentolamine in a dose of 1 mg/kg is SMP. Three general ideas have been advanced to ex- given over 10 minutes. Skin temperature is monitored. plain this phenomenon: 1) the anesthetic blocks “pain” If the skin temperature does not rise, then a higher dose fibers that course with the sympathetic efferent fibers; of phentolamine may have to be given. The test can 2) the sympathetic nervous system is overactive and be blinded, such that the patient does not know when thus induces pain; 3) the sympathetic nervous system the drug is given. A positive result is the finding that acquires the capacity to activate nociceptors and hence systemic phentolamine and α-adrenergic antagonist induce pain. Evidence from both human and animal relieve pain when given to patients with SMP (Raja et studies supports the latter hypothesis. al. 1991; Arner 1991). Stimulation of the sympathetic chain induces pain in patients with causalgia (Walker and Nulson 1948; White Alpha 1 or Alpha 2 Adrenergic Receptors and Sweet 1969), even when the sympathetic chain To sort out the adrenergic mechanisms in humans, is disconnected from the spinal cord. Thus, efferent further investigators have applied topical clonidine, an actions of the sympathetic nervous system account for α2-adrenergic agonist, to the painful skin in patients SMP. Injection of noradrenaline around stump neu- with SMP. Relief of hyperalgesia in the painful area re- romas or skin in patients with postherpetic neuralgia sulted (Davis et al. 1991). Activation of α2-adrenergic induces an increase in spontaneous pain (Chabal et al. receptors, located on sympathetic terminals, blocks 1992; Raja et al. 1998; Choi and Rowbotham 1997). norepinephrine release. Thus, clonidine appears to re- In patients relieved of pain after a sympathetic block, lieve pain by blocking norepinephrine release. When intradermal injection of norepinephrine into the previ- phenylephrine, a selective α1-adrenergic agonist, was ously hyperalgesic area in physiological concentrations applied to the clonidine-treated area, pain was rekindled induces pain (Ali et al. 2000). Norepinephrine injected in patients with SMP (Davis et al. 1991). Thus, clinical into normal subjects evokes little or no pain. This evi- data, as with the primate physiological data, suggest that dence strongly suggests that SMP does not arise from an the α1-adrenergic receptor plays a pivotal role in SMP. excess of epinephrine, but rather from the presence of Whether a phenotypic change or other change explains adrenergic receptors coupled to cutaneous nociceptors. this nociceptor chemical sensitization is unanswered. It Therefore, in SMP, norepinephrine that is normally is of interest that the density of α1-adrenoceptors in the released from the sympathetic terminals acquires the epidermis of hyperalgesic skin of patients with complex capacity to evoke pain by activating nociceptors. regional pain syndrome is increased (Drummond et al. 1996). Nerve Injury Induces Catechol Sensitization in Nociceptors In a primate model, the L6 root was lesioned leaving Treatment of Sympathetically Maintained Pain the dorsum of the foot partly dennervated (Ali et al. By definition, SMP is relieved by performance of a 1999). Intact nociceptors from adjacent uninjured roots sympathetic block. It has been frequently observed, developed spontaneous activity and a response to an that in some patients the pain relief outlives the phar- α1-adrenergic agonist, phenylephrine, applied to the macological action of the anesthetic block. A similar receptive field. In monkeys where no spinal nerve lesion long-lasting pain relief has also been reported following was applied, little or no catechol sensitivity and sponta- systemic phentolamine infusion (Galer et al. 1992). A neous activity was present. Using a somewhat different series of sympathetic blocks may lead to successful model, studies in rats have also demonstrated catechol resolution of the pain problem. 436 Complex Regional Pain Syndrome Type I

In cases where sympathetic blockade fails to provide 6. Davis K D, Treede R-D, Raja S N et al. (1991) Topical Ap- enduring pain relief other strategies are needed. Surgi- plication of Clonidine Relieves Hyperalgesia in Patients with Sympathetically Maintained Pain. Pain 47:309–317 cal sympathectomy provides permanent sympathetic 7. Devor M, Jänig W (1981) Activation of Myelinated Afferents denervation and offers lasting pain relief (Singh et al. Ending in a Neuroma by Stimulation of the Sympathetic Supply 2003). In the case of the upper extremity, the T2, 3, in the Rat. Neurosci Lett 24:43–47 4 ganglia are removed. The stellate ganglion provides 8. Drummond P D, Skipworth S, Finch P M (1996) Alpha no innervation of the hand, and injury of this ganglion is 1-Adrenoceptors in Normal and Hyperalgesic Human Skin. Clin Sci (Colch) 91:73–77 avoided in order to prevent development of a Horner’s 9. Galer B S, Rowbotham M C, Von Miller K et al. (1992) Treatment syndrome. The thoraco-endoscopic approach affords of Inflammatory, Neuropathic and Sympathetically Maintained excellent visualization of the sympathetic chain, and Pain in a Patient with Sjögren’s Syndrome. Pain 50:205–208 provides a minimally invasive technique by which to 10. Häbler H-J, Jänig W, Koltzenburg M (1988) A Novel Type of Un- myelinated Chemosensitive Nociceptor in the Acutely Inflamed achieve a thoracic sympathectomy.For the lumbar area, Urinary Bladder. Agents Actions 25:219–221 it is necessary to remove the sympathetic chain from 11. Kemler M A, Barendse G A, van Kleef M et al. (2000) Spinal L1 to L5. Typically, at least three ganglia are removed, Cord Stimulation in Patients with Chronic Reflex Sympathetic and the length of the excised chain is 10 cm. Dystrophy. N Engl J Med 343:618–624 12. Raja S N, Abatzis V, Frank S (1998) Role of α-Adrenoceptors Signs of sympathetic innervation to the foot may return in Neuroma Pain in Amputees. American Society of Anesthe- after weeks or months. This may be due to crossed in- siologists Abstracts nervation. In other words, sympathetic fibers from the 13. Raja S N, Treede R-D, Davis K D et al. (1991) Systemic Alpha-Adrenergic Blockade with Phentolamine: A Diagnostic contralateral side may reach the foot and provide suffi- Test for Sympathetically Maintained Pain. Anesthesiology cientinnervation thatthe SMPreturns. Thetestforthisis 74:691–698 to perform a contralateral sympathetic block. The block 14. Sato J, Perl E R (1991) Adrenergic Excitation of Cutaneous should lead to a striking increase in temperature in the Pain Receptors Induced by Peripheral Nerve Injury. Science 251:1608–1610 contralateral foot (this does not occur customarily), and 15. Scadding J W (1981) Development of Ongoing Activity, be associated with pain relief for at least the duration of Mechanosensitivity and Adrenaline Sensitivity in Severed theblock.Inthiscase,acontralaterallumbarsympathec- Peripheral Nerve Axons. Experimental Neurology 73:345–364 tomy may be performed, which will provide enduring 16. Singh B, Moodley J, Shaik A S et al. (2003) Sympathectomy for Complex Regional Pain Syndrome. J Vasc Surg 37:508–511 pain relief. 17. Walker A E and Nulson F (1948) Electrical Stimulation of the Up- Complications of sympathectomy include new pain at- per Thoracic Portion of the Sympathetic Chain in Man. Archives tributable to the surgery. These patients appear to have of Neurology and Psychiatry 59:559–560 a vulnerability to develop new pain with trauma. Com- 18. Wall P D and Gutnick M (1974) Ongoing Activity in Peripheral Nerves: The Physiology and Pharmacology of Impulses Origi- pensatory hyperhidrosis may develop, but this is more nating from a Neuroma. Experimental Neurology 43:580–593 of a problem in patients in whom the sympathectomy is 19. White J C, Sweet W H (1969) Pain and the Neurosurgeon: A done to treat hyperhidrosis. Forty Year Experience. Charles C. Thomas, Springfield Spinal cord electrical stimulation is an alternative treatment for SMP (Kemler et al. 2000). Of course spinal cord stimulation may be effective for treatment of sympathetically independent pain as well. The advantage of Complex Regional Pain Syndrome Type I this technique is that the morbidity is low. The disadvantage is that continued stimulation and maintenance Sympathetically Maintained Pain in CRPS I, Human of the device is required to maintain the therapeutic ef- Experimentation fect. Notably, use of one modality does not preclude the later use of the other modality. Complex Regional Pain Syndrome Type I References (CRPS I) and Type II (CRPS II) 1. Ali Z, Raja S N, Wesselmann U et al. (2000) Intradermal Injection of Norepinephrine Evokes Pain in Patients with Sympathetically Maintained Pain. Pain 88:161–168 Complex Regional Pain Syndrome 2. Ali Z, Ringkamp M, Hartke T V et al. (1999) Uninjured C-Fiber Nociceptors Develop Spontaneous Activity and Alpha Adrener- gic Sensitivity Following L6 Spinal Nerve Ligation in the Mon- key. J Neurophysiol 81:455–466 3. Arner S (1991) Intravenous Phentolamine Test: Diagnostic and Complex Regional Pain Syndromes, Prognostic use in Reflex Sympathetic Dystrophy. Pain 46:17-22 General Aspects 4. Chabal C, Jacobson L, Russell L C et al. (1992) Pain Response to Perineuromal Injection of Normal Saline, Epinephrine, and KOK E. KHOR Lidocaine in Humans. Pain 49:9–12 5. Choi B, Rowbotham M C (1997) Effect of Adrenergic Receptor Department of Pain Management, Prince of Wales Activation on Post-Herpetic Neuralgia Pain and Sensory Distur- Hospital, Randwick, NSW, Australia bances. Pain 69:55–63 [email protected] Complex Regional Pain Syndromes, General Aspects 437

Synonyms CRPS CRPS Type 1: Reflex sympathetic dystrophy; algodystrophy; Sudeck’s Atrophy; Traumatic Angiospasm; Shoulder-Hand Syndrome; Post-Infarction Sclero- C dactyly CRPS Type 2: Causalgia Definition CRPSType1isasyndromethatusuallydevelopsafteran initiating noxious event. It consists of spontaneous pain or allodynia/hyperalgesia, in a regional distribution not limited to the territory of a single peripheral nerve, and disproportionate in severity to the inciting event, associated at some point with evidence of oedema, changes in skin blood flow or abnormal sudomotor activity in the regionofpain(Complexregionalpainsyndromes1994). CRPS Type 2 is the same as Type 1, but the syndrome developsin association with a partial nerve injury(Com- plex regional pain syndromes 1994). Characteristics Clinical Manifestations CRPS can be initiated by events ranging from minor injuries to surgical lesions, visceral diseases (e.g. myocardial infarction) and central neurological disorders (e.g. acute stroke). Various stages of CRPS have been proposed, but have not been corroborated in population studies (Veldman et al. 1993). Pain is the essential feature and is disproportionate Complex Regional PainSyndromes, General Aspects, Figure 1 Patient to the severity of the injury (Complex regional pain with complex regional pain syndrome (CRPS). The patient developed CRPS syndromes 1994). It can be burning, aching, prick- following a crush injury to the right foot. ling, shooting or tearing, and felt distally, diffusely and deeply in the affected region. It can be spontaneous or evoked by light touch, thermal stimulation, Somatization, anxiety, depression and fear avoidance dependent position, palpation and joint movements behaviours found in patients with CRPS are identical (Walker and Cousins 1997; Birklein et al. 2000; Rib- to those of patients with chronic pain, and are a result, bers et al. 1995; Bogduk 2001). If the pain is relieved by rather than a cause, of pain (Walker and Cousins 1997). Sympathetic Nerve Block or intravenous infusions The diagnosis of CRPS is based solely on clinical crite- of an α–adrenoceptor antagonist, it is considered to ria. Investigations are used only to confirm clinical im- be sympathetically maintained pain (SMP) (Complex pressions about autonomic, sensory and motor dysfunc- regional pain syndromes 1994). If not so relieved, it tion. These include bone scintigraphy, quantitative sen- is considered to be sympathetically independent pain sory testing and tests for autonomic function (Baron and (SIP). Wasner 2001). Skin changes range from warm and red to cold and cyan- otic, and are associated with swelling and increased or Demographics decreasedsweating(WalkerandCousins1997).Trophic CRPS affects women more often (66%), and most often changes include increased or decreased nail and hair the upper limb (73%) (Birklein et al. 2000). The mean growth, thin shiny skin, musclewasting and fibrosis, and age of patients is 50.4 years, but CRPS also occurs in osteoporosis (Walker and Cousins 1997). Motor impair- children–mainly adolescentfemalesand affectinglower ments include weakness, tremor, dystonia, myoclonic limbs–but carries a more favourable prognosis (Walker jerks, joint stiffness, and difficulty initiating movements and Cousins 1997). CRPS 1 is 5 times more common (Walker and Cousins 1997;, Ribbers et al. 1995). These than CRPS 2. vasomotor, sudomotor, and trophic changes distinguish CRPS occurs in 2–5% patients with peripheral nerve CRPS from other painful conditions due to neuropathy, injuries, and in 1–2% of patients who sustain fractures, musculoskeletal injury or visceral diseases (Fig. 1). although the incidence is higher following Colles’ frac- 438 Complex Regional Pain Syndromes, General Aspects ture (Walker and Cousins 1997). In 10–26% of patients returns but vasoconstrictor innervation disappears, be- no significant precipitant cause is found (Ribbers et cause some sympathetic postganglionicneurons degen- al. 1995). A genetic predisposition to CRPS had also erate. Blood vessels develop denervation hypersensitiv- been suggested (Walker and Cousins 1997). ity with increased α–adrenoceptor density,leading to increased vasoconstriction with manifestation of chroni- Natural History cally cold, bluish limbs (Bogduk 2001; Baron and Was- Symptoms tend to improve in about two-thirds of pa- ner 2001; Bennett 1999). tients. After Colles’ fracture, although most patients im- Inflammatory responses, with proliferation of immune prove rapidly, pain and swelling persist in some 20–30% cell infiltrates and liberation of proinflammatory cy- patients at 6 months (Walker and Cousins 1997). In pa- tokines, accompany nerve injury. These chemicals can tientswhoareunresponsivetotreatmentduringtheacute sensitise sensory neurones, resulting in mechanical stage, pain may become refractory and associated with allodynia and hyperalgesia (Bennett 1999). The exces- significant impairment in activitiesofdailyliving,recre- sive production of free oxygen radicals by activated ational activities, work and mood (Ribbers et al. 1995). phagocytes in inflamed tissues may also play a role Recurrence or spread to another region occurs in 10% (Baron and Wasner 2001; Veldman 1999). of patients. Treatment Mechanisms Although CRPS has attracted treatment with a variety As the features of CRPS 1 and CRPS 2 are identical, it of agents and interventions, used alone or in combina- is likely that CRPS 1 involves an undetected nerve in- tion, systematic and pragmatic reviews have shown that jury. CRPS is thus a form of neuropathic pain (Baron fewinterventionshavebeenvindicatedbycontrolled tri- and Wasner 2001; Bennett 1999). The underlying mech- als (Kingery 1997; Robinson 2002; Hord and Oaklan- anism of CRPS has not been explicitly elucidated (Bog- der 2003). The management of CRPS, therefore, rests duk 2001). Multiple mechanisms appear to be involved, largely on recommendations(Stanton-Hicksetal. 1998) with somatosensory dysfunctions interacting with the rather than strong evidence. sympathetic nervous system and peripheral inflamma- Early recognition and treatment are associated with the tory reactions (Bogduk 2001; Bennett 1999). Peripheral bestchanceofagoodoutcome.Comprehensivemanage- and central mechanisms for pain generation have been mententailsphysicaltherapy and functionalrestoration, invoked (Bennett 1999). coupled with behavioural therapy, and drugs or injec- Injury of a peripheral nerve may result in a neuroma tions to reduce pain (Stanton-Hicks et al. 1998). formation or constriction of the nerve. These can gen- Recommended, but unproven, interventions include erate ectopic activity in the Aδ and C fibres, which dynamic splinting, exercises, and stress-loading pro- excites nociceptive neurons in the dorsal horn, result- grams in order to maintain limb function and min- ing in central hyperexcitability (Bogduk 2001; Ben- imise secondary effects due to disuse (Walker and nett 1999). This becomes the basis for neurogenic pain, Cousins 1997; Hord and Oaklander 2003). Although mechanical hyperalgesia, and allodynia. Sprouting of cognitive behavioural therapy may be effective for sympathetic efferent fibres onto dorsal root ganglia chronic pain in general (Walker and Cousins 1997; (DRG), and production of α–adrenoreceptors in the Hord and Oaklander 2003), its efficacy for CRPS has DRG and nerve terminals, renders the affected nerves not been demonstrated. more responsive to noradrenaline (NA) and sympathetic Sympathetic nerve blocks have been a traditional stimulation (Bogduk 2001; Baron and Wasner 2001; intervention for CRPS, but a systematic review showed Bennett 1999). that the response rates were no better than what could Deafferentation following peripheral nerve injury can be expected from a placebo effect (Cepeda et al. 2002). result in disinhibition of dorsal horn neurons, and conse- Sympathetic blocks or epidural infusions may be quent spontaneous activity and facilitation of nocicep- used to facilitate physical therapy, but their utility re- tive neurons (Bogduk 2001).CRPS following lesions in mainsunproven. Bretylium and ketanserinedeliveredas the central nervous system might also be due to disinhi- regional intravenous infusions have been vindicated bition of central nociceptive pathways (Bogduk 2001). in controlled trials, but phentolamine and guanethidine Itremainsuncertainiftheso-calledsympatheticfeatures have effects no greater than placebo (Robinson 2002; are caused by abnormalities in sympathetic nerve activ- Hord and Oaklander 2003). Clonidine may be effective ity, by inflammatory changes, or a combination of both, by intravenous, transdermal, or epidural application at different phases of CRPS. (Hord and Oaklander 2003). Nifedipine and phenoxy- In the early phase, central sympathetic activity is func- benzamine may be effective in recent onset CRPS (Hord tionallyreduced,withreducedreleaseofNAandrelative and Oaklander 2003). vasodilatation. Antidromic activity in C fibres may lib- There is some evidence that oral corticosteroids may be erate inflammatory mediators and enhance vasodilata- effective (Kingery 1997; Hord and Oaklander 2003). tion. In the advanced phase, central sympathetic activity There is emerging evidence that bisphosphonatescan Complex Regional Pain Syndromes, Clinical Aspects 439 relieve the pain of CRPS (Robinson 2002; Hord and 13. Veldman P (1999) Inflammatory Aspects of RSD. In: Max M Oaklander 2003). Topical dimethylsulfoxide cream, (ed) Pain 1999 – An Updated Review. Refresher Course Syllabus. IASP Press, Seattle, pp 343–345 which acts as a free radical scavenger, may reduce the 14. Veldman P, Reynen H, Arntz E et al. (1993) Signs and Symp- signs of CRPS (Veldman 1999). toms of Reflex Sympathetic Dystrophy: Prospective Study of 829 Gabapentin, lamotrigine, subcutaneous and transder- Patients. Lancet 342:1012–1016 C mal lignocaine appear to be effective in open label trials, 15. Walker S, Cousins M (1997) Complex Regional Pain Syndromes: Including “Reflex Sympathetic Dystrophy” and “Causalgia”. but there have been no published trials of oral opioids, Anaesth Intens Care 25: 113–125 anticonvulsants, mexiletine, ketamine, or amitriptyline (Robinson 2002; Hord and Oaklander 2003). The efficacy of NSAIDs (Baron and Wasner 2001) and Complex Regional Pain Syndromes, acupuncture (Hord and Oaklander 2003) has not been demonstrated. Amitriptyline and TENS appear to be Clinical Aspects effective in children (Hord and Oaklander 2003). RALF BARON For intractable CRPS, some authorities advocate neuro- Clinic for Neurology, Christian Albrechts University modulation with peripheral nerve stimulator and epidu- Kiel, Kiel, Germany ral spinal cord stimulator (Hord and Oaklander 2003; [email protected] Stanton-Hicks et al. 1998), but a controlled trial showed that although spinal cord stimulation did relieve pain, it Synonyms didnotimprovefunction(Kemleretal.2000).Fordysto- nia associated with CRPS, intrathecal baclofen has been CRPS;reflexsympatheticdystrophy;causalgia;Morbus effective(HordandOaklander2003).Intrathecaladmin- Sudeck; algodystrophy istration of morphine can also be considered, although Definition efficacy has only been reported in case series (Hord and Oaklander 2003). The “IASP classification of chronic pain” redefined pain syndromes formerly known as reflex sympathetic dystrophy and causalgia. The term Complex Regional References Pain Syndrome describes, “a variety of painful condi- 1. Baron R, Wasner G (2001) Complex Regional Pain Syndromes. tions following injury which appear regionally having Curr Pain Headache Rep 5:114–123 a distal predominance of abnormal findings, exceeding 2. Bennett G (1999) Scientific Basis for the Evaluation and Treat- in both magnitude and duration the expected clinical ment of RSD/CRPS Syndromes: Laboratory Studies in Animals and Man. In: Max M (ed) Pain 1999 – An updated review. Re- course of the inciting event often resulting in significant fresher Course Syllabus. IASP Press, Seattle, pp 331–337 impairment of motor function, and showing variable 3. Birklein F, Riedl N, Sieweke N et al. (2000) Neurological Find- progression over time”. These chronic pain syndromes ings in Complex Regional Pain Syndromes – Analysis of 145 Cases. Acta Neurol Scand 101:262–269 comprise of different additional clinical features includ- 4. Bogduk N (2001) Mechanisms of Complex Regional Pain Syn- ing spontaneous pain, allodynia, hyperalgesia, dromes. Aust Musculoskeletal Med 6:88–102 oedema, autonomic abnormalities and trophic signs. In 5. Cepeda MS, Lau J, Carr B (2002) Defining the Therapeutic Role CRPS type I (reflex sympathetic dystrophy), minor of Local Anesthetic Sympathetic Blockade in Complex Regional Pain Syndrome: A Narrative and Systematic Review. Clin J Pain injuries or fractures of a limb precede the onset of symp- 18:216–233 toms. CRPS type II (causalgia) develops after injury 6. Complex Regional Pain Syndromes (1994) In: Merskey H, to a major peripheral nerve (Merskey and Bogduk 1995; Bogduk N (eds) Classification of Chronic Pain: Descriptions Harden et al. 2001; Janig and Baron 2003). of Chronic Pain Syndromes and Definition of Pain Terms, 2nd edn. IASP Press, Seattle, pp 40–43 Characteristics 7. Hord E, Oaklander A (2003) Complex Regional Pain Syndrome: A Review of Evidence-Supported Treatment Options. Curr Pain CRPS Type I (Reflex Sympathetic Dystrophy) Headache Rep 7:188–196 8. Kemler MA, Barendse GAM, van Kleef M, de Vet HCW, Rijks The most common precipitating event is a trauma affect- CPM, Furnee CA, van den Wildenberg FAJM (2000). Spinal ing the distalpartof an extremity (65%), especially frac- Cord Stimulation in Patients with Chronic Reflex Sympathetic tures, postsurgical conditions, contusions and strain or Dystrophy. New Engl J Med 343:618–624 9. Kingery WS (1997) A Critical Review of Controlled Clinical sprain. Less common occurrences are central nervous Trials for Peripheral Neuropathic Pain and Complex Regional system lesions, like spinal cord injuries and cerebrovas- Pain Syndromes. Pain 73:123–139 cular accidents as well as cardiac ischemia (Allen et al. 10. Ribbers G, Geurts A, Mulder T (1995) The Reflex Sympa- 1999). thetic Dystrophy Syndrome: A Review with Special Reference to Chronic Pain and Motor Impairments. Int J Rehab Res CRPS I patients develop asymmetrical distal extremity 18:277–295 pain and swelling without presenting with a demon- 11. Robinson J (2002) The Treatment of Complex Regional Pain strable nerve lesion. These patients often report a Syndrome Type 1. Aust Musculoskeletal Med 7:101–105 spontaneous burning pain felt in the distal part of the 12. Stanton-Hicks M, Baron R, Boas R, Gordh T, Harden N, Hendler N, Koltzenburg M, Raj P, Wilder R (1998) Complex Regional affected extremity. Characteristically, the pain is dis- Pain Syndromes: Guidelines for Therapy. Clin J Pain14:155–166 proportionate in intensity to the inciting event. The pain 440 Complex Regional Pain Syndromes, Clinical Aspects usually increases when the extremity is in a dependent The pain component that is relieved by specific sym- position. Stimulus-evoked pains are a striking clini- patholytic procedures is considered ”sympathetically cal feature; they include mechanical allodynia and maintained pain” (SMP). Thus, SMP is now defined to thermal allodynia and/or hyperalgesia. These sensory be a symptom or the underlying mechanism in a subset abnormalities often appear early, are most pronounced of patients with neuropathic disorders and not a clinical distally, and have no consistent spatial relationship to entity. The positive effect of a sympathetic blockade is individual nerve territories or to the site of the inciting not essential for the diagnosis. On the other hand, the lesion (Sieweke et al. 1999). Movement of, and pressure only possibility of differentiating between SMP and on, the joints (deep somatic allodynia) can elicit pain, ”sympathetically independent pain” (SIP) is the effi- even if the inciting lesion does not directly affect these. cacy of a correctly applied sympatholytic intervention Autonomic abnormalities include swelling and changes (Stanton-Hicks et al. 1995). in sweating and skin blood flow (Chelimsky et al. 1995; Diagnostic Procedure Birklein et al. 1998; Wasner et al. 2002; Wasner et al. 2001). In the acute stages of CRPS I, the affected limb The diagnosis of CRPS I and II follows the IASP clinical isoften warmer than thecontralateral limb.Sweatingab- criteria (Stanton-Hicks and Jänig 1996). If two clinical normalities, either hypohidrosis or, more frequently, hy- signs are joined by “or”, if either sign is present or both, perhidrosisare presentin nearly allCRPSI patients. The the condition of the statement is satisfied. acute distal swelling of the affected limb depends very CRPS Type I critically on aggravating stimuli. Since it diminishes after sympathetic blocks, it is likely that it is maintained TypeIisasyndromethatdevelopsafteraninitiatingnox- by sympathetic activity. ious event. Trophic changes such as abnormal nail growth, in- Spontaneous pain or allodynia/hyperalgesia occurs, is creased or decreased hair growth, fibrosis, thin glossy not limited to the territory of a single peripheral nerve, skin and osteoporosis may be present, particularly in and is disproportionate to the inciting event. chronic stages. Restrictions of passive movement are There isor hasbeen evidence of oedema,skin bloodflow often present in long-standing cases, and may be re- abnormality, or abnormal sudomotor activity in the related to both functional motor disturbances and trophic gion of the pain since the inciting event. changes of joints and tendons. Thisdiagnosisisexcluded bytheexistenceofconditions Weakness of all muscles of the affected distal ex- that would otherwise account for the degree of pain and tremity is often present. Small accurate movements dysfunction. are characteristically impaired. Nerve conduction and CRPS Type II electromyography studies are normal, except in patients Type II is a syndrome that develops after nerve injury. in very chronic and advanced stages. About half of the Spontaneous pain or allodynia/hyperalgesia occurs and patients have a postural or action tremor representing an is not necessarily limited to the territory of the injured increased physiological tremor (Deuschl et al. 1991). nerve. In about 10 % of cases, dystonia of the affected hand or There isor hasbeen evidence of oedema,skin bloodflow foot develops (Bhatia et al. 1993). abnormality, or abnormal sudomotor activity in the re- CRPS Type II (Causalgia) gion of the pain since the inciting event. Thisdiagnosisisexcluded bytheexistenceofconditions Thesymptomsof CRPSII aresimilartothoseof CRPSI. that would otherwise account for the degree of pain and The only exception is that a lesion of peripheral nerve dysfunction. structures and subsequent focal deficits are mandatory Pain is essential for the diagnosis, whereby ‘sponta- for the diagnosis. The symptoms and signs spread be- neous‘ indicates pain without external cause. Motor yond the innervation territory of the injured peripheral symptoms and findings are not included in this classi- nerveandoftenoccurremotefromthesiteofinjury,how- fication, although they are common, and can include ever, a restriction to the territory is not in conflict with tremor, dystonia and weakness. the current definition. Possible inciting events of CRPS include: Sympathetically Maintained Pain (SMP) CRPS I On the basis of experience and recent clinical stud- • Peripheral tissues ies the term sympathetically maintained pain was re-defined: Neuropathic pain patients presenting with – fractures and dislocations similar clinical signs and symptoms can clearly be di- – soft-tissue injury vided into two groups, by the negative or positive effect – fasciitis of selective sympathetic blockade, selective activation – tendonitis of sympathetic activity or antagonism of alpha adreno- – bursitis ceptor mechanisms (Raja et al. 1991; Baron et al. 2002). – ligamentous strain Complex Regional Pain Syndromes, Clinical Aspects 441

– arthritis clinical studies on other neuropathic pain syndromes, – mastectomy include opioids, tricyclic antidepressants, gabapentin, – deep vein thrombosis pregabalin and carbamazepine. Additionally, systemic – immobilization corticosteroids treatment is frequently used. Calcium- regulating agents (calcitonin, bisphosphonates) are C used in case of refractory pain. Sympatholytic proce- • Idiopathic dures for SMP testing, preferably sympathetic ganglion CRPS often follows minor trauma that could not be re- blocks, are used if no or an insufficient pain relief is membered by the patient. Also some patients negate any achieved and should be perpetuated in case of efficacy. inciting event If resting pain subsides, first passive physical therapy, later active isometric followed by active isotonic train- • Viscera ing should be performed in combination with sensory – abdominal disease desensitization programmes until restitution of com- – myocardial infarction plete motor function. Psychological treatment has to flank the regime to strengthen coping strategies and discover contributing factors. In refractory cases spinal • Central nervous system cord stimulation could be considered. If refractory dys- – spinal cord lesions tonia develops intrathecal baclofen application is worth – head injury considering. – cerebral infarction – cerebral tumor References 1. Allen G, Galer BS, Schwartz L (1999) Epidemiology of Complex CRPS II Regional Pain Syndrome: A Retrospective Chart Review of 134 Patients. Pain 80:539–544 • Peripheral nerve and dorsal root 2. Baron R, Schattschneider J, Binder A, Siebrecht D, Wasner G (2002) Relation Between Sympathetic Vasoconstrictor Ac- – peripheral nerve trauma tivity and Pain and Hyperalgesia in Complex Regional Pain – brachial plexus lesions Syndromes: A Case-Control Study. Lancet 359:1655–1660 – root lesions 3. Bhatia KP, Bhatt MH, Marsden CD (1993) The Causalgia- Dystonia Syndrome. Brain 116(Pt 4):843–851 4. Birklein F, Riedl B, Neundörfer B, Handwerker HO (1998) Sym- pathetic Vasoconstrictor Reflex Pattern in Patients with Complex Treatment Algorithm Regional Pain Syndrome. Pain 75:93–100 Treatment should be immediate and most importantly 5. Chelimsky TC, Low PA, Naessens JM, Wilson PR, Amadio PC, Ot’Brien PC (1995) Value of Autonomic Testing in Reflex Sym- directedtowardrestorationoffullfunctionoftheextrem- pathetic Dystrophy. Mayo Clin Proc 70:1029–1040 ity. This objective is best attained in a comprehensive in- 6. Deuschl G, Blumberg H, Lücking CH (1991) Tremor in Reflex terdisciplinary setting, with particular emphasis on pain Sympathetic Dystrophy. Arch Neurol 48:1247–1252 management and functionalrestoration (treatment algo- 7. Harden RN, Baron R, Jänig W (2001) Complex Regional Pain Syndrome. IASP Press, Seattle rithm see (Stanton-Hicks et al. 1998)). The pain special- 8. Janig W, Baron R (2003) Complex Regional Pain Syndrome: ists should include neurologists, anesthesiologists, or- Mystery Explained? Lancet Neurol 2:687–697 thopedics, physiotherapists, psychologists and the gen- 9. Merskey H, Bogduk N (1995) Classification of Chronic Pain De- eral practicioner. scriptions of Chronic Pain Syndromes and Definition of Terms. IASP press, Seattle Destructive surgery on the peripheral or central afferent 10. Raja SN, Treede RD, Davis KD, Campbell JN (1991) Systemic nervous system in cases of CRPS always implicates fur- Alpha-Adrenergic Blockade with Phentolamine: A Diagnostic ther deafferentation, and thereby provides an increased Test for Sympathetically Maintained Pain. Anesthesiology 74:691–698 risk for persistent deafferentation type of pain. 11. Sieweke N, Birklein F, Riedl B, Neundorfer B, Handwerker HO The severity of the disease determines the therapeutical (1999) Patterns of Hyperalgesia in Complex Regional Pain Syn- regime. The reduction of pain is the precondition that drome. Pain 80:171–177 all other interventionshave to comply with. At the acute 12. Stanton-Hicks M, Janig W, Hassenbusch S, Haddox JD, Boas R, Wilson P (1995) Reflex Sympathetic Dystrophy: Changing stage of CRPS, when the patients still suffer from severe Concepts and Taxonomy. Pain 63:127–133 pain, it is often impossible to carry out intensive active 13. Stanton-Hicks M, Jänig W (1996) Reflex Sympathetic Dystro- therapy. Painful interventions, and in particular vigor- phy: A Reappraisal. IASP Press, Seattle, pp 1–249 ous physical therapy, at this stage leads to deterioration. 14. Stanton-Hicks M, Baron R, Boas R, Gordh T, Harden N, Hendler N, Koltzenburg M, Raj P, Wilder R (1998) Complex Regional Therefore, immobilization of the affected extremity Pain Syndromes: Guidelines for Therapy. Clin J Pain 14:155–166 and careful contralateral physical therapy should be the 15. Wasner G, Schattschneider J, Baron R (2002) Skin Temperature acute treatment of choice and pain treatment should Side Differences – A Diagnostic Tool for CRPS? Pain 98:19–26 be initiated immediately. There are only a few con- 16. Wasner G, Schattschneider J, Heckmann K, Maier C, Baron R (2001) Vascular Abnormalities in Reflex Sympathetic Dys- trolled treatment studies on CRPS. The first choice trophy (CRPS I): Mechanisms and Diagnostic Value. Brain analgesic drugs, in which efficacy has been shown by 124:587–599 442 Compliance

Compliance Conditioned Place Avoidance

Deﬁnition Deﬁnition The extent to which patients are obedient and follow the In thisparadigm, the animalreceived aversive footshock instructions and prescriptions of a health care provider. in one chamber (shock chamber) of a two chamber ap- Multidisciplinary Pain Centers, Rehabilitation paratus (Selden et al. 1991). On a subsequent day, the animal was placed in the non-shock (safe) chamber and the time spent in this chamber was recorded. Hippocam- pus lesioned animals spent less time in the safe chamber as compared to control animals. Complicated Migraine Nociceptive Processing in the Hippocampus and En- torhinal Cortex, Neurophysiology and Pharmacology Clinical Migraine with Aura

Conditioning Comprehensive Assessment Deﬁnition Multiaxial Assessment of Pain Mechanism through which repeated associations between two stimuli induces a new learned response. In particular, by pairing a neutral stimulus (conditioned stimulus) with an unconditioned stimulus (that induces Compression Fracture a physiological response) many times, the neutral stimulus alone will be capable of producing a conditioned physiological response. Deﬁnition Operant Perspective of Pain Placebo Analgesia and Descending Opioid Modula- Compression failure of the anterior column of the spine tion with an intact middle and posterior column. Chronic Back Pain and Spinal Instability

Conductance Computed Radiography Deﬁnition Passage of ions such as Na+,K+,Cl– or Ca++ through Plain Radiography channels in the plasma membrane. Entry of positively charged ions depolarizes a neuron and leads to the generation of action potentials, whereas their exit can cause hyperpolarizationandasuppressionofactionpotentials. Computerised Axial Tomography Conductances may be activated by ligands binding to theirreceptor,suchasinthecaseofγ-aminobutyricacid, or by changes in resting membrane potential. CT Scanning Descending Circuitry, Opioids

Conditioned Analgesia Conduction Velocity

Definition Definition Conditioned Analgesia is a learned activation of pain- Speedofpropagationofanactionpotentialalonganerve inhibitory systems. fiber. Pain Modulatory Systems, History of Discovery Nociceptor, Categorization Congenital Insensitivity to Pain with Anhidrosis 443

Definition Confidence in Coping Abilities Congenital Insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by Psychology of Pain, Self-Efficacy a lack of pain sensation, recurrent episodes of high, unexplained fever, anhidrosis, i.e. absence of sweating, C self-mutilating behavior and mental retardation (Swan- son 1963; Pinsky and DiGeorge 1966; Dyck 1993; Confusional Migraine Axelrod 2002; Hilz et al. 1999) Characteristics Definition CIPAisthesecondmostfrequentamongthefiveHSANs An unusual migraine aura that consists of a sudden classified by Ohta and Dyck (Dyck 1993). The combi- onset of agitation, confusion and disorientation. It may nation of distinctive anhidrosis and insensitivity to deep be associated with dysarthria or aphasia. The episode as well as superficial pain, with manifestation already in lasts from a few minutes to an hour and is followed early childhood, is among the most prominent findings by headache consistent with migraine. The individ- differentiating CIPA from the other HSANs, in particu- ual is usually amnestic for the period of confusion. lar from the most common of the five disorders, HSAN It often occurs in teenagers, and may be triggered by III, also called Riley-Day-syndrome or familial dysau- mild head trauma or can occur spontaneously. The tonomia. Familial dysautonomia is characterized by ex- differential diagnosis includes complex partial seizure, cessive sweating during autonomic crises and by signif- intoxication/drug ingestion and encephalitis. icantly impaired perception of superficial pain but pre- Migraine, Childhood Syndromes served deep pain perception (Axelrod 2002). CIPA manifests in infancy or early childhood with frequent bouts of extreme, at first sight unexplained, fever and heat intolerance. Anhidrosis is present on the trunk and upper extremi- Congener ties in all CIPA patients while other body parts may be variably affected. Particularly with high environmental Definition temperatures, anhidrosis induces hyperpyrexia, which in turn can lead to recurrent febrile convulsions and has Acongenerisoneoftwoormorethingsofthesamekind, been reported to account for death within the first three as of animal or plant, with respect to classification. years in up to 20 percent of CIPA children (Axelrod Headache Attributed to a Substance or its Withdrawal 2002; Indo 2002). Anhidrosis also contributes to the development of a cal- loused,thickenedskinwithlichenification,i.e.aleathery induration and thickening of the epidermis with exag- Congenital Hypomyelinating Neuropathy geration of normal skin lines, giving it a bark-like appearance and hyperkeratosis particularly at palms and soles (Fig. 1) (Indo 2002). The skin is dry and warm and Hereditary Neuropathies frequently shows deep and persistent ulcers at the heels (Fig. 2), nails are dystrophic (Axelrod 2002; Indo 2002; Pinsky and DiGeorge 1966). Initially insensitivity to pain may not be apparent. Yet Congenital Insensitivity to Pain with with increasing mobility, children sustain severe, fre- Anhidrosis quently unrecognized injuries without complaint. They incur repeated bruises or inadvertently self-inflicted MAX J. HILZ burn injuries and cuts and multiple scars. Insensitivity University of Erlangen-Nuernberg,Erlangen, Germany to pain also accounts for, often self-inflicted corneal [email protected] scarring with opacities and even perforation of the cornea (Axelrod 2002, Indo 2002). With dentition, children start to bite their tongue, lips and fingers, leading to Synonyms a mutilated, bifid tongue with decubital ulcers or absent Hereditary Sensory and Autonomic Neuropathy Type tip of the tongue, mutilated lips (Fig. 3), jaw malforma- IV,HSAN IV,HSAN 4; CIPA; Congenital Sensory Neu- tion with edentate areas due to self-extraction of teeth ropathy with Anhidrosis; Familial Dysautonomia Type (Bodner et al. 2002), or to amputated finger tips. Open II wounds with poor healing, continuous self-mutilation 444 Congenital Insensitivity to Pain with Anhidrosis

Congenital Insensitivity to Pain with Anhidrosis, Figure 1 Hyperkeratosis and leathery induration of the skin with Congenital Insensitivity to Pain with Anhidrosis, Figure 3 Neuropathic exaggeration of normal skin lines in the palm of a CIPA patient. ankle joint (Charcot joint) due to repetitive fractures. Tissue swelling as Fingernails are dystrophic. Fingertips show signs of chronic inﬂammation a result of chronic inﬂammation and osteomyelitis. Chronic ulcer at the due to repeated self-mutilation. bottom of the heel. Mutilation of lower left lip due to repeated lip biting.

Chronic inflammation may lead to secondary amyloido- sis (Axelrod 2002; Indo 2002). Local and systemic infections often induce sepsis, which accounted for 20% fatalities in one patient group (Shorer et al. 2001). Most CIPA children are mentally retarded and have learning problems. 50 % show irritability, hyperactivity and a tendency to rages and tantrums (Axelrod 2002). Clinical examination confirms the absence of responses to superficial or deep, visceral pain, e.g. with electrical shock during neurophysiologic examination, intramuscular injection or urinary catheterization (Swanson 1963), Moreover, temperature perception and discrimination between hot andcoldstimuliisimpaired (Indo 2002). Similarly, discrimination of sharp and dull stimuli is compromised while light touch, vibration and position senses are normal. Deep tendon reflexes are preserved and there are no pathological reflexes. Corneal reflexes may be inconsistent. In contrast to HSAN III, emotional tear flow and fungiform papillae of the tongue are present (Axelrod 2002). Motorandsensorynerveconduction,somatosensory,visual or brainstem evoked potentials are usually normal, while quantitative sensory testing of warm, cold or heat perception is highly abnormal. The sympathetic skin response (SSR) is abnormal in all CIPA patients (Hilz Congenital Insensitivity to Pain with Anhidrosis, Figure 2 Deep persistent ulcer and chronic inflammation at the area of the heel in a CIPA et al. 1999; Shorer et al. 2001). patient. Intradermal injection of diluted histamine does not induce the typical triple response of a C-nerve fiber axon reflex mediated vasodilatation with diffuse ery- and frequent, often unnoticedfracturesand jointinjuries thema and itching pain, but only results in a circumscript lead to osteomyelitis and - over the years - to grotesque wheal at the site of injection (Axelrod 2002; Indo 2002). joint deformities with neurogenic arthropathy (Fig. 3) Similarly, local sweating cannot be induced by injection or amputations (Axelrod 2002). Even with active or of pilocarpine or methacholine (Pinsky and DiGeorge passive movement of fractured joints or bones, there is 1966). no tenderness or discomfort (Swanson 1963). Radio- Apart from anhidrosis, autonomic dysfunction is not grams frequently show numerous fractures, particularly a predominant characteristic of CIPA, though present. of the weight-bearing bones with neuropathic Charcot There may be orthostatic hypotension with preserved joints (Indo 2002). reflex tachycardia, and supersensitivity to exogenous Connective Tissue Disease 445 vasopressor drugs (Pinsky and DiGeorge 1966). Pupil- 2. Bodner L, Woldenberg Y, Pinsk V et al. (2002) Orofacial man- lary responses to cocaine are absent, yet preserved ifestations of congenital insensitivity to pain with anhidrosis: a report of 24 cases. ASDC J Dent Child 69:293–296 with epinephrine instillation into the conjunctival sac, 3. Dyck PJ (1993) Neuronal atrophy and degeneration predomi- also suggesting sympathetic denervation (Indo 2002). nantly affecting peripheral sensory and autonomic neurons. In: Subcutaneous injection of cholinergic methacholine or Dyck PJ, Griffin PK, Low PA et al. (eds) Peripheral Neuropathy. C neostigmine in a dosage that would normally induce WB Saunders, Philadelphia, pp 1065–1093 4. Hilz MJ (2002) Assessment and evaluation of hereditary sensory tearing does not result in lacrimation in CIPA patients and autonomic neuropathies with autonomic and neurophysio- although emotional tearing is preserved (Pinsky and logical examinations. Clin Auton Res 12 Suppl 1:I33–I43 DiGeorge 1966). 5. Hilz MJ, Stemper B, Axelrod FB (1999) Sympathetic skin re- Thedeficiencyinpainandtemperatureperceptionandin sponse differentiates hereditary sensory autonomic neuropathies III and IV. Neurology 52:1652–1657 sweating can be explained by the bioptic findings of ab- 6. Indo Y (2002) Genetics of congenital insensitivity to pain with an- senceofsmallmyelinatedandunmyelinatednervefibers hidrosis (CIPA) or hereditary sensory and autonomic neuropathy in the cutaneous branch of the radial nerve and a sig- type IV. Clinical, biological and molecular aspects of mutations nificant reduction of these fibers in the sural nerve (for in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res 12 Suppl 1:I20–I32 review see Indo 2002). 7. Indo Y, Tsuruta M, Hayashida Y et al. (1996) Mutations in the Skin biopsies show preserved sweat glands but absent TRKA/NGF receptor gene in patients with congenital insensitiv- innervation with loss of unmyelinated sudomotor fibers ity to pain with anhidrosis. Nat Genet 13:485–488 (for review see Indo 2002). 8. Pinsky L, DiGeorge AM (1966) Congenital familial sensory neuropathy with anhidrosis. J Pediatr 68:1–13 Absence of intradermal C- and A-delta fibers appears to 9. Shorer Z, Moses SW, Hershkovitz E et al. (2001) Neurophysio- be the morphological basis of insensitivity to pain and logic studies in congenital insensitivity to pain with anhidrosis. anhidrosis (for review see Indo 2002). Pediatr Neurol 25:397–400 10. Swanson AG (1963) Congenital insensitivity to pain with an- Verzé et al. found no nerve branches or endings in the hidrosis. Arch Neurol 8:299–306 epidermis and only a few nerve fibers in deeper layers 11. Swanson AG, Buchan GC, Alvord EC (1965) Anatomic changes of the dermis (for review see Indo 2002). in congenital insensitivity to pain. Arch Neurol 12:12–18 Autopsy of one CIPA patient showed absence of small neurons in dorsal root ganglia, absence of small nerve fibers in the dorsal roots, absence of Lissauer’s tract and paucity of smallfibersin thespinaltractofthe trigeminal nerve (Swanson etal. 1965), i.e. lack of afferentpain and Congenital Sensory Neuropathy with temperature mediating structures (Swanson 1963). Anhidrosis The genetic basis for CIPA are not mutations in the genes encoding neurotrophins, but mutations in the geneencoding the tyrosine kinase Areceptor (TRKA/ Congenital Insensitivity to Pain with Anhidrosis NTRK1) located on chromosome 1 (1q21-q22) (Indo et al. 1996). So far, 37 mutations have been identified in CIPA patients of various ethnicities (Indo 2002). The similarities of anatomical and clinical changes in Conjunctival Injection TrkA knockout mice and in CIPA patients led Indo and co-workers to the discovery that mutations of the trkA (NTRK1) gene are the genetic basis of CIPA. Defect Definition NGF signal transduction at the trkA receptor causes Redness of the conjunctiva (white) of the eye. failure to survive and probably apoptosis of developing Hemicrania Continua small nerve fiber neurons (Indo et al. 1996; Indo 2002). The only tool for prenatal diagnosis of CIPA is the identification of trkA (NTRK1) mutations (Indo 2002) but there are numerous mutations which prevents simple DNA diagnosis of the disease (Axelrod 2002). Connective Tissue Disease There is no specific therapy, but treatment remains supportive and attempts to control hyperthermia,to prevent Definition injuries, self-mutilation and orthopedic or dental complications and to modify behavioral problems such as The autoimmune disease is characterized by an abnor- hyperactivity or rages (Axelrod 2002). mal structure or function of one or more of the elements References of connective tissue, i.e. collagen, elastin, or the mu- copolysaccharides, including, for example, rheumatoid 1. Axelrod FB (2002) Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs. Clin Auton arthritis, systemic lupus erythematosus, scleroderma. Res 12 Suppl 1:I/2–I/14 Vascular Neuropathies 446 Connective Tissue Manipulation

Complex Adaptive System Connective Tissue Manipulation A complex adaptive system is a large set of units that interact with each other and with an external environ- Definition ment, to produce overall patterns that are significantly A superficial form of myofascial manipulation is the more complex than the behaviors of the individual en- simple definition of connective manipulation. It in- tities comprising the system. A complex adaptive sys- volves manipulating the skin and superficial connective tem changes according to three key principles: order is tissues above muscle to achieve reflex and local effects, emergentasopposed to predetermined, thesystem’shis- which is believed to be based on a viscerocutaneous re- tory is irreversible, and the system’s future is often un- flex. Reflex reactions include vasodilatation and diffuse predictable. Simpler complex systems nest within more or localized increase in sudomotor activity. elaborate complex systems (Morowitz and Singer 1995; Chronic Pelvic Pain, Physical Therapy Approaches Dooley 1996). and Myofascial Abnormalities The essence of a complex adaptive system is that it organizes itself to optimize its adaptation to its environment. Its dynamic instability gives it the flexibility it needs to accommodate quickly to environmental Conscious Laparoscopic Pain Mapping change. Complex adaptive systems are dynamic in that they constantly change and adjust to disturbances. Such a system does not always undergo linear changes when Chronic Pelvic Pain, Laparoscopic Pain Mapping it reorganizes to accommodate a disturbance; instead, it may demonstrate abrupt transitions in organizational patterns known as state transitions. Conscious Pain Mapping Self-Organization Self-organization is a process whereby a pattern at the global level of a system emerges solely from inter- Chronic Pelvic Pain, Laparoscopic Pain Mapping actions among lower-level components of the system. The global pattern is an emergent property of the system itself. A self-organizing, adaptive system tends to take on life-like qualities such as self-directedness, Consciousness and Pain self-correction, self-preservation, and intelligence (Ca- mazine et al. 2001). C. RICHARD CHAPMAN,YOSHIO NAKAMURA Pain Research Center, Department of Anesthesiology, Emergence University of Utah School of Medicine, Salt Lake City, Emergence is the process by which a system of UT, USA interacting elements spontaneously acquires a qualita- [email protected] tively new pattern and structure, which is unpredictable from knowledge of the individual elements (Camazine, Synonym et al. 2001). For example, combining hydrogen and oxygen gases at room temperature produces liquidity. Awareness Intentionality Definitions A complex adaptive system has intentionality when it exhibits directedness toward some future state or goal. Pain as Conscious Experience Intentcomprisestheendogenousinitiation,construction Pain is the unique meaning of a tissue injury event that and direction of perception, action and goal-directed be- the brain, as a complex adaptive system, constructs. havior (Freeman 1995; 2000). Pain emerges from large scale patterns of brain activity that reflect sensory, emotional and cognitive processing. Schemata As it is an aspect of consciousness, pain is distinct from A schema is a perceptual hypothesis that serves as nociception. the fundamental unit for constructing awareness (Mar- cel 1983). Schemata are fuzzy, preconscious and Consciousness dynamical patterns, roughly related to dynamically sta- Consciousness is an emergent, self-organizing feature ble patterns in neural networks (Rumelhart et al. 1986). of brain activity that makes complex, adaptive interac- The brain, as a complex adaptive system, adapts to the tions with the internal and external environments and world and the body in which it dwells, by constantly self-referenceinthoseenvironmentspossible(Chapman forming, evaluating, and refining these global percep- and Nakamura 2003). tual hypotheses. Ongoing awareness of the body and the Consciousness and Pain 447 world depends upon a continual process of reconstruc- The construction of consciousness, at any given motion based on schemata. Simpler schemata nest within ment, proceeds in response to the intentional and situa- more complex schemata (for review see Martin 1994). tional imperatives of each person. The intentionality of the person perceiving, feeling and emoting constrains Characteristics and drives the construction of consciousness (Free- C Pain and Nociception man 2000). This process involves integrating sensory Pain is an unpleasant, compelling aspect of somatic signals, memory and priorexperience,expectations,and awareness. Like other aspects of consciousness, it is immediate and long-term goals and plans. It weaves all emergent, dynamic, intentional and constructed. Also, of these into a coherent, stable macro-emergent-pattern likeotheraspectsofconsciousness,painistheproductof that seems to underlie awareness of the world and one’s the brain operating as a pattern forming, self-organized self. Far from being a passive entity that merely registers complex adaptive system. information coming in from various sensory channels, Nociceptive traffic within the nervous system has many the brain is an active, adaptive system that constantly consequences (Willis and Westlund 1997; Craig 2003). models the world and the body in which it dwells. Nociception is a reflexive motor stimulus and a trigger This modeling can change gradually from moment to for autonomic arousal. In addition to activating sensory moment or in abrupt state transitions. processes, nociceptive traffic activates the limbic brain Acute versus Chronic Pain via multiple pathways. Functional brain imaging studies reveal that complex patterns of processing occur In the consciousnessstudiesframework, painisa state of in mesencephalic, limbic and cortical structures dur- the brain. Nociceptive signaling from acute tissue injury ing the emergence of pain as a conscious experience. can perturb the complex adaptive system and force non- These processes appear to be complex, dynamic self- stable reorganization. It tends to provoke a state transi- organization that makes the construction of subjective tion from ordinary purposeful activity focused on im- experience possible (Kelso and Fuchs 1995). Nocicep- mediate goals or needs, to somatic preoccupation and tion is normally necessary, but not sufficient, for pain, protection. However, the system will tend to return to which as an aspect of consciousness is an emergent its normal, habitual patterns when the nociception de- feature of brain activity. creases or terminates. Properties of consciousness in general are also proper- When pain becomes chronic, the complex adaptive sys- tiesofpain.Thesepropertiesincludethefollowing.Con- tem undergoes reorganization to a stable, global state sciousness: characterized by low dynamic instability that makes the system resistant to change. The stable state is a complex • Is personal, with a necessarily limited point of view; adaptation to the physical health of the body, the social • Has mental contents that are stable for short periods environment and role expectations, interpersonal rela- and vary over longer intervals; tionships, and mood. Patients tend to demonstrate so- • Has mental contents that are unified at any one mo- matic preoccupation, conservation ofenergy,and illness ment and continuous over time; behavior. • Is selective, with a foreground and background, and The consciousness studies perspective holds that has a limited capacity at a given moment; chronic pain is difficult to treat, because an effective • Is intentional because it is directed at the world or the intervention must do more than eliminate the element body. of nociceptive signaling. It must disturb the complex adaptive system sufficiently to permit adaptive reorga- Pain and the Construction of Consciousness nization to a stable state of well-being, normal function The brain deals, not with reality as the physical sci- and optimal somatic awareness. The termination of ences study it, but rather with an internal, autonomous nociceptive activity often fails to disturb the system representation of reality that it builds and revises from sufficiently to enable reorganization in the desired di- moment to moment, using sensory information and rection. Psychological intervention, social adjustments schemata that involve networks of association in and increased physical activity are often necessary memory. Subjective reality undergoes constant self- adjuncts for chronic pain therapy, because the syner- organized revision, which integrates sensory infor- gistic effect of these combined has a better chance of mation, emotion, ratiocination and other aspects of perturbing the complex adaptive system than a single cognition to produce meaning. Therefore, brain rep- intervention alone. resentations of external objects and bodily events are dynamic constructions, not replications, of the external Individual Differences world or the body (Mountcastle 1998). Pain is not a Individuals differ markedly from one another in the static entity that an individual possesses, but rather a pain they experience in response to virtually identical dynamic construction of bodily awareness, typically tissue trauma. Although this stems in part from ge- based on nociception. netic factors that influence nociceptive transduction 448 Consolidated Standards of Reporting Trials Statement and/or transmission, most inter-individual variance re- 8. Marcel A (1983) Conscious and Unconscious Perception: Ex- flects each individual’s unique construction of the pain periments on Visual Masking and Word Recognition. Cognitive Psychology 15:197–237 experience. Personal past experience and personal in- 9. Martin B (1994) The Schema. In: Cowan G, Pines D, Meltzer terpretation of the immediate situation generate highly D (eds) Complexity: Metaphors, Models and Reality. Addison- varied schemata, and these in turn construct highly in- Wesley, Reading, MA, pp 263–285 dividual personal experiences of pain. Put more simply, 10. Morowitz HJ Singer JL (1995) The Mind, the Brain, and Complex Adaptive Systems. Morowitz H, Singer JL (eds) Addison-Wesley pain is the unique meaning of a tissue injury event that Pub. Co., Reading, Mass, p 237 the brain, as a complex adaptive system, constructs. 11. Mountcastle VB (1998) Brain Science at the Century’s Ebb. Different people construct different meanings in highly Daedalus vol 127:1–36 similar tissue injury situations. 12. Nakamura Y, Chapman CR (2002) Measuring Pain: An Intro- spective Look at Introspection. Conscious Cognition 11:582–592 13. Rumelhart DD, Smolensky P, McClelland JL, Hinton GE (1986) Culture and Pain Schemata and Sequential Thought Processes in PDP Models. In: Conscious experience is subject to cultural influences McCleeland JL, Rumelhart DE (eds) Parallel Distributed Pro- because the brain, as a complex adaptive system, is em- cessing: Explorations in the Microstructure of Cognition, vol 2: Psychological and Biological Models. MIT press, Cambridge, bedded within larger social and cultural complex adap- MA, pp 7–57 tive systems. Consequently, cultural meaning systems 14. Willis WD, Westlund KN (1997) Neuroanatomy of the Pain Sys- may determine the possible range of states of conscious- tem and the Pathways that Modulate Pain. J Clin Neurophys- ness.Someculturesmaypredisposethosetheyinfluence iol 14:2–31 to experience pain differently than others in a particular situation. Consolidated Standards of Reporting Pain Measurement Trials Statement As pain is a personal experience, subjective report is the onlywaytoaccessit.Conventional painmeasurement CONSORT Statement practice assumes that patients and research subjects can exercise introspection to gauge the magnitude of some feature of pain, assign numbers accordingly, and report such numbers without bias. In principle, different peo- CONSORT Statement ple reporting pain should use a common scale. From the consciousness studies perspective, pain is the meaning Synonyms of an injury event that the brain constructs. In contrived Consolidated standards of reporting trials statement research contexts, pain reports behave more or less as conventional practice requires, albeit with substantial Definition measurement error. It is less clear if clinical pain states, as personal meanings, possess the assumed feature of A group of scientists and editors developed the CON- numerical scalability. Future progress in pain measure- SORT (Consolidated Standards of Reporting Trials) ment must reexamine conventional assumptions about statement to improve the quality of reporting of clinical pain measurement, recognize the uniqueness of con- trials. The statement consists of a checklist and flow scious individual experience as meaning, and evolve diagram that authors can use for reporting a trial. Many improved methods for pain assessment (Nakamura and leading medical journals and major international edito- Chapman 2002). rial groups have adopted the CONSORT statement. The CONSORT statement facilitates critical appraisal and References interpretation of trials by providing guidance to authors about how to improve the reporting of their trials. 1. Camazine S, Deneubourg J, Franks NR, Sneyd J, Theraulaz G, Bonabeau E (2001) Self-Organization in Biological Systems. Central Pain, Outcome Measures in Clinical Trials Princeton Univ Press 2. Chapman CR, Nakamura Y (2003) Feeling Pain: A Construc- tivist Perspective. In: Kalso E, Estlander A, Klockars M (eds) Psyche, Soma and Pain. The Signe and Ane Gyllenberg Foun- Constitutive Gene dation, Helsinki, Finland, pp 115–123 3. Craig AD (2003) Interoception: The Sense of the Physiological Condition of the Body. Cur Opin Neurobiol 13:500–505 Definition 4. Dooley K (1996) A Nominal Definition of Complex Adaptive Systems. The Chaos Network 8:2–3 A gene that is continuously expressed without regula- 5. Freeman WJ (1995) Societies of Brains: A Study in the Neuro- tion, i.e. the transcription can be neither suppressed nor science of Love and Hate. Erlbaum L (ed) Hillsdale, New Jersey. encouraged. Constitutive genes often encode proteins 6. Freeman WJ (2000) How Brains Make Up Their Minds. with housekeeping functions. Columbia University Press, New York 7. Kelso JAS (1995) Dynamic Patterns: The Self-Organization of COX-1 and COX-2 in Pain Brain and Behavior. MIT Press, Cambridge, MA NSAIDs, Adverse Effects Contingent Negative Variation 449

Construction of Consciousness Contingencies

Deﬁnition Deﬁnition The construction of consciousness, at any given mo- Contingencies are events that occur in response to be- C ment, proceeds in response to the intentional and situa- havior. According to the operant model, contingencies tional imperatives of each person. The intentionality of can be reinforcing, punishing, or neutral with respect the person perceiving, feeling and emoting constrains to their effects on behavior. Reinforcing contingencies and drives the construction of consciousness. This strengthen (increases the probability of future occur- process involves integrating sensory signals, memory rence of) behavior, punishing contingencies weaken and prior experience, expectations, and immediate and behavior, and neutral contingencies have no impact on long-term goals and plans. Far from being a passive the future occurrence of behavior. entity that merely registers information coming in from Cognitive-Behavioral Perspective of Pain various sensory channels, the brain is an active, adaptive Motivational Aspects of Pain system that constantly models the world and the body in which it dwells. Consciousness and Pain Contingencies of Reinforcement

Definition Contact Stimulator The nature of the responses that the behaviors of individuals elicit from significant people in their environ- Definition ment. Patternsof reinforcementwill influencetheoccur- rence or nonoccurrence of behaviours, with reinforce- The most commonly used heat/cold contact stimulators ment leading to an increase in the behaviors and punish- rely on the Peltier principle (a thermoelectric effect in ment contributing to a reduction in behaviors. The prox- which passage of an electric current through a junction imity, strength, desirability, and frequency of responses between two different solids causes heat to be produced by others will influence the behaviors. or absorbed at that junction, according to the direction Cognitive-Behavioral Perspective of Pain of current). Motivational Aspects of Pain Pain in Humans, Thermal Stimulation (Skin, Muscle, Viscera), Laser, Peltier, Cold (Cold Pressure), Radi- ant, Contact Contingency Management

Deﬁnition Contemplation A system in which an individual’s successful task completion is consistently rewarded. Deﬁnition Chronic Pain in Children, Physical Medicine and Re- habilitation A readiness to change stage, in which a person recognizes the potential importance of making a change in be- Training by Quotas havior, but has not yet made a commitment to changing behavior. Motivational Aspects of Pain Contingent Negative Variation

Synonyms Contextual Factors CNV Definition Definition The CNV is a negative slow cortical potential that is typ- Contextual factors consist of two components: Environ- ically observed between a warning signal and a follow- mental factors and personal factors. Contextual factors ing imperative signal requiring a response. The CNV re- are factors that together constitute the complete context flectsattention, arousal, expectancy and response prepa- of an individual’s life, and in particular the background ration. For time intervals between the warning and the against which health states are classified in ICF. imperative signal that exceed 3 sec, an early CNV com- Disability and Impairment Definitions ponent during the first 500 ms after the warning signal, 450 Continuous Video-Tape Recordings and a late CNV component starting at about 1 sec prior Chronic Pain in Children, Physical Medicine and Re- to the imperative signal, can be distinguished. The early habilitation CNV component presumably reflects an orienting re- Muscular Cramps sponse and contingency processing, while the late CNV is closely related to response preparation. In migraine, an enhanced CNV amplitude and an impaired habituation of the CNV have been observed, which has been Contralateral interpreted as evidence for abnormal cortical information processing in migraine. Definition Modeling, Social Learning in Pain On or relating to the opposite side of the body. Psychological Treatment of Pain in Children The output of the primary motor cortex is principally to the opposite side of the body. Thus, to relieve pain restricted to one side of the motor cortex, the opposite side is stimulated. Continuous Video-Tape Recordings Motor Cortex, Effect on Pain-Related Behavior Opioid Receptor Trafficking in Pain States Definition PET and fMRI Imaging in Parietal Cortex (SI, SII, In- ferior Parietal Cortex BA40) Non-stop recordings of animals’ spontaneous behavior Spinothalamocortical Projections from SM via a telecamera connected to a time-lapse videotape with a wide range (3-960 hr/tape) of recording/reading speeds. This system allows a detailed analysis of animals’ movements. An infrared lighting system permits Controlled Trial filming during the dark phase (8:00 p.m. – 8:00 a.m.) (Giamberardino et al. 1995) Definition Visceral Pain Model, Kidney Stone Pain A clinical trial that compares the effect of the drug to be tested with either a standard treatment or a placebo treatment. Contract-Release Antidepressants in Neuropathic Pain

Deﬁnition Contract-releaseisamanualtechniqueusedforthetreat- Contusion ment of myofascial trigger points that can serve as a patient self-treatment. It is a repeated series of brief (2 or Deﬁnition 3 seconds), gentle (10% of maximum effort), voluntary A hematoma or bruise. contractions of the muscle harboring the trigger point. Spinal Cord Injury Pain Model, Contusion Injury This is followed immediately by either passive or active Model stretching of the same muscle. Myofascial Trigger Points Conus medularis DREZ

Contracture DREZ Procedures

Definition Conventional TENS Involuntary muscle contractions are called contracture. There are three types of contractures: antalgic contractures, painful contractures and myotactic con- Definition tractures. Antalgic contractures mainly consist of a The delivery of TENS to stimulate selectively large di- compensating phenomenon, related to a polysynaptic ameter non-noxious cutaneous afferents, without con- reflex, secondary to pain (for example the contracture currentlyactivatingsmalldiameternociceptiveafferents of paraspinal muscles due to discal herniation), and or muscle efferents. This is achieved by high frequency usually last from several days to weeks. By contrast, (50 – 120 Hz), low (sensory) intensity pulsed currents painful contractures (also called contractures) include to generate a ’strong but comfortable’ non-painful elec- various types of cramps. trical paresthesia. Coordination Exercises in the Treatment of Cervical Dizziness 451

Transcutaneous Electrical Nerve Stimulation Out- Definitions comes Vestibular rehabilitation (VR) is a physiotherapy TranscutaneousElectricalNerveStimulation(TENS) program for persons with symptomatic lesions of in Treatment of Muscle Pain the vestibular system (Foster 1994). The program is designed to decrease dizziness, improve balance C function and increase activity level. It is based on exercises to promote central vestibular compensation Convergent (Herdman and Whitney 2000). Vertigo is an illusory sensation of motion (rotational, translational or tilting of the visual environment) of Definition either the self or the surroundings (Wrisley et al. 2000). Characteristic of the receptive field size increase at each Dizziness is a non-specific term that describes an altered synaptic relay level, because ascending projections con- orientation in space, reflecting a discrepancy between verge onto a single neuron in the subsequent synaptic re- internal sensation and external reality, creating sensory lay. Like a single ganglion cell receives input from sev- conflicts. The conflicts can occur between any of the eral primary afferents. vestibular, visual or somatosensory systems, or dizzi- Postsynaptic Dorsal Column Projection, Functional ness may be caused by central problems involving the Characteristics integration and weighting of the different modalities and their relation to memory (Berthoz and Viaud- Delmon 1999). Dizziness may include sensations of light-headedness, faintness, giddiness, unsteadiness, imbalance, falling, waving or floating (Wrisley et al. Conversion Disorder 2000). Cervical vertigo can be defined as a syndrome of imbalance arising from disturbance of the cervicaljointrecep- Definition tors and associated with a sensation of dizziness (Brown One or more symptoms occur, involving voluntary mo- 1992). Cervical dizziness is a non-specific sensation of tor or sensory functions that suggest a neurological or altered orientation in space and disequilibrium originat- general medical condition (e.g. inability to move an arm ing from abnormal afferent activities in the neck (Wris- or leg). The beginning or worsening of the symptoms ley et al. 2000). must be linked to a psychological stressor. In children, pseudoseizures are the most common conversion dis- Characteristics order manifestation. Conversion Disorders occur more Cervical Vertigo frequently in girls than boys, and more frequently post- A large number of patients seek physiotherapy for neck- pubertythanpre-puberty.UnlikeadultswithConversion associated disorders (Clendaniel 2000). Different syn- DisorderwhoshowLaBelleIndifference,childrenshow onyms exist, but commonly used terms are cervical ver- concern for their symptoms. tigo and cervical dizziness. According to the definitions Somatization and Pain Disorders in Children given, the two concepts seem to reflect the same type of functional problems from the patient’s point of view. Cervical vertigo is described as a condition of dizziness following neck trauma, usually caused by flexion- Coordination Exercises in the Treatment extension movement of the neck (cf. whiplash trauma). of Cervical Dizziness Neck pain is associated with the injury and precedes all other symptoms (Brown 1992; Wrisley et al. 2000). KJERSTI WILHELMSEN,ANNE E. LJUNGGREN True vertigo, which is found in patients with acute Section for Physiotherapy Science, Department of vestibular conditions, is rare in patients with cervical Public Health and Primary Health Care, Faculty of vertigo (Brown 1992). The sensation of dizziness is Medicine, University of Bergen, Bergen, Norway vague and non-specific in character; the same type of [email protected], dizziness is often described by patients with chronic [email protected] vestibular deficits and by patients with neurological disorders (Clendaniel 2000). Patients may use words like light-headedness, faintness, giddiness, unsteadi- Synonyms ness, imbalance, falling, waving and floating. Other Vestibular rehabilitation; Cawthorne and Cookseys’ symptoms are disequilibrium, ataxia, limited range Eye-Head Exercises; vestibular compensation; vestibu- of motion in the cervical region (Clendaniel 2000) laradaptationexercises;vestibularhabituationexercises and disturbance of vision (Tjell 2001). It is a common 452 Coordination Exercises in the Treatment of Cervical Dizziness experience to find that head movements and / or move- in static as well as more challenging dynamic situa- ments in the environment, aggravate the visual problem. tions. Complete recovery depends on the restoration of Headache and tinnitus as well as hearing loss may also symmetry between the incoming signals to the different be present (Brown 1992; Clendaniel 2000). Accord- components constituting the balance system, i.e. vision, ing to some authors, cervical vertigo is classified as a somatosensory and vestibular systems (Luxon 1997). central vestibular disorder (Whitney and Rossi 2000). The central compensatory process seems to involve There is dispute as to whether the condition exists as both physical and chemical changes in the brain. It can an independent diagnosis; no definite diagnostic test is be divided into acute and chronic stages (Herdman and available (Wrisley et al. 2000). Diagnosis is inferred Whitney 2000). Four neurophysiological mechanisms from the patient’s history in conjunction with exclusion are described. Tonic rebalancing (spontaneous, phys- of other causes. iological process by which the system tries to restore The cause of cervical vertigo is still debated (Clen- symmetry at the level of the vestibular nuclei) is the daniel 2000). It has been proposed to be a subset of most important process in the acute stage. Vestibu- post-concussion syndrome (Brown 1992). Patients lar adaptation (the long-term adjustments in the basic with cervical dizziness usually have normal responses vestibulo-ocular and vestibulo-spinal reflexes) and on vestibular function tests, with the exception of pos- vestibular habituation (the long-term reduction in the turography (Clendaniel 2000; Wrisley et al. 2000). neurological responses to a noxious stimulus) (Shepard There seems to be consensus regarding the neck’s and Telian 1996) are compensatory processes in the contribution to postural control and balance (Brown chronic phase. Vestibular adaptation and habituation are 1992; Clendaniel 2000; Karlberg et al. 1996), but con- facilitated by error signals, i.e. dizziness, which can be troversies as to whether cervical mechano-receptor brought on in different ways. The facilitating stimulus dysfunction contributes to dizziness and influences the in adaptation is termed retinal slips, i.e. movements function of the vestibular system (Brown 1992; Clen- of images across the retina. The error signal is brought daniel 2000). Neck receptors have a role in eye-head on by a combination of visual fixation and head move- co-ordination through the cervico-ocular reflex and in ments. The brain tries to minimize the error signal the perception of balance, according to Brown (1992). by increasing the gain of the vestibulo-ocular reflexes Focus on dizziness and balance may therefore be of (Herdman and Whitney 2000). With habituation, dizzi- interest for patients with cervical vertigo. ness is provoked by repeated exposure to movements Traditionally, treatment of cervical vertigo has been provoking it, that is performance of certain movements directed towards relieving pain and consequences of will produce dizziness (Shepard and Telian 1996). The pain (Furman and Whitney 2000). Karlberg et al (1996) last mechanism described is substitution, i.e. alterna- have shown that an intervention consisting of traditional tive strategies are chosen to compensate for deficient physiotherapy aimed at reducing cervical discomfort, vestibular functions. The latter mechanism comes into also managed to decrease the frequency and intensity of action when optimal compensation is lacking. dizziness. Exercises intended to reduce dizziness may In the acute phase, compensation (the tonic rebalancing enhance these effects. process) is a pathophysiological process occurring independently of the patient’s activities. In the so-called Vestibular Rehabilitation (VR) chronic phase, activities and exposure to visual input are VRwasdevelopedinEnglandinthe1940sbyCawthorne necessary pre-requisites in order to keep up the recovery and Cooksey. Patients with post-concussion syndrome process. For some patients, a systematic and structured and vestibular deficiencies were introduced to exercises program of exercises often referred to as vestibular re- designed to train the eyes, muscle and joint sense to habilitation (VR), may be required to enhance the com- compensate for vestibular dysfunction and to restore pensatory process in the chronic stages. Based on the balance (Cooksey 1946). The program incorporated underlying neurophysiological understanding of com- head and neck exercises, which the patient practiced in pensatoryprocesses,twomajorapproachestoVRcanbe different starting positions (Dix 1974). identified. The exercise strategies are founded on either Today’s approaches can be traced back to the treatment adaptation or habituation, but in clinical practice there principles developed in England. Increased knowl- arenoclear-cutbordersbetweenthetwoapproaches.Ba- edge of the brain’s ability to compensate for deficient sically, if there is a visually provoked vertigo, exercises structures, along with development of theories of motor that promote adaptation might be choice number one, controland learning, havegivenriseto an understanding whilehabituationmaybeusedwithpatientswhosedizzi- of the vestibular compensatory mechanisms as learning ness primarily is produced by a change in head and / or processes. Vestibular compensation is the process by bodily positions. which vestibular symptoms are brought to resolution. Examples of gaze adaptation exercises are: Exercise 1: The patient may take advantage of different strategies in look at a stationary target placed on the wall. Move the the compensatory process. The overall goal of the pro- head from side to side as fast as possible, keeping the tar- cess is to achieve stability of gaze and postural control, getin focus. Repeatafter a shortrest, moving the head up Coping 453 and down, and Exercise 2: hold a card in the hand at arm- as relaxation techniques are included. Every-day activi- length. Move the head and card in opposite directions, ties that provoke dizziness are emphasised as important again keeping the target in focus. Exercise 1 can also and necessary premises for compensation. The signifi- be performed holding a card in the hand. This reduces cance of having a focus on body awareness as described the distance between the eyes and target and stresses an- elsewhere in this volume (see Body Awareness Ther- C other part of the visual-vestibular system. Varying the apies), is stressed throughout the program. Alteration tasks with regards to tempo, starting-positions and sur- in body alignment in general as well as specifically in roundings are ways to progress, the guiding lines should the cervical region might be a pre-requisite for allowing always be the patient’s ability to keep the visual target changes in the other systems responsible for balance. in focus (Herdman and Whitney 2000). A program of habituation exercises involves exposing References the patient to positional changes that cause dizziness. 1. Bandura A (1986) Models of human nature and causality. So- Systematic assessment of various positional changes cial foundation of thought and action, a social cognitive theory. should be carried out and movements provoking the Prentice-Hall, New Jersey, pp 1–46 2. Berthoz A, Viaud-Delmon I (1999) Multisensory integration in dizziness make up the program. If, in lying, turning spatial orientation. Curr Opin Neurobiol 9:708–712 from supine and on to the side provokes dizziness, this 3. Brown JJ (1992) Cervical contribution to balance: cervical ver- movement should be included in the patient’s program. tigo. In: Berthoz W, Graf P, Vidal P (eds) The head-neck sensory The actual number of movements included should not motor system. Oxford University Press, New York, pp 644–647 4. Clendaniel RA (2000) Cervical vertigo. In: Herdman SJ (ed) exceed 3–4 at the time (see Shepard and Telian 1996). Vestibular rehabilitation. F.A. Davies, Philadelphia, pp 494–509 There seem to be only a few articles describing the use 5. Cooksey FS (1946) Rehabilitation in vestibular injuries. Proc R of VR in the treatment of cervical vertigo. Wrisley et al. Soc Med 39:273–277 (2000) present the successful treatment of two patients 6. Dix MR (1974) Treatment of vertigo. Physiotherapy 60:380–384 7. Foster CA (1994) Vestibular rehabilitation. Baillieres Clin Neurol with cervical dizziness having used a combination of 3:577–592 traditional physiotherapy (such as ice treatment, mas- 8. Furman JM, Whitney SL (2000) Central causes of dizziness. Phys sage, mobilisation and exercises) to decrease pain and Ther 80:179–187 9. Herdman SJ, Whitney SL (2000) Treatment of vestibular hy- increase the range of movement, VRin theform of adap- pofunction. In: Herdman SJ (ed) Vestibular rehabilitation. F.A. tation (exercises1 and 2 aspresented above)andbalance Davies, Philadelphia, pp 387–423 exercises. Tjell (2001) uses a habituation approach in 10. Karlberg M, Magnusson M, Malmstrom EM et al. (1996) Postu- the treatment of whiplash-associated disorders. The ral and symptomatic improvement after physiotherapy in patients with dizziness of suspected cervical origin. Arch Phys Med Re- program comprises gaze and walk-gaze exercises and habil 77: 874–882 progression is based on the patient’s experience of pain 11. Luxon L (1997) Vestibular compensation. In: Luxon L, Davies R following each treatment session. It is a slow process, (eds) Handbook of vestibular rehabilitation. Singular Publishing but improvement in pain and dizziness is reported. A Group, San Diego, pp 17–29 12. Revel M, Minguet M, Gregoy P et al. (1994) Changes in cervico- program with special focus on eye-neck coordination cephalic kinesthesia after a proprioceptive rehabilitation program was administered to a group of patients with chronic in patients with neck pain: a randomized controlled study. Arch neck pain (Revel et al. 1994). The aim of the program Phys Med Rehabil 75:895–899 was to improve neck proprioception and to decrease 13. Shepard NT, Telian SA (1996) Vestibular rehabilitation programs. In: Shepard NT, Telian SA (eds) Practical management pain and discomfort. The program included passive and of the balance disorder patient. Singular, San Diego, pp 169–185 active movements of eye and head, gaze stability and 14. Tjell C (2001) Cervicogenic vertigo: with special emphasis on cervical repositioning exercises. The exercises were whiplash-associated disorder. In: Vernon H (ed) The cranio- cervical syndrome Mechanisms, assessment and treatment. performed in different starting positions over a period Butterworth-Heinemann, Oxford, pp 231–243 of 8 weeks. The authors suggest that the program could 15. Whitney SL, Rossi MM (2000) Efficacy of vestibular rehabili- be useful for patients with cervical vertigo. tation. Otolaryngol Clin North Am 33:659–672 It is our experience that a comprehensive approach is 16. Wrisley DM, Sparto PJ, Whitney SL et al. (2000) Cervicogenic dizziness: a review of diagnosis and treatment. J Orthop Sports needed in the rehabilitation of patients with cervical Phys Ther 30:755–766 vertigo. Reports from patients indicate optimal compensation in situations with few challenges, i.e. settings where the head and thus vision can be kept stable. In more dynamic and thus demanding surroundings, the Coping impression of a condition of disablement still exists and many patients choose a sedentary lifestyle to avoid the dizziness. A rehabilitation program should therefore Definition challenge dizziness through specific as well as gen- Psychological or behavioral strategies invoked in order eral activity. Our program consists of group treatment to minimize the impact of specific stressors on an indi- based on a cognitive behavioural approach promoting vidual’ physical or emotional well-being. direct and indirect learning processes (Bandura 1986). Catastrophizing Adaptation, habituation and balance exercises as well Coping and Pain 454 Coping and Pain

Psychological Assessment of Pain ing strategies and moderate important outcomes such as Psychology of Pain, Assessment of Cognitive Vari- disability and depression (Schmitz et al. 1996). In addi- ables tion to these clearly dispositional processes, much of the existing literature uses measures of pain coping strategies that encompass an indeterminate time frame, and Coping and Pain thereby measure general use of a strategy-style – as opposed to specific use of a coping strategy at a given point JENNIFER A. HAYTHORNTHWAITE in time. While this approach has provided valuable data Johns Hopkins University, Baltimore, MD, USA on stylistic use of pain coping strategies, the loss of in- [email protected] formation about the dynamic process of coping may explain the inconsistencies in the literature. Recent tech- Synonyms nologicaldevelopmentshaveofferedimprovedmethods for assessing specific use of pain coping strategies with Adaptation; coping strategies; coping style thedistinctpossibilityofdeterminingshort-termimpact. Since coping is inherently a dynamic process, daily di- Definition aries(Keefeetal.1997),andmorerecentlyelectronicdi- Cognitive and behavioral efforts to manage pain or pain- aries(Petersetal.2000),arejuststartingtoyieldvaluable related experiences, such as disability or negative mood. information about the interplay of coping, pain, mood, and disability over time. This technology also offers the Characteristics potential for identifying social interactions and environ- How individuals cope with pain is a consistent predictor mental characteristics that influence these evolving proof various aspects of pain, including physical function cesses. and psychological adaptation, with catastrophizing being by far the most consistent correlate of pain-related Active vs. Passive Coping phenomena. Much of the pain coping literature has a strong theoretical foundation in the larger literature Early conceptualizations of pain coping in rheuma- examining how individuals cope with stress. Coping toid arthritis distinguished between active and passive is usually defined as “constantly changing cognitive coping. Active coping strategies are strategies used to and behavioral efforts to manage specific external directly control pain or pain-related dysfunction (e.g. and/or internal demands that are appraised as taxing distracting one’s attention), whereas passive strategies or exceeding the resources of the person” (Lazarus relinquish control to others or limit activities (Brown and Folkman 1984, p 141). Note that this definition and Nicassio 1987; e.g. the use of rest). Although suggests that intention underlies the efforts made by the originally conceptualized as adaptive (active) vs. mal- individual, and emphasizes a process that may or may adaptive (passive), more recent work has refined this not be successful. Complex issues arise in determining characterization to include more detailed coping strate- the “adaptive” or “maladaptive” nature of any coping gies that are associated with both positive and negative strategy used to manage pain, and, when pain becomes adjustment, although the distinction between active and chronic, coping attempts necessarily broaden to en- passive coping remains valuable (Jensen et al. 2001). compass not only pain itself but also negative emotions, social connectedness, and pain-related disability across Specific Pain Coping Strategies multiple domains of function. A seemingly maladaptive coping strategy at one point in time may be adaptive Distraction, Ignoring Pain, or Distancing at another time; similarly, an adaptive strategy in one Distraction – directing attention to something other than domain (e.g. physical function) may be maladaptive in pain – may be more useful for managing acute pain than another domain (e.g. social function). For example, the chronicpain(Boothbyetal.1999).Evenwithacutepain, person with low back pain who spends the weekend in however, distraction may not relieve the severe levels bed during a pain flare may experience less pain in the of pain often seen in clinical settings (Haythornthwaite short run, but may also become de-conditioned if this et al. 2001). Although some studies indicate distraction use of rest persists across weeks or months. Time spent can improve function and well-being, others suggest in bed may reduce pain, but may endanger employment distraction correlates with greater pain, pain-related or social relationships. interference and distress. Ignoring pain is conceptually similar to distraction but focuses more on blocking out Style vs. Strategy the pain; it has been associated with lower ratings of Specific coping styles – assimilative (active attempts to pain and improved pain-related functioning (Boothby alter the situation to accomplish personal goals) vs. ac- et al. 1999), as well as with perceptions that pain is commodative (revision of personal goals to accommo- controllable (Haythornthwaite et al. 1998). Ignoring date limitations or losses) – can interact with pain cop- pain is reported more frequently in individuals with Coping and Pain 455 a longer duration of chronic pain (Peters et al. 2000), Social Support suggesting that this strategy may be one that increases as When social interactions, including some expressions individuals gain experience dealing with the challenges of pain, are intended to elicit help in managing pain or of chronic pain. Distancing includes thinking of the pain-related difficulties, these social interactions are pain as outside one’s body (Robinson et al. 1997) and conceptualized as coping strategies. The measurement C overlaps with reinterpreting pain as another sensation of social support usually focuses on the individual’s (e.g. numbness). Although inconsistently related to overall perceptions of support, typically incorporating positive outcomes, distancing may contribute to the two primary domains: instrumental support – the per- perception that pain is controllable (Haythornthwaite ception that the social environment provides resources et al. 1998). Increases in the use of these strategies as or information, completes tasks to help the individual, seen following multidisciplinary treatment (Jensen et or facilitates problem-solving; and emotional sup- al. 2001), are consistent with the cognitive-behavioral port – the perception that the social network provides formulation that these strategies are generally adaptive, sympathy, distraction, and sources of positive affect. As and contribute to the individual’s perception that pain is the case with other coping strategies, the beneficial is controllable. and/or harmful effects of social support may differ across domains of functioning and may interact with Positive Coping Statements other coping strategies, such as catastrophizing. Re- Coping self-statements refers to the positive, encour- cent prospective analyses have indicated that perceived aging thoughts people use to manage pain. Certain social support predicted reductions in pain-related studies have found positive self-statements to be as- disability and depression over 5 months following a sociated with the perception that pain is controllable limb amputation (Jensen et al. 2002). Diary analyses (Haythornthwaite et al. 1998); however, the positive provid further details about the process by which these impact of coping self-statements is not consistent across changes may transpire. Provision of social support is as- studies. Recent reviews have concluded that positive sociated with lower same-day negative mood and lower coping self-statements do not generally show a con- next-day pain (Feldman et al. 1999). In the context sistent relationship with reduced pain or improved of high pain, social support reduced depressed mood functioning (Boothby et al. 1999). However, these on the next day, suggesting a buffering role for social coping self-statements are an integral component of support. Very little research has examined what hap- most psychological interventions for pain manage- pens during these supportive exchanges, but qualitative ment, and show changes with treatment (Jensen et information suggests that the sources of support are al. 2001). affirming their commitment to help, encouraging active coping – coping self-statements in particular – and dis- Spirituality/Religiosity couraging helplessness and catastrophizing (Feldman Although spiritual beliefs and religious activities are et al. 1999). These responses contrast with more general often used to cope with stress and painful chronic ill- social responses to pain that derive from the operant nesses, this domain has generally received surprisingly literature and are conceptualized as negative, or punish- little attention in the pain literature. Historically, the ing, responses to pain expression (i.e., anger, irritation primary method of measuring this domain has relied or ignoring) from a significant other, or attentive and on a subscale of the Coping Strategies Questionnaire solicitous responses (i.e., encouraging rest or taking (Rosenstieland Keefe 1983) thatassessespassiveprayer over responsibilities), the latter being associated with and hope. Higher scores on this scale are consistently poorer adaptation following a limb amputation (Jensen associated with greater pain severity, disability, and et al. 2002). distress across a number of studies. The measurement of praying and hoping has been empirically linked to Rest catastrophizing, probably due to the shared passive Resting in response to pain is a pain coping strategy that quality of these scales. Since this strategy may be a derives largely from the operant pain literature, and has response to difficult times, longitudinal or diary studies been consistently related to poorer outcomes (Jensen et are needed to confirm its “maladaptive” function. In al. 1991) when studied in heterogenous samples of pa- fact, more detailed assessments of day-to-day spiritual- tients, typically seen in multidisciplinary specialty clin- ity as a coping strategy, have found that daily spiritual ics. Most of the studiesexamining the deleteriouseffects experiences and positive spiritual coping are associ- of rest on pain-related interference and mood are cross- ated with greater positive mood and lower negative sectional (Jensen et al. 2002). Although use of rest fol- mood, but this coping strategy does not impact on pain lowing a limb amputation is not prospectively associ- reports (Keefe et al. 2001). Further research investigat- ated with poorer function (Jensen et al. 2002), reducing the spiritual dimensions of coping may discover tions in rest are seen following multidisciplinary treat- that actively seeking spiritual experiences forms a key ment and remain an important target for these interven- dimension of accepting pain. tions (Jensen et al. 2001). 456 Coping Repertoire

To date, coping research has focused on pain coping strategiesthatinfluence pain and pain-related outcomes. Coping Repertoire Little attention, however, has been paid to the possibility that strategies for managing pain-related disability or Definition negative mood are likely to differ from strategies for Resources that individuals have for responding to prob- managing pain, or that people suffering from chronic lems and sources of stress and distress. These consist pain may not report use of these strategies when ori- of methods to change the situation, adjust to emotional ented to describe how they cope with pain. Recent arousal and uncontrollable circumstances, and accep- data indicating that the use of pain coping strategies tance of limitations. The coping repertoire includes the differs by pain duration (Peters et al. 2000) and site of internal resources, the external supports that are avail- pain (Heinberg et al. 2004), highlight the difficulties of able, and the instrumental means that facilitate response summarizing this complex literature across these, and such as financial means to assist in accommodation. other yet to be identified, dimensions. Cognitive-Behavioral Perspective of Pain References 1. Boothby JL, Thorn BE, Stroud MW, Jensen MP (1999) Coping with Pain. In: Gatchel RJ, Turk DC (eds) Psychosocial Factors Coping Strategy/Style in Pain. Guilford Press, New York, pp 343–359 2. Brown GK, Nicassio PM (1987) Development of a Questionnaire for the Assessment of Active and Passive Coping Strategies in Definition Chronic Pain Patients. Pain 31:53–64 3. Feldman SI, Downey G, Schaffer-Neitz R (1999) Pain, Nega- A cognitive-behavioral response to a stressor (e.g. prob- tive Mood, and Perceived Support in Chronic Pain Patients: A lem solving, recruiting social support) that mediates a Daily Diary Study of People with Reflex Sympathetic Dystrophy person’s response to a stressor and can impact the stress- Syndrome. J Consult Clin Psychol 67:776–785 pain relationship. 4. Haythornthwaite JA, Lawrence JW, Fauerbach JA (2001) Brief Cognitive Interventions for Burn Pain. Ann Behav Coping and Pain Med 23:42–49 Stress and Pain 5. Haythornthwaite JA, Menefee LA, Heinberg LJ, Clark MR (1998) Pain Coping Strategies Predict Perceived Control Over Pain. Pain 77:33–39 6. Heinberg LJ, Fisher BJ, Wesselmann U, Reed J, Haythornthwaite Coprevalence JA (2004) Psychological Factors in Pelvic/Urogenital Pain: The Influence of Site of Pain versus Sex. Pain 108:88–94 7. Jensen MP, Ehde DM, Hoffman AJ, Patterson DR, Czerniecki Definition JM, Robinson LR (2002) Cognitions, Coping and Social Environment Predict Adjustment to Phantom Limb Pain. Coprevalence refers to the rates of co-occurrenceof two Pain 95:133–142 specific disorders or clinical problems. 8. Jensen MP, Turner JA, Romano JM (2001) Changes in Beliefs, Depression and Pain Catastrophizing, and Coping are Associated with Improve- ment in Multidisciplinary Pain Treatment. J Consult Clin Psychol 69:655–662 9. Jensen MP, Turner JA, Romano JM, Karoly P (1991) Cop- ing with Chronic Pain: A Critical Review of the Literature. Cord Glial Activation Pain 47:249–283 10. Keefe FJ, Affleck G, Lefebvre J, Underwood L, Caldwell DS, JULIE WIESELER-FRANK,ERIN D. MILLIGAN, Drew J, Egert J, Gibson J, Pargament K (2001) Living with STEVEN F. MAIER,LINDA R. WATKINS Rheumatoid Arthritis: The Role of Daily Spirituality and Daily Department of Psychology and Center for Religious and Spiritual Coping. J Pain 2:101–110 Neuroscience, University of Colorado at Boulder, 11. Keefe FJ, Affleck G, Lefebvre JC, Starr K, Caldwell DS, Ten- nen H (1997) Pain Coping Strategies and Coping Efficacy in Boulder, CO, USA Rheumatoid Arthritis: A Daily Process Analysis. Pain 69:35–42 [email protected] 12. Lazarus RS, Folkman S (1984) Stress, Appraisal, and Coping. Springer Publishing Company, New York 13. Peters ML, Sorbi MJ, Kruise DA, Kerssens JJ, Verhaak PF, Bens- Synonyms ing JM (2000) Electronic Diary Assessment of Pain, Disability Spinal Cord Astrocyte; Microglia Activation and Psychological Adaptation in Patients Differing in Duration of Pain. Pain 84:181–192 14. Robinson ME, Riley JL, III, Myers CD, Sadler IJ, Kvaal SA, Definition Geisser ME, Keefe FJ (1997) The Coping Strategies Ques- Cord glial activation refers to the activation of dorsal tionnaire: A Large Sample, Item Level Factor Analysis. Clin J Pain 13:43–49 spinal cord microglia and astrocytes,whichin- 15. Rosenstiel AK, Keefe FJ (1983) The Use of Coping Strategies in duces exaggerated pain via the release of substances Chronic Low Back Pain Patients: Relationship to Patient Char- that excite nocisponsive neurons (reviewed in Watkins acteristics and Current Adjustment. Pain 3:1–8 et al. 2001). Activation is evidenced by upregulation of 16. Schmitz U, Saile H, Nilges P (1996) Coping with Chronic Pain: Flexible Goal Adjustment as an Interactive Buffer Against Pain- immunohistochemically-detectable cell-type specific Related Distress. Pain 67:41–51 activation markers, and increased release of neuroactive Cord Glial Activation 457 glial products including proinflammatory cytokines, Glia, specifically astrocytes, are intimately entangled excitatory amino acids (EAA), nitric oxide (NO), with neurons insofar as they encapsulate neuronal adenosine triphosphate (ATP), and prostaglandins. synapses, as well as wrap their processes around neu- These released substances then act on neurons, thereby ronal somas, axons and dendrites (Araque et al. 1999). amplifying the pain response. Some evidence points to This proximity puts astrocytes in a unique position to C the activation of microglia leading to the activation of modulate the activity of nocisponsive neurons. Garrison astrocytes (Raghavendra et al. 2003). et al. were the first to investigate the relationship between exaggerated pain and glial activation (1994). Characteristics Using the sciatic chronic constriction injury (CCI) Glia are non-neuronal cells traditionally thought of model, they compared the expression of CCI-induced as “supportive cells” for neurons(Araque et al. 1999). hyperalgesia and immunohistochemical markers of Many of their functions involve the release of growth astrocyte activation (Garrison et al. 1991). In addition, they evaluated whether CCI-induced astrocyte activa- factors, protecting neurons from excitotoxicity, regulating extracellular ion concentrations, and removal of tion would be affected by an N-methyl-D-aspartate cellular debris (Fig. 1). (NMDA) receptor antagonist (MK801), known to in- As discussed here, the term glia refers to astrocytes and hibit CCI-induced hyperalgesia (Garrison et al. 1994). microglia. While these are distinct cell types, most stud- They found that 1) hyperalgesia induced by CCI is iesinvestigatingexaggeratedpainandgliaarenotableto associated with astrocyte activation, and 2) this glial isolate the individual contribution of the two cell types. activation (like CCI-induced hyperalgesia) is inhibited The glia in the dorsal spinal cord differ from glia in other by MK801. Thus, these studies revealed a predictive regions of the central nervous system (CNS). Several relationship between glial activation and exaggerated linesof evidence point toastrikingheterogeneityamong pain. Since then, positive correlations between exag- glial cells, which isinfluenced by the regional biochemi- gerated pain and activation of spinal cord microglia (see cal milieu. That is, spinal cord glia express receptors not caption of Fig. 2 for discussion) and astrocytes have foundongliaderivedfromvariousbrainregionsandvice been revealed by diverse animal models of exaggerated versa. For example, spinal cord is one of the few CNS pain, including those induced by inflammation and/or regions in which glia express receptors for substance P trauma to tissues, peripheral nerves, spinal roots, and/ (Beaujouan 1990). Differences have also been reported or spinal cord (DeLeo and Colburn 1999; Watkins et between dorsal spinal cord and ventral spinal cord, and al. 2001). Such data naturally raise the question of even between superficial dorsal horn and the remainder whether glial activation is necessary and/or sufficient of the gray matter (Ochalski et al. 1997). for induction and maintenance of exaggerated pain. That glial activation plays a prominent role in the induction of exaggerated pain has been demonstrated using glial inhibitors. Fluorocitrate selectively blocks glial metabolic activity by inhibiting aconitase, a Krebs cycle enzyme (Paulsen et al. 1987; Hassel 1992). Blocking the activation of spinal cord glial cells with fluorocitrate blocks exaggerated pain states, including thermal and mechanical hyperalgesia and mechanical allodynia (Meller et al. 1994; Milligan et al. 2000). Recently, a similar pattern has also been observed with the microglia specific inhibitor, minocycline. Minocycline selectively inhibits the release of several neuroexcita- tory substancesfrom microglia, including inflammatory mediators. Administration of minocycline attenuates the development of mechanical allodynia and thermal hyperalgesia in response to spinal nerve transection, Cord Glial Activation, Figure 1 Glia are activated by three sources: 1) peripheral nerve inflammation, or spinal cord inflam- bacteria and viruses which bind specific activation receptors expressed by mation (Raghavendra et al. 2003). Thus microglial microglia and astrocytes, 2) substance P, excitatory amino acids (EAAs), and activation plays a significant role in the development adenosine triphosphate (ATP) released by either A-delta or C fiber presy- of exaggerated pain. Intriguingly, minocycline failed to naptic terminals or by brain to spinal cord pain enhancement pathways, and 3) nitric oxide (NO), prostaglandins (PGs), and fractalkine released from reverse, or minimally reversed, these exaggerated pain pain transmission neurons. Following activation, microglia and astrocytes states once they were fully expressed. These data, sup- cause pain transmission neuron hyperexcitability and exaggerated release ported by parallel analyses of glial activation markers, of substance P and EAAs from presynaptic terminals. These changes are created by the glial release of NO, EAAs, PGs, reactive oxygen species (ROS), revealing upregulation of GFAP (astrocyte activation and proinflammatory cytokines. Reprinted with permission from Watkins marker), suggest that microglial activation may lead to et al. 2001. astrocyte activation. Astrocytes may then play a more 458 Cord Glial Activation

Cord Glial Activation, Figure 2 Example of microglial activation in response to a stimulus that creates exaggerated pain states. Peri-spinal administration of HIV-1 envelope glycoprotein gp120 creates exaggerated responses to both thermal and touch/pressure stimuli. Disruption of glial activation abolishes the pain changes. Furthermore, these pain changes are correlated with anatomical evidence of activation of both astrocytes and microglia. An example of such microglial activation is illustrated here. Panel A illustrates the dorsal horn of a rat injected peri-spinally with vehicle. Panel B is identical except that the rat received peri-spinal HIV-1 gp120 at a dose that creates exaggerated pain states. These photomicrographs are from the tissues collected for analysis reported in Milligan et al. 2001. Activation of microglia induces these cells to upregulate their expression of complement type 3 receptors. Thus enzyme labeled antibodies directed against complement receptor type 3 (OX-42 monoclonal antibodies) can be used to detect microglial activation by light microscopy. In the photomicrographs shown here, the bound enzyme labeled antibodies catalyzed a reaction leading to precipitation of a colored reaction product. Thus, more antibodies bound (and hence more colored reaction product produced) reflects upregulation of the complement receptor type 3 microglial activation marker. By this method, activated microglia appear darker and more densely stained in accordance with their increased expression of OX-42 antibody bound receptors. Scale bar, 25 μm in (a) and (b). (Reproduced from Milligan et al. 2001 with permission). significant role in the maintenance of the pain facili- substance P, prostaglandins, ATP, and NO among oth- tatory process. Taken together, these data suggest that ers, by incoming sensory neurons and/or by intrinsic glial activation is important for both the induction and dorsal horn neurons in proximity to glia. While each of maintenance of exaggerated pain. these substances excites spinal cord neurons in the pain It is important to note another key finding from studies pathway, they also activate astrocytes and microglia. of minocycline and fluorocitrate. That is, glia are not in- Thus these traditional neuronal mediators may exert volved in normal pain processing (Milligan et al. 2000). their pain modulating effects, at least in part, via glial Normally, glia are quiescent, releasing nothing that en- activation hances pain. However, in situations leading to exagger- Once glia are activated, the question becomes what ated pain states, glia become activated. Once activated, signal(s) maintains the persistent glial activation. One theybeginreleasingsubstancesthatcontributetotheam- possible answer is that the signal is something released plification of pain. Therefore the involvement of glia in from dying or degenerating neurons associated with pain is determined by their state of activation. some models of chronic pain (Sugimoto et al. 1990; The data strongly suggest the glial activation is im- Coggeshall et al. 2001; Moore et al. 2002). It is well portant for the expression of exaggerated pain, but is known that neuronal injury and degeneration activate it sufficient? To assess this question, glia alone need glia via different pathways. Degenerating neurons have to be directly activated. While glia can be activated by porous membranes, through which proteins such as classical pain neurotransmitters, including EAA, NO, heat-shock proteins can pass. These proteins may serve prostaglandins and extracellular ATP, these substances as signals of dying cells, thereby activating glia. Addi- also activate neurons. To activate spinal cord glia with- tionally, neurons inhibit glial activation via cell-to-cell out activating neurons, the portions of bacteria and contact (Chang et al. 2001; Neumann 2001). When a viruses that bind to and activate the immune-like glial neuron dies, this contact is disrupted leading to glial cellshave been used. Administrationof these substances activation. Thus it seems possible that persistent glial induces mechanical allodynia and thermal hyperalgesia activation may be the end result. (Meller et al. 1994; Milligan et al. 2000). Thus, taken There are a number of peripheral signals that may po- together, spinal cord glial activation is implicated in tentially trigger glial activation, such as altered neuronal both the creation and maintenance pain facilitation. activity, transported molecules from sensory neurons, or the removal of tonic inhibitory signals. However, Bidirectional Neuron-Glia Communication little is know about the signal resulting in glial activa- The discussion above describes glia as integral to the tion. One signal currently being explored is the putative creation and maintenance of exaggerated pain. The neuron-to-glia signal fractalkine, a protein expressed question remains as to what signal from the periph- on the extracellular surface of sensory neuronsaswellas ery induces glial activation in the dorsal horn of the dorsal horn neurons. Fractalkine is tethered to neuronal spinal cord, thereby inducing exaggerated pain. As membranes by a mucin stalk (Chapman 2000). When described, one way is via the release of classical pain neurons are sufficiently activated, the mucin stalks neurotransmitters/ neuromodulators including EAA, break, releasing fractalkine into the extracellular fluid. Cord Glial Activation 459

Cord Glial Activation, Figure 3 Mixed astrocyte and microglia culture from neonatal rat pups showing selectivity of fractalkine for microglia. (a) Astrocytes labeled with glial fibrillary acidic protein (GFAP) visualized by a fluorescent antibody conjugated to Alexa 488. GFAP is a cytoskeletal protein that is highly specific to astrocytes. Note, that despite these astrocytes being in a mixed culture containing microglia, no microglia are labeled for GFAP. (b) Microglia labeled with fractalkine, which is directly conjugated to the Cy3b fluorochrome. In the dorsal spinal cord, fractalkine receptors are found exclusively on microglia. Note that, despite these microglia being in a culture containing astrocytes, no astrocytes are labeled by fractalkine. (c)Overlay of(a)and(b)toprovidethetruepictureofthemixedculture.

Within the spinal cord, only microglia express receptors pharmacologically blocking their activity does not al- for fractalkine, supporting the concept of fractalkine as ter normal pain responsivity. However, in conditions a neuron-to-glia signal (Fig. 3). leading to exaggerated pain, including CCI, sciatic Spinal administration of fractalkine induces mechanical inflammatory neuropathy (SIN), and spinal nerve tran- allodynia and thermal hyperalgesia, while spinal ad- section, blocking proinflammatory cytokine activity in ministration of a fractalkine receptor antagonist blocks spinal cord blocks mechanical allodynia and thermal exaggerated pain, including neuropathic pain (Watkins hyperalgesia (reviewed in DeLeo and Colburn 1999). and Maier 2003). Whether fractalkine-induced mi- Proinflammatory cytokines are,therefore, necessary for croglial activation leads, in turn, to astrocyte activation these exaggerated pain states. Mechanical allodynia and is a question that remains to be explored. mechanical and thermal hyperalgesia are induced by These neuron-to-glia signals point to a means by which spinal administration of proinflammatory cytokines (re- sensory nocisponsive neurons and dorsal horn neurons viewed in Watkins et al. 2001). Thus, proinflammatory communicate to glia, thereby inducing activation. In re- cytokines are sufficient for exaggerated pain. sponse to neuron-to-glia signals, glia release substances In addition to released signals acting on glia, astrocytes that then excite other glia and neurons. For example, mi- are also able to communicate with other astrocytes via croglial binding of fractalkine rapidly induces the re- gap junctions. This spread of excitation leads to the lease of the neuro- and glial-excitatory substances (inactivation of distant glia (Fig. 4) and their release of neu- cluding interleukin-1beta and nitric oxide) from dorsal roexcitatory substances (Araque et al. 1999). spinal cord (Watkins and Maier 2003). The release of The importance of this type of astrocyte-to-astrocyte these excitatory substances induces exaggerated pain. communication, causing excitationof distant glia,raises As immunocompetent cells, activated glia release the question of whether gap junctions may potentially classical immune products in response to neuronal sig- provide an explanation for the spread of human pain nals. These include proinflammatory cytokines such as beyond the original site of trauma; that is, mirror image interleukin-1beta, interleukin-6, and tumor necrosis pain and extraterritorial pain. Such a communication factor alpha (TNF-α) reduced. In their role as classical network could, theoretically at least, lead to release immune signals, these cytokines are “proinflammatory” of pain enhancing substances by newly activated glia because they orchestrate the early immune response distant from the initial site of gap junctional activation. to infection and damage by recruiting immune cells While no data yet exist in humans, the spread of pain to the site and activating them. In spinal cord, these in animal models is indeed blocked by spinal adminis- proinflammatory cytokines are signal molecules that tration of the gap junction decoupler carbenoxolone. activate neurons as well as glia, via binding to specific Carbenoxolone blocks the spread of mechanical allody- receptors on these cells. This is one means by which nia in CCI and SIN (Spataro et al. 2003). Control studies, glia can signal neurons. Proinflammatory cytokines using glycyrrhetinic acid, verify that carbenoxolone- are not constitutively released in the spinal cord, and induced disruption of CCI and SIN-induced mirror 460 Cord Glial Activation

Cord Glial Activation, Figure 4 Illustration of the spread of a calcium wave among astrocytes. Astrocytes are electrically coupled by gap junctions into vast networks. These electrical couplings allow astrocytes to rapidly communicate with one another over widespread areas. These images show a sequence of time-lapse photographic images, illustrating the rapid spread of excitation that occurs after the activation of a single glial cell at time 0. These newly activated, distant cells can then release pain-enhancing substances, thereby activating nearby pain neurons. Such gap junctional spread of excitation has recently been linked to pain facilitation, especially to mirror-image pain. (Modiﬁed from Araque et al. 1999. Reprinted with permission.)

image pains are indeed due to its disruption of gap Spinal Cord Increases Following a Sciatic Nerve Constriction junctions. This is the first example of gap junctions, Injury. Brain Res 565:1–7 9. Hassel B, Paulsen RE, Johnson A, & Fonnum F (1992) Selective most likely of glial origin, being implicated in pain. Inhibition of Glial Cell Metabolism by Fluorocitrate. Brain Res Thus, gap junctional communication among astrocytes 249:120–124 provides an intriguing and novel explanation for pain 10. Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF that arises in otherwise healthy body parts. (1994) The Possible Role of Glia in Nociceptive Processing and Hyperalgesia in the Spinal Cord of the Rat. Neuropharmacology In summary, cord glial activation is integrally involved 33:1471–1478 in diverse exaggerated pain phenomena. The powerful 11. Milligan ED, Mehmert KK, Hinde JL, Harvey LO, Martin D, role that glia play in pain facilitation suggests that drugs Tracey KJ, Maier SF, Watkins LR (2000) Thermal Hyperalgesia targeting this non-neuronal cell type may hold promise and Mechanical Allodynia Produced by Intrathecal Administra- tion of the Human Immunodeficiency Virus-1 (HIV-1) Envelope for effective clinical pain control. Glycoprotein, gp120. Brain Res 861:105–116 12. Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ (2002) Partial Peripheral Nerve Injury Promotes a Selective References Loss of GABAergic Inhibition in the Superficial Dorsal Horn of 1. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite the Spinal Cord. J Neurosci 22:6724–6731 Synapses: Glia, The Unacknowledged Partner. Trends in Neu- 13. Neumann H (2001) Control of Glial Immune Function by Neu- rosci 22:208–215 rons. Glia 36:191-199 2. Beaujouan JC, DaguetdeMontety MC, Torrens Y, Saffroy M, 14. Ochalski PA, Frankenstein UN, Hertzberg EL, Nagy JI (1997) Dietl M, Glowinski J (1990) Marked Regional Heterogeneity Connexin-43 in Rat Spinal Cord: Localization in Astrocytes and of 125I-Bolton Hunter Substance P Binding and Substance P- Identification of Heterotypic Astro-Oligodendrocytic Gap Junc- Induced Activation of Phospholipase C in Astrocyte Cultures tions. Neuroscience 76:931–945 from the Embryonic or Newborn Rat. J Neurochem 54:669–675 15. Paulsen RE, Contestabile A, Villani L, Fonnum F (1987) An In 3. Chang RC, Chen W, Hudson P, Wilson B, Han DS, Hong Vivo Model for Studying Function of Brain Tissue Temporarily JS (2001) Neurons Reduce Glial Responses to Lipopolysac- Devoid of Glial Cell Metabolism: The Use of Fluorocitrate. J charide (LPS) and Prevent Injury of Microglial Cells from Neurochem 48:1377–1385 Over-Activation by LPS. J Neurochem 76:1042–1049 16. Raghavendra V, Tanga F, DeLeo JA (2003) Inhibition of Mi- 4. Chapman GA, Moores K, Harrison D, Campbell CA, Steward croglial Activation Attenuates the Development but not Existing BR, Strijbos PJLM (2000) Fractalkine Cleavage from Neuronal Hypersensitivity in a Rat Model of Neuropathy. J Pharmacol Exp Membranes Represents an Acute Event in the Inflammatory Re- Ther 306:624–630 sponse to Excitotoxic Brain Damage. Journal of Neuroscience 17. Spataro LE, Sloane E, Milligan ED, Maier SF, Wieseler-Frank J, 20: RC87 pp 81–85 Schoeniger D, Jekrich BM, Barrientos RM, Watkins LR (2004) 5. Coggeshall RE, Lekan HA, White FA, Woolf CJ (2001) A-Fiber Spinal gap junctions: potential involvement in pain facilitation. Sensory Input Induces Neuronal Cell Death in the Dorsal Horn J Pain 5:392–405 of the Adult Rat Spinal Cord. J Comp Neurol 435:276–282 18. Sugimoto T, Bennett GJ, Kajander KC (1990) Transsynaptic De- 6. DeLeo JA, Colburn RW (1999) Proinflammatory Cytokines and generation in the Superficial Dorsal Horn after Sciatic Nerve In- Glial Cells: Their Role in Neuropathic Pain. In: Watkins L (ed) jury: Effects of a Chronic Constriction Injury, Transection, and Cytokines and Pain. Birkhauser, Basel, pp 159–182 Strychnine. Pain 42:205–213 7. Garrison CJ, Dougherty PM, Carlton SM (1994) GFAP Expres- 19. Watkins LR, Maier SF (2003) Glia: A Novel Drug Discovery Tar- sion in Lumbar Spinal Cord of Naive and Neuropathic Rats get for Clinical Pain. Nature Reviews Drug Discovery 2:973–985 Treated with MK-801. Exp Neurol 129:237–243 20. Watkins LR, Milligan ED, Maier SF (2001) Glial Activa- 8. Garrison CJ, Dougherty PM, Kajander KC, Carlton SM (1991) tion: A Driving Force for Pathological Pain. Trends Neurosci Staining of Glial Fibrillary Acidic Protein (GFAP) in Lumbar 24:450–455 Cordotomy Effects on Humans and Animal Models 461

Characteristics Cordotomy The intent of surgical section of anterolateral spinal Definition white matter is to interrupt axons of the spinothalamic tract that originate predominantly in the contralateral Originally anterolateral chordotomy, referring to the C gray matter in spinal segments below the lesion. The geometric term “chord” to indicate interruption of white targeted projection cells receive input from nocicep- matter. Cordotomy was developed as a surgical proce- tive peripheral afferents selectively sensitive to stimuli dure, to sever the spinothalamic tract at a spinal level that elicit pain or temperature sensations, and some above dermatomes to which extreme chronic pain was are excited by non-nociceptive afferents. Other axons referred. It is generally performed percutaneously at situated posteriorly in the spinal white matter, ipsilat- the cervical level, which interrupts the ascending lateral eral to their cells of origin, convey non-nociceptive spinothalamic tract. Cordotomy is most useful in the information that subserves sensations of touch and management of intractable, unilateral lower extremity proprioception. Therefore, cordotomy reduces pain cancer pain. Cordotomy tends to be more effective andtemperaturesensitivitywithoutproducingclinically for nociceptive pain syndromes than for neuropathic relevant deficits of touch or proprioception. Sensations syndromes. Unilateral pain is a better indication than reported to be lost or diminished by cordotomy are bilateral pain, and midline pain tends to respond poorly pain, itch, discrimination of sharpness with or without a even to bilateral cordotomy. painful quality, wetness, cold, warmth and voluptuous Cancer Pain Management, Opioid Side Effects, Un- sensations elicited by genital stimulation (Vierck et al. common Side Effects 1986). It is important to recognize that these effects of Cancer Pain Management, Overall Strategy cordotomy probably result from combined interruption Central Nervous System Stimulation for Pain of ascending pathways to cerebral sites that include Postherpetic Neuralgia, Pharmacological and Non- numerous thalamus nuclei, the hypothalamus and the Pharmacological Treatment Options amygdaloid complex (Giesler et al. 1994). Spinal Cord Injury Pain Model, Cordotomy Model Often chronic clinical pain is referred to deep tissues Thalamus, Receptive Fields, Perceptive Fields, Hu- and appears to be particularly attenuated by cordotomy man (Nathan and Smith 1979). The upper segmental levels for reduction of clinical pain and of pain from deep pressure stimulation have been reported to be well correlated Cordotomy Effects on Humans and Animal and lower than the upper level of hypoalgesia for cutaneous stimulation. Similarly, visceral pain is reported Models to be well controlled by cordotomy (White and Sweet 1 2 CHARLES J. VIERCK ,ALAN R. LIGHT 1969), but the upper level of visceral pain reduction can 1Department of Neuroscience, McKnight Brain differ from the upper level of diminished pain elicited by Institute, University of Florida College of Medicine, cutaneous pin prick testing. These differences in “sen- Gainesville, FL, USA sory level” for deep and superficial pain are probably 2Department of Anesthesiology, University of Utah, based on different entry levels for visceral and somatic Salt Lake City, UT, USA afferents and on a more extensive rostrocaudal disper- [email protected]fl.edu sioninthespinalcordofafferentinputfromdeepsomatic structures. The effectiveness of anterolateral cordotomy for attenuation of visceral pain is surprising in view of Definition evidence that interruption of a pathway located in the Cordotomy is a surgical procedure introduced in the dorsal spinal columns can attenuate visceral pain (Nauta early 1900s for reduction of chronic intractable pain et al. 2000). It appears that different aspects (qualitative in humans. An anterolateral column of spinal white features?) of visceral sensation depend on rostral con- matter is cut or coagulated at a spinal level above and duction by dorsal and ventral spinal pathways. contralateral to a source of clinical pain, intention- The dorsoventraland mediolateral extents of lateral and ally interrupting the spinothalamic tract. For weeks, ventral column damage are important determinants of months or years after successful interruption of as- the sensory effects of cordotomy. A somatotopic orga- cending pathways in the anterolateral column, pain and nization exists dorsoventrally, with sacral dermatomes temperature sensations are diminished contralaterally dorsal and rostral dermatomes ventral. Accordingly over dermatomes beginning several segments below restriction of cordotomy to the anterolateral column (caudal) to the lesion. The reduction of pain is apparent can miss the most dorsal spinothalamic axons and result for clinical pain and for nociceptive stimulation of hu- in sacral sparing. In addition, there are differences in mans, other primates and mammals (Vierck et al. 1986; dorsoventral distribution of rostrally projecting axons Vierck et al. 1995; White and Sweet 1969). with distinguishable origins. For example, spinotha- 462 Cordotomy Effects on Humans and Animal Models lamic axons originating in the deep dorsal horn are tioned by cordotomy, and 2) enhanced transmission of more ventrally located in the anterolateral and ventral nociception by diffusely projecting ascending pathways column, relative to cells from the superficial dorsal spared by cordotomy. horn (Zhang et al. 2000). This appears to be the case in Return of clinical pain and of painful sensations elicited general for cells originating in the superficial and deep by stimulation after cordotomy is consistent with devel- dorsal horn, which have overlapping, but differential, opment of chronic pain that can occur following strokes functional properties and projections to targets in the that produce deficits of elicited pain and temperature brain stem and thalamus (e.g. Craig 1998). These re- sensations and, by implication, damage the spinotha- lationships could influence the long-term effects of a lamic tract at some level of the neuraxis (Boivie et cordotomy. al. 1989). Numerous human studies involving thalamic For the mediolateral dimension of the anterolateral recording have demonstrated abnormal spontaneous ac- column, clinical investigators have postulated that tivity in regions deafferented by these and other lesions pain from mechanical stimulation of the skin depends (Lenz 1992). The presence of abnormally high levels of upon peripherally located axonal projections, while activity among populations of neurons that previously temperature sensations and pain from stimulation of received nociceptive input can potentially be interpreted deep tissues depend upon more medially located ax- as pain. If this occurs, the distribution of pain would be ons (Walker 1940). These suppositions encouraged a expected to involve much of the deafferented region, clinical strategy involving medially extensive antero- rather than the more restricted site of pain experienced lateral cordotomy, in order to maximally attenuate pain before cordotomy. Furthermore, recordings from the from deep tissues. Given this surgical approach, the thalamus of monkeys after medially extensive cordo- expectation is that a successful unilateral cordotomy tomy have shown that abnormal spontaneous activity is would produce contralateral analgesia, particularly for not restricted to the region of primary deafferentation cutaneous stimulation. However, human and animal within the nucleus ventralis posterolateralis (Weng et studies involving nociceptive cutaneous stimulation al. 2000). That is, the effects of deafferentation can within dermatomes maximally affected by cordotomy extend beyond the somatotopically appropriate region indicate that pain sensitivity is not eliminated (King of a principal target of spinothalamic projections to the 1957; Vierck et al. 1990; Vierck et al. 1995; Vierck and thalamus. Luck 1979). Other clues relevant to an eventual return of clinical Not only is pain sensitivity partially preserved contralat- pain and pain sensitivity are offered by the stimuli erally, but chronic pain returns and pain sensitivity incapable of eliciting pain sensations after cordotomy. creases over time for some but not all cases after an ini- Thresholds for elicitation of pain are clearly elevated, tially successful cordotomy. Early on, the explanation but strong suprathreshold stimulation is perceived as for this was that the anterolateral lesion for cases of re- painful (King 1957). This is apparent for electrical covery was incomplete dorsally, ventrally or medially. stimulation of the skin or a peripheral nerve, which However this possibility is contradicted by human and progressively activates A-delta and C afferents as no- animal studies with histological confirmation of highly ciceptive stimulus intensity increases. A cordotomy restricted lesions (superficially located in the anterolat- that eliminates pain elicited by stimulation of A-delta eral column) that produced very long-term hypoalgesia afferents can preserve pain from electrical stimulation (Nathan and Smith 1979; Vierck and Luck 1979). Direct at intensities sufficient to excite C nociceptors (Collins comparisons of cordotomy effects in monkeys indicate et al. 1960). Similarly, pain elicited by the standard that recovery of pain sensitivity over time is more sub- pinprick test involving single stimuli can be eliminated stantial for extensive lesions (primarily medially) than by a cordotomy, but repetitive pinprick stimulation at for superficial lesions (Vierck et al. 1990). Explanations the same location produces pain (Nathan and Smith for these results may be 1) that all spinothalamic axons 1979; Walker 1940), presumably because of temporal shift laterally with ascension of the spinal cord (Zhang summation. Temporal summation by repetitive stimu- et al. 2000) and 2) that the more extensive lesions par- lation has been shown to depend upon stimulation of C tially damage spinal projection systems other than the nociceptors (e.g. Vierck et al. 1997). Also, when pain spinothalamic tract (Fig. 1) (see Spinal Cord Injury from application of focal pressure to deep tissues is Pain Model, Cordotomy Model). eliminated by cordotomy, pain from muscular cramps When chronic pain returns after cordotomy, it appears can be perceived (White 1968). In this example, spatial to be qualitatively distinct from that experienced before summation from simultaneous stimulation of many C surgery. Discrimination between qualitative features of nociceptors may be responsible for break through pain. chronic pain is difficult, but recovered pain can be more The varieties of pain retained after cordotomy suggest diffuse in character and bilaterally distributed (White that pathways of rostral projection outside the contralat- and Sweet 1969). Several possible mechanisms for this eral lateral column are particularly sensitive to C noci- are related to 1) deafferentation of neurons normally ceptor input. The following evidence indicates that this receiving input from rostrally projecting axons sec- conduction system is diffusely distributed in the antero- Cordotomy Effects on Humans and Animal Models 463

Cordotomy Effects on Humans and Animal Models, Figure 1 (a) Diagrams of 4 unilateral cervical cordotomies in humans that produced enduring reductions of chronic clinical pain and sensitivity to nociceptive stimulation. Note that the lesions are restricted to the peripheral portions of the anterolateral white matter (after Nathan and Smith, 1979). (b) Plots of the uniformly peripheral distribution of anterolateral axons (at the C2 segment of monkeys) that project to the ipsilateral thalamus from cells of origin in the contralateral gray matter. Upper diagram: solid circles: axons from cells in the superficial dorsal horn; open circles: axons from cells in the deep dorsal horn. Overall, axons from superficial cells are distributed more dorsally, especially at thoracic levels (not shown). Lower diagram: cells with input from different populations of peripheral afferents: solid circles: wide dynamic range neurons; open circles: low threshold neurons; stars: high threshold neurons (from Zhang et al. 2000). lateral and ventral spinal cord and is responsible for re- alleviation of chronic, intractable pain, available ev- turn of pain sensitivity after cordotomy. Bilateral cor- idence favors interruption of superficial axons in the dotomy does not prevent recovery of pain or eliminate anterolateral column. pain that has developed after interruption of one anterolateral column (White and Sweet 1969). Therefore, it is unlikely that sparing of spinothalamic axons underlies References the return of pain after cordotomy. Also, secondary lesions of dorsal spinal pathways in monkeys do not atten- 1. Boivie J, Leijon G, Johansson I (1989) Central post-stroke pain - a study of the mechanisms through analyses of the sensory uate pain sensitivity that has returned after cordotomy abnormalities. Pain 37:173–185 (Vierck and Luck 1979). However, complete interrup- 2. Collins W, Nulsen F, Randt C (1960) Relation of peripheral nerve tion of both ventral spinal quadrants (ventral hemisec- fibre size and sensation in man. Arch Neurol 5:381–385 3. Craig, AD (1998) A new version of the thalamic disinhibition tion) appearsto eliminate pain sensitivity without recov- hypothesis of central pain. Pain Forum 7:1–14 ery (Vierck and Luck 1979). Obvious candidates for dif- 4. Giesler GJ Jr, Katter JT, Dado RJ (1994) Direct spinal pathways to fuserostralpaintransmissionarethespinoreticularpath- the limbic system for nociceptive information. TINS 17:244–250 ways, with bilateral relays to cerebral systems involved 5. King RB (1957) Postchordotomy studies of pain threshold. Neu- rology 7:610–614 inpaincodingandmodulation(e.g.spinomesencephalic 6. Lenz FA (1992) The ventral posterior nucleus of thalamus is and spinoreticulothalamic). involvedinthegeneration of central pain syndromes. APSJournal In summary, clinical and laboratory animal studies with 1:42–51 histologicalverificationofspinallesionsindicatethatin- 7. Nathan PW, Smith MC (1979) Clinico-anatomical correlation in anterolateral cordotomy. Adv Pain Res Ther 3:921–926 terruption of spinothalamic axons located superficially 8. Nauta HJW, Soukup VM, Fabian RH et al (2000) Punctate mid- in the anterolateral spinal column effectively reduces line myelotomy for the relief of visceral cancer pain. J Neursurg chronic pain and pain sensitivity, long term. However, 92:125–130 partial interruption of diffuse ventral spinal projection 9. Vierck CJ Jr, Luck MM (1979) Loss and recovery of reactivity to noxious stimuli in monkeys with primary spinothalamic chordo- systems by more extensive lesions can initiate a re- tomies, followed by secondary and tertiary lesions of other cord covery process with adverse effects on pain sensitivity. sectors. Brain 102:233–248 Complete interruption of the bilateral ventral projection 10. Vierck CJ Jr, Greenspan JD, Ritz LA et al (1986) The spinal pathways contributing to the ascending conduction and the de- system and the spinothalamic tract produces analgesia, scending modulation of pain sensations and reactions. In: Yaksh in contrast to the hypoalgesia produced by anterolat- TL (ed) Spinal systems of afferent processing. Plenum Press, eral cordotomy. Unfortunately, ventral hemisection New York, pp 275–329 also produces profound motor deficits by interrupting 11. Vierck CJ Jr, Greenspan JD, Ritz LA (1990) Long term changes in purposive and reflexive responses to nociceptive stimulation a number of descending spinal pathways. Therefore, in monkeys following anterolateral chordotomy. J Neurosci when employment of spinal surgery is considered for 10:2077–2095 464 Core and Matrix

12. Vierck CJ Jr, Lee CL, Willcockson HH et al. (1995) Effects of anterolateral spinal lesions on escape responses of rats to hindpaw Correct Rejection stimulation. Somatosens Motor Res 12:163–174 13. Vierck CJ Jr, Cannon RL, Fry G et al. (1997) Characteristics of temporal summation of second pain sensations elicited by brief Definition contact of glabrous skin by a preheated thermode. J Neurophysiol 78:992–1002 Correctrejectionistheprobabilityofresponse„B“when 14. Walker AE (1940) The spinothalmic tract in man. Arch Neurol event B has occurred. Psychiat 43:284–298 Statistical Decision Theory Application in Pain As- 15. Weng H-R, Lee J, Lenz F et al. (2000) Functional plasticity in sessment primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord. Neurosci 101:393–401 16. White JC, Sweet WH (1969) Pain and the neurosurgeon: A forty- year experience. Thomas CC, Springfield 17. White J (1968) Operations for the relief of pain in the torso and Correlation extremities: Evaluation of their effectiveness over long periods. In: Soulairac A, Cahn J, Charpentier J(eds) Pain. Academic Press, New York, pp 503–519 Definition 18. Zhang X, Honda C, Giesler GJ Jr (2000) Position of spinothalamic tract axons in upper cervical spinal cord of monkeys. J The degree to which variables change together. Neurophysiol 84:1180–1185 PainintheWorkplace,RiskfactorsforChronicity,Job Demands

Core and Matrix Cortex and Pain

Spinothalamic Terminations, Core and Matrix Deﬁnition Cortical areas (anterior cingulate, parietal operculum, insula, primary somatic sensory cortex) that show pain- Coronary Artery Disease related activity, usually based on imaging studies. Pain Treatment, Motor Cortex Stimulation Visceral Pain Model, Angina Pain Cortical Feedback

Coronary Insufﬁciency Deﬁnition

Back projections from cortical regions that receive for- Visceral Pain Model, Angina Pain ward projections from the thalamus. Thalamic Plasticity and Chronic Pain

Corpus Callosum Cortical Information Flow Definition Thalamocortical Loops and Information Processing The largest bundle of fibers connecting the two hemispheres. The corpus callosum is subdivided into four sub-regions with the splenium located in the most posterior region, the body extending anterior from the Cortical Plasticity splenium, the genu consisting in the most anterior part, and the rostrum below the genu. Each region of the corpus callosum connects specific regions of one hemi- Definition sphere of the cerebral cortex to the homologous area in Flexible organization of the cortical texturesandcircuits the other hemisphere. adapting to input variability and regulated by ’experi- Cingulate Cortex, Functional Imaging ence’, i.e. preferential use increase/reduction of definite Nociceptive Processing in the Cingulate Cortex, Be- pathways. At the synaptic level, strengthening or weak- havioral Studies in Humans ening of the synaptic connections depending on a cor- Pain Processing in the Cingulate Cortex, Behavioral relation principle. Studies in Humans Deafferentation Pain Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior 465

in recent reviews of the cerebral cortical mechanisms Cortical and Limbic Mechanisms mediating pain (Treede et al. 1999). Mediating Pain and Pain-Related Behavior Spatial Distribution of Function C KENNETH L. CASEY The clinical observation that pain can be relieved, at Department of Neurology, Department of least partially, by spinothalamic tractotomy (Spiller Molecular and Integrative Physiology, University of and Martin 1912) supports the concept of an anatom- Michigan, and Consultant in Neurology, Veterans ically distinct pain pathway, but subsequent clinical Administration Medical Center, Ann Arbor, MI, andneurosurgicalexperiencehasemphasizedthelong- USA term unpredictability of the results obtained follow- [email protected] ing most ablative procedures, especially those involving cerebral structures (Sweet 1982). Current meth- Scope of This Review ods of analyzing brain function show that all cortical and limbic functions are mediated by networks This article will briefly review pain related functions of interconnected cortical areas, each with a specific, of the cerebral cortex and limbic system. For the pur- although incompletely characterized, neuronal func- poses of this review, the limbic system is defined as tion. This concept is in accord with the results of cur- the medial and orbital portions of the frontal, parietal rent functional imaging studies of pain (Casey 1999; and temporal lobes that form a ring around the upper Casey 2000; Davis 2000; Derbyshire 2000; Peyron et brainstem and diencephalon. The cingulate gyrus is a al. 2000) and the contemporary view that distributed defining structure of the limbic system, the major com- parallel systems mediate cortical functions (Mesulam ponents of which have direct or oligosynaptic connec- 1990). tionswithcingulatecortex(seealso cingulatecortex, functional imaging; pain processing in the cingulate cortex, behavioral studies in humans; cingulate cor- Temporal Distribution of Function tex, nociceptive processing, behavioral studies in ani- Cortical and limbic functions are also distributed over mals) and with the hypothalamus(MacLean 1955; Pa- time. This concept is important for considering corti- pez 1937). The subcortical limbic structures such as cal functions as they affect both acute and chronically the amygdala (see also amygdala, functional imag- painful conditions. How cortical functions influence ing; nociceptive processing in the amygdala, neu- the perception of pain and pain related behavior may rophysiology and neuropharmacology), which is cov- change with time from injury or, in the experimental ered thoroughly in the essay in this Section by Volker setting, with time following a noxious stimulus. Some Neugebaurer,willnotbediscussed.Modulatorymech- temporal variance may be due to the sequential acti- anismsmediatedbypathwaysdescendingfromthecor- vation of different cortical areas. Imaging studies of tex and brainstem are discussed elsewhere in this vol- pain, for example, show that changes in the cortical re- ume and will not be discussed here. sponse to noxious stimulation occur over a time span Theneurobiologicalresponsetoinjurycomplicatesthe of approximately 45 s (Casey et al. 2001). Other tem- analysis of cortical function during pain. Peripheral or poral variation in cortical influence may occur simply central nervous system injuries trigger complex bio- because an injury or the context surrounding the injury chemical mechanisms that result in varying degrees of has changed over time, so that the perceptual and be- anatomical and functional reorganization of the cere- havioral impact of that function changes. All cortical bral cortex (Kaas et al. 1997). In this review, cortical areas are active to some degree throughoutall time pe- functionswillbeconsideredonlyasmediatednormally riods during which pain is experienced. Neurophysio- in the absence of clinically significant reorganization. logical and functional brain imaging studies (cited below) show that each of thecorticalstructureslistedhere Conceptual Issues is active within milliseconds following a noxious stim- “Function” refers to the mix of psychological, be- ulus.However,theclinicallyrelevantimpactofspecific havioral and physiological manifestations of cere- cortical structures on pain and pain behaviors deserves bral cortical activity, including somatic and auto- emphasis within particular time frames. Figure 1 is in- nomic responses that may be independent of the tendedtosummarizethishypothesizedtemporaldistri- fully developed sensation of pain and the sensory, butionoftheinfluenceandimpactofcorticalandlimbic affective-motivational and cognitive components of functions over time. Unfortunately, information about pain(MelzackandCasey1968;Price1988;Price1999) cortical and limbic function over periods ranging from as recognized by the International Association for the hours to years is available only in the clinical setting Study of Pain (IASP) (Merskey and Bogduk 1994) and and only when long-term follow-up is available. 466 Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior

with an impairment of somesthetic spatial and temporal discriminative functions (Marshall 1951; Russell 1945). However, direct anatomical corroboration was not available at the time and subsequent studies have shown that even relatively modest impact trauma to the cortex can result in otherwise unrecognized and clini- callysigniﬁcantsubcorticallesionsthatcouldinterrupt deep nociceptive pathways (Lighthall 1988; Lighthall et al. 1989). Selective surgical lesions of S1 cortex for the relief of clinical pain have produced poor results over time (Sweet 1982). Furthermore, infarctions limited to the territoryofthepostcentralgyrusandsuperior-posterior parietal region produce a somatotopically limited impairment of tactile and kinesthetic discriminative functions with sparing of pain and temperature sensations (Bassetti et al. 1993). This suggests that the S1 cortex is not essential for mediating the perceptual aspects of clinically relevant chronic pain states.

Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Stimulation Behavior, Figure 1 Relative influence of cortical function on pain and Despite the strong evidence for nociceptive informa- pain-related behavior. The figure summarizes the distribution of the in- tion reaching the S1 cortex (see below), electrical stim- fluence of cerebral cortical and limbic functions on pain perception and pain related behavior over time. All structures listed in the left column ulation of the postcentral gyrus rarely, if ever, evokes have some influence on pain and behavior throughout the experience pain in the conscious or partially sedated human (Nii et of pain, but the degree of this influence and its clinical and behavioral al. 1996; Sweet 1982). However, these stimuli do not impact varies over time as indicated by the size and boldness of the X marks. The sensory-discriminative function (blue) is largely limited to typicallyactivateneuronsinthesulcaldepthsofS1cor- the primary (S1) somatosensory cortex. Affective function is indicated tex, where nociresponsive neurons may be located. by shades of red and cognitive function by green. Hippocampal (and entorhinal cortex) function is a mixture of affective and cognitive elements. S1, primary somatosensory cortex; S2, secondary somatosensory Electrophysiology cortex; AI, anterior insula; ACC, anterior cingulate cortex; PCC, posterior The detailed somatotopic organization of neurons re- cingulate cortex; IPL, inferior parietal lobule; Pr.Mot., premotor cortex; PI, posterior insula; MPC, medial prefrontal cortex; OFC, orbitofrontal cortex; sponding to tactile stimuli (Whitsel et al. 1971) has HIPP, hippocampus and entorhinal cortex; DLPFC, dorsolateral prefrontal been confirmed in numerous investigations (Kaas et cortex. al. 1979; Kaas 1993). Single cell recordings from the monkey reveal that there are nociceptive neurons Early Cortical and Limbic Processing (Milliseconds) within S1 cortex and that these have restricted receptive fields and responses that could mediate ther- Primary Somatosensory Cortex (S1) mal nociceptive discrimination in the monkey (Ken- TheS1cortex(seealso PrimarySomatosensoryCor- shalo and Isensee 1983; Kenshalo et al. 1988; Ken- tex (S1), Effect on Pain-Related Behavior in Humans) shalo et al. 2000). In humans, the earliest nocicep- within the postcentral gyrus is composed of Brodmann tive information to reach the cerebral cortex, as de- areas 1, 2, 3a and 3b, the latter two areas lying in the termined by magnetoencephalographic (MEG) (see depths of the central sulcus and generally considered also Insular Cortex, Neurophysiology and Func- to be the major recipient of spatially refined cutaneous tional Imaging of Nociceptive Processing) and evoked somatosensory input. potential (EP) (see also insular cortex, neurophysiology and functional imaging of nocicepetive pro- Lesions cessing, nociceptiveprocessing in the hippocampus There is evidence from clinical, neurophysiological and entorhinal cortex, neurophysiology and pharma- and functional brain imaging that the S1 cortex is a cology) studies with noxious laser or brief mechan- major site for identifying noxious stimuli along the ical stimulation, arrives nearly simultaneously in the temporo-spatial and intensity domains. Early clini- primary somatosensory (S1), secondary somatosen- cal analysis based on wartime missile wounds sug- sory (S2) (see also secondary somatosensory cor- gestedthatsmalllesionswithintheS1cortexcouldpro- tex (S2) and insula, effect on pain related behavior in duce a somatotopically restricted hypoalgesia along animals and humans), anterior insular (AI) (see also Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior 467

insular cortex, neurophysiology and functional prefrontal(seealso prefrontalcortex,effectsonpain- imaging of nocicepetive processing) and the rostral related behavior) and orbital frontal cortices, via insu- anterior cingulate cortex (ACC) (see also cingulate lar connections (Mesulam and Mufson 1982a; Mesu- cortex, nociceptive processing, behavioral studies in lam and Mufson 1982b). animals, pain processing in the cingulate cortex, be- C havioral studies in humans, cingulate cortex, func- Lesions tional imaging) (Arendt-Nielsen et al. 1999; Kakigi Lesions involving the human S2 cortex or the adjacent et al. 1995; Ploner et al. 1999; Schnitzler and Ploner subcortical white matter have been associated with a 2000). Kanda and colleagues used recordings from the central pain syndrome and a clinically detectable con- scalp and from implanted subdural electrodes to show tralateral hypalgesia (Horiuchi et al. 1996; Schmah- that painful infrared laser stimulation evokes a poten- mann and Leifer 1992), but a contributing effect of in- tial with a peak latency of 220 ms in human S1 cortex jury to the insular cortex could not be completely elim- (Kanda et al. 2000). A recent MEG study with laser inated. Greenspan and colleagues (1999) found that evoked selective stimulation of C fibers found nearly lesions involving the posterior opercular (S2) cortex simultaneous responses within approximately 750 ms were associated with a clinically detectable elevation in both the S1 and S2 cortices (Tran et al. 2002). ofpainthresholdinhumans,whilepatientswithlesions Functional Imaging sparing S2 cortex had normalheatpain thresholdseven when the lesion also involved the insula (Greenspan et Functional imaging studies support the concept that al. 1999). theS1cortexparticipatesinthesensory-discriminative aspect of pain although cognitive variables modify Stimulation the intensity of the response significantly (Bushnell et al. 1999; Hofbauer et al. 2001). High-resolution op- Recent studies using imaging methods to confirm the tical imaging studies show unique and possibly spe- location of implanted depth electrodes have not thus cific responses to noxious heating in subdivisions of far reported pain sensations or pain related behavior area 3a (Tommerdahlet al. 1996). However, functional during direct stimulation of the S2 cortex in humans magnetic resonance imaging (fMRI) studies (see also (Ostrowsky et al. 2000; Ostrowsky et al. 2002). How- PET and fMRI imaging in parietal cortex (Si, Sii, ever, these investigations were focused on stimulation inferior parietal cortex BA40)) show that responses to of the insular cortex, so a more definitive assessment noxious stimuli are also likely to be obtained from area awaitsasystematicexplorationofthehumanS2cortex. 1 of the S1 cortex (Gelnar et al. 1999), a finding in general agreement with the results of cellular recording Electrophysiology (Kenshalo and Isensee 1983; Kenshalo et al. 1988). Cellular recordings from S2 cortex in anesthetized pri- In summary, the weight of evidence from a variety of mates reveal very few neurons that respond to noxious sourcesfavorstheviewthatS1corticalneuronsarespe- stimuli. The somatotopic organization of primate S2 cialized to engage in the earliest processes mediating is quite coarse compared to that of S1 cortex and the thediscriminativeaspectsofsomaticsensation,includ- receptive fields are typically large - often bilateral or ing pain. Clinical observations suggest that these neu- covering most of a single limb (Burton et al. 1995). In rons are essential for nociceptive discriminative func- contrast with the observations in recordings from ani- tions, but are less likely to be essential for mediating or mals, noxious stimulation regularly evokes distinctive modulating the affective or cognitive aspects of chron- electrical and magnetic responses in human S2 cortex ically painful conditions. (Arendt-Nielsenetal.1999;Bromm2001;Kakigietal. 2000; Ploner et al. 2002). Nociceptive information ar- Secondary Somatosensory Cortex (S2) rivesnearlysimultaneouslyatthehumanS2andS1cor- The S2 cortex occupies the posterior parietal oper- tex(approximately150–200mstopeak)but,following culum over the lateral (Sylvian) fissure and is adja- a brief stimulus, the duration of neuronal activity issig- cent to the posterior insula (see also insular cor- nificantly longer in S2 than in the S1 cortex (Inui et al. tex, neurophysiology and functional imaging of noci- 2003; Kanda et al. 2000; Ploner et al. 2002). Selective cepetive processing, secondary somatosensory cor- C fiber stimulation also evokes MEG and EP responses tex (s2) and insula, effect on pain related behavior in in S2 cortex (Opsommer et al. 2001; Tran et al. 2002). animals and humans, nociceptive processing in the Frot and colleagues (2001) revealed differences in the secondary somatosensory cortex). Because the S2 cor- latency and amplitude of S2 cortical responses to in- tex receives input via the spinothalamic tract (Stevens nocuous electrical and noxious (laser) stimulation dur- et al. 1993) and has strong projections to the insula, it ing depth electrode recording in humans, suggesting is in a position to transmit nociceptive information to that this cortex integrates both tactile and nociceptive limbic cortical structures, such as the cingulate, medial inputs (Frot et al. 2001). 468 Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior

Functional Imaging Greenspan and colleagues, however, identified 2 pa- The S2 cortex is one of the most consistently activated tients with lesions involving the anterior insula, both structures in positron emission tomographic (PET) of whom had normal heat pain thresholds. Their 3 pa- and fMRI studies (see also PET and fMRI imag- tients with anterior insular sparing and involvement of ing in parietal cortex (SI, SII, inferior parietal cor- both S2 and posterior insulahowever,had contralateral tex BA40))designed to distinguish among responses elevated thresholds for heat or mechanically induced to noxious and innocuous stimuli (Burton et al. 1993; pain (Greenspan et al. 1999). These observations sug- Casey 1999; Davis 2000; Derbyshire 2003; Peyron et gest that the anterior insula is not an essential compo- al. 2000). An fMRI study revealed a coarse somato- nent of the cortical network mediating pain. topic organization within the S2 cortex (Ruben et al. Stimulation 2001). However, Peyron and colleagues (2002), using a multi-modality approach involving PET, fMRI, In a study confirming the site of stimulation in con- and scalp LEP recording with dipole localization in the scious humans, stimulation of the anterior insula pro- same subjects, could not determine whether the pain duced visceral sensory experiences and visceral mo- related activations they obtained were localized to the tor responses, but not reports of pain (Ostrowsky et al. S2 cortex, the insula or both structures. Their results 2000). led the authors to suggest the term “operculoinsular” Electrophysiology cortex to refer to responses within the S2-insular region (Peyron et al. 2002). However, the recent results A neurophysiological study directed specifically at the obtained from detailed depth recording favor the inter- anterior (granular) portion of the primate insula found pretation that both the S2 and insular cortices are in- that all responsive neurons had large receptive fields dependent generators of responses to noxious stimuli and were excited by innocuous somatic stimuli; how- (Frot and Mauguiere 2003). ever, the investigatorssearchedfor responsesonlywith Insummary,theevidencesupportstheviewthathuman innocuous stimuli (Schneider et al. 1993). S2cortexisacriticalcomponentofthecorticalnetwork Functional Imaging mediating pain. Although there is a crude somatotopic organization within this cortex, it seems unlikely that PET imaging shows that the anterior insula is active it is critical for spatial discrimination. Rather, the S2 during the early phase of a series of repetitive noxious cortex appears to be involved in the early identification heat stimuli, but not after the stimulation continues for of noxiouseventsthatarecombined with thelocalizing 45 s (Casey et al. 2001). This is consistent with the information provided through the S1 cortex and trans- findings of Ploghaus and colleagues who showed, us- mitted to other cortical areas for further analysis. ing fMRI, that the anterior insula was active specifi- callyduringtheanticipationofexperimentallyinduced Anterior Insula pain rather than during the experience of pain itself The anterior insula (see also insular cortex, neu- (Ploghaus et al. 1999). However, Porro and colleagues rophysiology and functional imaging of nocicepetive showedthatactivityintheanteriorinsula,togetherwith processing, secondary somatosensory cortex (s2) the S1, anterior cingulate, and medial prefrontal cor- and insula, effect on pain related behavior in ani- tices, increases during the anticipation of pain and is mals and humans, nociceptive processing in the sec- also correlated with perceived pain intensity (Porro et ondary somatosensory cortex) lies rostral to the most al. 2002). Nonetheless, a recent fMRI study reveals lateral point of the central sulcus, which also approx- that the anterior insula is among the frontal and tempo- imately defines the vertical plane extending through ral brain structures responding specifically to stimulus the anterior commissure perpendicular to the sagittal novelty(Downaretal.2002).Theseresultsconfirmand plane. The cortex of the anteroventral part of the in- elaborate on earlier imaging studies showing pain re- sula is agranular, receives input from entorhinal cortex lated activity in the anterior insula (Casey et al. 1996; (see also nociceptive processing in the hippocampus Coghill et al. 1994; Davis et al. 1998; Hsieh et al. 1994; and entorhinal cortex, neurophysiology and pharma- Svensson et al. 1997). cology, hippocampusand entorhinalcomplex, func- In summary, the results suggest that the anterior insula tionalimaging)andsendsprojectionstolimbiccortical is an essential component of the cortical network me- structures such as the entorhinal, periamygdaloid and diating some early aspects of pain perception includ- anterior cingulate cortices (Augustine 1996). ing the anticipation of pain. Because anticipation implies the influence of past experience with pain, the Lesions anatomical connections of the anterior insula with lim- There are no studies of the effects of localized an- bic structures, such as the entorhinal cortex of the tem- terior insular lesions specifically on pain perception. poral lobe (see also hippocampus and entorhinal Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior 469

complex, functional imaging nociceptive pro- tional imaging) for intractable pain and was examined cessinginthehippocampusandentorhinalcortex:neu- pre- and post-operatively. The lesions were limited to rophysiology and pharmacology) are likely to be of thesupracallosalmid-anteriorcingulatecortex.There- critical importance in mediating this function. sponsetoacuteexperimentalpainwasnottested.How- ever, the patients reported only a modest relief of the C Cingulate Cortex intensity of their clinical pain but a significant reduc- Based on clinical observations and recent experimen- tion in the degree to which the pain interferedwith their tal studies, Vogtand colleagues have proposed that the daily behavior and social function anterior cingulate cortex (ACC; rostral to the plane of Animal studies of rostral ACC lesions reveal deficits the anterior commissure) mediatesprimarily executive in avoidance learning and nociceptively conditioned functions related to the emotional control of visceral, place avoidance, but the normal response to acute pain skeletal and endocrine outflow; the posterior cingulate appearsunimpaired(Gabrieletal.1991;Johansenetal. cortex (PCC) (see also cingulate cortex, nocicep- 2001). Lesions involving the rodent mid-anterior, but tive processing, behavioral studies in animals, pain not the pregenual cingulate cortex however, impair the processing in the cingulate cortex, behavioral studies execution of escape responses to gradually increasing in humans, cingulate cortex, functional imaging), heat, while sparing other nocifensive behaviors (Pas- however, is thought to subserve evaluative functions toriza et al. 1996). such as monitoring sensory events and personal be- Overall, the results show that different sectors of the havior in relation to spatial orientation and memory ACCparticipate in the acquisition of learnedresponses (Vogt et al. 1992). The results of a more recent PET to noxious stimuli, the association of negative hedo- study suggested further that increased responses (acti- nic attributes with acute noxious stimuli and the exe- vation) in subdivisions of the ACC signal participation cutionofmotorresponsestoacutenoxiousstimuli.The in response selection and affective elaboration, while longer-term effects of ACC lesions will be considered reduced responses (deactivation) in the PCC may rein subsequent sections of this review. flect disengagement from visually guided processes (Vogtet al. 1996). However, other studies have shown Stimulation strong neurovascular (Gelnar et al. 1999) and laser The most consistent responses during electrical stim- evoked responses ( insular cortex, neurophysiology ulation in humans are visceromotor changes associ- and functional imaging of nocicepetive processing, ated with nausea, sensations of fullness, changes in nociceptive processing in the secondary somatosen- blood pressure and heart rate and cutaneous flushing sory cortex) in the PCC (Bentley et al. 2003). (Talairachetal. 1973). Unpleasantemotionalreactions Anatomical data shows that sectors of the ACC and a are occasionally reported (Laitinen 1979;von Cramon mid-cingulate area just below the supplementary mo- and Jurgens 1983). In the rodent, biochemical stim- tor area are strongly connected to the ventral horns of ulation of the rostral ACC (see also cingulate cor- the spinal cord, thus providing direct access to motor tex, nociceptive processing, behavioral studies in ani- mechanisms and the direct modulation of voluntary mals, pain processing in the cingulate cortex, behav- responses to noxious stimuli (Dum and Strick 1993; ioral studies in humans, cingulate cortex, functional Hutchins et al. 1988). imaging) produced conditioned avoidance and biochemical suppression of the same site impairs condi- Anterior Cingulate Cortex (ACC) tioned avoidance learning (Johansen and Fields 2004). Lesions Overall, the results suggest a negative affective state Anteriorcingulatelesionsdonotinterferewiththeabil- that must be associated with noxious stimuli for the ity of humans to recognize or respond to acute nox- normal experience of pain. ious stimuli. This is most clearly demonstrated in clinical cases. There are very few studies in which the lo- Electrophysiology cation and extent of the lesion is known to be con- Severalevokedpotentialandsinglecellrecordingstud- fined to the anterior cingulate cortex and the response iesshowthatnoxiousstimulievokeneuronalresponses to pain is tested specifically. However, Cohen and col- within the rostral and mid-anterior sectors of the ACC leagues (Cohen et al. 1999) examined 12 patients, ofhumansandexperimentalanimals.Inthehuman,no- all with normal neurological examinations except for ciceptive responses appear within 300 ms of a noxious peripheral findings related to their pain syndrome. laser stimulus(Inuietal. 2003;Kakigietal. 2000;Lenz Each underwent cingulotomy (see also cingulate et al. 1998). Neurophysiological studies show that the cortex, nociceptive processing, behavioral studies in ACC becomes active nearly simultaneously with the animals, pain processing in the cingulate cortex, be- S1 and S2 cortices, indicating that spatio-temporal and havioral studies in humans, cingulate cortex, func- intensity analysis begins in parallel with the process- 470 Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior

ing of affective related information (Ploner et al. 2002; leagues presented evidence that, in the visual system, Schnitzler and Ploner 2000). The early parallel pro- the application of attentional mechanisms requires up cessing of affective and sensory information is consis- to 500 ms (Wardet al. 1996). Following this very early tent with the concept that noxious stimuli have an in- stage, there is an elaboration of the identity of the stim- trinsic, primary unpleasantness (Fields 1999; Melzack ulus so that its location, physical property and affec- and Casey 1968; Price 2000). tive qualities are recognized more clearly and begin to The limited sample of cellular recordings from human form the basis for further analysis and response. This subjects shows that some mid-anterior ACC neurons earlyidentificationoftheaffectivecomponentofanox- responded only to noxious thermal (heat or cold) stim- ious stimulus is probably identical to the “primary un- uli but also responded in anticipation of noxious stim- pleasantness” of Fields (Fields 1999) and the “imme- ulation (Hutchison et al. 1999); the receptive field size diate pain unpleasantness” of Price (Price 2000) and is could not be determined. In experimental animals, no- closely tied to perceived stimulus intensity. ciceptively responding cells had large receptive fields Somatic, visceral and autonomic responses may be re- (Sikes and Vogt 1992; Yamamura et al. 1996). In the flexive and preconscious at the earliest stages of cor- conscious monkey, neurons in the ACC and in the tical engagement, but may be facilitated or prolonged anatomically associated caudate nucleus responded by the action of specific cortical mechanisms. Immedi- during the anticipation of pain in a pain avoidance task ate withdrawal from the stimulus and the facilitation of (Koyama et al. 1998; Koyama et al. 2000, 2001). flexion reflexes is an example of an early somatomotor response that may be modified quickly to include more Functional Imaging elaborate voluntary escape maneuvers. Early cogni- Reviews of functional imaging studies showthat either tive reactions at this stage may include the recogni- the rostral or mid-anterior or both sectors of the ACC tion of tissue injury, the experience of fear or anger are activated consistently during pain (Bushnell et al. and the development of immediate defensive actions. 1999; Casey 1999; Derbyshire 2000,2003). Davis and Cortical connections with the amygdala are important colleagues showed that a sector of the ACC rostral to for these affective and autonomic responses (LeDoux that responding during pain is activated specifically by 2000; Neugebauer et al. 2004). a pain independent attention-demanding task (Davis et al. 1997). Rainville and colleagues (1997) showed that Inferior Parietal Lobule (B40) an anterior, supragenual area of this cortex participates Lesionsinvolvingtheinferiorparietallobule(IPL)(see specifically in the affective coding of pain (Rainville 2002; Rainville et al. 1997). During prolonged, repeti- also PET and fMRI imaging in parietal cortex (SI, tive heat stimulation, the most rostral sectoroftheACC SII, inferior parietal cortex BA40)), particularly of the isactiveonlyduringtheearlyphase,whileactivationof right hemisphere, are associated classically with hemi- themorecaudalpartoftheACCappearsduringthelater body neglect syndromes (Adams and Victor 1993; De- phase (Casey et al. 2001). This result is in accord with Jong 1979; Mesulam 1990). In humans, lesions in- the observation that the most rostral sector of the ACC volving this cortical area, which includes the poste- is associated with the anticipation of pain (Ploghaus et rior parietal operculum and Brodmann’s area 40, have al. 1999). clinically obvious deficits in detecting and responding to noxious stimuli (Bassetti et al. 1993). Neurons re- Posterior Cingulate Cortex (PCC) sponding to noxious stimulation or the visual threat of noxious stimulation have been recorded from the pos- Nociceptive information arrives at the PCC within ap- terior parietal (7b) cortex of monkeys and a lesion in proximately 200–250 ms of the application of a nox- this same area was associated with contralateral hy- ious laser stimulus (Bentley et al. 2003; Bromm 2001), palgesia (Dong et al. 1994, 1996). Functional imaging so, like the ACC, it is involved in the earliest stages studies have frequently revealed activity in this lateral of nociceptive analysis. As noted above in the general posterior parietalcortex duringpain, particularly when discussion of the cingulate cortex, there is neurophys- the task involves attending specifically to the painful iological and functional imaging (Gelnar et al. 1999) stimulation (Coghill et al. 2001; Duncan and Albanese evidence that the PCC participates in both the sensory 2003; Peyron et al. 1999; Peyron et al. 2000; Svens- and behavioral aspects of pain processing. son et al. 1997) or during simulated pathological pain states (Baron et al. 1999; Hsieh et al. 1994; Hsieh et Intermediate Cortical and Limbic Processing (Millisec- al. 1995a). However, Karnath (Karnath 2001; Karnath onds–Minutes) et al. 2001) has presented and summarized evidence As the nociceptive identification process is sustained, that pure spatial neglect follows lesions of the superior it leads to the allocation of attentional resources and temporalgyrus(STG)andthatlesionsinvolvingthehu- the distraction from competing stimuli. Ward and col- man IPL are more likely to reflectdeficitsin organizing Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior 471 movements directed within extrapersonal, body ori- cal observations also show that lesions involving the ented hemispace. Downar and colleagues showed that deep parasylvian cortex are associated with significant activation of the cortex at the temporo-parietal junc- hypalgesia (Bassetti et al. 1993; Davison and Schick tion, which includes the inferior parietal lobule and su- 1935; Greenspan and Winfield 1992; Horiuchi et al. perior temporal gyrus, is associated with the perceived 1996; Schmahmann and Leifer 1992). Involvement of C salience of both painful and painless stimuli (Downar the insula also leads to the clinical phenomenon of pain et al. 2002; Downar et al. 2003). In summary, there is asymbolia, in which the patient fails to recognize or re- substantial evidence that the cortex in the area of the spond to the threat of noxious stimuli (Berthier et al. temporo-parietaljunction,includingtheIPL(B40)and 1988). STG, participates in attentional mechanisms that are likely to be critical for the normal perception of and Stimulation attention to injurious stimuli. This interpretation is of Ostrowsky and colleagues (Ostrowsky et al. 2000, interest in view of the strong connections between this 2002) explored the insular cortex in 43 patients under- cortex and the premotor cortical areas (see below). going evaluation for epilepsy surgery and were able to verify the location of the stimulating electrodes with Premotor Cortex (B6) MR imaging. Stimulation within the posterior insula The premotor cortex (see also prefrontal cortex, ef- evokedpainfulsensationsintheupperposteriorinsular fects on pain-related behavior) is active during pain as cortexat17of93(18.2%)insularstimulationsitesin14 shown in many functional imaging studies of normal patients. The patients described the stimulus-evoked humansubjects(Casey1999;Caseyetal.2001;Coghill sensations as burning, stinging or disabling, located et al. 1999; Ladabaum et al. 2000; Tracey et al. 2000), either contralaterally or bilaterally and rarely outlast- including those focused on the related sensation of itch ingthestimulation.Non-painfulsomatosensorysensa- (Drzezga et al. 2001; Hsieh et al. 1994). Fibromyal- tions, described as warmth, cold or tingling, were also gia patients who show a high degree of catastrophizing evoked in 21 of these 93 insular sites (37.2%). The pain about their pain have an increased response in the me- related region shows a striking overlap with the dorsal dial premotor cortex (B6) to somatic pressure stimuli posterior insular site activated by heat pain (Craig et al. (Gracely et al. 2004). 2000). Although these electrical stimuli did not evoke There is a strong anatomical and functional relation- after-discharge,itislikelythatothercorticalareaswere ship between the parietal and frontal motor (see also activated during the insular stimulation and may have prefrontal cortex, effects on pain-related behavior, participated in the elaboration of the sensory experi- PET and fMRI imaging in parietal cortex (SI,SII, in- ences. ferior parietal cortex BA40)) areas of the monkey and human brain (Rizzolatti et al. 1998). The circuits con- Electrophysiology necting predominantly somatosensory posterior pari- A small number of neurons responding to noxious etal association areas with the dorsal and ventral pre- stimuli have been recorded from the posterior insula motor cortex are important for nociceptive processing (Robinson and Burton 1980). Zhang and colleagues in the cortex. For example, a component of the dorsal recorded single insular neurons that responded to both premotor circuit is involved in motor planning based innocuous and noxious somatic stimuli; some of these primarily on somatosensory information (Rizzolatti et cells were localized to the more posterior granular area al. 1998). A functional imaging study has now shown and also responded to baroreceptorstimulation(Zhang thattheboththeventralanddorsalpremotorcortexpar- et al. 1999). In addition, numerous electrophysiolog- ticipate in the development of the sense of ownership ical studies in humans have shown insular responses of a body part (Ehrsson et al. 2004). Therefore, it is to painful cutaneous stimulation (Kakigi et al. 2000; possible that the premotor cortex contributes to stim- Kakigi et al. 2003; Treede et al. 2000). ulus recognition and identification in addition to par- ticipating in the development of a motor response to a Functional Imaging stimulus. The anterior insula is activated early in the course of repetitive stimulation with noxious heat, but this re- Posterior Insula sponse is replaced by a shift of the peak activity cau- Lesions dally to the mid-posterior insulaasthestimulation con- The recent observations by Greenspan and colleagues tinues (Casey et al. 2001). The mid- and posterior- show that lesions involving the posterior insula may insula is among the most regularly responsive regions not attenuate pain threshold but are associated with a found among a variety of functional imaging studies significant increase in pain tolerance as assessed by (Casey 1999; Craig et al. 2000; Peyron et al. 2000; the cold pressor test (Greenspan et al. 1999). Clini- Peyron et al. 2002). Derbyshire (2003) has reviewed 472 Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior

evidence showing that visceral distention activates patient with a surgical lesion confined to the right mid- both the anterior and posterior insula, but the intensity, anterior cingulate gyrus had impaired executive con- timing and duration of stimulation varied across stud- trol of manual but not verbal responses; responses to ies (Derbyshire 2003). noxious stimuli were not tested (Turken and Swick 1999).Surgicallesionswithinthemorerostral,pregen- Anterior and Posterior Cingulate Cortex ual (“affective”) sector of the ACC are associated with The more rostral perigenualsectors of the ACC are ac- affective blunting and a reduction of concern about tive only early in the course of prolonged repetitive clinical pain, but the responses to acute experimentally heat stimulation. Such stimulation is followed by sus- inducedpainaregenerallynotdescribedindetail(Foltz tained activity more caudally within Brodmann area and White 1962; Hornak et al. 2003; Hurt and Bal- 24 (Casey et al. 2001). Both attentional mechanisms lantine 1973); the same is true of an extensively an- and the perception of pain activate adjacent but sep- alyzed case of medial prefrontal damage (Damasio et arate sectors of the ACC (Davis et al. 1997). Gelnar al.1994).Thereisinsufficientdatatowarrantcomment and colleaguesshowed thattheposterior cingulatecor- on the long-term pain related effects of posterior cin- tex, which receives input from thalamic targets of the gulate lesions in humans. spinothalamic tract (Apkarian and Shi 1997), responds specifically during painful heat stimulation (Gelnar Medial Prefrontal Cortex (B9, 10, 11) et al. 1999); the PCC also participates in identifying Although the medial prefrontal cortex participates in the salience of prolonged (1 minute) noxious stimuli the elaboration of emotional and high order cognitive (Downar et al. 2003). states that are independent of noxious somatic and visceral stimuli (Ramnani and Owen 2004; Simpson et Long-Term Cortical and Limbic Processes (Minutes— al. 2001; Wager et al. 2003), a significant minority of Years) functional imaging studies have shown that this cor- Unlike the preceding responses, whichgenerallyoccur tex is active during experimental somatic or visceral over periods of seconds or less, a more detailed eval- pain (Derbyshire 2003; Peyron et al. 2000; Wager et uation of an injury proceeds over time periods rang- al. 2004) or simulated pathological states (Hsieh et al. ing from minutes to years and, especially in the case 1995b; Iadarola et al. 1998). Extensive lesions of the of chronic pain, may change over time. The qualita- human mesialprefrontalcortex extending rostralto the tive evaluation includes mnemonic processes such as cingulate gyrus (see also cingulate cortex, nocicep- a comparison of present and past experiences with in- tive processing, behavioral studies in animals, pain jurious physical stimuli such as heat, mechanical dis- processing in the cingulate cortex, behavioral stud- tortions and chemical changes in the tissue. Most crit- ies in humans, cingulate cortex, functional imaging) ically, a global assessment of the environment and the are associated with profound and lasting neurological context in which the noxious event occurred is an im- deficits ranging from blunting of emotional responses portant determinant of the perceived severity of the (abulia) to the syndrome of akinetic mutism and mo- noxiousstimulationorinjury.Theaffectivecomponent tor neglect (Damasio et al. 1994; Mochizuki and Saito of the experience may vary over time but is fully devel- 1990; Kumral et al. 2002; Minagar and David 1999; oped at this stage; it is probably related to what Fields Mochizuki and Saito 1990). Although extensive dam- has called “secondary unpleasantness” (Fields 1999) age to this cortex precludes an unbiased examination and Price refers to as “secondary pain unpleasantness” of pain sensations, it is likely that it participates in the (Price 2000). Cognitive mechanisms are engaged at long-term evaluation of the emotional impact of pain this stage and these may include mnemonic functions, and the need to apply cognitive strategies to adapt ac- adjustments to daily living and planning for the future. cordingly. Overall, this aspect of pain related cortical function is closely related to the concept of pain as a “need-state” Orbitofrontal Cortex (OFC) (Wall 1979) or a homeostatic function (Craig 2002). The orbitofrontal cortex (see also hypothalamus and nociceptive pathways, prefrontal cortex, effects on Anterior Cingulate Cortex pain-related behavior) is the major cortical output to Patients with lesions specifically confined to the ACC the hypothalamus (see also hypothalamus and no- have an attenuation of the affective component of pain ciceptive pathways) and also has direct efferent con- that is sustained for many months and, where informa- nections to the amygdala and periaqueductal gray mat- tion is available, for years (Cohen et al. 1999; Hurt and ter (Ongur et al. 1998). Functional imaging studies of Ballantine 1973). Unfortunately, these patients may pain show OFC activation during experimental pain also show impairmentof sustained attention and spon- studies of heat (Craig et al. 2000), visceral stimulation taneous behavioral responses (Cohen et al. 1999). A (Derbyshire 2003) and simulated pathological pain Cortical and Limbic Mechanisms Mediating Pain and Pain-Related Behavior 473 states (Lorenz et al. 2002). Other imaging investiga- and pharmacology) and its major input, the entorhi- tions show that the OFC plays a critical role in assign- nal cortex, are part of a cortical network, including ing affective valence to sensory information and in es- the DLPFC and anatomically related frontal cortices, tablishing the rewarding or punishing value of experi- for the encoding, storage and retrieval of polymodal ences including pain (Rolls et al. 2003), which in turn sensory information emanating from parietal associa- C guide behavioral responses (Rolls 2000). In studying tion areas (Sakai 2003; Simons and Spiers 2003). In 43 patients with a variety of prefrontal cortical lesions, the rodent, the synaptic excitability of hippocampal Hornack and colleagues (Hornak et al. 2003) identi- pyramidal neurons undergoes a prolonged, choliner- fied 6 patients with bilateral circumscribed surgical le- gically dependent depression following noxious stim- sions involving the OFC. These patients had difficulty ulation; this evoked depression shows a marked habit- identifying emotions and impairments in their subjec- uation to repeated stimulation (Khanna and Sinclair tive emotionalstates. Therefore, the greatestlong-term 1989;Khannaand Sinclair1992).Noxiousstimulialso clinical significance of OFC participation in pain re- activate immediate early genes in neurons within the lated behavior may be a sustained impairment of the same hippocampal sector (Khanna et al. 2004), further abilitytorecognizepainasaprimaryreinforcer,which, suggesting a role in mnemonic circuitry. Prolonged in- in turn, leads to adaptive behaviors and emotional re- creases in neuronal activity are also seen in the rodent sponses to injury (Kringelbach and Rolls 2004). entorhinalcortex (FrankandBrown2003). Hippocam- Dorsolateral Prefrontal Cortex (DLPFC; B9, 46) pal or entorhinal activation or deactivation is rarely seen in mostneuroimaging studies, butappearsinstud- The DLPFC (see also prefrontal cortex, effects on ies in which the stimulus intensity increases during the pain-related behavior) is active during executive pro- scan period (Derbyshire et al. 1997) or when painful, cesses involving shifts of attention between or among but not painless, stimulation is unexpected (Ploghaus tasks (Smith and Jonides 1999). Cortical activations et al. 2000). When the expectation of a noxious stim- that include the DLPFC are observed in a majority ulus is manipulated so as to produce anxiety, there is of neuroimaging studies of pain (Peyron et al. 2000). an anxiety related increase in pain and in the pain re- However, as Peyron and colleagues have shown, the sponse in the entorhinal cortex (Ploghaus et al. 2001). activation appears to be due to the participation of at- Together, these findings show that these medial tempo- tentional and executive processes involved in attempt- ral lobe structures participate in elaborating the experi- ing to attend to or ignore the painful stimulation, rather ence of pain based on emotional state, expectation and than an analysis of the sensory or affective dimensions past experience. The author suggests that this elabora- of the stimulus (Peyron et al. 1999). Thus, during the tion follows the earlier sensory identification and af- pain of heat allodynia (Lorenzet al. 2002), a high level fective labeling of the noxious stimulation and that its of activation intensity in the left DLPFC is correlated sustained clinical impact is on the ability of patients to with reduced pain unpleasantness and reduced func- interpret the long-term significance of internal states, tional connectivity between the midbrain and medial including clinically painful conditions. 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Cortical Projections Corticolimbic Circuits

Corticothalamic and Thalamocortical Interactions Deﬁnition Pathway through parietal opercular cortex, including SII, and insula cortex to the medial temporal lobe including amygdala and hippocampus Cortical Reorganization Angina Pectoris, Neurophysiology and Psycho- physics

Deﬁnition A functional or structural change in the primary sensorimotor areas of the cortex that can also occur in the adult Corticortical Pathways nervous system but was long thought possible only in the developing organism. Phantom Limb Pain, Treatment Thalamocortical Loops and Information Processing

Cortical Spreading Depression Corticospinal Tract

Deﬁnition Deﬁnition Awaveofactivationfollowedbydeactivationthatmoves Amotor pathway originating in themotorcortex and ter- across the surface of the brain typically at 2–6 mm/min. minating in brainstem and spinal motor nuclei. Injury of It is widely considered to be the animal equivalent of this pathway can lead to paresis of the ipsilateral lower migraine aura. limb. Migraine, Pathophysiology Percutaneous Cordotomy

Cortical Stimulation for Relief of Pain Corticosteroid Injections

Pain Treatment, Motor Cortex Stimulation Steroid Injections 478 Corticothalamic and Thalamocortical Interactions

arising in the underlyingdorsalthalamus. Because of the Corticothalamic and Thalamocortical differences in the diameters of the corticothalamic and Interactions thalamocortical fibers that provide collateral inputs to the reticular nucleus, it is possible physiologically to EDWARD JONES identify the two kinds of collateral synapse. A brief elec- Center for Neuroscience, University of California, trical stimulus applied to the cerebral cortex or underly- Davies, CA, USA ing white matter elicits short latency EPSCs in retic- [email protected] ular nucleus cells due to antidromic invasion of thalamocortical collaterals and longer latency EPSCs due Synonyms to orthodromic activation of the slower corticothala- Bursting activity; 40 Hz oscillations; Reticular Nucleus mic fibers (Golshani et al. 2001; Liu et al. 2001). EPSCs Inputs from Cortex; CorticalProjections; Thalamic Pro- attributable to collateral corticothalamic synapses have jections; Thalamocortical and Corticothalamic Interac- a consistent amplitude, reflecting their small size and a tions single vesicle release site, but a wide range of rise times, reflecting their wide distribution over the dendritic tree Definition of reticular nucleus cells (Liu et al. 2001). Unitary EP- Cortical projections to dorsal thalamic nuclei and SCs attributable to collateral thalamocortical synapses to thalamic reticular nucleus, together with projec- tend to have large, although more variable amplitudes, tions from the thalamus to the cortex form the basic reflecting their large size and multiple release sites, but thalamocortical- corticothalamic loop. Neuronal con- very consistent rise times, reflecting their proximal lo- nectivity in these loops, involved neurotransmitters and cation on the dendritic tree. synaptic mechanisms define distinct dynamical states In the dorsal thalamus, more than 40% of the synapses of this network. on a thalamic relay cell are derived from layer VI corticothalamic fibers and are concentrated on secondary Characteristics and especially on tertiary dendrites (Liu et al. 1995a). Corticothalamic fibers arise in every area of the cere- Less than 20% are derived from medial lemniscal or op- bral cortex and every dorsal thalamic nucleus receives tic tract or other subcortical fibers and are concentrated the terminations of corticothalamic fibers. The cells of onproximaldendrites.Theseterminalstendtohavemul- origin of these fibers form two distinct classes. Both tiple points of synaptic contact, including on dendritic areaformof pyramidal neuron, with spiny dendrites protrusions and the parent shafts. The remaining 40% of and utilize glutamate as the transmitter. One class, with synapses are inhibitory and tend to be concentrated on soma located in layer VI is characterized by small size, proximal and second order dendrites and on the soma. a thin ascending apical dendrite that devolves into a tuft Themajorityoftheseterminalsarederivedfromaxonsof of branches in layer IV where it receives monosynap- the reticular nucleus (Liu et al. 1995b). A lesser number tic inputs from thalamic fibers and strongly recurrent, are derived from the presynaptic dendrites of intrinsic columnar axon collaterals (Fig. 1). The thin primary interneurons in animals that possess these neurons. The axon of these cells returns to the thalamic nucleus from terminals of layer V-originating corticothalamic fibers which the cortical area in which it lies receives thalamic end in large terminals concentrated proximally, in num- input, giving off collateral branches to the thalamic bers that have not yet been quantified. reticular nucleus en route (Fig. 2). A second class, with The glutamatergic nature of corticothalamic synapses is soma located in layer V is larger, with an apical dendrite evidencedbytheabilitytorecord NMDA-, AMPA- that ascends to layer I, ending there in a tuft of spiny and metabotropic glutamate receptor-based EPSCs in branches and a set of lengthy horizontal axon collater- relay cells and in reticular nucleus cells under appropri- als that connect extensive stretches of layers III and V ate conditions (McCormick and VonKrosigk 1992; Kao (Fig. 1). The relatively thick primary axon of these cells and Coulter 1997; Turner and Salt 1998, 1999; Golshani descends and sends branches to multiple subcortical etal.1998;ZhangandJones2004).However,corticotha- sites, such as the spinal cord, brainstem, tectum, basal lamic stimulation can also engendera powerful disynap- ganglia and thalamus. The thalamic branches traverse tic, feed-forward inhibition of relay cells, resulting from the reticular nucleus without giving off collaterals and co-activation of the reticular nucleus. The importance end primarily in nuclei other than the primary sensory of this corticothalamic-induced inhibition of the relay nuclei, especially in those characterized by a high den- cells is that it drives them towards the burst-firing mode. sity of matrix cells (see Spinothalamic terminations, As they recover from this inhibition, the low thresh- core ans matrix) (Fig. 2). old calcium conductance, I T, is de-inactivated and the The reticular nucleus, which is innervated by the collat- cells fire a burst of action potentials. This has the ef- eralsofthelayerVIcorticothalamiccells,occupiesakey fect of re-exciting, via the collaterals of thalamocorti- place in the circuitry connecting thalamus and cortex; it cal fibers, the reticular nucleus cells, which then fire a isalsoinnervatedbycollateralsofthalamocorticalaxons new burst of action potentials. These re-inhibit the relay Corticothalamic and Thalamocortical Interactions 479

Corticothalamic and Thalamocortical Interactions, Figure 1 Schematic view of the background matrix (left) of the ventral posterior complex, with its input from the spinothalamic and spinal trigeminothalamic systems and widespread projection to superficial layers of the cerebral cortex, contrasted with the core, restricted to the VPM and VPL nuclei, with its input from the lemniscal system and topographically-organized projection to middle layers of the primary somatosensory cortex. Based on Jones (2006). Abbreviations: VMb, basal ventral medial nucleus; VPI, ventral posterior inferior nucleus; VPL, ventral posterior lateral nucleus; VPM, ventral posterior medial nucleus. cells, which burst again on recovering and so the cycle sections of the reticular nucleus by bursting relay cells continuesat7–14 Hz, thespindlefrequency.Recordings (Steriade and Amzica 1996). Although the corticothala- made simultaneously from reticular nucleus and relay mic system is particularly powerful in inducing spindle cells in the underlying dorsal thalamus clearly demon- oscillations, it is the reticular nucleus that is the prime strate synchrony of their discharges at spindle frequen- mover in synchronizing the oscillations of virtually all cies, a result of the synaptic interplay between the two cells in the network. Its capacity to do this is enhanced sets of cells. when the weak inhibitory effectsofone reticular nucleus Apart from causing repetitive burst firing in relay cells, cell on another are removed (Sohal et al. 2000). a reticular nucleus cell, by reason of the widespread The power of the corticothalamic projection to induce terminations of its axon within the dorsal thalamus, low frequency oscillationsin thespindlerangeclearly has the effect of distributing the disynaptic inhibitory depends upon the capacity of the disynaptic inhibitory effects of corticothalamic stimulation across many relay effect of the reticular nucleus to overcome the direct, cells, thus helping to promote synchrony throughout monosynaptic excitatory effectof corticothalamic fibers the whole thalamo-cortico-thalamicnetwork. Spread of upon the relay cells of the dorsal thalamus. To effect corticothalamic effects across many reticular nucleus this, the strength of the corticothalamic input to the cells and recruitment of others by collateral inputs from reticular nucleus is stronger than that to the relay cells. the thalamocortical axons of bursting relay cells will Corticothalamic EPSCs in the reticular nucleus cells are also serve to spread spindle oscillations across most nearly three times larger than in relay cells (Golshani et of the thalamus and cortex. The simultaneous onset al2001). The basisfor thisdifference in AMPA-receptor of spindles throughout cortex and thalamus implies based synaptic strength depends upon the presence of rapid diffusion of reticular nucleus effects on relay cells nearly three times as many GluR4 receptor subunits at and equally rapid collateral excitation of widespread the corticothalamic synapses on the reticular nucleus 480 Corticothalamic and Thalamocortical Interactions

Corticothalamic and Thalamocortical Interactions, Figure 2 Photomicrographs of adjacent frontal sections through the thalamus of a macaque monkey, showing the parvalbumin immunoreactive core of the ventral posterior nucleus (a) and the calbindin immunoreactive matrix (b). Bar 500 μm. s, enhanced matrix region of VPM; CL, central lateral nucleus; CM, centre median nucleus; other abbreviations as in Fig 1. Arrow indicates region of parvalbumin and calbindin overlap in medial VPM. From Jones (2005).

Corticothalamic and Thalamocortical Interactions, Figure 3 Laminar and areal projections of neurons in the ventral posterior nucleus of monkeys. Core regions (gray) receiving inputs from different classes of peripheral mechanoreceptors project to middle layers of specific cortical fields. Matrix regions (crosses) receiving inputs fro the spinothalamic and spinal trigeminothalamic systems project to superficial layers of all fields. From Jones (2006).

cells than at corticothalamic synapses on relay cells Unlike the corticothalamic synapses at which GluR4 re- (Liu et al. 2001). Increases in channel opening time ceptor subunits are enriched in comparison with other consequent upon this enrichment should account for AMPAreceptor subunits, notably GluR3,the larger col- the larger EPSCs in the reticular nucleus cells. lateral thalamocortical synapses in the reticular nucleus Cost Shifting 481 possess GluR4 and GluR3 subunits in equal propor- the ventral posterior thalamic nucleus of the cat. J Comp Neurol tions. The collateral thalamocortical synapses provide 352:69–91 7. Liu X-B, Bolea S, Golshani P et al. (2001) Differentiation of cor- the capacity for the powerful re-entrant excitation of ticothalamic and thalamocortical collateral synapses on mouse the reticular nucleus cells by bursts of action potentials reticular nucleus neurons by EPSC amplitude and AMPA recep- in relay cells during the course of spindle oscillations. tor subunit composition. Thalamus Related Systems 1:15–29 C When thalamic relay cells are relatively depolarized, as 8. Llinás R, Paré D (1997) Coherent oscillations in specific and non- specific thalamocortical networks and their role in cognition. In: in the alert attentive state, they tend to display intrin- Steriade M, Jones EG, McCormick DA (eds) Thalamus Volume sic membrane oscillations at 20–50 Hz (Pedroarena and II Experimental and Clinical Aspects. Elsevier, Amsterdam, pp Llinás, 1997). Under these circumstances, with the disy- 501-516 naptic inhibition of the reticular nucleus rendered less 9. McCormick DA, von Krosigk M (1992) Corticothalamic activation modulates thalamic firing through glutamate “metabotropic” effective, corticothalamic stimulation tends to promote receptors. Proc Natl Acad Sci USA 89:2774–2778 oscillatory activity at ~40 Hz in the connected thalamo- 10. Pedroarena C, Llinás R (1997) Dendritic calcium conductances cortico-thalamic network. Forty Hz Oscillations is an generate high-frequency oscillation in thalamocortical neurons. accompaniment of attention, perception and higher cog- Proc Natl Acad Sci USA 94:724–728 11. Sohal VS, Huntsman MM, Huguenard JR (2000) Reciprocal in- nitive states. hibitory connections regulate the spatiotemporal properties of In cooperation with the corticothalamic system, the intrathalamic oscillations. J Neurosci 20:1735–1745 cells of the thalamic matrix form a basis for dispersion 12. Steriade M, Amzica F (1996) Intracortical and corticothalamic of activity across larger areas of cortex than those of coherency of fast spontaneous oscillations. Proc Natl Acad Sci USA 93:2533–2538 the core with their focused projections to an individual 13. Turner JP, Salt TE (1998) Characterization of sensory and corti- area. Within an area, the terminations of matrix cell cothalamic excitatory inputs to rat thalamocortical neurones in axons on distal dendrites in superficial layers and of vitro. J Physiol 510:829–843 14. Turner JP, Salt TE (1999) Group III metabotropic glutamate re- matrix cell axons on more proximal dendrites in middle ceptors control corticothalamic synaptic transmission in the rat layers should serve as a coincidence detection circuit thalamus in vitro. J Physiol 519:481–491 leading to a high degree of temporal integration (Llinás 15. Zhang L, Jones EG (2004) Corticothalamic inhibition in the tha- and Paré 1997) (Fig. 3). This in turn should promote lamic reticular nucleus. J Neurophysiol 91:759–766 synchronous activity in the cells of individual cortical columns and in a group of columns activated by the same stimulus. Oscillatory activity in these cortical Corticothalamic Fibers columns should be fed back by layer VI corticothalamic cells to the thalamic nucleus from which they receive Definition input, serving to reinforce the synchrony. Synchronous activity would be spread across other cortical columns Axons with cell bodies located in the cortex with terminations in the thalamus. in the same cortical area and in adjacent cortical areas by the diffuse projections of matrix cells in the thalamic Corticothalamic and Thalamocortical Interactions nucleus. However, other thalamic nuclei and, through their matrix cells, other cortical areas should also be recruited into large scale coherent activity by the diffuse Cortisol intracortical and corticothalamic projections of layer V corticothalamic neurons. This is thought to be a key Definition to the binding together of the various elements of a Hormone released by the adrenal glands. It is regulated cognitive event. by many endogenous substances, e.g. the serotonin 5- References HT1receptors,whichinduceabiphasicresponse.Infact, 1. Golshani P, Warren RA, Jones EG (1998) Progression of change 5-HT1 agonists first induce a cortisol increase, followed in NMDA, non-NMDA, and metabotropic glutamate receptor by a decrease. function at the developing corticothalamic synapse. J Neurophys- Placebo Analgesia and Descending Opioid Modula- iol 80:143–154 tion 2. Golshani P, Liu X-B, Jones EG (2001) Differences in quantal amplitude reflect GluR4- subunit number at corticothalamic synapses on two populations of thalamic neurons. Proc Natl Acad Sci USA 98:4172–4177 Cost Shifting 3. Jones, EG (2005) The Thalamus – Revisited. Cambridge Uni- versity Press, Cambridge 4. Kao CQ, Coulter DA (1997) Physiology and pharmacology of Definition corticothalamic stimulation- evoked responses in rat somatosensory thalamic neurons in vitro. J Neurophysiol 77:2661–2676 Cost shifting can be said to occur in health care when 5. Liu X-B, Warren RA, Jones EG (1995a) Synaptic distribution changes in the reimbursement for the delivery of health of afferents from reticular nucleus in ventroposterior nucleus of services, or alterations in the parameters of health cat thalamus. J Comp Neurol 352:187–202 6. Liu X-B, Honda CN, Jones EG (1995b) Distribution of four benefits displace part of the cost of health care expendi- types of synapse on physiologically identified relay neurons in tures from one sphere of healthcare to another, or from 482 Costoclavicular Syndrome healthcare institutions to patients and/or their families. Examples of this would include attempts by state Cotunnius Disease governments to attempt to restrict reimbursement for medications to cheaper non-brand name medications, Sciatica or to limit access to categories of medications such as the Cox B anti-inflammatory medications. This cost is displaced onto underinsured consumers. Often as Counterirritation a result of inability to absorb such costs, patients are hospitalized or placed in skilled nursing facilities. Cancer Pain Management, Undertreatment and Clini- Definition cian-Related Barriers The mechanisms by which any kind of intense and noxious stimulus elicits an analgesic effect distant from the site of the pain producing effect. Costoclavicular Syndrome Acupuncture Mechanisms Tourniquet Test Thoracic Outlet Syndrome Coupling Media of Ultrasound Co-Transmission Definition Definition Coupling media are mineral oil or several commercially Many neurons synthesize two different types of neu- available coupling gels. They have similar transmissivi- rotransmitters. Small molecule neurotransmitters such ties to the reference standard of distilled degassed water. as glutamate and acetylcholine, are recycled or syn- UltrasoundTherapyofPainfromtheMusculoskeletal thesized at the level of the nerve terminal and stored System in small synaptic vesicles. Peptidergic transmitters are synthesized as part of large precursor proteins on the rough endoplasmic reticulum in the cell body and Coupling of Sympathetic Postganglionic transported into the Golgi apparatus where they are packaged into large, dense-core vesicles that are trans- Neurons onto Primary Afferent Nerve ported to the nerve terminal. Transmitters released Fibers from small clear vesicles generate rapid synaptic responses, because small vesicles are located closest to Sympathetic-AfferentCouplingintheAfferentNerve the voltage-dependent Ca2+ channels that provide the Fiber, Neurophysiological Experiments influx of Ca2+ that activates the release process, and small molecule transmitters in synaptic vesicles activate ionotropic receptors. As large, dense-core vesicles are located at a greater distance from the site of Ca2+ COX influx, higher firing frequencies are required to initiate release of transmitter from these vesicles. Peptidergic Cyclooxygenases transmitters activate metabotropic receptors that couple Cyclooxygenases in Biology and Disease to intracellular signaling pathways. Thus, peptidergic NSAIDs, COX-Independent Actions transmission is capable of modulating neurotransmis- NSAIDs, Mode of Action sion of small molecule transmitters. COX-1 and COX-2 in Pain Spinothalamic Tract Neurons, Peptidergic Input

COX Isozymes Cotrimoxazol Deﬁnition Deﬁnition Are subsets of the cycloxygenaseenzymes that catalyze Treatment of choice in the limited stage of WG (combi- the conversion of arachidonic acid to prostaglandins and nation of 2 x 800 mg sulfamethoxazol and 2 x 160 mg other products involved in pain signaling. trimethoprime). Drugswith Mixed Action and Combinations, Empha- Headache Due to Arteritis sis on Tramadol COX-1 and COX-2 in Pain 483

neurons in the spinal cord, which is mediated through COX-1 prostaglandin E (EP2) receptors (Baba et al. 2001). In addition, PGE2 causes a dys-inhibition of nociceptive COX-1 and COX-2 in Pain neurons by suppressing inhibitory glycinergic synaptic transmission in the spinal cord (Ahmadi et al. 2002). C Enhanced or mal-controlled PGE2 release results in COX-1 and COX-2 in Pain spontaneous pain and hyperalgesia, i.e. increased sensitivity to painful stimuli. The functional disparity IRMGARD TEGEDER of COX-1 and COX-2 has encouraged the development Center of Pharmacology, University Clinic Frankfurt, of COX-2 selectiveinhibitors. Thesedrugsaresupposed Frankfurt, Germany to inhibit only the “pain"-related PG synthesis with- [email protected] out affecting physiological prostaglandins. Multiple clinical trials have demonstrated that COX-2 selective Synonyms inhibitors cause somewhat less gastrointestinal toxicity than unselective agents, and are equally effective Cyclooxygenase-1; Cyclooxygenase-2; COX-1; COX- in the treatment of arthritis (pain and function) and 1; PGHS-1; PGHS-2; prostaglandin endoperoxide syn- postoperative pain in clinical studies. However, there thase 1; prostaglandin endoperoxide synthase 2; Ptgs1; are some exceptions from the COX-1/COX-2 rule, in Ptgs2 that COX-2 is also constitutively expressed in some Definition tissues and COX-1 might contribute to pain-associated PG-release. The isoenzymes Cyclooxygenases -1and-2(COX-1 and COX-2) catalyze the conversion of arachidonic acid Contribution of COX-1 Derived Prostaglandins to Nociception (AA) to prostaglandin H2 (PGH2) which is the rate lim- Some experimental studies suggest that COX-1 is in- itingstepinthebiosynthesisofvarious prostaglandins volved in the “injury"-induced immediate release of and thromboxanes. The subsequentspecificstep isac- PGE2 in the spinal cord and periphery, and thereby complished by various prostaglandin synthases which contributes to the activation and sensitization of noci- convert PGH2 to PGE2, PGD2, PGF2alpha, PGI2 and ceptive neurons (Tegeder et al. 2001a; Wallace et al. TXA2.ProstaglandinE2(PGE2)playsaparticularlyim- 1998). However, this is contradicted by others (Ghilardi portant role in pain signaling (Fig. 1). et al. 2004; Yaksh et al. 2001). The debate is primarily fuelled by a controversy about the exact localization of Characteristics constitutive COX-2 and the time needed for its upreg- COX-1 and COX-2 are the key enzymes in the prosta- ulation. For example, constitutive COX-2 expression glandin and thromboxane biosynthetic pathway. Al- was observed in motor neurons of the ventral horn, but though the structure and enzymatic activity of both neither in dorsal horn sensory neurons nor glial cells enzymes are very similar, COX-1 and COX-2 perform (Maihofner et al. 2000). In line with the lack of baseline different tasks which is allowed for by a different local- expression of COX-2 in nociceptive neurons, celecoxib ization and regulation. COX-1 is expressed in all tissues (COX-2 inhibitor, injected i.p.) had no antinocicep- in certain cell types, and produces prostaglandins and tive effect in a model of acute nociception, whereas a thromboxanes that are needed for the maintenance of COX-1 inhibitor was effective (Tegeder et al. 2001a). physiological functions such as regulation of blood Another study, however, reported a constitutive ex- flow, platelet aggregation and mucus production in the pression of COX-2 in dorsal horn sensory neurons and stomach. On the other hand, COX-2 is not normally radial glial cells (Ghilardi et al. 2004). In this study, the expressed in “healthy” tissue but only occurs follow- COX-2 inhibitor reduced acute nociceptive behavior ing adequate stimulation, which may be any kind of and the COX-1 inhibitor was ineffective (Ghilardi et tissue damage such as trauma, ischemia, infection or al. 2004). In this study, the drugs were delivered onto inflammation. Such stimuli result in activation of COX- the lumbar spinal cord via a chronically implanted 2 regulating transcription factors including nuclear spinal catheter. The catheter may by itself cause an factor kappa B (NFkappaB), activator protein-1 (AP- activation of radial glia and COX-2 upregulation in the 1), CCAAT Enhancer-binding protein-1 (C/EBPbeta) dorsal horn. Hence, the nociceptive system might have and cAMP response element binding protein (CREB), been pre-activated in this study, which would explain which translate the stimulus into COX-2 upregulation the antinociceptive effect of the COX-2 inhibitor. The and excessive prostaglandin production. PGE2 is par- studies generally agree upon the COX-2 upregulation ticularly involved in the activation and sensitization in dorsal horn neurons following inflammatory or no- of the nociceptive system. This effect is mediated by ciceptive stimulation (Beiche et al. 1996; Dolan et al. stimulation of nociceptors in the periphery, and 2003; Ghilardi et al. 2004; Samad et al. 2001; Tegeder direct depolarization of postsynaptic nociceptive et al. 2001b). 484 COX-1 and COX-2 in Pain

COX-1 and COX-2 in Pain, Figure 1 Synthesis of prostaglandins and thromboxanes.

COX-1 and COX-2 in Clinical Pain COX-2 in Higher Brain Regions In clinical studies, COX-2 inhibitors were generally Results of some clinical studies, however, cannot be as effective as traditional NSAIDs in the treatment satisfactorily explained by COX-2 upregulation. For of arthritis, postoperative pain, gout, migraine, dental example, preemptive treatment with a COX-2 inhibitor pain, dental surgery and dysmenorrhea. Thus, selective before starting surgery resulted in a reduction of postop- COX-2 inhibitors not only reduce chronic inflamma- erative pain, although the time from the skin incision to tory pain caused, for example, by chronic arthritis, but the first pain assessment was very short and no pain was also “acute” pain, although COX-2 is not constitutively reportedbeforesurgery.Thissuggeststhatprostaglandin expressed in most peripheral human tissues or in hu- release from constitutively expressed COX-2 in higher man sensory neurons in the spinal cord (Maihofner et brain regions also contributes to nociception. This idea al. 2003). Hence, the potential contribution of COX-1 is supported by experimental data showing that COX-2 derived prostaglandins to “acute” clinical pain is ap- derived prostaglandins in the pre-optic hypothalamus parently of minor importance. This is explained by the mediate lipopolysaccharide (LPS) induced hyperalge- fact that even “acute” pain (such as postoperative pain, sia in rats (Abe et al. 2001). An experimental pain study acute gout, dental pain, dysmenorrhea) that requires in humans also suggests an involvement of constitutive treatment with non-opioid analgesics lasts for at least brain COX-2 (Koppertetal. 2004).Thisstudyemployed several hours, and hence, COX-2 is going to be upreg- electrically evoked non-inflammatory pain, where the ulated in the course of the affection and contributes electrical current directly stimulated axons without to PG-production. The onset of effects will probably affecting the nociceptive nerve terminals. Intravenous depend more on pharmacokinetic issues than on the parecoxib (prodrug of valdecoxib) reduced secondary speed of COX-2 upregulation. hyperalgesia and allodynia within 30 min after starting COX-2 Inhibitor 485 the stimulation, so that COX-2 upregulation at any site 6. Dolan S, Kelly JG, Huan M et al. (2003) Transient Up-Regulation was highly unlikely. The analgesic effects are therefore of Spinal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase following Surgical Inflammation. Anesthesiology 98:170–180 probably caused by inhibition of constitutive COX-2 in 7. Ghilardi JR, Svensson CI, Rogers SD et al. (2004) Constitutive higher brain regions such as hypothalamus or cortex. Spinal Cyclooxygenase-2 Participates in the Initiation of Tissue Injury-Induced Hyperalgesia. J Neurosci 24:2727–2732 Peripheral versus Central Effects in Humans 8. Koppert W, Wehrfritz A, Korber N et al. (2004) The Cyclooxy- C In light of the growing evidence for central effects of genase Isozyme Inhibitors Parecoxib and Paracetamol Reduce Central Hyperalgesia in Humans. Pain 108:148–153 COX-inhibitors, it is interesting to dissect the relative 9. Maihofner C, Probst-Cousin S, Bergmann M et al. (2003) Ex- contributions of peripheral and central effects, particu- pression and Localization of Cyclooxygenase-1 and -2 in Hu- larly because NSAID gels and creams that only provide man Sporadic Amyotrophic Lateral Sclerosis. Eur J Neurosci COX inhibition in the skin and directly underlying tis- 18:1527–1534 10. Maihofner C, Tegeder I, Euchenhofer C et al. (2000) Local- sue are very popular in some countries. A recent clinical ization and Regulation of Cyclooxygenase-1 and -2 and Neu- study has addressed this question, employing local and ronal Nitric Oxide Synthase in Mouse Spinal Cord. Neuroscience systemicdiclofenacinthe freezelesionmodel(Burian 101:1093–1108 11. Samad TA, Moore KA, Sapirstein A et al. (2001) Interleukin- et al. 2003). In this study, diclofenac gel significantly re- 1beta-Mediated Induction of Cox-2 in the CNS Contributes to duced mechanical hyperalgesia. However, overall pain Inflammatory Pain Hypersensitivity. Nature 410:471–475 relief with systemic diclofenac was stronger with equal 12. Tegeder I, Niederberger E, VetterG et al. (2001a) Effects of Selec- tissue concentrations. Thus, both peripheral and central tive COX-1 and -2 Inhibition on Formalin-Evoked Nociceptive Behaviour and Prostaglandin E(2) Release in the Spinal Cord. effects do contribute to the analgesic efficacy in this in- J Neurochem 79:777–786 flammatory model. The relative contribution of periph- 13. Tegeder I, Niederberger E, Israr E et al. (2001b) Inhibition of eralversuscentraleffects, however, mayvarydepending NF-{kappa}B and AP-1 Activation by R- and S-flurbiprofen. on the type and source of pain. FASEB J 15:2–4 14. Wallace JL, Bak A, McKnight W et al. (1998) Cyclooxygenase- Neuropathic Pain 1 Contributes to Inflammatory Responses in Rats and Mice: Implications for Gastrointestinal Toxicity. Gastroenterology The role of prostaglandins in neuropathic pain is 115:101–109 highly controversial and depends on the model used. It 15. Yaksh TL, Dirig DM, Conway CM et al. (2001) The Acute Anti- hyperalgesic Action of Nonsteroidal, Anti-Inflammatory Drugs has recently been suggested that COX-1 plays a signif- and Release of Spinal Prostaglandin E2 is Mediated by the In- icant role because an increase of its expression in the hibition of Constitutive Spinal Cyclooxygenase-2 (COX-2) but spinalcord wasobserved. However,COX-1isexpressed not COX-1. J Neurosci 21:5847–5853 in microglial cells in the spinal cord. These cells proliferate in response to a peripheral nerve injury. Thus, the observed COX-1 “upregulation” is probably caused COX-1 Inhibitor by an increase in the number of microglial cells, rather than an increase of its transcription in the individual cell. The role of microglia proliferation for neuropathic Definition pain is still elusive. COX-2 is not upregulated in the A drug that inhibits type 1 of the enzyme cyclo-oxidase, spinal cord in response to a peripheral nerve injury, which takes part in production of prostaglandins that suggesting that its contribution, if any, to neuropathic cause inflammation and pain, cause blood platelets to pain is of minor importance. In support, inhibitors of become sticky and stop bleeding, protect the gastric cyclooxygenase activity (traditional NSAIDs and se- mucosal cells (and also have many other physiologic lective COX-2 inhibitors) are generally considered to functions). be ineffective in reducing neuropathic pain in clinical COX-1andCOX-2inPain practice. Postoperative Pain, Acute Pain Management, Princi- ples References 1. Abe M, Oka T, Hori T et al. (2001) Prostanoids in the Preoptic Hy- pothalamus Mediate Systemic Lipopolysaccharide-Induced Hy- peralgesia in Rats. Brain Res 916:41–49 COX-2 2. Ahmadi S, Lippross S, Neuhuber WL et al. (2002) PGE(2) Se- lectively Blocks Inhibitory Glycinergic Neurotransmission onto Rat Superficial Dorsal Horn Neurons. Nat Neurosci 5:34–40 COX-1andCOX-2inPain 3. Baba H, Kohno T, Moore KA et al. (2001) Direct Activation of Rat Spinal Dorsal Horn Neurons by Prostaglandin E2. J Neurosci 21:1750–1756 4. Beiche F, Scheuerer S, Brune K et al. (1996) Up-Regulation of COX-2 Inhibitor Cyclooxygenase-2 mRNA in the Rat Spinal Cord following Pe- ripheral Inflammation. FEBS Lett 390:165–169 5. BurianM, TegederI, SeegelM et al. (2003) Peripheral and Central Synonyms Antihyperalgesic Effects of Diclofenac in a Model of Human Inflammatory Pain. Clin Pharmacol Ther 74:113–120 Coxib; NSAIDs 486 Coxibs

Definition Synonyms Non-steroidal anti-inflammatory drugs (NSAIDs) are NSAIDs and Coxibs; Cyclooxygenase Inhibitors, increasingly used for postoperative analgesia. While Chemistry lacking some of the troublesome adverse effects of opioids, non-selective NSAIDs may cause bleeding, Definition gastric ulceration, and renal injury as a result of their As most NSAID s are believed to act via a substrate inhibitory effects on cyclo-oxygenase–1 (COX–1). analogue of arachidonic acid mechanism at the ac- Cyclo-oxygenase–2 (COX–2) is normally present in tive site of the molecular target, Cyclooxygenases small concentrations, but is induced peripherally un- (COX), chemical structure and biological activity are der conditions of inflammation. Cyclo-oxygenase–2 closely linked. Acidic groups and π-electron systems (COX–2) is constitutively expressed in the brain and of NSAIDs mimic key structural features of the genuine spinal cord and is further up-regulated after persistent substrate, arachidonic acid. COX-1/COX-2 selectiv- noxious inputs. Spinal COX–2 inhibition may be an ity is mainly determined by different conformational important mechanism for reducing post-injury hyper- requirements rather than specific interactions. algesia. For this reason, COX–2-selective inhibitors (COXIBS) could uncouple the therapeutic and adverse Characteristics effects of the non-selective NSAIDs. COX–2-selective inhibitors are effective for the treatment of preoperative Unselective COX Inhibitors and postoperativepain and reducepost-surgicalrequire- Structure and Metabolic Function of COX-1 ments for opioids. They have similar analgesic efficacy COX-1 is a 70 kD enzyme, catalyzing the reaction of to the non-selective NSAIDs. Data from large multi- arachidonic acid to PGG2 (cyclooxygenase reaction) centre, multi-dose comparative studies are needed to and consecutively PGG2 to PGH2 (peroxidasereaction) establish whether COX–2-selective inhibitors are more as outlined in Fig. 1. efficacious, cost-effective and safe compared to the Therearedistinctactivesitesforthecyclooxygenaseand non-selective NSAIDs with respect to gastric, renal and peroxidase reactions (Fig. 2). coagulation problems, and whether COX–2-selective inhibitors confer greater cardiovascular risk in the Inhibitors perioperative setting. Differentchemicalclassescanprovidethestructuralfea- Multimodal Analgesia in Postoperative Pain tures necessary to mimic arachidonic acid at the active Postoperative Pain, Acute Pain Management, Princi- site. The substrate, arachidonic acid is a C20 carboxylic ples acid with 4 isolated double bonds at positions 5, 8, 11 Postoperative Pain, Cox-2 Inhibitors and 14. For the enzyme reaction, arachidonic acid must adapt to a “folded” conformation, allowing the oxygen to insert between C9 and C11 and the ring closure between C8 and C12 (Fig. 3). To fix arachidonic acid in Coxibs such a conformation, several interactions to the active site of the enzyme are necessary, e.g. ionic interaction Definition (a salt bridge) between the carboxylic group and argi- nine 120, π-π interactions between the double bonds of Structural heterogenous class of compounds inhibiting arachidonic acid and aromatic amino acids and numer- COX–2, more or less selectively. ous hydrophobic interactions (Fig. 4). COX–2 Inhibitor NSAIDs All these structural features can be identified in many COX–1 and COX–2 in Pain NSAIDs. Most acidic NSAIDs are therefore believed to COX-2 Inhibitor mimic arachidonic acid in its folded conformation at the Coxibs and Novel Compounds, Chemistry active site of COX. The structure activity relationship NSAIDs, Chemical Structure and Molecular Mode of follows these structural constrictions closely. The activ- Action ity against COX-1 clearly correlates with torsion angles Postoperative Pain, COX-2 Inhibitors aroundtheπ-electronsystemsandtheoveralllipophilic- ity of the molecule (Moser at al. 1990). Twoclassesofcompoundshoweverhaveadistinctlydif- ferent molecular mode of action, Coxibs and Novel Compounds, Chemistry • ASS irreversibly acetylates Ser 530 at the active site STEFAN A. LAUFER of the enzyme Institute of Pharmacy, Eberhard-Karls University of • Theoxicamesarebelievedtointerferewiththeperox- Tuebingen, Tuebingen, Germany idase active site, which also explains their structural [email protected] difference. Coxibs and Novel Compounds, Chemistry 487

Coxibs and Novel Compounds, C Chemistry, Figure 1 Reactions catalyzed by COX enzymes.

Most of the currently used NSAIDs, including diclofenac, ibuprofen, naproxen, piroxicam and indomethacin for instance, may produce full inhibition of both COX-1 and COX-2 with relatively poor selectivity under therapeutic conditions (Warner et al. 1999). Acidic NSAIDs like diclofenac accumulate particularly in blood, liver, milt and bone marrow, but also in tissues with acidic extracellular pH values. Such tissues are mainly inﬂamed tissues, such as gastric tissue and the manifolds of the kidney. In inﬂamed tissue, NSAIDs inhibit the pathological overproduction of prostaglandins. In contrast neutral NSAIDs (paracetamol) and weakly acidic NSAIDs (metamizol) distribute themselves quickly and homogeneously in the organism. They also penetrate the blood-brain-barrier.

Fenamate Group Coxibs and Novel Compounds, Chemistry, Figure 2 A ribbon representation of the Co3+-oPGHS-1 monomer with AA bound in the COX channel. The core structure is 2-aminobenzoic acid (anthranilic The EGF domain, MBD and catalytic domain are shown in green, orange acid). The 2-amino group is substituted with aromatic and blue, respectively; Co3+-protoporphyrin IX is depicted in red, disul- residues. fide bonds (Cys36-Cys47, Cys37-Cys159, Cys41−Cys57, Cys59-Cys69 and Cys569-Cys575) in dark blue and side chain atoms for COX chan- • flufenamic acid nel residues Arg120, Tyr355 and Tyr385 in magenta (from Malkowski et • mefenamic acid al. (2000)). • meclofenamic acid • nifluminic acid (core structure, 2-amino-pyridyl- 3-carboxylic acid). For topical application, the

Coxibs and Novel Compounds, Chemistry, Figure 3 Mechanistic sequence for converting AA to PGG2. Abstraction of the 13-proS hydrogen by the tyrosyl radical leads to the migration of the radical to C-11 on AA. An attack of molecular oxygen, coming from the base of the COX channel, occurs on the side interfacial to the hydrogen abstraction. As the 11R-peroxyl radical swings over C-8 for an R-side attack on C-9 to form the endoperoxide bridge, C-12 is brought closer to C-8 via rotation about the C-10/C-11 bond, allowing the formation of the cyclopentane ring. The movement of C-12 also positions C-15 optimally for addition of a second molecule of oxygen, formation of PGG2 and the migration of the radical back to Tyr385 (from Malkowski et al. (2000)). 488 Coxibs and Novel Compounds, Chemistry

Coxibs and Novel Compounds, Chemistry, Figure 4 A schematic of interactions between AA and COX channel residues. Carbon atoms of AA are yellow, oxygen atoms red and the 13proS hydrogen blue. All dashed lines represent interactions within 4.0 Å between the speciﬁc side chain atom of the protein and AA (from Malkowski et al. (2000)).

carboxylic acid group is esteriﬁed with diethyleneg- lycol • etofenamate

Fenac Group The core structure is 2-aminophenylacetic acid. The 2- amino group is substituted with aromatic residues. • diclofenac • felbinac (only used topically)

Heteroaryl Acetic Acid Group • indomethacin • acemetacine • proglumetacine • tolmetin (and its ring closed analog ketorolac) • ionazolac

Profene Group Core structure: 2-arylpropionic acid • ibuprofen • ketoprofen • thiaprofen • naproxen • ketorolac (can be seen formally as a ring closed profene)

Oxicame Group Core structure: 1,2-benzothiazine Coxibs and Novel Compounds, Chemistry, Figure 5 Comparison of the • piroxicam active sites of COX-1 (PGHS-1) and COX-2 (PGHS-2) (from Wong et al. • tenoxicam (1997). Coxibs and Novel Compounds, Chemistry 489

Coxibs and Novel Compounds, Chemistry, Figure 6 Chemical structures of NSAIDs and coxibs. 490 CPH

• lornoxicam Methylsulfone Structure • droxicam • rofecoxib • cinoxicam • etoricoxib • sudoxicam • meloxicam Aryl Acetic Acid • lumiracoxib Pyrazolone Group The mode of action of the pyrazolones remains un- Others: clear. It is thought that they may not be involved in • parecoxib (water soluble prodrug for parenteral ap- the inhibition of COX-1 or COX-2. The compounds of plication, rapidly metabolized to valdecoxib) the pyrazol-3-on series at least are neutral molecules with no acidity. A central mode of action is suggested. They also act antispasmodically and they are effective References against visceral pain. In the past, pyrazolones were 1. Dannhardt G, Laufer S (2000) Structural approaches to explain among the nonsteroidal anti-inﬂammatory drugs used the selectivity of COX-2 inhibitors: Is there a common pharma- very frequently. They show a high plasma protein bind- cophore? Current Med Chem 7:1101–1112 2. Malkowski M, Ginell SL, Smith WL, Garavito RM (2000) ing and therefore have a high rate of interaction with The Productive Conformation of Arachidonic Acid Bound to other pharmaceuticals. Agranulocytosis is a rare but Prostaglandin Synthase. Science 289:1933–1937 severe side effect. 3. Moser P, Sallmann A, Wiesenberg L (1990) Synthesis and quan- The core structure is 3H-pyrazol-3-on titative structure-activity relationships of diclofenac analogues. J Med Chem 33:2358–2368 • propyphenazone 4. Warner T, Giuliano F, Vojnovic I et al. (1999) Nonsteroid drug • metamizol-Na selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase 2 are associated with human gastrointestinal toxicity: A full in • phenazone vitro analysis. Proc. Natl Acad Sci USA 96:7563–7568 5. Wong E, Bayly E, Waterman HL et al. (1997) Conversion of Pyrazolidindione prostaglandin G/H synthase-1 into an enzyme sensitive to PGHS- 2-selective inhibitors by a double His513→Arg and Ile523→Val The core structure is pyrazolidin-3,5-dion mutation. J Biol Chem 272:9280–9286 • phenylbutazone • mofebutazone

COX-2 Selective Inhibitors CPH Isoform 2 of the COX enzyme catalyzes the identical reaction, AA to PGG2; the active site however is slightly different from that of COX-1 (Fig. 5). Chronic Paroxysmal Hemicrania Isoleucine 523 is replaced by valine 509, making the active site of COX-2 more “spacious”. This difference can be used to generate COX-2 selective inhibitors, as this active site tolerates more bulky molecules. Celecoxib Cranial Arteritis is capable of producing full inhibition of COX-1 and COX-2. However it shows a preferential selectivity toward COX-2 (>5 fold). The newer coxibs like rofecoxib Headache Due to Arteritis strongly inhibit COX-2 with only weak activity against Temporal Arteritis COX-1 (Warner et al. 1999). A common pharmacophore cannot be identified; however vicinal diaryl systems (celecoxib, rofecoxib, valdecoxib) and sulfone or sulphonamide groups seem to be advantageous (Dannhardt and Laufer 2000). Lumira- Cranial Nerve Neuralgia coxib is an excellent example of the fact that spatial demanding substituents (bulky groups) alone are sufficient to generate selectivity, even with a diclofenac-like Definition pharmacophore. A family of chronic neuropathic pain states associated Structural Features of Selective COX-2 Inhibitors with injury or dysfunction of a cranial nerve, most often in the trigeminal or glossopharyngeal nerve. Ongoing Sulfonamide Structure pain and/or hypersensibility is felt primarily in the dis- • celecoxib tribution of the injured nerve. • valdecoxib Tic and Cranial Neuralgias Credibility, Assessment 491

Disability Evaluation in the Social Security Admin- Cranial Nerves istration

Deﬁnition Credibility, Assessment The 12 pairs of nerves originating from the brain that C provide motor, sensory, and autonomic function to the KENNETH D. CRAIG structures of the head and neck. The N. vagus (X) also University of British Columbia, Vancouver, BC, innervates the viscera. Canada Diabetic Neuropathies [email protected]

University of British Columbia, Vancouver,BC, Canada Cranial Neuralgias Synonyms Deception; malingering Tic and Cranial Neuralgias Deﬁnition Pain reports and disability are regularly subjected to Craniomandibular Disorders scrutiny to establish their veracity, with contextual factors, self-report, nonverbal behavior, the reports of Temporomandibular Joint Disorders signiﬁcant others, and medical information variably useful as determinants of judgments.

Cranium Characteristics Pain enmeshes people in complex social transactions, Definition with the credibility of complaintsinvariablysubjectedto careful appraisal by others. A substantial range of care- The skull and its associated soft tissues. givingresourcesmaybeavailable,whethermotivatedby Orofacial Pain, Taxonomy/Classification sympathy, professional responsibility, contractual obligation (e.g. disability insurance), legislated entitlement (e.g. workers’ compensation benefits) or court order. In CRD all instances, optimal caregiving and prudent steward- shipofresourcesrequirejudgmentsaboutthelegitimacy Colorectal Distension of the representations of the person in distress. In healthcare settings, it would be ideal if norms of trust were to prevail, and negotiation of care did not require patients CREB to persuade health care practitioners of the legitimacy of their concerns. However, patients sometimes warrant Cyclic Adenosine Monophosphate-Responsive Ele- and often encounter distrust, particularly when physical ment-Binding Protein pathology is not manifestly obvious. Patients are likely to be scrutinized to discover whether financial incentives, efforts to obtain illicit drugs, or avoidance of oner- Credibility Finding ous responsibilities are involved. Werner and Malterud (2003)describewomenwithmedicallyunexplaineddis- ordersencountering skepticism, lack ofcomprehension, Definition rejection,beingblamedfortheircondition,andsuffering An adjudicative finding of the extent to which a person’s feelings of being ignored or belittled. statements about the intensity, persistence, and func- The real incidence and costs of various forms of decep- tional effects of his or her symptoms can be believed tion is unknown, because people work hard to avoid dis- and accepted as true. The credibility finding takes into covery of dishonesty (Craig et al 1999). Denial of pain consideration the objective medical evidence and the to avoid noxious treatments or imposition of sick roles other evidence in the case record, to include the person’s is an often ignored but widespread form of deception, statements, the statements and other evidence provided because its immediate effects do not usually inflict de- by physicians and psychologists who have treated or mandsonothers,despitethepotentialforcollapseofper- examined the person, evidence from other health care sonal health and long-term medical costs. Opportunis- professionals, and statements from other persons, to in- tic feigning or exaggeration of minor pain is relatively clude the person’s spouse, family members, neighbors, common and may beapprovedby others(e.g. sick days), friends, co-workers, etc. despite substantial costs (e.g. to employers). Flagrant, 492 Credibility, Assessment plannedfraudisgenerallyestimatedtoberare;neverthe- course, disincentives for assuming the life of a per- less systems costs to employers, health care providers, son with persistent pain also must be considered (e.g. insurance companies, and social service could mount loss of employment or impaired family and friendship dramatically. relationships). The American Psychiatric Association Decisions that another is malingering require a judg- diagnostic manual (2000) implicates malingering when ment of intentional production of false symptoms to there is a medicolegal context, a strong discrepancy obtain financial incentives or other privileges. Many between claimed stress and disability and objective clinicians eschew providing reports on credibility be- findings, or limited cooperation with assessment or cause they perceive them inconsistent with their role as lack of compliance in treatment. However, these are patient advocate. Challenging patients is also fraught commonplace and their use can cast inappropriate with a substantial risk of reprisal and angry, emotional aspersions on people. confrontations. Patients reasonably perceive serious consequences, including denial of treatment, loss of Use of Self-Report income, or criminal investigations. Capitalizing on the unique capacity of humans to use so- Regrettably, universally acceptable and valid measures phisticated language to describe subjective states, self- of neither pain nor deception are available, and judg- report has been favored as a communication medium for ments require inferences based upon information that the measurement of pain. Guidelines on pain manage- hasdemonstrablelimitations.Effortstodetectdeception ment often assert, “Pain is what the patient says it is.” generally appear not to be particularly effective. There But self-report is also a prime medium for dissembling are considerable individual differences in detecting de- pain. Distrust of self-report in reality is widespread. ception.HillandCraig(2004)reportedthatsuccessrates Scarry (1985) captures the suspicion in the observation in accurately differentiating genuine and faked or sup- that, “To have great pain is to have certainty, to hear that pressed facial expressions of pain varied across individ- another person has pain is to have doubt”. Nevertheless, uals between 18 and 63%. analyses of the content of verbal statements can disclose useful information. Mendelson and Mendelson (2004) Strategies for Assessing Credibility reviewed questionnaire studies contrasting people gen- Useful information often emerges during pain assess- uinely in pain with people coached to pretend they were ments, when listening to complaints, symptoms, and in pain, finding that simulators exaggerated the genuine personal histories, observing nonverbal manifestations pattern of response. However, cutting scores yielded of distress and disability, examining standardized ques- substantial numbers of misidentified false positives tionnaires and physical examinations, and studying and negatives. A review of the MMPI-2 (Arbisi and archival documents and reports of significant others, Butcher 2004) concluded that it is useful in detecting including reports of laboratory tests. Assessors usually inconsistent and inaccurate self-report responding, un- look at matches between their personal conceptions as cooperative responding, unusually positive or virtuous to how one should behave and the actual behavior of the self-presentation, and general defensiveness. individual, with inconsistencies indicative of deception. We know more about cues that have “illusory correla- Biomedical Approaches tions” with deception than about sensitive and specific The biomedical model of pain requires physical lesions cues to honest or dishonest representations. Erroneous to account for pain complaints. The model persists cues to deception, not unique to pain, include signs of because it is adequate for painful conditions arising nervousness, clearing the throat, faltering speech, and from serious injury or surgery, provided there is some biting the lips (Porter et al 2002). Concerning pain, peo- allowance for variability related to the individual andthe ple who respond to placebos have been misconstrued as situation. However, patients encounter medical distrust not experiencing“real” pain, despite clear evidence that and resistance when physicians cannot find evidence placebos can dramatically reduce pain instigated by in- of physical pathology. The reality is that medically jury and surgery. unexplained pain is common and a serious health care problem. Some patients do not receive adequate med- Contextual Analysis ical examinations or expert use of diagnostic tests, but The contexts in which people present themselves to be even when used properly these are not as reliable and in pain are important. Sometimes a discrete, precipitat- valid as might be expected (Hunt et al 2001). Controlled ing event may be required to legitimize work-related in- diagnostic blocks serve as useful diagnostic tools when juries, or engineering reports must describe substantial a specific source of pain can be posited and is subject to physical forces in motor vehicle accidents, but these are being anaesthetized (e.g. spinal pain) (Bogduk 2004). controversial as pain onset can occur without trauma. Analyses of the settings in which people lead their lives Nonverbal Cues may disclose circumstances leading to deception, for Nonverbal information weighs heavily when people example, work dissatisfaction or domestic distress. Of make judgments about others’ reports of pain, includ- Creep 493 ing their credibility. Painful distress can be manifest in family and others can lead people to engage in vigorous facial expression, qualities of speech, guarded posture, activities, despite severe immediate or delayed pain. protective movements, and other actions as people en- Conclusion gage their daily lives. Reflexive, automatic reactions are less subject to ongoing self-monitoring and per- Assessment of credibility is an evolving process. Those C sonal control than voluntary actions. The latter provide who would deceive can be well motivated and well tu- the basis for misrepresenting pain, but require ongo- toredbypriorpersonalexperience,orinstructionalmod- ing careful scrutiny. Inconsistencies with self-report els in their families. In turn, those interested in assessing and failure to match the reflexive pattern can disclose credibilitymustuseabroadrangeofinformationsources misrepresentation (Hill and Craig 2002). that will hopefully improve in sensitivity and specificity Severalillustrationsofspurioususeofcuespresumedin- to deceptive behavior. Sequential, progressive evalua- dicative of deception are available. Evidence that pain tion seems the best strategy, using broad screening ap- behavior can be controlled by social consequences (e.g. proaches to trigger suspicion, followed by progressively releasefromresponsibilities,potentmedication,sympa- more rigorous methods. thy) has been taken to suggest, incorrectly, that the be- References havior represented voluntary dishonesty or efforts to se- cure incentives. However, environmental contingencies 1. American Psychiatric Association (2000) Diagnostic and Statis- tical Manual of Mental Disorders. Fourth edition. Text revision. can operate on behavior without consciousness Washington, DC Therehavebeensimilarmisinterpretationsofdiagnostic 2. Arbisi PA and Butcher JN (2004) Psychometric Perspectives on signs related to low back pain that could not have a basis Detection of Malingering of Pain: Use of the MMPI-2. Clin J inphysicalpathology,asweunderstandcurrentanatomy Pain 20:383–391 3. Bogduk N (2004) Diagnostic blocks: A Truth Serum for Malin- and physiology (e.g. nonanatomic or superficial tender- gering. Clin J Pain 20:409–414 ness).MainandWaddell(1998)andFishbainetal(2004) 4. Craig KD, Hill ML, McMurtry B. Detecting Deception and Ma- concluded that there waslittle evidenceofanassociation lingering. In A.R. Block AR, Kramer EF, Fernandez E (1999) between these signs and secondary gain or malingering. Handbook of Chronic Pain Syndromes: Biopsychosocial Per- spectives. Mahwah NJ: Lawrence Erlbaum Associates, pp 41–58 Main and Waddell (1998) warn that these signs “are not 5. Fishbain DA, Cutler RB, Rosomoff HL, Rosomoff RS (2004). Is on their own a test of credibility or faking” and consider There a Relationship Between Non-Organic Physical Findings inferences based on that supposition to be misuse, both (Waddell Signs) and Secondary Gain/Malingering? Clin J Pain 20:399–408 clinically and medico-legally. 6. Hill ML, Craig KD (2002) Detecting Deception in Pain Expres- Other measures have pursued observations that people sions: The Structure of Genuine and Deceptive Facial Displays. who sincerely exercise effort in strength testing appear Pain 98:135–144 less likely to be misrepresenting themselves. Displays 7. Hill ML, Craig KD (2004) Detecting Deception in Facial Expres- sions of Pain: Accuracy and Training. Clin J Pain 20:415–422 of weakness and decreased range and velocity of mo- 8. Hunt DG, Zuberbier OA, Kozlowski A, Robinson J, Berkowitz J, tion have been interpreted as conscious attempts to de- Schultz IZ, Milner RA, Crook JM, Turk DC (2001) Reliability of ceive. Investigations of a variety of indices of this type the Lumbar Flexion, Lumbar Extension and Passive Straight Leg led Robinson and Dannecker (2004) to conclude “that Raise Test in Normal Populations Embedded within a Complete Physical Examination. Spine 26:2714–2718 the current ‘state of the art’, while promising in some 9. Main CJ, Waddell G (1998) Behavioral Responses to Examina- instances, does not warrant the clinical application of tion: A Reappraisal of the Interpretation of “Nonorganic Signs. muscle testing as a means of sincerity of effort”. Prob- Spine 23:2367–2371 lems arise because performance is also influenced by 10. Mendelson G, Mendelson D (2004) Malingering Pain in the Medico-Legal Context. Clin J Pain 20:423–432 fear of injury, pain, medications and other motivational 11. Porter S, Campbell MA, Stapleton J, Birt AR (2002) The In- and cognitive factors, and discriminating maximal and fluence of Judge, Target, and Stimulus Characteristics on the submaximal effort remains a problem. Accuracy of Detecting Deceit. Can J Behav Sci 34:172–185 12. Robinson ME, and Dannecker EA (2004) Critical Issues in the Use of Muscle Testing for the Determination of Sincerity of Ef- fort. Clin J Pain 20:392–398 Reports of Significant Others 13. Scarry E (1985) The Body in Pain. Oxford University Press, New Reports of family members, friends, colleagues and York 14. Werner A and Malterud K (2003) It is Hard Work Behaving as a others can provide valuable collateral information able Credible Patient: Encounters between Women with Chronic Pain to confirm or disconfirm patient self-report. Collusion and their Doctors. Social Science and Medicine 57:1409–1419 would be possible, but contradiction seems more likely, unless there has been very careful grooming. Unobtru- sive behavioral observation can be undertaken using Creep covert surveillance, to provide photographic or video records of people claiming to have severely disabling Definition pain engaging in vigorous physical activity. While this appears to represent flagrant abuse, careful analysis Creep is a physiologic property of collagenous tissue. In often suggests the need for income or commitments to response to the application of a constant force, collagen 494 Criterion-Referenced Assessment starts to deform (stretch). However, this deformation is not directly proportional to time. Initially, the deforma- Cross-Excitatory Discharge tion is small, but the longer the constant force is applied, the more rapidly collagen will deform (and weaken), Definition even if the magnitude of the force remains constant. Excitation evoked within the dorsal root ganglion be- This phenomenon is defined as creep and may lead to tween repetitively discharging neurons and their passive complete failure of the collagen fibre. neighbors. This excitatory interaction between neurons Ergonomic Counseling is believed to be chemically and not electrically mediated. Ectopia, Spontaneous Criterion-Referenced Assessment Cross-System Viscero-Visceral Definition Interactions In criterion-referenced assessment, the critical aspects of a job are analyzed to determine standards essential Gynecological Pain, Neural Mechanisms for the for the worker’s adequate performances of a job. The results are stated in terms of skills mastered, e.g. Method Time Methods (MTM) (the time it would take the average, well-trained worker to complete the work Cross-System Viscero-Visceral or sample tasks if they were carried out over the eight-hour Viscero-Somatic Convergence work day in a typical industrial context), and the Worker Qualification Profiles given in Jist’s Enhanced DOT. Definition Vocational Counselling A connective situation in which neurons in the CNS receive converging input from different organs (viscero- visceral),sometimesindifferentfunctionalsystems(e.g. reproductive and urinary), and from different types of Crohn’s Disease structures such as skin, muscle, and internal organs (viscerosomatic). Animal Models of Inflammatory Bowel Disease Gynecological Pain, Neural Mechanisms

CRPS Cross Excitation Complex Regional Pain Syndrome Deﬁnition Complex Regional Pain Syndromes, Clinical Aspects Complex Regional Pain Syndromes, General Aspects Electrophysiologicalphenomenonwherebyneurotrans- Sympathetically Maintained Pain, Clinical Pharma- mittermolecules,andprobablyalsoK+ions,arereleased cological Tests into the extracellular space from active neurons. These diffuse towards neighboring neurons and excite them. Cross excitation occurs within sensory ganglia and at sites of nerve injury. CRPS, Evidence-Based Treatment Pain Paroxysms ANNE LOUISE OAKLANDER Nerve Injury Unit, Departments of Anesthesiology, Neurology, and Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Cross Sectional Study MA, USA [email protected] Deﬁnition Aresearch methodology thatexaminesrelationshipsbe- Synonyms tween variables at one point in time. • Complex regional pain syndrome (CRPS): term des- PainintheWorkplace,RiskfactorsforChronicity,Job ignated by International Association for the Study of Demands Pain (IASP) in 1994 CRPS, Evidence-Based Treatment 495

• Reflex sympathetic dystrophy (RSD): term first used of pain and dysfunction. Note: Criteria 2–4 must be by Evans in 1946 satisfied (Merskey and Bogduk 1994) • Algodystrophy:mostcommondesignationinEurope • Shoulder-hand syndrome: refers specifically to IASP Diagnostic Criteria for CRPS-II (Causalgia) CRPS originating in hand, spreading to shoulder 1. The presence of continuing pain, allodynia or hyper- C • Causalgia: from Greek, causos = heat; algia = pain algesia after a nerve injury, not necessarily limited to (OxfordEnglishDictionaryfirstuse:S.WeirMitchell the distribution of the injured nerve. 1872) 2. Evidence at some time of edema, changes in skin • Sudeck’s atrophy (1901) blood flow or abnormal sudomotor activity in the • Major or minor causalgia region of the pain. • Post-traumatic dystrophy 3. This diagnosis is excluded by the existence of con- • Pourfour du Petit syndrome ditions that would otherwise account for the degree • Postinfarctional sclerodactylia of pain and dysfunction. Note: All three criteria must • Traumatic angiospasm be satisfied (Merskey and Bogduk 1994) • Peripheral acute trophoneurosis • Post-traumatic neuralgia Characteristics CRPS is a “pain plus” syndrome comprising regional Definition neuralgia plus additional symptoms. Most cases follow trauma, but symptoms persist after apparent healing Because the biological cause of CRPS is unknown, of injuries. Autonomic dysregulation (hyperhidrosis, the definition is currently based on the presence of vasomotor instability causing edema, abnormal skin various non-specific symptoms. Many investigators color or temperature) is part of the definition. Motor ab- create their own definitions, hampering comparison normalities are common and increasingly recognized. of study results. The International Association for the Some patients have mild or transient symptoms; others Study of Pain (IASP) formulated consensus defini- are chronically disabled. CRPS was first characterized tions in 1994 (see below) (Merskey and Bogduk 1994). in Weir Mitchell’s astute descriptions of Civil War sol- “Type I” classifies patients without diagnosed nerve diers with causalgia after penetrating wounds. It is not injury; “type II” classifies those with known neural known why rare nerve injury patients develop CRPS-II injuries. This dichotomy depends more on the skill of and why identical symptoms develop without obvious the examiner than the patient and contributes to the cause in CRPS-I. The fundamental lesion in CRPS-I confusion. Although flawed, the use of IASP criteria is appears to involve specific peripheral axons, the small encouraged until a better definition is developed. diameter unmyelinated and thinly myelinated axons More rigorous definitions proposed for research use that subserve pain and some autonomic functions (van require visual confirmation of autonomic dysfunction. der Laan et al. 1998; Albrecht et al. 2006; Oaklander This improves specificity, but at the cost of reducing et al. 2006). Relative sparing of motor and large fiber sensitivity. Rigorous diagnostic criteria may limit study sensory axons can preserve enough function to give to severely affected patients, who do not represent the some patients a misleadingly normal appearance. overall population and who may be least likely to improve in clinical trials. This author suggests adopting Treatments for Recent Onset CRPS the hierarchy of definitions used for other neurological Early on, medications must be secondary to and sup- research (definite CRPS, probable CRPS and possi- portive of efforts to mobilize the affected limb and ble CRPS) to permit greater or less sensitivity and to restore its function. Several trials have evaluated specificity for use in individual research projects. treatments for CRPS symptoms present for less than 6 months. Inflammation and remodeling from the orig- IASP Diagnostic Criteria for CRPS-I (Reflex Sympathetic Dys- inal trauma may still be present and the final effects of trophy) injury on the CNS may not yet have occurred, making it 1. The presence of an initiating noxious event or a cause possible to find treatments to modify the disease course of immobilization. (provide permanent cure or improvement) rather than 2. Continuing pain, allodynia,or hyperalgesia in merely alleviate symptoms. It has not been examined which the pain is disproportionate to any inciting whether these early treatments are also effective for event. chronic CRPS, and their mechanisms are completely 3. Evidence at some time of edema, changes in skin unknown. Two small, unblinded trials (Braus et al. blood flow or abnormal sudomotor activity in the 1994) support the use of oral corticosteroids. Sys- region of the pain. tematic meta-analysis (Perez et al. 2001) of several 4. This diagnosis is excluded by the existence of con- placebo controlled randomized controlled trials (RCT) ditions that would otherwise account for the degree of intranasal calcitonin (100–400 IU) support its use. 496 CRPS, Evidence-Based Treatment

Calcitonin is a neuropeptide with direct antihyperal- Topical Local Anesthetics gesic effects independent of its effects on bone (Braga The most important characteristic of topically applied 1994). Use of bisphosphonates, which also inhibit medications (whose active ingredient remains in the osteoclast mediated bone resorption, is supported by skin) is the low incidence of adverse effects. These are several small RCT (Varenna et al. 2000). One study available in various forms including gels, creams and found pamidronate (30 mg daily for 3 days) effective in sprays. The 5% lidocaine patch is probably the most 35 patients with acute or chronic CRPS. Single RCTs commonly topical medication prescribed for CRPS. support the efficacy of topical dimethylsulfoxide, and The patch itself protects allodynic skin from contact of oral vitamin C in CRPS-I. The alpha-adrenergic and the local anesthetics within reduce hyperalgesia. antagonist phenoxybenzamine was effective in small An RCT of 40 patients with focal neuropathic pain trials in early CRPS (Muizelaar et al. 1997) and various including CRPS documents its efficacy (Meier et al. neuralgias including CRPS-II. 2003), as does an earlier uncontrolled open label add on study of six CRPS patients. Conservative Treatments for Established CRPS Rehabilitation is essential. In addition to preventing Tricyclic Antidepressants (TCA) secondary problems including deconditioning, con- TCAs that augment noradrenergic neurotransmis- tractures, weight gain and depression, it now appears sion are perhaps the most effective option for treating that abnormal cortical reorganization in CRPS may neuralgia. Generic forms are available. TCAs have be ameliorated by aggressive restoration of function. several mechanisms that contribute to efficacy, includ- Psychotherapy and/or psychotropic medications are ing potentiation of descending inhibitory pathways to indicated for many patients who develop reactive de- decrease dorsal horn hyperactivity, μ-opioid receptor pression or other psychological difficulties caused by activation and cation channel blockade. There are no their chronic pain and disability. The limited evidence studies specifically documenting the efficacy of TCAs suggests that acupuncture, magnets, and other alterna- in CRPS, but their efficacy in neuralgias including di- tive treatments are ineffective. abetic neuropathy (Max et al. 1992) and PHN is better documented than for any other medications. TCAs Medical Treatments for Established CRPS that increase norepinephrine are effective; those with Pharmacotherapy becomes the major treatment for serotonergic effects only are not, whereas those that patients whose symptoms do not improve substantially increase both may work best. Adverse effects, which despite aggressive rehabilitation. Few pharmaceutical limit TCA use, are more common with amitriptyline companies consider CRPS a suitable condition for clin- than nortriptyline (Watson et al. 1998) or desipramine ical trials and so there are no strong drug trials in chronic (Max et al. 1992). CRPS patients are often younger than CRPS. Clinicians must currently extrapolate from the other neuralgia patients and thus may tolerate TCAs results of well-designed and conclusive trials for related better. conditions (primarily painful diabetic neuropathy and postherpetic neuralgia (PHN)). No medication has Antiepileptic Drugs (AED) a U.S. Food and Drug Administration indication for AEDs decrease central neuronal hyperexcitability to CRPS. Regardless, most chronic CRPS patients take treat neuralgic pain as well as seizures. Gabapentin, medications, of necessity “off label”. well studied in PHN and diabetic neuropathy, is a pri- Randomized, controlled, clinical trials studying the mary option. It binds to the α2δ subunit of voltage gated treatment of neuralgia have established the efficacy calcium channels and decreases calcium-mediated re- and safety of four classes of medication. There are not lease of excitatory neurotransmitters. Gabapentin has enough data to support the use of one class over another no drug interactions and serum levels do not usually and efficacy data must be tempered with consideration need to be monitored. Serious adverse effects appear to of possible adverse effects and cost. Standard princi- be less common than with TCAs, though this may not ples should be applied, namely selection of medication be true for minor ones. In CRPS, gabapentin was useful based not only on the patient’s symptoms, but also on in an open label uncontrolled study of nine adult pa- their overall medical, social and financial situations. tients given 600 mg/day (a lower dose than is now used) Each medication should be tried in an adequate dose (Mellick and Mellick 1997) and in a single pediatric and for long enough (1 to 2 months for tricyclics). case. Carbamazepine, FDA-approved for trigeminal If ineffective or ill tolerated, a medication should be neuralgia, is supported by a single small, uncontrolled tapered, discontinued and then replaced with the next study adding it to spinal cord stimuation (Harke et al. choice. Multiple medications are indicated only when 2001). each provides added benefit and there are no adverse interactions. Usually, a selection of medications from Opioids different classes is required. Polytherapy is common in Reluctance to prescribe is common, though some CRPS CRPS because pain relief is often elusive. patients do benefit from opioid treatment and remain on CRPS, Evidence-Based Treatment 497 stable doses. Like other options, opioids help some but of medications and major functional gains. Experi- not all sufferers and usually provide only partial relief. enced clinicians have noted that, unlike medications, Physical dependence or tolerance do notalwaysde- stimulators can have disease modifying effects, such as velop and can usually be managed by avoiding dose es- pain relief that persists for longer and longer periods calation and sudden withdrawal. There are inadequate after the stimulator is turned off. Similar properties C data to support preference for any particular opioid, al- have also been documented after CNS stimulation in though methadone is attractive because of its low cost. other diseases. Stimulation of the dorsal column is the Direct evidence from CRPS patients is almost nil; the most common procedure, because the electrode can rationale for use is based largely on the results of well- be placed percutaneously. Although device trials are designed studies in other neuralgic conditions (Raja et difficult to control for, there is at least one well-designed al. 2002). An add-on study of morphine in CRPS pa- study (Kemler et al. 2000) and several case series that tients with spinal cord stimulators did not demonstrate demonstrate efficacy in about half of implanted CRPS efficacy, but the subjects were too unique to generalize patients. Expense and not infrequent complications are its conclusions. Current or former substance abuse is the the major limitations. For patients whose CRPS is due major contraindication to opioid use, although they can to single nerve damage, surgically implanted peripheral sometimes be prescribed for abusers with severe pain if nerve stimulators have had even higher efficacy in a they are rigorously monitored. prospective trial (Hassenbusch et al. 1996).

Other Medications to Consider References Systemic local anesthetics are sometimes efficacious 1. Albrecht PJ, Hines S, Eisenberg E et al. (2006) Pathologic al- but require invasive or subcutaneous administration. terations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain Such use was supported by the results of a small RCT 120:244–266 in 16 patients with CRPS-I and -II (Raja et al. 2002) 2. Braga PC (1994) Calcitonin and its antinociceptive activity: and a case series. Administration must be carefully animal and human investigations 1975–1992. Agents Actions 41:121–131 monitored to prevent seizures or cardiac arrest. The 3. Braus DF, Krauss JK, Strobel J (1994) The shoulder-hand evidence supporting clonidine is weak. A case series of syndrome after stroke: a prospective clinical trial. Ann Neu- four CRPS patients screened by regional and system- rol 36:728–733 atic sympathetic blocks found that the antihyperalgesic 4. Davis KD, Treede RD, Raja SN et al. (1991) Topical application of clonidine relieves hyperalgesia in patients with sympatheti- effect was restricted to skin directly under the clonidine cally maintained pain. Pain 47:309–317 patch (Davis et al. 1991). Thalidomide, which inhibits 5. Harke H, Gretenkort P, Ladleif HU et al. (2001) The response of release of TNF-alpha, is under evaluation. neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients Surgical Treatments for Established CRPS pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg 92:488–495 If medications have not provided significant relief after 6. Hassenbusch SJ, Schoppa D, Walsh JG et al. (1996) Long-term adequate trials, two surgical options deserve consider- results of peripheral nerve stimulation for reflex sympathetic dys- ation and one does not, namely cutting nerves or neu- trophy. J Neurosurg 84:415–423 7. Kemler MA, Barendse GA, van Kleef M et al. (2000) Spinal cord ral structures transmitting pain sensations from the af- stimulation in patients with chronic reflex sympathetic dystrophy. fected areas. Ablative neurosurgery has a simplistic ap- N Engl J Med 343:618–624 peal and occasionally provides a pain-free interval to 8. Max MB, Lynch SA, Muir J et al. (1992) Effects of desipramine, terminal patients; it is not indicated for most CRPS pa- amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326:250–1256 tients who have largely preserved motor function and 9. Meier T, Wasner G, Faust M et al. (2003) Efficacy of lidocaine long life expectancy. Limb amputation is still occasion- patch 5 % in the treatment of focal peripheral neuropathic pain ally performed and may very rarely be indicated for se- syndromes: a randomized, double-blind, placebo-controlled study. Pain 106:151–158 rious complications such as gangrene, but it should not 10. Mellick GA, Mellick LB (1997) Reflex sympathetic dystrophy be performed for pain control. CRPS pain is almost cer- treated with gabapentin. Arch Phys Med Rehabil 78:98–105 tainly maintained by CNS abnormalities not addressed 11. Merskey H, Bogduk N (1994) Classification of chronic pain: by peripheral ablation. Descriptions of chronic pain syndromes and definitions of pain terms, 2nd edn. IASP Press, Seattle In contrast, the possibility of nerve entrapment or com- 12. Muizelaar JP, Kleyer M, Hertogs IA et al. (1997) Complex re- pression should more often be considered. Surgical gional pain syndrome (reflex sympathetic dystrophy and causal- decompression can provide dramatic cures in these sit- gia): management with the calcium channel blocker nifedipine uations (Thimineur and Saberski 1996). Occasionally, and/or the alpha-sympathetic blocker phenoxybenzamine in 59 patients. Clin Neurol Neurosurg 99:26–30 unexpected causes of CRPS such as leprosy, tumors 13. Oaklander AL, Rissmiller JG, Gelman LB et al. (2006) Evidence or vascular malformations are diagnosable only by of focal small-fiber axonal degeneration in complex regional pain exploratory surgery. The single most powerful treat- syndrome-I (reflex sympathetic dystrophy). Pain 120:235–243 ment for severe established CRPS is implantation of a 14. Perez RS, Kwakkel G, Zuurmond WW et al. (2001) Treatment of reflex sympathetic dystrophy (CRPS type 1): a research syn- bipolar neural stimulator. Properly selected patients can thesis of 21 randomized clinical trials. J Pain Symptom Man- achieve dramatic pain relief permitting discontinuation age 21:511–526 498 CRPS Type-I

15. Raja SN, Haythornthwaite JA, Pappagallo M et al. (2002) Opioids Definition versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 59:1015–1021 The diagnostic criteria for CRPS -1 were established 16. Thimineur MA, Saberski L (1996) Complex regional pain syn- in 1995 (Stanton-Hicks et al. 1995): drome type I (RSD) or peripheral mononeuropathy: A discussion of three cases. Clin J Pain 12:145–150 1. An eliciting event, but no demonstrable injury to a 17. van der Laan L, ter Laak HJ, Gabreels-Festen A et al. (1998) peripheral nerve Complex regional pain syndrome type I (RSD): pathology of 2. Pain, spontaneous or evoked, often with evidence of skeletal muscle and peripheral nerve. Neurology 51:20–25 18. Varenna M, Zucchi F, Ghiringhelli D et al. (2000) Intravenous allodynia in a limb clodronate in the treatment of reflex sympathetic dystrophy syn- 3. Dysautonomic signs drome. A randomized, double blind, placebo controlled study. 4. No other explanations for the pain J Rheumatol 27:1477–1483 19. Watson CPN, Vernich L, Chipman M et al. (1998) Nortriptyline CRPS occurs more frequently in girls, than boys. The versus amitriptyline in postherpetic neuralgia: a randomized trial. mostcommonageofonsetisapproximately10–14years Neurology 51:1166–1171 of age. The site of CRPS-1 is predominantly in the lower extremities. The cause is unknown but children have often had a history of psychosocial stress, such as bullying inschool.However,themostcommonstressfactoristhat CRPS Type-I children have atypically high expectations for achieve- ment in school and / or sports. Harden et al. performed a factor analysis of symptoms Definition and signs associated with CRPS-1 and proposed an- Pain syndrome thatdevelopsafter minor injuriesor frac- other diagnostic classification: 1. pain, 2. vasomotor tures of a limb disturbances, 3. oedema and sweating changes, 4. motor Complex Regional Pain Syndromes, Clinical Aspects changes (Harden et al. 1999; Wilson et al. 2005). They Postoperative Pain, Acute Presentation of Complex suggested that the criteria of an eliciting event should be Regional Pain Syndrome dropped because no eliciting trauma could be identified Sympathetically Maintained Pain in CRPS I, Human in 8% of the cases in a large case series in adults. Experimentation Characteristics Age and Gender CRPS-1 is much more common in girls; approximately CRPS Type-II 85% of affected children are girls (Bernstein et al. 1978; Olssonetal.1997;Wilderetal.1992;Sherryetal.1999). It is most commonly reported for children in the pre- Definition teen or early teen years (11–14 years of age), although Complex regional pain syndrome type 2, previously there are case reports on children as young as 3 years old called causalgia. A pain syndrome that develops after (Kozin et al. 1977). injury to a major peripheral nerve. Localisation Complex Regional Pain Syndromes, Clinical Aspects The foot is the most commonly affected site, followed Postoperative Pain, Acute Presentation of Complex by other parts of the leg and then the upper extremities, Regional Pain Syndrome including hands, elbowsand shoulders. Although thedi- Sympathetically Maintained Pain in CRPS II, Human agnosis of CRPS-1 in other regions is controversial, I Experimentation have treated a girl with CRPS-1 in the forehead. Dysautonomic Signs For adults with CRPS-1, the skin temperature often in- CRPS-1 in Children creases initially so that the affected region feels warm; later a cold dystrophic phase ensues. In contrast, chil- GUNNAR L. OLSSON dren usually first experience a lower temperature in Pain Treatment Services, Astrid Lindgren Children’s the affected region. An infrared skin thermometer is Hospital/Karolinksa Hospital, Stockholm, Sweden of great value in the clinical setting for temperature [email protected] determination. Discoloration is usually bluish, blue and red or pale and appears intermittently rather than consistently. Oedema may be very soft and subcuta- Synonyms neous and may also recur intermittently. Many children Complex regional pain syndrome; Reflex Sympathetic have had a MRI before their referral to the pain clinic. Dystrophy; RSD In several of our cases the radiologist has described a CRPS-1inChildren 499

CRPS-1 in Children, Figure 1 An 11 year old girl with a severe CRPS-1 including contractures of knee and hip. She was successfully treated with spinal stimulation. bone marrow oedema, but its relevance is not known. In form an intravenous alfentanil test in a standardised the more classic cases of CRPS-1 the child’s extremity double blind manner. CRPS-1 children who typically is continuously cold, swollen, blue-reddish and very experience spontaneous pain do not experience relief, allodynic (Fig. 1). while children with nociceptive pain usually experience complete pain relief. Motor Disturbances According to the criteria from 1995, a history of dysau- Some motor weakness and even paresthesias may be tonomia was sufficient for a CRPS-1 diagnosis when a attributed to reflexes associated with pain. However, child had pain without any other explanation. Dysauto- even active motor disturbances are sometimes involun- nomic signs may also prevail in connection with acute tary movements and contractures due to predominance trauma. However, such signs usually resolve when of flexors or extensors. wounds and fractures have healed. An updated review of CRPS in adults and children has recently been pub- Psychosocial Stress lished as a proceeding from a meeting of the Special Certain chronic pain syndromes in children are associ- Interest Group on Pain and the Sympathetic Nervous ated with high levels of psychosocial stress. Child abuse system in Budapest August 2003 (Wilson et al. 2005). and bullying in school is not uncommon among girls withCRPS.Howeverthemosttypicalstressfactorseems Treatment to be a child’s unrealistically high expectations of per- Children and families require reassurance that the pain formance in school and athletics. isnotasign of continuing damageand thatthepain isnot a symptom of correlating injury. Many children require Diagnosis psychological counselling in order to be able to resume First, physicians must determine whether the pain their previous activities. arises from a known cause. This determination is often difficult. CRPS-1 is classified as a neurogenic pain Physiotherapy syndrome. Although there is no identified lesion in the Physiotherapy (PT) is a mainstay in the treatment of nervous system, there is a dysfunction of the sympa- CRPS-1. Bernstein and colleagues described the first thetic nervous system and pain transmission. CRPS-1 case series in children; they treated the children as inpa- does not respond to traditional analgesics, even to opi- tients with intensive physiotherapy including massage oids in normal doses. Thus, pharmacological testing is and“towelling”(Bernstein1978).Morerecently,Sherry a valuable diagnostic tool to investigate the presences advocated 6 h daily PT, including desensitisation and of ongoing noxious stimulation. We often administer touching allodynic areas, for a large case series of 103 a course of oral NSAIDs in a reasonably high dose, children. However, in the only randomized controlled e.g. diclofenac or ibuprofen, for 1 week where chil- trial evaluating PT for children with CRPS-1, Lee et al. dren have not had any analgesics. . We assess pain (2002) used a more intense PT treatment (3 × weekly) by self-report 3 × a day and note the time of day when that was not more effective than a weekly program. The children experience their worstpain. Sometimeswe per- positive effect of PT is probably due to the increased 500 CRPS-1 in Children activity of affected extremities (i.e. increasing normal Prognosis sensory input) and to the increased overall activity of The long-term prognosis for CRPS in children is un- the children (i.e. resuming normal social and physical known and studies to date yield contradictory informa- activities), rather than avoiding activity due to fear of tion. CRPS-1 in childhood seems to be milder, with less pain and further injury. atrophy and with a good short-term prognosis, in com- Drugs parison to CRPS-1 in adults. Veldman and Goris (1997) reported 118 cases of recurrence in 1183 consecutive Analgesics do not relieve pain associated with CRPS- patients, in a predominantly adult sample. Recurrences 1. There are no published studies evaluating the effect occurred especially in younger patients, often not only of other drugs in childhood CRPS, despite clinical prac- in the originally affected limb. In a 5 year follow up tice in which tricyclic antidepressants (TCA) are widely at our centre, 25% of children continued to experience used and effective in certain cases (Olsson 2003). How- pain (Olsson et al. 1991). Only 50% of 70 children with ever TCA’s may have adverse effects, the drug must be CRPS in the Boston series were free from pain (Wilder very slowly titrated and the child must be closely mon- et al. 1992). In a series of 1006 RSD patients aged itored to ensure compliance. Common side effects in- 10–84 years, 7% developed severe complications such cludesedation,drymouth,nightmares,dizzinessandoc- as infection, ulcers, chronic oedema, dystonia and / or casional nausea. The effective dose is not known, with myoclonus. Patients affected were younger and more some physicians prescribing a maximum dose of 10 mg. often female. The skin temperature at onset was in these In our centre, we slowly increase the dose from 10 mg patients lower than in non-complicated cases (van der until the child benefits or there are adverse effects, to a Laan et al.1998). The long-term prognosis has to be maximum of 100 mg. There are no published studies in- further evaluated in children. dicating effects of other drugs used for neurogenic pain such as gabapentin or other antiepileptic drugs in children. References Sympathetic Blocks 1. Bernstein BH, Singsen BH, Kent JT et al. (1978) Reflex neu- Some children obtain pain relief by a sympathetic block rovascular dystrophy in childhood. J Pediatr 93:211–215 2. Harden RN, Bruehl S, Galer BS et al. (1999) Complex regional (Olsson 1990; Olsson 2003). In Europe, this block is pain syndrome: are the IASP diagnostic criteria valid and suffi- often performed as an intravenous regional block us- ciently comprehensive? Pain 83:211–219 ing guanethidine. Paravertebral blocks using local 3. Kozin F, Haughton V, Ryan L (1977) The reflex sympathetic anaesthetics seldom have long-lasting effects. Epidu- dystrophy syndrome in a child. J Pediatr 90:417–419 4. Lee BH, Scharff L, Sethna NF et al. (2002) Physical therapy and ral analgesia with an indwelling catheter may provide cognitive-behavioral treatment for complex regional pain syn- longer relief in severe cases. The long-term effect of dromes. J Pediatr 141:135–140 this treatment is not well documented. Sympathectomy 5. Olsson GL (2003) The effect of i.v. regional sympathetic block in children with CRPS-1. SIG Pain in Childhood ISPP2003, Syd- should not be used in children due to the nature of the ney procedure and the tendency to improve non-surgically. 6. Olsson GL, Arnér S, Hirsch G (1991) Reflex sympathetic dystrophy in children. Advances in Pain research and theraphy Dorsal Column Stimulation 15:323–331 Neurogenic pain can often be treated with spinal stimu- 7. Olsson GL, Linderoth B, Meyerson B (2003) Spinal cord stimulation as a treatment option in severe cases of complex regional lation. In our centre, we have applied dorsal column pain syndrome. SIG Pain in Childhood ISPP2003, Sydney stimulation to seven children with severe CRPS (Olsson 8. Robinson P, Wicksell R, Olsson GL (2004) ACT with chronic 2003) and achieved good pain relief for most children. pain patients. In: Hayes S, Strosahl KD (eds) A practical guide However, this therapy is very invasive, expensive and to acceptance and commitment therapy. Springer New York 9. Sherry DD, Wallace CA, Kelley C et al. (1999) Short- and long- usually performedon conscious patients, so it should be term outcomes of children with complex regional pain syndrome considered only in very special, severe, selected cases. type I treated with exercise therapy. Clin J Pain 15:218–23 10. Stanton-Hicks M, Janig W, Hassenbusch S et al. (1995) Reflex Psychological Treatment sympathetic dystrophy: changing concepts and taxonomy. Pain Psychologicaltreatmentsareanimportantcomponentin 63:127–33 11. van der Laan L, Veldman PH, Goris RJ (1998) Severe complica- the treatment of CRPS-1. Specific therapies range from tions of reflex sympathetic dystrophy: infection, ulcers, chronic reassurance and education to sophisticated programs of edema, dystonia, and myoclonus. Arch Phys Med Rehabil cognitive behavioural therapy. There are no published 79:424–429 studies proving the efficacy of CBT in CRPS although 12. Veldman PH, Goris RJ (1997) Multiple reflex sympathetic dystrophy. Which patients are at risk for developing a recurrence of it is included in the treatment program in many studies reflex sympathetic dystrophy in the same or another limb. Pain (Lee et al. 2002; Wilder et al. 1992). In our centre, we 71:207–208 use a well-defined form of CBT called acceptance and 13. Wilder RT, Berde CB, Wolohan M et al. (1992) Reflex sympa- commitmenttherapy (Robinson etal. 2004)based onac- thetic dystrophy in children. Clinical characteristics and follow- up of seventy patients. J Bone Joint Surg Am 74:910–919 ceptance, fear / avoidance, activation and exposure to 14. Wilson PR, Stanton-Hicks M, Harden RN (2005) CRPS: Current valued life. diagnosis and therapy. IASP Press, Seattle CT Scanning 501

Crura of Clitoris CSF Leak

Definition Spontaneous Cerebrospinal Fluid (CSF) Leak The crura or bulbs extend posteriorly and horizontally C as two cylinders of erectile tissue arising from the body of the clitoris where it meets the pubic bone for up to 9 CT Myelography cm. Clitoral Pain Definition Imaging of the spinal cord using computerized analysis of cross-sectional scans (tomograms) after injection of Cryoablation a contrast agent into the spinal fluid. Chronic Low Back Pain, Definitions and Diagnosis Definition The use of sub-zero temperatures to destroy tissue. CT Scanning Cancer Pain Management, Neurosurgical Interven- tions PETER LAU Department of Clinical Research, Royal Newcastle Hospital, University of Newcastle, Newcastle, NSW, Australia Cryoglobulinemia [email protected]

Definition Synonyms Conditionwhereincryoglobulins,aclassofimmunoglob- CAT Scan; Helical CT; Spiral CT; Multichannel CT; ulins that precipitate when cooled and re-dissolve when Computerised Axial Tomography heated, are present in the blood. Viral Neuropathies Definition Computerised axialtomography(CATor CT)isameans by which images of the internal structure of the body can be obtained in selected planes and at selected depths. Cryotherapy Characteristics Definition Principles Application of cold to body surfaces. In CT scanning, a computer is used to synthesise im- Chronic Pain in Children, Physical Medicine and Re- ages based on X-ray absorption data. The object to be habilitation scannedisplacedatthecentreofacirculargantry,around which an X-ray camera and its receiver rotate. As the camera rotates, X-rays are beamed through the object along multiple, selected diameters. Along each diame- CSF ter the X-ray shadows (see Plain Radiography)ofthe object and its internal structure are transmitted to the re- Cerebrospinal Fluid ceiver and stored by a computer. Using an iterative program, the computer then analysesthe stored information to generate a synthetic image of what the internal, three- dimensional structure of the object must be, in order to CSF Examination account for all of the different patterns of X-ray absorption obtained along each of the diameters across which the object was viewed. Definition The plane across which the object is studied is typically Shows pleocytosis, elevation of protein, or oligoclonal transverse to the long axis of the object; but this plane banding in Neuro-Behcet, collagene vascular disease, can be varied by tilting the gantry. Also, the object can systemic vasculitidesand the isolated angiitisof the cen- be translated relative to the gantry so that it can be stud- tral nervous system. ied across multiple, selected sections, also referred to as Headache Due to Arteritis “slices”. By scanning across its entire length, images of 502 CT Scanning

CT Scanning, Figure 1 Sagittal CT scans of the cervical spine in which the vertebrae C4 to C7 have been fused with interbody grafts and an anterior metal plate. (a) Midline section. (b) 3-D reconstruction. Reproduced courtesy of Toshiba Medical. the entire object can be synthesized. By using special computer programs, images can be synthesized to view the object from any angle or perspective, at any depth. The images can be planar, i.e. depicting the appearance of a single, selected slice through the object (Fig. 1a) or they can be simulated, three-dimensionalreconstruc- tions of the internal structure of the object (Fig. 1b).

Capabilities The first generation scanner took about 7 min to perform a single scan. Since then, the technology involved has been improved greatly, through at least five generations of development. Today, with multi-slice or multichannel, slip-ring CT systems, which allow continuous scanner gantry motion, coupled with synchronous table feed provide the basis for so-called helical or spiral CT scanning (Fox et al. 1998). Ultra-fast scanners are capable of performing as many as 32 scans in half a CT Scanning, Figure 2 A CT scan through the temporal bone, showing the second which is the time taken per rotation of the gantry. external ear and contents of the middle and internal ear. (a) Transverse This is achieved by unique design of detectors, isotropic section showing the ossicles of the middle ear. (b) Transverse section scanning and fast reconstruction. Sub-millimetre thin showing the cochlea and semicircular canals. and ultra-thin slices can be obtained. There is now commercially available CT scanner capable of more than 64 slices per half a second. tionofthesestructuresbytumours,infiltration,infection In the past, using slow scanners, CT provided images andinflammation(Fig.4).Ofparticularrelevancetopain of all but the smallest of soft tissues. Today with sub- medicine is the ability of CT to demonstrate intracranial millimetre, micro-voxel scanning (Pretorius and Fish- pathology in patients with headaches and the relation- man 1999), the smallest structures in the body, particu- ship between spinal nerves and the vertebral column in larly small bony structures such as those of the middle patients with radicular pain. and inner ear, can be well demonstrated (Fig. 2). The However, CT still relies on detecting the X-ray shad- cardinal advantage of CT is that it allows observers to ows of internal structures. Consequently, although CT “see inside” cavities such as the chest, abdomen, skull can demonstrate the location, shape and density of tis- and vertebral canal (Fig. 3). The ability to demonstrate sues it cannot reveal their internal architecture, although soft tissues allows CT to detect displacement and distor- hollow or permeable structures can be indirectly visu- CT Scanning 503

canbevisualisedbyinjectionofcontrastintothenucleus (Fig. 6) and intravenous infusion of a rapidly excreted contrastmediumwillenhancethestructureofthekidney and urinary tract. Multichannel techniques have had a signiﬁcant impact C on the style and quality of spine CT. Coverage is no longer limited by practical problems. Lumbar studies routinely extend from T12 to S1 and cervical spine studies from C2 to T2. With a 64-channel scanner, the full spine scan may be obtained in the duration of one breath-hold, which is easier for patients to tolerate than MRI scans.

Applications Microvoxel volumetric acquisition techniquesprovide a significant boost in spatial and contrast resolution. They can be used to create exquisite sagittal images of the intervertebral foramina in patients with radicular pain, especially in those with persisting pain after surgery, when missed foraminal stenosis is a major source of chronic pain. With the advent of fine, sub-millimetre technology, CT is becoming the modality of choice for the assessment of failed back surgery syndrome. Artifacts from intervertebral metal cages or pedicular screws can be min- imised, which allows for assessment of failure of spinal fixation hardware by loosening or metal fracture and fatigue. CT Scanning, Figure 3 Sagittal CT scan of the abdomen showing internal CT can demonstrate the progress of healing in the skele- viscera and vessels. a aorta. l liver. m superior mesenteric artery. c colon. tal system and can detect pseudoarthrosis in the spine af- s small intestine. Reproduced courtesy of Toshiba Medical. terattemptedarthrodesis.Similartechniquescanbeused for the assessment of joint replacement in the hip, shoulder and knee. Microvoxelscantechniquesminimise partial volume artefact and allow evaluation of the state of bone surrounding hardware implants, as well as evalua- tionofpossiblelooseningandmigrationoftheprosthesis as a chronic source of pain. With the advent of 32 and 64 slice scanners, dynamic, real-time imaging of joint movements and spinal movement in order to assess biomechanical abnormalities is possible. Real time fluoroscopy-CT is used to perform pain interventional procedures. It enables drugs to be injected accurately and safely. Itenablesthe accurate andsafede- livery of ablation devices, such as radio-frequencyelec- trodes,todeepsitesthatwereconsidereddifficult,unsafe and inaccurate in the past. This opens up a new arena of oncological pain management by using radiofrequency CT Scanning, Figure 4 Axial CT scan of the thoracic spine showing os- ablation to destroy pain-producing tumoursthat havein- teomyelitis of a vertebral body. vaded nerve plexuses e.g. metastatic carcinoma of the rectum with invasion of the lumbo-sacral plexus. Abla- tion of painful bone tumours, such as osteoid osteoma, alised by injection or infusion of radio-opaque agents, is another avenue of application of CT in pain manage- whichlocaliseintargetedtissues. Thus,injectionofcon- ment. trastmediumwilloutlinethelumenofholloworgansand High-contrast resolution and the seamless multi-planar blood vessels, joint cavities and the subarachnoid space capability of the latest multi-channel CT imagers have (Fig. 5). The internal structure of the intervertebral disc their greatest application in musculoskeletal pain after 504 CT Scanning

CT Scanning, Figure 5 Parasagittal and sagittal CT scans of the entire spine. Contrast medium has been injected into the subarachnoid space, which appears white (sa), and outlines the spinal cord (sc), which appears dark. Reproduced courtesy of Toshiba Medical.

CT Scanning, Figure 7 A sagittal CT scan of the ankle, showing an oblique CT Scanning, Figure 6 An axial CT scan of a lumbar intervertebral disc. fracture (arrow) through the posterior tibia, extending into the talocrural Contrast medium fills the nucleus pulposus (NP), a left posterolateral radial joint. Reproduced courtesy of Toshiba Medical. fissure (1) that extends into the annulus fibrosus and a right posterolateral fissure (2) that has a circumferential extension (3). trauma. Fractures are now delineated easily in any plane presence and extent of subtle cortical fractures, fracture while the patient is situated comfortably on the table. fragments, intra-articular loose bodies and articular sur- Positioning during the scan is not critical, as any plane face offset / depression; this was not possible by plain can be created from the volumetric data. Trauma series radiography (Fig. 7). are typically performed in less than 30 s, minimizing the Whereas magnetic resonance imaging is superior for the likelihood of patient motion (Tanenbaum 2003). Treat- delineation of the extent of tumours in medullary bone, ment can be better planned when CT demonstrates the CT isbetter able to delineate cortical bone,calcifications Cuban Neuropathy Fabry’s Disease 505 in the matrix of lesions and periosteal new bone forma- are studies in which the presence and absence of mor- tion. phological abnormalities are correlated with the presence and absence of pain. Such studiesare necessary lest Utility abnormalitiessimply be assumed to be relevanttothe di- The utility of CT emerges from a tension between what agnosis of pain. C can be seen with CT and what is relevant and valid. Al- Another opportunity lies in the fusion of morpho- though CT can provide detailed images of the internal logical CT technology with physiological imaging structure of the body, abnormalitiesdemonstratedbyCT techniques such as positron emission tomography are not necessarily the cause of a patient’s pain. In the (PET) (Erickson 2003). Already PET-CT can produce context of pain medicine, CT is useful as a diagnostic the physiological properties of certain neoplasms com- test only if and when it reliably shows the cause of pain. bined with anatomical imaging. In the same way, it Reliability may become possible to demonstrate the physiology of lesions, seen on CT, that are suspected of being causes For major and obvious lesions, the reliability of radiol- of pain. ogists using CT has not been questioned. Such lesions, however,arerarelypertinenttopainmedicine.Ofgreater References relevanceareminorabnormalitiesthataresometimesre- 1. Bogduk N (2003) Diagnostic procedures in chronic pain. In: ported in scans of patients with pain.Conspicuously, re- Jensen TS, Wilson PR, Rice ASC (eds) Clinical Pain Manage- liability data are largely lacking in the radiology litera- ment: Chronic Pain. Arnold, London, pp 125–144 ture. There has been a tradition to assume that all radi- 2. Erickson JE (2003) TRIP 3-Possible Future Technologies. Paper ologists agree on what they report. When this has been presented at the 89th Annual Meeting of the Radiological Society of North America. Chicago, Illinois, November 2003 studied, however, the converse emerges. 3. Fox SH, Tanenbaum LN, Ackelsberg S et al. (1998) Future di- In reading CT scans of the lumbar spine, radiologists fail rections in CT technology. Neuroimaging Clin N Am 8:497–513 to agree on the presence of such features as spinal steno- 4. Pretorius ES, Fishman EK (1999) Volume-rendered three- sis, degenerative joint disease and even herniated nu- dimensional spiral CT: musculoskeletal application. Radio- graphics19:1143–1160 cleus pulposus (Wiesel et al. 1986). Unfortunately, data 5. Tanenbaum LN (2003) Multichannel helical CT of the muscu- have not been presented in a manner from which kappa loskeletal system. Appl Radiol 32:15–22 scores can be calculated. 6. Wiesel SW, Tsourmas N, Feffer HL et al. (1986) A study of computer-assisted tomography. 1. The incidence of positive CAT Validity scans in an asymptomatic group of patients. Spine 9:549–551 In the joints of the appendicular skeleton, CT can show abnormalities of joint space, subchondral bone and even internal and external ligaments. However, there are no CT Scans data that incriminate these abnormalities as the cause of pain (Bogduk 2003). Definition In CT scans of the lumbar spine, abnormalities, such as degenerative joint disease, disc bulges and disc herni- CT (computed tomography), sometimes called CAT ations are the most commonly encountered abnormali- scan (computed axial tomography), uses x-ray images ties. These abnormalities, however, also frequently oc- taken at different angles around the body, and then by cur in asymptomatic individuals (Wiesel et al. 1986). computer processing of the information produces two- or three-dimensional slice images. Indeed, some 20–30% of asymptomatic individuals ex- hibitherniatedlumbarintervertebraldiscs.Thesefigures Motor Cortex, Effect on Pain-Related Behavior warn thatfinding such abnormalitiesin symptomatic patients does not necessarily prove that they are the cause of pain. CTDs Tumours and infections are assumed to be valid causes of pain but they are rare causes of either acute or Disability, Upper Extremity chronic pain. The same applies for conditions, such as osteonecrosis. For most patients with pain, there is nothing demonstrable by CT that has actually been CTrP proven to be a cause of pain. Even pseudoarthrosis following spine surgery has not been validated as a Central Trigger Point cause of pain. Future Trends Improvements in the technology of CT are likely to con- Cuban Neuropathy Fabry’s Disease tinue. There is an urgent need, however, for clinical science to catch up with the technology. Urgently needed Metabolic and Nutritional Neuropathies 506 Cumulative Trauma Disorders

Characteristics Cumulative Trauma Disorders The CFS technology is based on the organization of en- Definition dogenous intermodality interactions and allows tolera- δ A descriptive term used to label pain associated with ble stimulation of cutaneous A and C afferent fibers repetitive activities. (McMahon and Koltzenburg 1992; Ward et al. 1996). Disability, Upper Extremity For example, mechanical stimulation inhibits ongoing pain (Bromm et al. 1995; Sjölund et al. 1990; Wall and Cronly-Dillon 1960; Ward et al. 1996). In fact, particularly strong interactions are found between submodali- Cuneate Nucleus ties of the nociceptive system (here including itch), e.g. low frequency electrical stimulation of Aδ fibers may Definition cause a durable depression of nociceptive C fiber transmission both in vivo (Sjölund 1985; Sjölund 1988) and A nucleus at the upper cervical spinal cord where the in vitro spinal preparations (Sandkühler et al. 1997) and first synapse of the dorsal columns occurs. Discrimina- noxious mechanical stimulation, such as scratching, re- tive sensory information from cutaneous regions from duces itch. These interactions occur at several levels in the upper half of the body is relayed to this nucleus. the somatosensory system, the dorsal horn of the spinal Brainstem Subnucleus Reticularis Dorsalis Neuron cord (Cervero et al. 1979; Melzack and Wall 1965), the Postsynaptic Dorsal Column Projection, Anatomical dorsal column nuclei (Saade et al. 1985) and the thala- Organization mus(Olausson etal. 1994)andareoftentopographically well organized. To use these interactions for the symptomatic relief of itch and pain, a new technique, termed Cutaneous cutaneousfieldstimulation(CFS),wasintroduced(Nils- son et al. 1997). CFS allows topographically restricted δ Definition and tolerable electrical stimulation of thin (A and C) cutaneous fibers. Relating to, or affecting, the skin. CFS uses a flexible rubber plate with multiarray needle- Psychiatric Aspects of Visceral Pain like electrodes regularly fixed at 2 cm intervals (Fig. 1). Each electrode is surrounded by a “stop-device” 2.0 mm in diameter that protrudes 2.0 mm from the plate. The Cutaneous Allodynia electrode tip protrudes 0.3 mm from the stop-device. When the electrode plate is gently pressed against the skin, the electrode tips are introduced close to the recep- Definition tors in the epidermis and the superficial part of dermis. Pain elicited by a non-noxious stimulus that is not nor- Since the electrodes traverse the electrically isolating mally painful. horny layer of the epidermis and the current density Migraine Without Aura is high near the sharp electrode tips, the voltage and current necessary to stimulate cutaneous nerve fibers are small, typically less than 10 V and up to 0.8 mA, respectively. As the current density decreases rapidly Cutaneous Field Stimulation with distance, localized stimulation is achieved. The JENS SCHOUENBORG electrodes are stimulated consecutively with a constant Section for Neurophysiology, Department of current stimulator (64 pulses / s), each electrode with Physiological Sciences, Lund University, Lund, a frequency of 1–10 Hz (pulse duration 1.0 ms). Treat- Sweden ment duration is 5–45 min. A self-adhesive surface [email protected] (TENS) electrode serves as anode and is placed about 5–30 cm away from the needle electrode plate. Synonyms Several pieces of evidence demonstrate that CFS acts via stimulation of nociceptive Aδ and C fibers (Nilsson CFS et al. 1997; Nilsson et al. 2003). 1) The needle-like electrodes of the CFS plate are introduced close to the Definition dermo-epidermal junction, known to be richly inner- Cutaneous field stimulation (CFS) allows topograph- vated by thin afferent fibers (Fundin et al. 1994; Kruger ically restricted and tolerable electrical stimulation of et al. 1985), 2) CFS evokes a sensation of pricking thin (Aδ and C) cutaneous fibers for the symptomatic and slightly burning pain of weak / moderate intensity, relief of itch and pain. indicating an activation of nociceptive Aδ-and/or Cutaneous Field Stimulation 507

Cutaneous Field Stimulation, Figure 1 (a) Schematic of CFS apparatus with electrodes. (b) The needle-like electrodes are inserted into the dermo- epidermal junction, permitting stimulation of thin nerve ﬁbers with low electrical voltage and current.

C-fibers, respectively (Bromm and Treede 1987), 3) sites) CFS, abolishes itch evoked by histamine in normal during a selective blockade of the impulse conduction in humans and reduces CO2-laser evoked Aδ-andC-fiber A fibers, CFS still produces a burning sensation, known mediated heat pain and pinch evoked pain (Nilsson and to be due to heat sensitive nociceptive C fibers and 4) Schouenborg 1999) but has no effect on fabric evoked a flare, known to be caused by nociceptive C fibers prickle (assumed to be mediated by high threshold (Kenins 1981), develops around the CFS electrodes. It mechanoreceptive Aδ and C fibers; Garnsworthy et al. should be noted that while Aβ-fibers are presumably 1988) (Fig. 2). The relative potency of CFS on noci- also activated by CFS due to their low electrical thresh- ceptive skin senses is thus, in a descending order, itch, old, the stimulation frequencies used for CFS are very secondary heat pain, primary heat pain, pinch-evoked low for Aβ fibers (but relatively high for C fibers). pain and prickle. Regarding innocuous senses, CFS CFS acts preferentially on nociceptive senses, since increases the warm and cold thresholds somewhat but homo- but not hetero-topical (with respect to testing has no effect on tactile sensibility. 508 Cutaneous Field Stimulation

quency appears to be around 4 Hz per electrode (Nilsson et al. 2003). Notably, the effective stimulation parameters are similar to those known to cause long-term depression(LTD)(Sandkuhleretal.1997)–amemory-like mechanism – in the spinal cord and elsewhere. Figure 3 shows the results from a randomized controlled clinical study on chronic itch due to localized atopic dermatitis (n = 27; Nilsson et al. 2004). As can be seen, CFS depresses itch signiﬁcantly for more than 7 h. Peak inhibitory effect(down to about25%of control) isreached between 1 and 5 h postconditioning. Similarresultshave recently been reached for chronic itch due to neuroder- matitis (n = 30; Bäck et al, in preparation). In the latter

Cutaneous Field Stimulation, Figure 2 Differential effect on different sensory qualities of nociception after CFS (n = 10 subjects except for itch where n = 7 subjects) and lack of effect after conventional high frequency TENS (n = 10 subjects except for itch where n = 7 subjects). The conditioning stimulations and all sensory testings were performed on the right volar forearm. The mean magnitude of sensation after CFS (black bars) or TENS (hatched bars) is indicated as percentage of control (unﬁlled bars). Top diagram shows effects after CFS, bottom diagram shows effects after TENS. Statistical comparisons (Wilcoxons signed ranks test, 2-tailed) were made both between control values and values obtained after conditioning stimulation and also between values obtained after CFS and TENS respectively. Normalized visual analogue scale (VAS) on the vertical axes. * P<0.05, ** P<0.01, *** P<0.001; ns, non-signiﬁcant. Error bars indicate +S.E.M. (From Nilsson et al. 1997, 1999).

CFS causes a dramatic reduction in histamine-induced itch. In fact, all subjects tested have reported a complete or near complete inhibition of itch evoked by histamine. Cutaneous Field Stimulation, Figure 3 Effects of CFS (top diagram) and This inhibitory effect lasts 4–8 h and extends 10–20 cm TENS (bottom diagram) on chronic itch due to atopic dermatitis. For com- along the same dermatome, but appears to be more re- parison, the mean VAS values were normalized with respect to control stricted in a direction across dermatomal borders (Nils- (unfilled bars). The mean sensory intensities after CFS (black bars, n = 15) son et al. 1997). Maximal effects are reached already af- and TENS (hatched bars, n = 12) are shown. ANOVA repeated measures with Dunnet’s post hoc test was applied for matched comparisons within ter 8–10 min and more prolonged CFS stimulation (up a group, whereas the Mann-Whitney U test was used when comparing to 45 min tested) does not appear to add to the inhibitory effects of the two treatments; ns, non-significant, * p<0.05, ** p<0.01. effect (Nilsson et al. 2003). The optimal stimulation fre- Error bars indicate + S.E.M. (From Nilsson et al. 2004). Cutaneous Hyperalgesia 509 single-blind study, CFS was compared to conventional 9. Martinsson K, Sjölund BH (2004) Cutaneous field stimulation TENSoveratreatmentperiodof2weeks(twotreatments (CFS) in TENS-resistant chronic pain. In manuscript 10. McMahon SB, Koltzenburg M (1992) Itching for an explanation. a day). It was found that CFS provided effective relief Trends in Neurosci 15 / 12:497–501 of itch in practically all patients and also markedly im- 11. Melzack R (1975) Prolonged relief of pain by brief, intense tran- proved the skin condition. The improvement of the skin scutaneous somatic stimulation. Pain 1:357–373 C condition may be due to a reduced urge to scratch the 12. Melzack R, Wall PD (1965) Pain mechanisms: a new theory. A gate control system modulates sensory input from the skin before skin (or care not to scratch the treated skin), thus stop- it evokes pain perception and response. Science 150:971–979 ping the vicious itch –scratch circle that may sustain this 13. Nilsson H-J, Schouenborg J (1999) Differential inhibitory effect type of condition. Other workers have reported similar on human nociceptive skin senses induced by local stimulation findings on the relief of chronic itch by CFS in various of thin cutaneous fibers. Pain 80:103–112 14. Nilsson H-J, Levinsson A, Schouenborg J (1997) Cutaneous Field dermatoses (Wallengren 2002; Wallengren and Sundler Stimulation (CFS) – a new powerful method to combat itch. Pain 2001) In addition, a normalized innervation of the skin 71:49–55 may result from CFS (Wallengren and Sundler 2001). 15. Nilsson H-J, Psouni E, Schouenborg J (2003) Long term de- No adverse effects of CFS have been reported (Wallen- pression of human nociceptive skin senses induced by thin fibre stimulation. Eur J Pain 7:225–233 gren 2002). 16. Nilsson H-J, Psouni E, Carstam R et al. (2004) Profound inhi- CFS not only affects cutaneous nociception but also bition of chronic itch induced by stimulation of thin cutaneous musculoskeletal nociception. In a recent study on 142 nerve fibres. J Eur Acad Dermatol Venereol 18:37–43 TENS resistant patients with chronic musculoskeletal 17. Olausson B, Xu Z-Q, Shyu B-C (1994) Dorsal column inhibition of nociceptive thalamic cells mediated by gamma-aminobutyric pain (i.e. a group of patients that received no pain re- acid mechanisms in the cat. Acta Physiol Scand 152: 239–247 lief from established treatments of electrostimulation), 18. Saade NE, Dajani BM, Atweh SF et al. (1985) Inhibition of 30% received clinically relevant pain relief from CFS dorsal column nuclei by stimulation of trigeminal afferents in decerebrate-decerebellate cats. Brain Res 348:405–407 (Martinsson and Sjölund, in preparation). The group 19. Sandkühler J, Chen JG, Cheng G et al. (1997) Low-frequency studied consisted of 91 patients with nociceptive pain stimulation of afferent Aδ-fibers induces long-term depression and 51 patients with neuropathic pain according to at primary afferent synapses with substantia gelatinosa neurons established criteria. 33 / 91 patients with nociceptive in the rat. J Neurosci 17:6483–6491 20. Sjölund B H (1985) Peripheral nerve stimulation suppression pain and 10 / 51 with neuropathic pain got clinically of C-fiber-evoked flexion reflex in rats. Part 1: parameters of relevant pain relief from CFS for more than 3 months. continuous stimulation. J Neurosurg 63:612–616 In conclusion, CFS preferentially affects nociceptive 21. Sjölund B H (1988) Peripheral nerve stimulation suppression senses via endogenous inhibitory memory-like mecha- of C-fiber-evoked flexion reflex in rats. Part 2: parameters of low-rate train stimulation of skin and muscle afferent nerves. J. nisms and has no significant adverse side effects. The Neurosurg. 68:279–283 findings that CFS causes a strong inhibitory effect on 22. Sjölund BH, Eriksson M, Loeser JD (1990) Transcutaneous and itch and that skin conditions improve considerably and implanted electric stimulation of peripheral nerves. In: Bonica J the lack of adverse side effects demonstrate that CFS is (ed), Management of Pain, 2nd edn. Lea & Fegiber, Philadelphia, pp 1852–1861 a useful itch therapy. Moreover, CFS is clearly worth 23. Wall PD, Cronly-Dillon JR (1960) Pain, itch, and vibration, trying for the treatment of chronic musculoskeletal A.M.A. Archives of Neurology 2:365–375 pain. 24. Wallengren J, Sundler F (2001) Cutaneous field stimulation in the treatment of severe itch. Arch Dermatol 137:1323–1325 References 25. Wallengren J (2002) Cutaneous field stimulation of sensory nerve fibers reduces itch without affecting contact dermatitis. Allergy 1. Bäck O, Svensson Å, Thelin I et al. (2004) Chronic itch in neu- 57:1195–1199 rodermatitis is dramatically reduced by Cutaneous Field Stim- 26. Ward L, Wright E, McMahon SB (1996) A comparison of the ef- ulation (CFS). In manuscript fects of noxious and innocuous counterstimuli on experimentally 2. Bromm B, Scharein E, Darsow U et al. (1995) Effects of menthol induced itch and pain. Pain 64:129–138 and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 187:157–160 3. Bromm B, Treede R-D (1987) Human cerebral potentials evoked by CO2 laser stimuli causing pain. Exp Brain Res 67:153-162 4. Cervero F, Iggo A, Molony V (1979) An electrophysiological study of neurones in the substantia gelatinosa rolandi of the cat’s Cutaneous Freeze Trauma spinal cord. Quart J Exp Physiol 64:297–314 5. Fundin BT, Rice FL, Pfaller K et al. (1994) The innervation of the mystacial pad in the adult rat studied by anterograde transport of HRP-conjugates. Exp Brain Res 99:233–246 Freezing Model of Cutaneous Hyperalgesia 6. Garnsworthy RK, Gully PL, Kenins P et al. (1988) Identification of the physical stimulus and the neural basis of fabric-evoked prickle. J Neurophysiol 59:1083–1097 7. Kenins P (1981) Identification of the unmyelinated sensory nerves which evoke plasma extravasation in response to antidromic stimulation. Neurosci Lett 25:137–141 Cutaneous Hyperalgesia 8. Kruger L, Sampogna SL, Rodin BE et al. (1985) Thin-fiber cutaneous innervation and its intraepidermal contribution studied by labelling methods and neurotoxin treatment in rats. Somatosens Res 2:335–356 Freezing Model of Cutaneous Hyperalgesia 510 Cutaneous Mechanoreception

Cutaneous Mechanoreception Cyclic Alternating Pattern

Definition Definition Repetition of micro-arousal every 20–60 s as a sentinel Neuronal responses to mechanical stimuli applied to the that allows for a „reset“ of physiological functions (e.g. skin are transduced by specialized receptive endings of heartrate,respiration,muscletone),orpreparesthebody afferent nerve fibers. for an appropriate response if an event could be poten- Postsynaptic Dorsal Column Projection, Anatomical tially disrupting. Organization Orofacial Pain, Sleep Disturbance

Cyclic Pain Cutaneous Pain Model Deﬁnition Autologous Thrombocyte Injection as a Model of Cu- Cyclic pain occurs with deﬁnite association to the men- taneous Pain strual cycle, generally 1–2 days prior to the onset of or during menses. Dyspareunia and Vaginismus

Cutaneous Stimulation Cyclooxygenase Inhibitors Definition NSAIDs, Adverse Effects Chemical, thermal, or mechanical input delivered to the NSAIDs and Cancer skin to activate one or more superficial or cutaneous sen- NSAIDs and Cardio-Vascular Effects sory receptor types. PostoperativePain, Non SteroidalAnti-Inflammatory Postsynaptic Dorsal Column Projection, Functional Drugs Characteristics

Cyclooxygenase Inhibitors, Chemistry

CWP Coxibs and Novel Compounds, Chemistry

Chronic Widespread Pain Cyclooxygenase-2 Inhibitors

Definition Cyclic Adenosine A class of drugs related to non-steroidal anti-inflam- Monophosphate-Responsive matory drugs (NSAIDs) that prevent the synthesis Element-Binding Protein of prostaglandins by the enzyme cyclooxygenase–2. These drugs are relatively new additions to the standard treatment regimen of osteoarthritis, and include Synonyms Celebrex® and Vioxx®. Arthritis Model, Osteoarthritis CREB Postoperative Pain, COX-2 Inhibitors Definition CREB is a transcription factor that is activated by the Cyclooxygenases cAMPsignaltransduction pathway. Itisphosphorylated by protein kinase A, enters the nucleus of a neuron and can alter gene expression. Synonyms Spinothalamic Tract Neurons, Role of Nitric Oxide COX Cyclooxygenases in Biology and Disease 511

Definition fluid contained activity that contracted uterine smooth COX is a 70–72 kD enzyme, catalyzing the reaction of muscle, and also caused a fall in blood pressure. Von Euler identified the active principle as a lipid-soluble Arachidonic acid to PGG2 (cyclooxygenase reaction) and consecutively PGG to PGH (peroxidase reac- acid, which he named ‘prostaglandin’ (PG) because 2 2 he thought it originated from the prostate gland. In the tion). Prostaglandin H2 (PGH2) is further converted C into various prostaglandins and thromboxanes There is 1960’s, technical advances allowed the characterisa- a distinct active site for both cyclooxygenase and per- tion of the PGs as a family of lipid compounds with a oxidase reaction. There are at least 3 isoforms, COX1, unique structure. They proved to be 20–carbon unsat- COX2 and COX3, which are also slightly different urated carboxylic acids with a cyclopentane ring, and at the active site, explaining particular selectivities in 1964, PGE2 was synthesised using arachidonic of inhibitors. Prostaglandins are involved in pain, in- acid and an enzyme preparation from ram seminal flammation and fever, but also in cytoprotection in vesicles (Bergström et al. 1964). Prostaglandins and the stomach and blood flow regulation in the kidneys. related compounds are some of the most prevalent of NSAIDS (non steroidal anti-inflammatory drugs) are autocoids and can be released from every tissue except therapeutic agents that block this enzyme and thus act red blood cells. As local hormones, they produce, in as pain killers, antipyretic and anti-inflammatory drugs. minute concentrations, an incredibly broad spectrum COX-1 and COX-2 in Pain of effects that modulate almost every biological function. They derive mostly from the 20–carbon fatty acid, Coxibs and Novel Compounds, Chemistry ω Cyclooxygenases in Biology and Disease arachidonic acid (C20:4 6), and almost 100 different NSAIDs, Adverse Effects derivatives have been identified, including lipoxins and NSAIDs and Cancer isoprostanes. Prostaglandinsareimportantto inflamma- NSAIDs, Chemical Structure and Molecular Mode of tory processes, as evidenced by the anti-inflammatory Action effects of drugs that interfere with their synthesis, such NSAIDs, COX-Independent Actions as the steroid and non-steroid anti-inflammatory drugs NSAIDs, Mode of Action (NSAIDs). The discovery 15 years ago of a second Wind-Up of Spinal Cord Neurons cyclooxygenase (COX–2), inducible by cytokines, has led to an important clarification of the roles of PGs as mediators of inflammation. COX–2 is induced in inflammation and makes PGs locally, whereas COX–1 Cyclooxygenases in Biology and Disease is a ‘housekeeping’ enzyme involved in the modulation of physiological events. REGINA M. BOTTING Cyclooxygenase had long been studied in preparations The William Harvey Research Institute, The John Vane from ram seminal vesicles and a homogeneous, enzy- Science Centre, Queen Mary University of London, St matically active prostaglandin endoperoxide synthase Bartholomew’s and the London School of Medicine was isolated in 1976 (Hemler et al. 1976), and cloned and Dentistry, Charterhouse Square, London, UK in 1988 (DeWitt and Smith 1988). This membrane- [email protected] bound haemo– and glycoprotein, with a molecular weight of 71kDA, is found in greatest amounts in the Synonyms endoplasmic reticulum of prostanoid-forming cells. It both cyclizes arachidonic acid and adds the 15- Cyclooxygenase; COX; Prostaglandin Endoperoxide hydroperoxy group to form PGG . The hydroperoxy Synthase; Ptgs 2 group of PGG2, is reduced to the hydroxy group of Definition PGH2, by a peroxidase (in the same enzyme protein) that utilizes a wide variety of compounds to provide Cyclooxygenases are enzymes which synthesise the requisite pair of electrons. The hydroperoxides prostaglandins. also drive the cyclooxygenase reaction by maintaining a ‘hydroperoxide tone’. The three dimensional Characteristics structure of COX–1 was determined in 1994 (Picot et Three isoenzymes of cyclooxygenase have been charac- al. 1994). This enzyme consists of three independent terised:cyclooxygenase–1(COX–1;Ptgs–1),cyclooxy- folding units: an epidermal growth factor-like domain, genase–2 (COX–2; Ptgs–2) and a putative cyclooxyge- a membrane-bindingsection and an enzymatic domain. nase–3 (COX–3; Ptgs–3), which is currently under in- The sites for peroxidase and cyclooxygenase activity vestigation. are adjacent but spatially distinct. Three of the helices of the COX–1 structure form an entrance channel to the Cyclooxygenase–1 active site, which is a long, hydrophobic channel. Since In the 1930s, Goldblatt in England (Goldblatt 1935) and the enzyme integrates into only a single leaflet of the vonEulerinSweden(vonEuler1934)foundthatseminal membrane lipid bilayer, the position of the cyclooxy- 512 Cyclooxygenases in Biology and Disease

Cyclooxygenases in Biology and Disease, Figure 1 The arachidonic acid cascade. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) utilise arachidonic acid to form the unstable endoperoxide intermediates, prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2). From these intermediates the more stable prostaglandins are synthesised by individual synthases. Prostaglandin E2 (PGE2) is mostly involved in pain, fever and inﬂammation, prostaglandin F2 α (PGF2 α) in labour and parturition and prostaglandin D2 (PGD2) is a mediator in brain and mast cells. Prostacyclin (PGI2)witha half life of 3 minutes, protects the stomach mucosa from damage and prevents aggregation of blood platelets. It breaks down spontaneously to inactive 6-keto-PGF1 α. Thromboxane A2 is mainly found in blood platelets and promotes clotting of blood by inducing platelet aggregation. It has a half life of 30 seconds and breaks down to inactive thromboxane B2. The activity of COX-1 and COX-2 is inhibited by aspirin and similar drugs, the non steroid anti-inﬂammatory drugs (NSAIDs), thereby preventing formation of prostanoids.

genase channel allows arachidonic acid to gain access ism. The concentration of the enzyme remains largely to the active site from the interior of the bilayer. stable, but small 2– to 4–fold increases can occur in Most NSAIDs compete with arachidonic acid for bind- response to stimulation with hormones or growth facing to the active site (Fig. 1). Flurbiprofen,forexam- tors. COX–1 has clear physiological functions (Vane ple, inhibits COX–1 by excluding arachidonic acid from and Botting 2001). Its activation leads, for instance, the upper portion of the channel, and blocking its access to the production of prostacyclin (PGI2), which when to tyrosine (Tyr) 385 and serine (Ser) 530 at the apex released by endothelial cells is antithrombogenic, and of the long active site. Uniquely, aspirin irreversibly in- when released by the gastric mucosa, is cytoprotective. hibits COX–1 by acetylation of (Ser) 530, thereby ex- However, it is likely that in humans endothelial PGI2 is cluding access for the arachidonic acid to (Tyr) 385 by also synthesised by COX–2, induced by Shear Stress steric hindrance. on endothelial cells. Release of PGI2 and PGE2 made Before 1971, many biochemical effects of the NSAIDs by COX–1 also sensitises nociceptors on peripheral had been reported, and there were many hypotheses sensory nerve terminals and thus acutely amplifies about the mechanism of action of these drugs. How- painful stimulation. Since COX–2 is induced by in- ever, in 1971, John Vane elegantly demonstrated that flammatory stimuli and by cytokines in migratory and aspirin, salicylate and indomethacin inhibited COX of other cells, it appears likely that the anti-inflammatory guinea pig lung homogenates, and thus prevented the actions of NSAIDs are due to the inhibition of COX–2, formation of PGs (Vane 1971). Two other reports from whereas the unwanted side effects such as irritation the same laboratory, that aspirin prevented the release of the stomach lining are due to the inhibition of the of prostanoids from aggregating human platelets and constitutive enzyme, COX–1. that NSAIDs blocked PG release from the perfused The inhibition of PG synthesis explains all the actions isolated spleen of the dog, lent support to and extended of the NSAIDs. They prevent the pathological over- his finding. production of PGs by COX–2 which contribute to the COX–1 is constitutively expressed in most tissues, inflammatory process (therapeutic effects), and prevent and performs a ‘housekeeping’ function to synthesize the physiological formation of prostanoids by COX–1 PGs which regulate normal cell activity (Fig. 2). The (side effects). For instance, the ulcerogenic activity PGs produced are therefore protective to the organ- of aspirin arises from the inhibition of prostacyclin Cyclooxygenases in Biology and Disease 513

Cyclooxygenases in Biology and Disease, Figure 2 Physiological and pathological functions of COX-1 and COX-2. Cyclooxygenase-1 (COX-1) functions as a constitutive enzyme and produces prostaglandins which are involved in physiological processes. For example, thromboxane A2 (TXA2)madeby platelets promotes the clotting of blood when required, prostacyclin (PGI2) made by the stomach mucosa protects it from damage by gastric acid and PGE2 made in kidney cells is involved in kidney function. PGI2made by COX-1 in vascular endothelial cells inhibits aggregation of platelets and the clotting of blood. PGI2 is also formed by COX-2 induced in endothelial cells by shear stress produced by laminar blood flow. Cyclooxygenase-2 is mainly induced in inflammation and by mitogens and growth factors. It is induced in macrophages and other inflammatory cells by bacterial lipopolysaccharide and cytokines. It forms mainly PGE2, which with other inflammatory mediators causes pain and fever. Some constitutive COX-2 is also expressed, particularly in the brain. In pain, PGE2 is hyperalgesic, sensitising peripheral sensory nerve terminals to nociceptive stimuli. production, which has an important cytoprotective Many of these studies revealed a lack of correlation be- function in the gastric mucosa. Administration of var- tween COX activity and the induction of COX mRNA. ious PGs reverses or prevents experimental gastric For example, the levels of 2.8 kb COX–1 mRNA in ulcers, and some of these PG derivatives are available epithelial cells of sheep trachea stimulated with growth for clinical use. In addition, the inhibition of COX–1 factors, did not reflect the increase in enzyme activ- by NSAIDs correlates with their capacity to erode the ity. However, a second mRNA (4.0 kb) recognised by gastric mucosa. NSAIDs also inhibit the aggregation the COX–1 cDNA probes and formed from a separate of blood platelets, by preventing the formation of the gene increased in parallel with PG production. Dexam- potent pro-aggregatory and vasoconstrictor eicosanoid, ethasone inhibited only the inducible COX activity in thromboxane A2 (TXA2), synthesised by COX–1 human IL–1 treated dermal fibroblasts, and in human in platelets. Aspirin irreversibly inhibits COX–1 in bacterial lipopolysaccharide (LPS)-stimulated mono- platelets by acetylation of the enzyme, thus completely cytes (Masferrer et al. 1990). Basal levels of COX were preventing synthesis of TXA2 until new platelets are not affected by dexamethasone. produced after 8-11 days. The presence of the gene encoding for a second COX The inhibition of PG synthesis by NSAIDs has been enzyme was discovered by Xie et al. while character- demonstrated in a wide variety of cell types and tissues, ising ‘immediate early’ genes, switched on by expres- ranging from whole animals and humans to microsomal sion of the v-src oncogene in chicken embryo fibroblasts enzyme preparations. For example, the concentration of (Xie et al. 1991). This new COX isoenzyme was also in- PGE2 is about 20 ng/ml in the synovial fluid of patients duced by serum, tetradecanoyl phorbol acetate (TPA)or with rheumatoid arthritis. This decreases to zero in pa- forskolin in established murine fibroblast cell lines. The tients taking aspirin; a good demonstration of the effect chicken and mouse COX–2 gene, at 8.3 kb, is similar to of this drug on PG synthesis clinically. Several classes the COX–2 gene of human, but smaller than the 22 kb of NSAIDs have been identified, and at least 12 major human COX–1 gene. The gene products also differ, with chemical series are known to affect PG production by the size of the mRNA for COX–2 being approximating COX–1 and COX–2. 4.5kbandthatforCOX–1being2.8kb.Attheaminoacid level, the protein sizes of COX–1 and COX–2 enzymes Cyclooxygenase–2 from different sources are approximately 80–90% iden- The cloning of COX–1 from sheep seminal vesicles tical, with just over 600 amino acids, ofwhich63% are in provided useful probes for the study of the relationship an identical sequence. Both enzymes have a molecular between PG production and COX mRNA induction. weight of 71 kDA and similar Km and Vmax values for 514 Cyclooxygenases in Biology and Disease metabolismofarachidonicacid.Bothenzymesalsohave comparator drugs. Millions of arthritic patients were similaractivesitesfortheattachmentofarachidonicacid then prescribed these drugs. However, the rofecoxib or NSAIDs, although the active site of COX–2 is larger trial revealed that 4 times as many patients receiv- thanthatofCOX–1andcanacceptawiderrangeofstruc- ing rofecoxib suffered a myocardial infarction than tures as substrates. those treated with naproxen. This was interpreted as Theresiduesthatform thesubstratebindingchannel, the a protective effect of naproxen, which would inhibit catalyticsites,andtheresiduesimmediatelyadjacentare aggregation of platelets and therefore prevent heart all identical in COX–1 and COX–2 except for two small attacks. Following these initial trials, Merck and Pfizer variations.Theprimarysequencedifferenceintheactive began large scale trials of rofecoxib and celecoxib in site itself is the valine 523 side chain in COX–2, which patients with recurrent neoplastic polyps of the large is smaller by a single methyl group than the isoleucine bowel, a precancerous condition preceding colorectal side chain that it replaces in COX–1. This opens up ac- neoplasia. These trials were instituted since cancer cess to a side pocket off the main substrate channel in cells have high levels of COX–2, while surrounding COX–2, allowing an enzyme inhibitor to reactwith argi- healthy colon cells have none. In these anti-cancer nine 513, which replaces histidine in COX–1. Another trials, the effects of rofecoxib and celecoxib were com- sequence difference is situated outside, but close to, the pared with patients receiving placebo treatment. Both activesite,andcanindirectlyinfluenceitsconformation. trials were terminated after eighteen months, when The large residue, phenylalanine 503, in COX–1 is re- it became clear that the incidence of adverse cardio- placed by the smaller leucine in COX–2. This allows vascular events, primarily myocardial infarctions and leucine 384, which bordersthe active site, to re-orientate ischemic cerebrovascular events, was greater in the its methyl side chain out of the active site, and thus leave patients receiving selective COX–2 inhibitors. At this more space available for a larger inhibitor molecule in stage, Merck decided to withdraw rofecoxib from the COX–2 than in COX–1. market. The most plausible explanation for this increase TheimportanceofthediscoveryoftheinducibleCOX–2 in heart attacks is that selective COX–2 inhibitors pre- is highlighted by the differences in pharmacology of vent synthesis of anti-aggregatory prostacyclin in the the two enzymes (Warner et al. 1999). Aspirin, in- vascular endothelium. Since these drugs do not affect domethacin and ibuprofen are much less active against TXA2 synthesis by COX–1 in blood platelets, the COX–2 than against COX–1. Indeed, the strongest aggregatory action of TXA2 progresses unopposed and inhibitors of COX–1 such as aspirin, indomethacin and thrombotic emboli form to cause myocardial infarc- piroxicam are the NSAIDs which cause the most dam- tions. age to the stomach. The spectrum of activities of some ten standard NSAIDs against the two enzymes ranges Cyclooxygenase–3 from a high selectivity towards COX–1 (166-fold for Paracetamol (acetaminophen) has potent analgesic aspirin), through to equiactivity on both (for example, and antipyretic actions but very little anti-inflammatory diclofenac). The range of activities of NSAIDs against activity. Its mechanism of action has remained a mys- COX–1 compared with COX–2 explains the variations tery for many years, since it is only a weak inhibitor of in the side effects of NSAIDs at their anti-inflammatory PG biosynthesis by either COX–1 or COX–2 in vitro, doses. Drugs which have a high potency against COX–2 but inhibits PG biosynthesis in vivo. Reduction of PG and a low COX–2/COX–1 activity ratio will have po- biosynthesis by paracetamol varies in different tissues, tent anti-inflammatory activity with few side effects and COX activity in brain is particularly sensitive to on the stomach and kidney. Published epidemiological inhibition (Flower and Vane 1972). In 2002, Simmons data on the side effects of NSAIDs reported that pirox- and colleagues cloned, characterised and expressed a icam and indomethacin in anti-inflammatory doses variant of COX–1 from dog and human brain, which showed high gastrointestinal toxicity. These drugs have they named COX–3 (Chandrasekharan et al. 2002). a much higher potency against COX–1 than against This enzyme, expressed in insect cells, was sensitive COX–2. to inhibition with low concentrations of paracetamol The discovery of COX–2, induced by inflammatory and other related antipyretic analgesic drugs, such as stimuli and cytokines in migratory and other cells, antipyrine and aminopyrine. However, significantly stimulated several laboratories to develop highly selec- increased concentrations of paracetamol were needed tive inhibitors of this enzyme (Fig. 2). Monsanto/Searle to inhibit COX–1 and COX–2 under the same ex- (now Pfizer) are marketing celecoxib and its successor, perimental conditions. COX–3 was also sensitive to valdecoxib, whereas Merck and Company developed inhibition with low concentrations of non-selective the selective COX–2 inhibitors, rofecoxib and etori- NSAIDs, which may explain the antipyretic action of coxib. Early trials of celecoxib (Silverstein et al. 2000) these drugs. and of rofecoxib (Bombardier et al. 2000) demon- Similarly to COX–1 and COX–2, COX–3 was shown strated good analgesia and anti-inflammatory activity, to possess COX and peroxidase active sites and to have with less adverse effects on the stomach mucosa than the same cellular localisation. COX–3 was also shown Cytochrome Oxidase Staining 515 to be glycosylated and to have the capacity to metabolise Cyclophosphamide arachidonic acid, leading to the formation of PGE2.The major difference between COX–3 and COX–1 is that at the mRNA level, COX–3 retains intron–1, which en- Definition codes a 30aa sequence inserted into the N-terminal hy- C drophobic signal peptide of the enzyme. Although in ca- An alkylating agent frequently used as immunosup- nine COX–3 mRNA, intron–1 is within frame, in the hu- pressant. The treatment of choice, in combination with man there is a frameshift in intron–1 of the COX–3 tran- steroids, in systemic vasculitides like WG. script. The conversion of COX–3 mRNA into enzyme Headache Due to Arteritis protein in humans requires further investigation. Vascular Neuropathies

References 1. Bergström S, Danielsson H, Samuelsson B (1964) The En- Cyclosporin, Methotrexate zymatic Formation of Prostaglandin E2 from Arachidonic Acid. Prostaglandins and related factors 32. Biochim Biophys Acta 90:207–210 Definition 2. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B et al. (2000) Comparison of Upper Gastrointestinal Drugs used to suppress immune functions in organ- Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid transplanted patients and in patients with diseases with Arthritis. N Engl J Med 343:1520û1528 disturbances in immune functions, e.g. rheumatoid 3. Chandrasekharan NV, Dai H, Roos KLT, Evanson NK, Tomsik J, Elton TS, Simmons DL (2002) COX–3, A Cyclooxyge- arthritis, psoriasis. nase–1 Variant Inhibited by Acetaminophen and Other Anal- Postoperative Pain, Acute Pain Management, Princi- gesic/Antipyretic Drugs: Cloning, Structure and Expression. ples Proc Natl Acad Sci USA 99:13926–13931 4. DeWitt DL, Smith WL (1988) Primary Structure of Prostaglandin G/H Synthase from Sheep Vesicular Gland Determined from the Complementary DNA Sequence. Proc Natl Acad Sci USA 85:1412–1416 5. Flower RJ, Vane JR (1972) Inhibition of Prostaglandin Syn- Cystitis Models thetase in Brain Explains the Antipyretic Activity of Paracetamol (4–acetamidophenol). Nature 240:410–411 6. Goldblatt MW (1935) Properties of Human Seminal Plasma. J Visceral Pain Model, Urinary Bladder Pain (Irritants Physiol (Lond) 84:208–218 or Distension) 7. Hemler M, Lands WEM, Smith WL (1976) Purification of the Cy- cloxygenase that Forms Prostaglandins: Demonstration of Two Forms of Iron in the Holoenzyme. J Biol Chem 251:5575–5579 8. Masferrer JL, Zweifel BS, Seibert K, Needleman P (1990) Se- lective Regulation of Cellular Cyclooxygenase and Endotoxin in Mice. J Clin Invest 86:1375–1379 Cytoarchitectural 9. Picot D, Loll PJ, Garavito RM (1994) The X-ray Crystal Struc- ture of the Membrane Protein Prostaglandin H2 Synthase–1. Na- ture 367:243–249 Definition 10. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A et al. (2000) Gastrointestinal Toxicity with Celecoxib Pertaining to the cellular composition of bodily struc- vs. Nonsteroidal Anti-Inflammatory Drugs for Osteoarthritis ture. and Rheumatoid Arthritis: The CLASS Study: A Randomised Pain Processing in the Cingulate Cortex, Behavioral Controlled Trial. Celecoxib Long-term Arthritis Safety Study. Studies in Humans J Am Med Assoc 284:1247–1255 11. Vane JR (1971) Inhibition of Prostaglandin Synthesis as a Mech- anism of Action for the Aspirin-Like Drugs. Nature 231:232–235 12. Vane JR, Botting RM (2001) Formation and Actions of Prostaglandins and Inhibition of their Synthesis. In: Vane JR, Botting RM (eds) Therapeutic Roles of Selective COX–2 Cytochrome Oxidase Staining Inhibitors. William Harvey Press, London, pp 1–47 13. von Euler US (1934) Zur Kenntnis der Pharmakologischen Wirkung von Nativsekreten und Extracten Männlicher Acces- Synonyms sorischer Geschlechtsdrüsen. Arch Exp Path Pharmak 175:78–84 14. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane CO staining JR (1999) Nonsteroid Drug Selectivities for Cyclooxygenase–1 Rather than Cyclooxygenase–2 are Associated with Human Gas- Definition trointestinal Toxicity: A Full In Vitro Analysis. Proc Natl Acad Sci USA 96:7563–7568 Type of staining that reflects mitochondrial activity in 15. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL neurons. (1991) Expression of a Mitogen-Responsive Gene Encoding Prostaglandin Synthase is Regulated by mRNA Splicing. Proc Spinothalamic Terminations, Core and Matrix Natl Acad Sci USA 88:2692–2696 Thalamus,ReceptiveFields,ProjectedFields,Human 516 Cytokine Modulation of Opioid Action

to induce hyperalgesia in animals, IL–6 knock-outmice Cytokine Modulation of Opioid Action showed reduced morphine analgesia and an early devel- 1 2 opment of morphine tolerance (Bianchi et al. 1999). We VASUDEVA RAGHAVENDRA ,JOYCE A. DELEO 1 have shown that neutralizing or blocking IL–6, IL–1β Algos Therapeutics Inc., Saint Paul, MN, USA α 2Dartmouth Hitchcock Medical Center, Dartmouth and TNF– spared the analgesic action of morphine Medical School, Lebanon, NH, USA in rats following a peripheral nerve injury (Raghaven- [email protected], dra et al. 2002). A sickness-inducing agent such as [email protected] lipopolysaccharide or lithium chloride, which induces proinflammatory cytokine release, reduces morphine Synonyms analgesia (Johnston and Westbrook 2003). Proinflam- matory cytokines also play a role in the development of Opioid Modulation by Cytokines morphine tolerance and withdrawal-induced hyperalgesia. Chronic administration of heroin or morphine to Definition mice or rats resulted in increased peripheral and central A conceptual framework has recently emerged to sup- expression of proinflammatory cytokines (Raghavendra port the hypothesis that an opioid may, in fact, be et al. 2002; Jolan et al. 2003). The central expression broadly defined as a cytokine. This is due to the of proinflammatory cytokines after chronic morphine presence of opioid receptors on immune cells, and the treatment, exhibited a temporal correlation with the ability of opioids to mediate interactions between cells development of analgesic tolerance and withdrawal- and regulate processes in the extracellular environment. induced hyperalgesia in rats (Raghavendra et al. 2002). In addition, it has been demonstrated that a bidirectional Conversely, IL–10, an anti-inflammatory cytokine, interaction exists among endogenous opioids and clas- spared the analgesic actions of opioids in dynorphin sically defined cytokines. In the central nervous system treated rats (Laughlin et al. 2000). Interferon-alpha (CNS), cytokines appear to be modulated by endoge- (IFN–α), which exhibits structural and functional simi- nous opioids, and the neural effects of opioids altered larities to endorphins, induces opioid receptor-mediated by cytokines. In particular, cytokines modulate opioid analgesia and prevents the development of tolerance to regulation of neuronal activity, sensory motor func- opioids (Dafny 1984). tion, body temperature, food intake and regulation of hypothalamic-pituitary-adrenocortical axis functions. Chemokines Recently, the role of cytokines in modulating opioid Chemokines (chemotactic cytokines) also influ- analgesia, tolerance and hyperalgesia has also been ence the perception of pain by interacting with G- reported. protein-coupled opioid receptors. Recent studies have shown that cross-desensitization between opioid and Characteristics chemokine receptors has significant implications in Opioids are a class of the most effective analgesics the regulation of leukocyte trafficking, progression for treating many forms of acute and chronic pain. In of inflammatory disease and regulation of opioid addition to the known adverse effects, the clinical utility receptor function in the CNS (Steele et al. 2002). of opioid analgesics is often hampered by the develop- The direct administration of chemokines, particu- ment of analgesic tolerance, hyperalgesia and physical larly CXCL12 and CCL5, into the periaqueductal gray dependence. A wide range of neurotransmitters and matter, inhibited opioid-induced analgesia by cross neuromodulators play a role in the development of desensitizing μ opioid receptors (Szabo et al. 2002). tolerance and dependence to opioids. Recent studies Opioid enhancement of chemokine up-regulation is also have demonstrated that cytokines are also capable of responsiblefor enhanced HIVinfection andprogression modulating opioid-induced analgesia, and play a role to AIDS in opioid abusers (Peterson et al. 1998). in the development of opioid tolerance and withdrawal- Glial Component induced hyperalgesia. Major sources of proinflammatory cytokines and Cytokines chemokines in the CNS are activated glial cells.The Cytokines, e.g. IL–1β, IL–6, IL–10, interferons, and presence of opioid receptors on microglia and astro- chemokines have the ability to modulate the analgesic cytes is well documented, and priming these cells with action of opioids. For example, the proinflammatory cy- opioids induces enhanced secretion of proinflammatory tokine, IL–1β directly attenuates opioid analgesia (Gul cytokines and chemokines (Peterson et al. 1998). Acti- et al. 2000). IL–1β also plays a role in the anti-analgesic vation of spinal proinflammatory cytokines by chronic activity of dynorphin and ligands of the peripheral ben- opioid treatment may be caused by its interaction with zodiazepine receptor (Laughlin et al. 2000; Rady and glialcells(Raghavendraetal.2002).Attenuationofglial Fujimoto 2001). The role of IL–6 in modulating opioid activation using the methylxanthine, propentofylline, analgesia is more complicated. Although IL–6 is known restored opioid analgesia, prevented the development of Cytokine Modulation of Opioid Action 517 morphine tolerance and morphine withdrawal-induced anti-hyperalgesic/analgesic mediators are produced by hyperalgesia, and opioid-induced neuroimmune acti- activated immune cells. Hyperalgesic mediators, such vation (Raghavendra and DeLeo 2004). This reduction as proinflammatory cytokines and chemokines, and in neuroimmune activation by propentofylline included anti-hyperalgesic mediators, such as anti-inflammatory decreased microglial, astrocytic activation and cytokine cytokines and adhesion molecules, modulate opioid C expression in the lumbar spinal cord following mor- analgesia. Drugs such as immunosuppressants that in- phine administration in a peripheral nerve injury in a fluence this interplay may also modulate endogenous rat model of neuropathy. or exogenously administered opioid analgesia.

Intracellular Signaling Cascades Conclusions Mitogen-activated protein (MAP) kinase or protein Of particular clinical interest, the glial modulating kinase C (PKC) pathways may be involved in opioid- agent, propentofylline, was shown to prevent opioid induced activation of proinflammatory immune re- tolerance and hyperalgesia in a rat model of neuropa- sponses. MAP kinase and PKC are intriguing, because thy (Raghavendra and DeLeo 2004; Raghavendra et they are key players in the intracellular signaling cas- al. 2003). Together, these data offer a novel clinical cade leading to the development of morphine tolerance therapy for the prevention or delay of opioid tolerance and production of proinflammatory immune activa- and hyperalgesia: the co-administration of cytokine tion (Raghavendra et al. 2002). Since proinflammatory inhibitors and/or glial modulators with opioids. Rec- cytokines and chemokines induce hyperalgesia in an- ognizing that opioids remain the gold standard for the imals, it is possible that activation of pro-nociceptive treatment of acute pain, improvement of their untoward pathways by these mediators could counteract opioid side-effect profile would enhance their clinical efficacy. analgesia. References Cellular Adhesion Molecules 1. Bianchi M, Maggi R, Pimpinelli F, Rubino T, Parolaro D, Poli V, Ciliberto G, Panerai AE, Sacerdote P (1999) Presence of a The immune system has the capacity to modulate pain Reduced Opioid Response in Interleukin–6 Knock-Out Mice. directly at the site of tissue injury by liberating opioid Eur J Neurosci 11:1501–1507 peptides from immune cells. In an inflammatory pain 2. Dafny N (1984) Interferon: A Candidate as the Endogenous Sub- model, the peripheral analgesic activity of opioids is stance Preventing Tolerance Dependence to Brain Opioids. Prog Neuropsychopharmacol 8:351–357 modulated by selectins and intracellular adhesion 3. Gul H, Yildiz O, Dogrul A, Yesilyurt O, Isimer A (2000) The molecule–1 (ICAM–1). ICAM–1, expressed on vas- Interaction between IL–1β and Morphine: Possible Mechanism cular endothelium, recruits immunocytes containing of the Deficiency of Morphine-Induced Analgesia in Diabetic opioids to promote the local control of inflammatory Mice. Pain 89:39–45 4. Holan V, Zajikova A, Krulova M, Blahoutova V, Wilczek H pain. Anti-selectin or anti-ICAM–1 treatment strongly (2003) Augmented Production of Proinflammatory Cytokines reduces endogenous peripheral opioid analgesia, ap- and Accelerated Allotransplantation Reaction in Heroin-Treated parently by blocking the extravasation of immune Mice. Clin Exp Immunol 132:40–45 cells containing β–endorphin, and by the consequent 5. Johnston IN, Westbrook RF (2003) Acute and Conditioned Sick- β ness Reduces Morphine Analgesia. Behav Brain Res 142:89–97 decrease of the –endorphin level in the inflamed tis- 6. Laughlin TM, Bethea JR, Yezierski RP, Wilcox GL (2000) sue (Machelska et al. 1998; Machelska et al. 2002). Cytokine Involvement in Dynorphin-Induced Allodynia. Therefore, the immune control of opioid action may Pain 84:159–167 demonstrate a dichotomous action in the periphery as 7. Machelska H, Cabot, PJ, Mousa SA, Zhang Q. Stein C (1998) Pain Control in Inflammation Governed by Selectins. Nat compared with the central nervous system. Med 4:1425–1428 8. Machelska H, Mousa,SA, Brack A, Schopohl JK, Rittner Clinical Relevance HL, Schafer M, Stein C (2002) Opioid Control of Inflamma- tory Pain Regulated by Intracellular Adhesion Molecule–1. J One of the reasons for decreased opioid analgesia in Neurosci 22:5588–5596 neuropathic pain conditions may be an enhanced ex- 9. Peterson PK, Molitor TW, Chao CC (1998) The Opioid-Cytokine pression of proinflammatorycytokines and chemokines Connection. J Neuroimmunol 83:63–69 in the CNS, which is evoked following peripheral nerve 10. Rady JJ, Fujimoto JM (2001) Confluence of Antianalgesic Ac- tion of Diverse Agents through Brain Interleukin1 β in Mice. J injury. It is well-established that exaggerated pain Pharmacol Exp Ther 299:659–665 states occur as a part of an inflammatory stress reaction. 11. Raghavendra V, DeLeo JA (2004) The Role of Astrocytes and Pre-clinical studies demonstrated that neutralizing pro- Microglia in Persistent Pain. In: Hertz L (eds) Non-Neuronal inflammatory cytokines restored the analgesic action Cells in the Nervous System: Function and Dysfunction. Elsevier, Amsterdam, pp 951–966 of opioids in neuropathic conditions, induced either 12. Raghavendra V, Rutkowski MD, DeLeo JA (2002) The by experimental diabetes or by L5 nerve transection Role of Spinal Neuroimmune Activation in Morphine Tol- in rats (Gul et al. 2000; Raghavendra et al. 2002). erance/Hyperalgesia in Neuropathic and Sham Operated Rats. Pathological pain is the result of a dynamic interplay J Neurosci 22:9980–9989 13. Raghavendra V, Tanga F, Rutkowski MD, DeLeo JA (2003) between hyperalgesic and analgesic mediators. During Anti-Hyperalgesic and Morphine-Sparing Actions of Propento- tissue injury or inflammation, both hyperalgesic and fylline following Peripheral Nerve Injury in Rats: Mechanistic 518 Cytokines

Implications of Spinal Glia and Proinflammatory Cytokines. Characteristics Pain 104:657–665 14. Steele AD, Szabo I, Bednar F, Rogers TJ (2002) Interaction be- Cytokines tween Opioid and Chemokine Receptors: Heterologous Desen- Cytokines are a heterogeneous group of proteins sitization. Cytokine Growth Factor Rev 13:209–222 15. Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim that were originally found to mediate activation of the JJ, Rogers TJ (2002) Heterologous Desensitization of Opioid immune system and inflammatory responses. They are Receptors by Chemokines Inhibits Chemotaxis and Enhances the produced by white blood cellsand a varietyof other cells Perception of Pain. Proc Natl Acad Sci USA 99:10276–10281 including neurons, Schwann cells and other glial cells. Most cytokines act on a variety of tissues, including the peripheral and central nervous systems. Cytokines are extracellular signaling proteins that form part of Cytokines a bi-directional circuit between the immune system and the nervous system, acting at hormonal concen- Definition trations through high-affinity receptors, and producing endocrine, paracrine and autocrine effects. In contrast Any of several small regulatory proteins (25 kDa), such to circulating hormones, they exert their effects over as the interleukins and lymphokines, that are released by short distances onto nearby cells. In vivo concentra- cells of the immune system and act as intercellular me- tions are in the range of a few pg to ng per ml. Due diators in the generation of immune and inflammatory to local cytokine effects at low concentrations, serum responses. They can act in an autocrine, paracrine, and levels may not reliably reflect activity. Cytokines are endocrine manner. Interleukins, interferons and tumor called ‘pleiotropic’, due to a broad range of redundant, necrosis factor (TNF) alpha are typical members of the frequently overlapping functions. Their activation or cytokine family. dysregulation is implied in a variety of disease states Adjuvant Analgesics in Management of Cancer- like sepsis, rheumatoid arthritis, Crohn’s disease, mul- Rated Bone Pain tiple sclerosis, skin diseases, and many more. Some Animal Models of Inflammatory Bowel Disease cytokines are labeled ‘pro-inflammatory’ or ‘Th1’, Cytokines as Targets in the Treatment of Neuropathic others ‘anti-inflammatory’or ‘Th2’, depending on their Pain effects on immune cells, in particular on lymphocytes. Cytokine Modulation of Opioid Action Cytokines, Regulation in Inflammation Cytokines and Pain Inflammatory Neuritis Muscle Pain in Systemic Inflammation (Polymyalgia Evidence from Experimental Studies Rheumatica, Giant Cell Arteritis, Rheumatoid Arthri- Numerous experimental studies provide evidence that tis) proinflammatory cytokines induce or facilitate inflam- Neutrophils in Inflammatory Pain matory aswellasneuropathic painandhyperalgesia.Di- Vascular Neuropathies rect receptor-mediated actions of cytokines on afferent Wallerian Degeneration nerve fibers have been reported, as well as cytokine effects involving downstream mediators. The first indications of a hyperalgesic effect of cytokines came from studies using intraplantar cytokine injections in the rat; Cytokines as Targets in the Treatment of interleukin-1β( IL-1beta)and tumornecrosisfactor Neuropathic Pain alpha (TNF-α) reduced mechanical nociceptive thresholds in a cyclooxygenase-dependent process. Cytokine 1 2 CLAUDIA SOMMER ,LINDA S. SORKIN antagonists reduced hyperalgesia in this animal model, 1Department of Neurology, University of Würzburg, indicating that the cytokines were activated in a classical Würzburg, Germany sequence (TNF⇒IL-1⇒ IL-6), and that activation of 2Anesthesiology Research, University of California, this pro-inflammatory cytokine cascade is an important San Diego, CA, USA stepinthedevelopmentofinflammatorypain(forreview [email protected], [email protected] see Poole et al. 1999). After nerve injury, cytokine production in the injured Synonyms nerve is upregulated, and blockade of the proinflamma- torycytokinesTNFαandIL-1βreducesbehavioralsigns NA; interleukins; Lymphokines; chemokines of hyperalgesia in experimental animals (for review see Sommer 2001). The mechanisms by which proinflam- Definition matory cytokines induce hyperalgesia have not yet been Extracellular signaling proteins within the immune sys- fully elucidated. tem and between the immune system and nervous sys- IL-1β, among its other actions involving secondary pro- tem. ductionofnitricoxide,bradykininorprostaglandins,has Cytokines as Targets in the Treatment of Neuropathic Pain 519 a direct excitatory action on nociceptive fibers, which nerve injury in animal models (Winkelstein et al. 2001). are activated within one minute by IL-1β application Spinal administration of exogenous TNFα and IL-1β (Fukuoka et al. 1994). In a skin-nerve in vitro prepara- produces pain behavior and neuronal sensitization in tion, brief exposure of the corium to IL-1β results in a vivo, with IL-1 being the more effective (Reeve et al. facilitation of heat-evoked calcitonin gene-related pep- 2000). In animals with nerve injury and pain behavior, C tide release from peptidergic neurons (Opree and Kress spinal administration of TNFα antagonists prevents or 2000). The short latency of the effect, and the absence reduces allodynia and hyperalgesia. Whereas spinal of the neuronal cell soma in the preparation, indicate IL-1β antagonists alone are seemingly without effect that the heat sensitization is independent of changes in in nerve injury models, they synergize with TNFα gene expression or receptor up-regulation. Further ex- antagonists causing a further reduction of allodynia. periments showed that IL-1β can act directly on sensory Interestingly, while this combination treatment reduces neurons to increase their sensitivity to noxious heat via the spinal cord expression of the pro-inflammatory cy- a mechanism involving IL-1 receptor I, tyrosine kinase tokine IL-6, spinal expression of the anti-inflammatory and protein kinase C (Obreja et al. 2002). cytokine IL-10 was unaffected. TNFα has been shown to lower mechanical activation Anti-inflammatory cytokines like IL-4 and IL-10 thresholds in C nociceptors of the rat sural nerve when seem to have anti-hyperalgesic actions in animal mod- injected subcutaneously (Junger and Sorkin 2000). els of pain (Wagner et al. 1998). IL-10 pretreatment While mechanisms of this action are unknown, the acute reduces the hyperalgesic responses to intraplantar in- TNF-induced decrease in K+ conductance may play an jections of carrageenan, IL-1β, IL-6 and TNFα (Poole important role (Diem et al. 2001). In vitro perfusion et al. 1999). Systemic IL-10 down-regulates local lev- of TNFα to dorsal root ganglia (DRG) elicits neuronal els of IL-1β,TNFα, and nerve growth factor (NGF) discharges in both A and C-fibers. Firing frequency after endotoxin injection into the hindpaw, and reduces is markedly higher and the discharge longer-lasting thermal and mechanical hyperalgesia. IL-4, delivered after nerve injury, indicating an increased sensitivity of by a viral vector, reduces behavioral signs of pain in an injured afferent neurons to TNFα (Schäfers et al. 2003). animal model of neuropathic pain. Furthermore, DRG neurons with injured afferents, and neighboring neurons attached to intact afferents running Clinical Applications within the same peripheral nerve, have an increased The most striking correlation between cytokine lev- immunoreactivity to TNFα (probable increased TNFα els and neuropathic pain comes from leprosy, where protein), and both display increased sensitivity to TNFα a subgroup of patients has elevated serum levels of (Schäfers et al. 2003, 2003a). Injection or perfusion of TNFα and IL-1; these patients suffer from excruciat- TNFα into/onto rat DRGs in vivo induces allodynia. ing pain. Treatment with thalidomide reduces TNFα Subthreshold quantities of TNFα, injected into a DRG secretion in peripheral blood mononuclear cells by at the same time that its spinal nerve was ligated resulted >90% and greatly reduces pain in the patients (Barnes in a synergy that manifests as faster onset of allodynia et al. 1992). In other human neuropathies, prelimi- and increased spontaneous pain behavior (Schäfers nary data also point to a correlation between cytokine et al. 2003). Thus, there is strong in vivo and in vitro expression and pain. Not all patients with elevated cy- evidence that injury results in increased endogenous tokine levels in their sural nerve biopsy had pain, but TNFα, and that injured nerve fibers are sensitized to the cytokine levels were increased more often in patients excitatory effects of TNFα. with painful neuropathies (Lindenlaub and Sommer Nucleus pulposus, the material within the verte- 2003), indicating that at least a subgroup of patients bral discs, is highly enriched with a variety of pro- with painful neuropathies might benefit from cytokine inflammatory cytokines. Subsequent to disc herniation, inhibition. Occasionally, inflammatory neuropathies it is likely that this material comes into contact with have been treated with TNFα inhibitors, but data on the dorsal roots. Application of autologous nucleus pain are lacking in these reports. One remarkable case pulposus to dorsal roots, or experimental disc herni- report describes remission of long standing complex ation in animals, results in pain behavior as well as regional pain syndrome (CRPS) after treatment with both ongoing and enhanced evoked activity in spinal thalidomide for Behçet’s disease (Ching et al. 2003). nociceptive neurons (Onda et al. 2003). Animals treated Anti-TNFα strategies have been used in various non- with either neutralizing antibodies to TNFα directly neuropathic painful conditions like AIDS-associated on the nerve root or with systemic TNFα antagonists, proctitis, rheumatoid arthritis, and HIV-associated aph- showed a marked reduction of both the neuronal activity thous ulcers. Many other reports have followed since (Onda et al. 2003) and the pain behavior, implicating a the advent of etanercept and infliximab :forex- role for TNFα in the process. ample, a controlled trial showing a beneficial effect of Increased spinal cord expression of TNFα,IL-1β,orIL- etanercept in ankylosing spondylitis, and a prospective 6 is associated with pain. Protein and mRNA levels of study with historical controls using infliximab in low all three cytokines increase in the spinal cord following back pain. 520 Cytokines, Effects on Nociceptors

Several studies have reported increased levels of cy- 15. Schäfers M, Lee DH, Brors D et al. (2003a) Increased Sensitivity tokines in the vicinity of herniated discs and a correla- of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-Alpha after Spinal Nerve tion of their presence to sciatica (Brisby et al. 2002). Ligation. J Neurosci 23:3028–3038 Inhibitors of TNFα have been used successfully for 16. Sommer C (2001) Cytokines and Neuropathic Pain. In: Hansson patients with chronic nerve root pain, but up to now P, Fields H, Hill R et al. (eds) Neuropathic Pain: Pathophysiology only data from case reports and uncontrolled studies and Treatment. IASP Press, Seattle, pp 37–62 17. Wagner R, Janjigian M, Myers RR (1998) Anti-Inﬂammatory have been available. Interleukin-10 Therapy in CCI Neuropathy Decreases Thermal In summary, evidence from numerous preclinical stud- Hyperalgesia, Macrophage Recruitment, and Endoneurial TNF- ies and preliminary data in humans point to a possible Alpha Expression. Pain 74:35–42 beneﬁcial role of cytokine inhibition in patients with 18. WinkelsteinBA,Rutkowski MD,SweitzerSM et al. (2001) Nerve Injury Proximal or Distal to the DRG Induces Similar Spinal painful neuropathy or radiculopathy. Randomized con- Glial Activation and Selective Cytokine Expression but Differen- trolled trials are needed to determine whether cytokine tial Behavioral Responses to Pharmacologic Treatment. J Comp inhibitors have a role in the treatment of neuropathic Neurol 439:127–139 pain.

References Cytokines, Effects on Nociceptors

1. Barnes PF, Chatterjee D, Brennan et al. (1992) Tumor Necro- VICTORIA C. J. WALLACE sis Factor Production in Patients with Leprosy. Infec Immun 60:1441–1446 Department of Anaesthetics, Pain Medicine and 2. Brisby H, Olmarker K, Larsson K et al. (2002) Proinflammatory Intensive Care, Chelsea and Westminster Hospital Cytokines in Cerebrospinal Fluid and Serum in Patients with Campus, London, UK Disc Herniation and Sciatica. Eur Spine J 11:62–66 [email protected] 3. Ching DWT, McClintock A, Beswick F (2003) Successful Treat- mentwithLow-DoseThalidomidein aPatient with BothBehcet‘s Disease and Complex Regional Pain Syndrome Type I. J Clin Synonyms Rheumatology 9:96–98 4. Diem R, Meyer R, Weishaupt JH et al. (2001) Reduction of Potas- Immunocytokines sium Currents and Phosphatidylinositol 3-Kinase-Dependent AKT Phosphorylation by Tumor Necrosis Factor-(alpha) Res- Definition cues Axotomized Retinal Ganglion Cells from Retrograde Cell Death In Vivo. J Neurosci 21:2058–2066 Cytokinesareafamilyofgrowthfactorproteinssecreted 5. Fukuoka H, Kawatani M, Hisamitsu T et al. (1994) Cutaneous primarily from leukocytes as part of the immune and Hyperalgesia Induced by Peripheral Injection of Interleukin-1β in the Rat. Brain Res 657:133–140 inflammatory response. 6. Junger H, Sorkin LS (2000) Nociceptive and Inflammatory Ef- fects of Subcutaneous TNFalpha. Pain 85:145–151 Characteristics 7. Lindenlaub T, Sommer C (2003) Cytokines in Sural Nerve Biop- sies from Inflammatory and Non-Inflammatory Neuropathies. Interactions with Peripheral Nociceptive Terminals Acta Neuropathol 105:593–602 Proinflammatory cytokines, such as IL-1, TNF-α and 8. Obreja O, Rathee PK, Lips KS et al. (2002) IL-1 Beta Potenti- IL-6, as well as other inflammatory mediators that cy- ates Heat-Activated Currents in Rat Sensory Neurons: Involve- ment of IL-1RI, Tyrosine Kinase, and Protein Kinase C. FASEB tokines influence as part of the inflammatory response, J 16:1497–1503 can directly stimulate and sensitise peripheral terminals 9. Olmarker K, Nutu M, Storkson R (2003) Changes in Spon- of small diameter nociceptors (C-fibres) influencing taneous Behavior in Rats Exposed to Experimental Disc transduction and transmission of the nociceptive sig- Herniation are Blocked by Selective TNF-Alpha Inhibition. Spine 28:1635–1641 nal contributing to peripheral sensitisation (Fig 1a). 10. Onda A, Yabuki S, Kikuchi S (2003) Effects of Neutralizing An- For example, a subcutaneous injection of IL-1, TNF-α tibodies to Tumor Necrosis Factor-Alpha on Nucleus Pulposus- or IL-6 has been shown to directly excite peripheral Induced Abnormal Nociresponses in Rat Dorsal Horn Neurons. α Spine 28:967–972 nociceptive fibres (Poole et al. 1999). Also, TNF- , 11. Opree A, Kress M (2000) Involvement of the Proinflammatory which causes the subsequent release of IL-1, produces Cytokines Tumor Necrosis Factor-Alpha, IL-1Beta, and IL-6 but thermal hyperalgesia and mechanical allodynia, as well not IL-8 in the Development of Heat Hyperalgesia: Effects on as endoneurial inflammation, demyelination, and ax- Heat-Evoked Calcitonin Gene-Related Peptide Release from Rat Skin. J Neurosci 20:6289–6293 onal degeneration whilst lowering C-fibre thresholds 12. Poole S, Cunha FQ, Ferreira SH (1999) Hyperalgesia from Sub- and inducing ectopic activity in single primary afferent cutaneous Cytokines. In: Watkins LR, Maier SF (eds) Cytokines nociceptive fibers (Junger 2000). Such stimulation of and Pain. Birkhäuser, Basel, pp 59–87 nociceptors not only results in signalling to the spinal 13. Reeve AJ, Patel S, Fox A et al. (2000) Intrathecally Adminis- tered Endotoxin or Cytokines Produce Allodynia, Hyperalgesia cord, leading to sensation/perception of pain, but also to and Changes in Spinal Cord Neuronal Responses to Nociceptive a local axon reflex. Importantly,SP acts directly via sur- Stimuli in the Rat. Eur J Pain 4:247–257 face expressed NK1 receptors, to degranulate mast cells 14. Schäfers M, Geis C, Svensson CI et al. (2003) Selective Increase causing release of histamine, which further sensitise of Tumour Necrosis Factor-Alpha in Injured and Spared Myeli- nated Primary Afferents after Chronic Constrictive Injury of Rat nociceptive terminals, and proinflammatory cytokines, Sciatic Nerve. Eur J Neurosci 17:791–804 thus inducing a SP-cytokine positive-feedback loop. Cytokines, Effects on Nociceptors 521

Cytokines, Effects on Nociceptors, Figure 1 (a) Interactions of cytokines with nociceptors at their peripheral terminals and in the DRG. Injurious stimuli induce immune and inflammatory cells to release cytokines and chemokines, which stimulate further release of cytokines and non-cytokine inflammatory mediators such as prostaglandins (PGs), NGF and nitric oxide (NO) from various tissue cells. Cytokines and various inflammatory mediators such as histamine (Hist) and bradykinin (BK) can activate nociceptor terminals to release neurotransmitters such as SP leading to neurogenic inflammation. Retrogradely transported signal proteins cause the release of cytokines and other factors from blood, neurones and glia (G) into the DRG which can activate intracellular cascades (see 1b) regulating gene transcription, cell phenotype and excitability and therefore sensory transmission to the spinal cord. (b) Highlighted region in (1a) (dashed line) representing examples of some of the intracellular mechanisms of proinflammatory cytokine-induced cell change. IL-1 via the IL-1R activates a number of protein kinase cascades including; protein tyrosine kinase (PTK), and protein kinase C (PKC) inducing intracellular Ca++ increase and phosphorylation of ion channels such as TRPV1 and others inducing changes in Na+ and Ca++ currents. Early events in all cascades involve MyD88, IL-1 receptor-associated kinase (IRAK-1) and a TNF receptor-associated factor (TRAF). Ras activation of p38 MAP kinase (MAPK) and Rac mediated transactivation of gene expression by NFkB regulation also occur. The IL-6/IL-6R complex activates; JAK which recruits STAT3 to the phosphorylated receptor, gp130, and activates the Ras/MAP kinase pathway via the SHP-2 pathway ultimately affecting nuclear transcription factors such as CREB, c-fos, and c-jun. In contrast to such kinase signalling, the TNF/TNFR complex is regulated by intracellular adaptor proteins (TRADD and TRAF), via which it activates the IKK complex to phosphorylate IkB, liberating NFkB to the nucleus (see Hanada et al. 2002; Obreja et al. 2002; Heinrich et al. 2003).

Proinflammatory cytokines can also modulate nocicep- receptors (Dray 1997), also upregulated by proinflam- tors indirectly, by stimulating the release of a variety of matory cytokines; prostaglandins, such as PGE2, which pronociceptive inflammatory mediators such as; BK, can be produced by almost all types of cells and is a which directly stimulates nociceptor terminals via BK well known key player in the inflammatory cascade and 522 Cytokines, Effects on Nociceptors inflammatory hyperalgesia (Samad et al. 2002); and age or of any action at receptors expressed by peripheral chemokines (small chemottractant cytokines) such nerveterminals,proinflammatorycytokinesactinginthe as IL-8 (CXCL8) which in turn stimulate the produc- DRG can rapidly induce aberrant responses in periph- tion of sympathomimetic amines capable of directly eral nociceptors (Sorkin et al. 1997, Watkins and Meier sensitising nociceptors (Sachs et al. 2001). 2000). Another major pronociceptive target of cytokine func- Retrogradely transported signals can also induce phe- tion is NGF, which is released by a variety of cells at the notypic changes in primary sensory neurons, such as in- site of infection/inflammation in response to proinflam- creased expression of BDNF, TRPV1, NAv1.8, CGRP, matory cytokines, and plays a role in exaggerated pain SP, and galanin (Watkins and Meier 2002), all of which states (Woolf et al. 1994) via direct (binding to TrκAre- can change the properties of nociceptive neurons. ceptorson nociceptive fibers) andindirect(via cytokine- In the DRG, G-protein coupled, chemokine recep- like actions, causing immune cells to accumulate and re- tors are expressed by small diameter nociceptors, lease their cellular contents exciting nociceptive fibers) suggesting a direct involvement of chemokines in no- actions on the nociceptive function. ciceptive signal transduction and the pathogenesis of Peripheral stimulation of nociceptive afferents can pain. This is supported by the fact that endogenous also produce an axon reflex, in which prodromic chemokines such as SDF1α/CXCL12, MDC/CCL22 nerve impulses travelling up the sensory axon initiate and RANTES/CCL5 or exogenous factors such as the antidromic impulses in neighbouring axons. This re- HIV-1 coat protein gp120, which is a ligand at the sults in a release of neuropeptides and neurogenic chemokine receptors CXCR4 and CCR5, have been inflammation at sites distant from the original stimuli shown to produce powerful excitatory effects on sen- increasing the area of sensitivity. sory neurons via increased calcium mobilization and Such cytokine driven, neurogenic inflammatory loops the lowering of the threshold for action potential gen- stimulate and sensitise nociceptors in the absence of fur- eration (Oh et al. 2001). Chemokine receptors are also ther peripheral stimulation, which could, in theory, cre- expressed by glial cells, the activation of which en- ateenough‘drive’tocreateandmaintainspinalcordsen- hances the release of neuroactive substances, including sitisation, resulting in persisting pain. NGF, NO, glutamate and other chemokines, which can further affect nociceptor activity and even lead to Influences in the DRG neurotoxicity. Cytokinescanalsohavedirectandindirecteffectsonno- ciceptor function, at the level of the DRG, resulting in Intracellular Mechanisms excitability and phenotypic changes. This contributes to Cytokines modulate nociceptor activity contributing altered synaptic transmission in the spinal cord (central to neural plasticity and pain, via the initiation of sensitisation) involved in the development of hyperalge- intracellular cascades of phosphorylation of constitu- sia and persistent pain (Fig. 1a). Levels of cytokines can tively expressed signal proteins involved in nociception increase in the DRG following inflammation and nerve and pain such as PKC, MAP kinase, Ras/Raf c-jun, damage in response to signal proteins produced at the c-fos and STAT (Fig 1b). As a result there are alter- site of damage, such as the cytokines LIF and IL-6 as ations to the transcription rate and/or posttranslational well as cytokine induced NGF, which are retrogradely changes in proteins involved in the pain pathway, transported by both intact and injured axons (Watkins which ultimately lead to a modification of transduction, and Maier 2000). Such signals can initiate the recruit- conduction and transmission functionality of these ment of immune cells to the DRG and induce prolifer- neurons. For example, IL-1 binds to the specific cell ation and activation of satellite (glial) cells, resulting in surface receptors, IL-1RI and IL-1RII; members of the release of a variety of growth factors, including cy- the Toll-like receptor superfamily of which IL-1R1 are tokines, into the extracellular fluid of the DRG where expressed by nociceptive neurons. IL-1RI-mediated they modulate sensory neuron, and/or glial cell function mechanisms, involving activation of tyrosine kinases via differentially expressed cytokine receptors. For ex- and PKC associated phosphorylation, lead to long last- ample, the proinflammatory cytokines IL-1 and TNF-α ing increases in voltage-sensitive sodium and calcium bind directly to neuronallyexpressed receptorsinducing channel conductance, increasing excitability of the rapid increases in sensory neuronal excitation, facilitat- cell as well as changes in specific receptor function ing pain transmission to the spinal cord. On the other (Obreja et al. 2002). In nociceptors, this may include hand, the primary receptor for IL-6 (IL6-R) is predom- phopshorylation of heat-transducing vanilloid recep- inantly expressed by glial cells and therefore IL-6, al- tors; TRPV1 or TRPVL-1, supported by evidence that though produced by DRG neurons, likely affects noci- IL-1β directly sensitises rat sensory neurons to heat. ceptor function indirectly (such as via Schwann cell re- Downstream pathways of IL-1Rs and TNF-α recep- lease of IL-1 and TNF-α), although receptor expression tors (TNFRI and TFNRII) ultimately activate NFκB, is likely to change under pathological conditions (De which modulates the expression of a variety of pro- Jongh 2003). In fact, even in the absence of nerve dam- teins implicated in nociceptor sensitivity and pain, Cytokines, Regulation in Inflammation 523 including growth factors and inducible enzymes such rons: Involvement of IL-1RI, Tyrosine Kinase and Protein Kinase as cyclooxygenase 2 (COX2) and inducible nitric oxide C. FASEB J 16:1497–1503 κ 8. Oh SB, Tran PB, Gillard SE, Hurley RW, Hammond DL, Miller synthase (iNOS) (Hanada 2002). NF B also promotes RJ (2001) Chemokines and Glycoprotein120 Produce Pain Hy- further proinflammatory cytokine and chemokine pro- persensitivity by Directly Exciting Primary Nociceptive Neu- duction, potentiating cytokine-mediated mechanisms rons. J Neurosci 21:5027–5035 C of nociceptor excitability and signalling. In addition 9. Poole S, Cunha FDQ, Ferreira SH (1999) Hyperalgesia from Sub- α cutaneous Cytokines. In: Watkins LR, Maier SF (eds) Cytokines to receptor function, the TNF- molecule itself may and Pain. Birkhauser, Basel, pp 59–88 cause changes in neuronal excitability due to pH facil- 10. Samad TA, Sapirstein A, Woolf CJ (2002) Prostanoids and Pain: itated insertion into lipid membranes, to form a central Unraveling Mechanisms and Revealing Therapeutic Targets. pore-like region forming voltage-dependent sodium Trends Mol Med 8:390–396 11. Song J, Jang YY, Shin YK, Lee C, Chung S (2000) N- channels, which may not only be associated with the Ethylmaleimide Modulation of Tetrodotoxin-Sensitive and generation of neuronal hyperexcitability, but may inter- Tetrodotoxin-Resistant Sodium Channels in Rat Dorsal Root act with endogenous sodium and calcium channels to Ganglion Neurons. Brain Res 855:267–273 increase membrane conductance (Kagan et al. 1992). 12. Sorkin LS, Xiao WH, Wagner R, Myers RR (1997) Tumour Necrosis Factor-Alpha Induces Ectopic Activity in Nociceptive In contrast, IL-6 signalling occurs via binding to the Primary Afferent Fibres. Neuroscience 81:255–262 α-subunit non-signalling receptor IL-6R (gp80), which 13. Watkins LR, Maier SF (2000) The Pain of Being Sick: Impli- leads to homodimerisation of the transmembranous cations of Immune-to-Brain Communication for Understanding signalling transducer receptor gp130, which signals Pain. Annu Rev Psychol 51:29–57 14. Watkins LR, Maier SF (2002) Beyond Neurons: Evidence that intracellularly via the JAK/STAT pathways to influence Immune and Glial Cells Contribute to Pathological Pain States. gene expression via MAPK (Heinrich et al. 2003). Physiol Rev 82:981–1011 IL-6R and gp130 are expressed predominantly on glial 15. Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J (1994) Nerve Growth Factor Contributes to the Generation of Inflam- cells; however, although peripheral nociceptors lack matory Sensory Hypersensitivity. Neuroscience 62:327–331 IL-6R subunits under normal physiological conditions, they do express gp130 molecules, and the expression patterns of each have been reported to change following nerve damage (De Jongh et al. 2003). Cytokines, Regulation in Inflammation

Antinociceptive Functions VICTORIA WALLACE In addition to the anti-inflammatory and antinocicep- Department of Anaesthetics, Pain Medicine and tive function of cytokines, such as IL-10, IL-4 and Intensive Care, Chelsea and Westminster Hospital IL-13 (Vale et al. 2003), there is evidence of the direct Campus, London, UK interaction of cytokines with nociceptorsin an antinoci- [email protected] ceptive manner. For example, IL-2 induces peripheral antinociception viatheIL-2Rspecificreceptor,which Synonyms is expressed in small and medium (i. e. nociceptive) Immunocytokines primary sensory neurons of DRG, and is transported to the peripheral axon terminals (Song et al. 2000). The Definition mechanism underlying cytokine-induced antinociception may include inhibition of neurotransmitter release, Cytokines are a large family of growth factor proteins due to Ca2+ channel blocking properties decreasing (MW 8-30 kD) secreted primarily from leukocytes (as nociceptor activity. well as a variety of cells) as part of the immune and inflammatory response. References Characteristics 1. De Jongh RF, Vissers KC, Meert TF, Booij LH, De Deyne CS, Heylen RJ (2003) The Role of Interleukin-6 in Nociception and Over 150 cytokines have been cloned, which may be Pain. Anesth Analg 96:1096–103 grouped into various sub-families, based upon func- 2. Dray A (1997) Kinins and their Receptors in Hyperalgesia. Can tional properties and receptor utilisation, although J Physiol Pharmacol 75:704–712 3. Hanada T, Yoshimura A (2002) Regulation of Cytokine Signaling nomenclature is somewhat confusing and arbitrary and Inflammation. Cytokine Growth Factor Rev 13:413–421 (Vilcek 1998). Cytokines that are particularly in- 4. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller- volved in regulation of inflammation are termed the Newen G, Schaper F (2003) Principles of Interleukin (IL)-6-type Cytokine Signalling and its Regulation. Biochem J 374:1–20 proinflammatory cytokines (which can also encom- 5. Junger H, Sorkin LS (2000) Nociceptive and Inflammatory Ef- pass the inflammatory chemokines) and the anti fects of Subcutaneous TNF-alpha. Pain 85:145–151 inflammatory cytokines. 6. Kagan BL, Baldwin RL, Munoz D, Wisnieski BJ (1992) For- mation of Ion-Permeable Channels by Tumor Necrosis Factor- Proinflammatory Cytokines Alpha. Science 255:1427–1430 7. Obreja O, Rathee PK, Lips KS, Distler C, Kress M (2002) IL-1 The major proinflammatory cytokines include tumour Beta Potentiates Heat-Activated Currents in Rat Sensory Neu- necrosis factor-α (TNF-α), interleukin-1α and β (IL-1α 524 Cytokines, Regulation in Inflammation and β) and interleukin-6 (IL-6), which are secreted in release of many cell specific neuroactive substances a sequential cascade (TNF-α>IL-1>IL-6), by a variety and inflammatory substances. of immune and inflammatory cells, in response to in- In general, proinflammatory cytokines act to increase flammation. A wealth of literature supports a role for vascular endothelial membrane permeability, and in- proinflammatory cytokines in the production of inflam- duce upregulation of endothelial adhesion molecules mation associated pain and hyperalgesia. For example, and thus leukocyte adhesion, migration and extrava- pain associated with signs of inflammation after periph- sation. Due to a self-promoting cytokine loop, there eral nerve injury in rodentscorrelateswith the number of is a rapid accumulation of proinflammatory cytokines proinflammatory cytokine-producing cells at the injury at the site of damage, ensuring a rapid onset of the site; and thermal hyperalgesia and mechanical allody- inflammatory response (Fig. 1). nia can be reduced via the blockade of IL-1 or TNF-α In the context of pain, which is a key component of (Watkins and Meier 2000). Furthermore, an intraplantar the inflammatory response designed to prevent fur- injection of TNF-α results in hyperalgesia, which lasts ther insult to the damaged site, it is important to note for several hours and can be associated with a cascade of that proinflammatory cytokines are released from and cytokine involvement, including IL-1 followed by IL-6, act upon neurones and glial cell, via which they sig- as well as the activation of IL-8 (Junger et al. 2000). nal to the brain that infection or injury has occurred TNF-α, a member of the TNF family of cytokines (Watkins and Maier 2000; Watkins and Maier 2002). is produced primarily by macrophages, and acts via This neuroimmune interaction can influence mech- the TNFRI and TNFRII receptors (Orlinick and Chao anisms implicated in the development of hyperalgesia 1998). Binding of TNF-α triggers intracellular sig- and persistent pain, which are associated with many in- nalling cascades to induce changes in gene expression, flammatory conditions. For example,cytokinesreleased mainly via the activation of NFκB. Effects can in- in damaged tissue can activate peripheral terminals of clude the upregulation of; proinflammatory cytokines, primary sensory neurones either directly, via neuronally adhesion molecules, chemokines, growth factors, in- expressed cytokine receptors, or indirectly via the stim- ducible enzymes such as cyclooxygenase 2 (COX2) ulation of other substances that have relevance to the and inducible nitric oxide synthase (iNOS) (Hanada production of pain such as prostaglandins, nitric oxide 2002), all of which can have effects on mechanisms of and nerve growth factor (NGF) (see cytokines, effects nociception. Importantly, TNF-α induces production on nociceptors ). Such activation enhances the release of IL-1, a member of the interleukin family, which is of neuroactive transmitters, such as substance P (SP), produced in two molecular forms (α and β)bymany enhancing neurogenic inflammation leading to sensi- cell types including mononuclear cells, fibroblasts, tisation and increased excitability of sensory primary synoviocytes, macrophages, keratinocytes, mast cells, afferents (Fig. 1) (Black 2002). Inflammation of, or glial cells, and neurons (Bianchi 1998). Additionally, damage to, the peripheral nerve itself causes the activa- the inactive precursor of IL-1 (pro-IL-1) is constantly tion of recruited and resident macrophages, fibroblasts, produced by keratinocytes and fibroblasts in the skin, mast cells, dendritic cells, and endothelial cells, all of and in increasing amounts following tissue damage, which can release proinflammatory cytokines which, during which degranulation of mast cells releases the due to their induction of oedema-associated disruption enzyme, chymase, which cleaves the IL-1 precursor to of the blood nerve barrier, can lead to further immune its active form. IL-1 binds to the specific cell surface invasion of the nervous system. Furthermore, activated receptors, IL-1RI and IL-1RII, which are members Schwann cells, which myelinate peripheral nerves, re- of the Toll-like receptor superfamily. Like TNF-α,the lease proinflammatorycytokines (as well as many other proinflammatoryand pronociceptiveactions of IL-1 are damaging substances such as NO, ROS, PGs and ATP). mediated via complex intracellular signalling cascades This can damage myelin, with resulting demyelination that ultimately activate NFκB. In the context of pain, and/or nerve degeneration ( Wallerian degeneration), IL-1 is likely to be the most important proinflammatory all of which can be associated with the development of cytokine, with many outcomes of other proinflamma- pain. tory cytokine actions occurring via IL-1 release. In most cell types, IL-1 and TNF-α induce the release of IL-6, a Chemokines member of the neuropoetic cytokine family. IL-6 plays Chemokines are a family of small chemoattractant a minimal role in inducing inflammatory mediators cytokines (MW 8-10kDa) that have potent leukocyte or other inflammatory cytokines in tissues, although activation and/or chemotactic activity. Over 50 have may play a role in inducing chemokine production. been identified so far, the majority of which are classed IL-6 binds to the α-subunit non-signalling receptor, into the CC group or CXC group based in their cys- IL-6R (gap80), leading to homodimerisation of the teine residues. Via actions on their specific G-protein transmembranous signal transducer receptor, gp130, coupled receptors, chemokines are intimately involved and an intracellulular cascade of phosphorylation (De in the orchestration of inflammatory responses, by in- Jongh 2003). This affects cell activity and initiates the ducing cell migration across a concentration gradient. Cytokines, Regulation in Inflammation 525

Cytokines, Regulation in Inflammation, Figure 1 A representation of the network of cytokine production in tissue, following typical injurious stimuli. Degranulation of local and infiltrating mast cells releases proinflammatory cytokines which stimulate further cytokine release from macrophages (Mac) attracted to the site of injury to phagocytose pathogens (* ), a process which in itself triggers cytokine production. Cytokines act to increase vascular permeability inducing leukocyte extravasation and further stimulating release of cytokines and non-cytokine inflammatory mediators such as PGs, growth factors and NO from various tissue cells (TC). IL-1 is also formed from its precursor pro-IL1 and chemokines are secreted enhancing further leukocyte migration from the bloodstream. Cytokines and various inflammatory mediators such as histamine and BK can activate primary sensory neurones to release neurotransmitters such as SP. Activation of Schwann cells causes further cytokine and chemokine release which can cause demyelination and degeneration of 1y afferents.

Although most pain research related to neuroimmune For example, the IL-1 receptor antagonist (IL-1ra), function has focussed on proinflammatory cytokines, a member of the interleukin cytokine family, is up- the involvement of chemokines in inflammatory pain regulated during inflammation and prevents binding and hyperalgesia has become more apparent (Boddeke of IL-1 to its receptors (Hopkins 2003). Additionally, 2001). In addition to immune cells, many nervous sys- the cellular receptors for both IL-1 and TNF-α exist temcells(neuronalandglial)arecapableofsynthesising in soluble forms, and are able to bind and neutralise chemokines and express a variety of chemokine recep- their cytokine ligands after being cleaved from the cell tors, suggesting that chemokines act as messengers surface. Some cytokines, such as IL-10, IL-4 (Hamilton between peripheral immune cells and sensory afferent et al. 2002) and LIF (see Gadient and Patterson 1999), neuronsfrominflamedsites.Evidencesupportsarolefor have anti-inflammatory activity and are able to down- a number of chemokines in inflammation and pain such regulate expression of pro-inflammatory cytokines. The as IL-8/CXCL8 (Bodekke 2001), SDF1α/CXCL12, actual role of LIF is however controversial, and has been MDC/CCL22 and RANTES/CCL5 (Oh et al. 2001), implicated as a proinflammatory cytokine (McKenzie which may act to increase intracellular calcium and, et al. 1996) and as an anti-inflammatory and analgesic therefore, cell excitability and release. cytokine (Banner et al. 1997). It is likely that the increased activation of leukocytes and, therefore, release Limiting Actions of Cytokines of proinflammatory cytokines, characteristic of chronic Since cytokines are potent mediators of potentially inflammation and associated persistent pain, involves damaging tissue responses, several mechanisms exist a dysfunction of these negative regulatory mechanisms to ensure that the effects of these cytokines are re- leading to sustained positive feedback cytokine-neural stricted, thereby limiting the inflammatory response. interactions. 526 Cytoprotection

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