Gathering/Management/Security DBS Deact

Daily Persistent Headache DBS

New Daily Persistent Headache Deep Brain Stimulation

DAMGO Deactivation

Definition Definition DAMGO is a μ opioid receptor selective enkephalin Many FMRI experiments show regions of cortex that derivative:[D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin. seem to respond in antiphase with the primary stimu- Opioids and Inflammatory Pain lus. This negative BOLD (blood oxygenated level dependent) response or deactivation is spatially and tem- porally linked to reductions in blood flow, and has been Dapsone shown to be primarily due to neuronal inhibition. Hippocampus and Entorhinal Complex, Functional Imaging Definition Nociceptor, Fatigue Dapsone is an antibacterial, belonging to a group of sulfonamide-like sulfones. It is used especially in the treatment of leprosy; administered orally. Dead Sea Hansen’s Disease Definition Dark Disc Disease This region in Israel is a major spa area for patients with various types of arthritis. Discogenic Back Pain Spa Treatment

Data Deafferentation

Deﬁnition Deﬁnition Data can be described in one of two of the following Deafferentation means interruption of afferent sensory ways: input due to nerve injury. This may be associated with i) Pieces of numerical or other information. chronic pain mainly due to mechanisms of peripheral ii) A set of facts from which conclusions can be drawn. and central sensitization. Although the lesion is usu- Postoperative Pain, Data Gathering and Auditing ally peripheral, lesions of ascending somatosensory pathways will lead to deafferentation of their target nuclei. Anesthesia Dolorosa Model, Autotomy Data Auditing/Collection/ Atypical Facial Pain, Etiology, Pathogenesis and Gathering/Management/Security Management Atypical Odontalgia Postoperative Pain, Data Gathering and Auditing Central Nervous System Stimulation for Pain 528 Deafferentation Pain

Cordotomy Effects on Humans and Animal Models Dorsal Root Ganglionectomy and Dorsal Rhizotomy Decision Theory Hyperpathia, Assessment Peripheral Neuropathic Pain Statistical Decision Theory Application in Pain As- Plexus Injuries and Deafferentation Pain sessment Thalamic Plasticity and Chronic Pain Thalamus, Dynamics of Nociception Deconditioned

Deafferentation Pain Definition Deconditioned refers to a state of poor physical condi- Definition tioning brought on by inactivity. Neuropathic pain generated in the central nervous sys- It is usually used to refer to a deterioration of physical tem, and secondary to interruption of afferent sensory conditioning, secondary to areduction in an individual’s pathways, projecting onto the concerned central struc- level of activity. The deconditioning may involve loss of ture.Theexistenceofhyperactiveneuronsinthedeaffer- strength, loss of flexibiIity, and reduced cardiovascular ented dorsal horn (DH) has been proven by microelec- function. trode recordings of the DH neurons, in humans as well Disability, Effect of Physician Communication as in animal experiments. Deafferentation pain may develop after avulsion of the brachial plexus, dorsal root rhizotomy or ganglionectomy, or other types of lesions Deep Brain Stimulation of peripheral nerves, or because of pathology of the central nervous system. N. WEISS,I.GARONZIK,A.SAMDANI,S.OHARA, Anesthesia Dolorosa Model, Autotomy F. A. LENZ BrachialPlexusAvulsionandDorsalRootEntryZone Johns Hopkins Medical Institutions, Department of Central Pain, Diagnosis Neurosurgery, Baltimore, MD, USA Dietary Variables in Neuropathic Pain fl[email protected] Dorsal Root Ganglionectomy and Dorsal Rhizotomy Synonyms DBS; Brain electrode Deception Definition Credibility, Assessment Electrical stimulation of subcortical structures in the brain including peri-ventricular grey; internal capsule somatic sensory and intralaminar nuclei of thalamus Decerebrated is a therapy for some patients with chronic pain.

Definition Characteristics Cerebral brain function (in an animal) and its impact on Introduction lower brain and spinal cord can be eliminated experi- The electrical stimulation of subcortical brain struc- mentally by removing the cerebrum, cutting across the tures for the treatment of chronic pain was first reported brain stem, or severing certain arteries in the brain stem. in the 1950s, when hypothalamic nuclei were stim- Postsynaptic Dorsal Column Projection, Anatomical ulated for pain control (Tulane University School of Organization Medicine, Dept. of Psychiatry and Neurology 1954; Pool et al. 1956). Over the next few decades, the sensory thalamus and periaqueductal gray (PAG) became Decidualization the most frequent targets for deep brain stimulation (DBS). This transition followed the observation of stimulation-evoked analgesia, first in animals and sub- Definition sequentlyinhumans(Hosobuchietal.1977;Richardson Forming of the deciduas, which is the changed en- and Akil 1977). dometrium (the lining of the uterus), after the blasto- Chronic pain is pain that occurs daily over a 6-month cyst (fertilized ovum after 4Ð9 days of development) is period. Nociceptive refers to pain produced by activa- implanted onto the endometrium. tion of peripheral nociceptors and transmitted to the NSAIDs, Adverse Effects central nervous system through intact somatosensory Deep Brain Stimulation 529 pathways. Examples of nociceptive pain include pain tered during an admission to a pain clinic. Often, they of acute trauma and cancer pain secondary to inva- underwent psychosocial assessment, and were selected sion of bone. This pain responds well to opiates. for stimulation if there is no evidence of psychological Neuropathic pain refers to pain arising from injury to or secondary gain issues. In many published studies, pa- the nervous system either peripherally (deafferentation tients have been subjected to intravenous morphine in- pain, e.g. diabetic neuropathy) or centrally (centralpain, fusion tests, based on the hypothesis that nociceptive but e.g. post-stroke pain) (Portenoy 1989). It has been pro- not neuropathic pain responds to opioids. Reversibility D posed that this type of pain does not respond to opiates of analgesia with naloxone is taken as further evidence (Arner and Meyerson 1988), although this proposal is of a nociceptive pain condition. If the patient’s pain was not universally accepted (Vecht 1989; Dellemijn 1999). likely to be nociceptive in origin, PAG stimulation was performed. If the pain appeared to be neuropathic, the Mechanisms of Action patient underwent thalamic stimulation. The mechanisms of action of deep brain stimulation of the PAG and sensory thalamus are not completely un- Intraoperative Targets derstood. Evidence supports the role of endogenous Localization of the surgical target for PAG has been opioid release in PAG stimulation: focal stimulation determined using different means by different authors. of the PAG attenuates nociceptive responses to painful All targets were determined relative to the anterior stimuli (Reynolds 1969), an effect that is reversed by commissure-posterior commissure (AC-PC) line, a opioid antagonists (Hosobuchi et al. 1977), and which third ventricular radiologic landmark with a relatively is associated with increased endogenous opioid levels fixed anatomic relationship to subcortical structures. in the third ventricle (Akil et al. 1978; Hosobuchi et al. Levy and co-workers targeted a point 1 mm below 1979). Several lines of evidence also suggest that the and 1 mm posterior to the posterior commissure, and mechanism of analgesia in PAG stimulation involves 3 mm lateral to the lateral wall of the third ventricle spinal connections (Basbaum and Fields 1984; Ma- (Levy et al. 1987). Young and Rinaldi targeted a point ciewicz and Fields 1986). PAG neurons synapse upon 2 to 3 mm below the AC-PC line, 12 to 14 mm poste- neuronsin themedullary nucleusraphemagnus(NRM), rior to the midpoint (MC) of the AC-PC line and 2 to which, in turn, sends a strong serotonergic projection to 3 mm lateral to the midline (Young and Rinaldi 1997). the dorsal horn. This analgesic effect is also abolished Hosobuchi targeted a site at the level of the opening of by cutting the descending pathways to the spinal cord. the aqueduct into the third ventricle and 3 mm lateral to The PAG, medullary NRM and dorsal horn all contain the midline (Hosobuchi 1986). The correct target was high levels of opiates and opiate receptors. Due to the identified by stimulation-evoked warmth, oscillopsia, important role apparently played by opioids, PAG stim- loss of up-gaze, elevation of both heart rate and blood ulation is usually indicated in chronic nociceptive pain pressure, or pain relief. If the electrode is implanted conditions. more ventrally and posterior Ð in periaquaductal grey, The mechanism by which sensory thalamic stimula- fear and anxiety are evoked by stimulation (Hosobuchi tion provides pain relief is less clearly understood. 1986). Periventricular gray, which is slightly rostral The target nucleus for this type of stimulation is the to PAG, has been targeted as an alternative site to PAG in principal somatosensory nucleus, known as ventral some studies. The periventriculargray is located 10 mm caudal (Vc) in humans and ventral posterior (VP) in posterior to MC, at the vertical level of the AC-PC line, other species. Stimulation of rat VP inhibits responses and 3 to 4 mm lateral to the midline (Youngand Rinaldi to noxious stimulation through an opioid-independent 1997). pathway (Benabid et al. 1983). The effects of so- Levy and co-workers described sites of thalamic targets matosensory thalamic stimulation on pain modulation for treatmentof deafferentationpain(YoungandRinaldi may be due to an inhibitory effect on Rexed’s laminae I 1997). Targets for facial deafferentation pain in the me- to V spinothalamic tract (STT) neurons, most likely dial Vc (facial representation of Vc) were chosen 8 mm through serotonergic pathways (Gerhart et al. 1984). posterior to the MC point, 8 mm lateral to the midline, Due to the relative independence of the opioid path- and 1 to 3 mm above the MC point. Deafferentation pain ways, somatosensory thalamic stimulation is indicated of the extremities was treated by stimulation of lateral in cases of chronic neuropathic pain. Vc (representation of the extremities), defined as a point 9mmposteriortoMC,10to12mmlateral,and2to3mm Patient Selection above the MC point. In other studies, targets were calcu- The issue of patient selection for placement of DBS for latedfromstandardatlasmaps.Allstudiesincludedape- the treatment of pain has been addressed in a number riod of postoperative testing with the electrode attached of published studies (Young and Rinaldi 1997; Levy et to an externalized lead. Patients were stimulated at dif- al. 1987; Hosobuchi 1986). These patients experienced ferent electrode combinations, voltages, pulse widths, chronic pain, unresponsive to medical or surgical ther- andfrequenciesuntiltheoptimalstimulationparameters apies over several years, and failed treatment adminis- forpainreliefweredetermined.Theresultsofthisperiod 530 Deep Brain Stimulation of postoperative testing were used to decide whether to common, and were usually treated adequately with implant the stimulator permanently. antibiotics. Removal of the hardware system and intravenous antibiotics were successful in treating the Results hardware infections. Ventriculitis (Propionobacterium) Three large studies have reported the results of deep and subdural empyema (Staphylococcus aureus) rarely brain stimulation for the treatment of pain. Young et al. occurred. retrospectively reviewed 178 patients over 14 years who Technical failures were reported in all studies, includ- had DBS for chronic pain (Young and Rinaldi 1997). ing electrode migration (2Ð10%) and insulation fracture Early in their experience, they relied on screening tests, (3Ð4%). Skin erosion was reported in 2% of cases. The such as response of pain to opiates and reversal of pain technicalcomplicationratehasdecreasedwiththenewly relief with naloxone, to determine the surgical target designed electrode. of DBS. Later in their experience, electrodes were im- Pain Treatment, Motor Cortex Stimulation planted in both PAG and Vc in most patients, and the Postherpetic Neuralgia, Pharmacological and Non- ideal stimulation parameters were determined through Pharmacological Treatment Options post-operative DBS programming. Of the 89 patients Stimulation Treatments of Central Pain with permanent implants, 62% experienced long-term pain relief. Long-term pain relief was obtained in 70% References of patients with nociceptive pain, and in 50% of patients 1. Akil H, Richardson DE, Hughes J, Barchas JD (1978) with neuropathic pain. Enkephalin-Like Material Elevated in Ventricular Cerebrospinal Another study reported the results of DBS for chronic Fluid of Pain Patients after Analgetic Focal Stimulation. Science pain in 161 patients over 80 months. Patients given pain 201:463Ð465 2. Arner S, Meyerson BA (1988) Lack of Analgesic Effect of Opi- relief with morphine infusion and reversal with nalox- oids on Neuropathic and Idiopathic Forms of Pain. Pain 33:11Ð23 one had PAG stimulation, those who had no response 3. Basbaum AI, Fields HL (1984) Endogenous Pain Control Sys- had Vcstimulation, and thosewith amixedresponsehad tems: Brainstem Spinal Pathways and Endorphin Circuitry. Ann Rev Neurosci 7:309Ð338 electrodes placed in both locations. Success was mea- 4. Benabid AL, Henriksen SJ, McGinty JF, Bloom FE (1983) Thala- sured by regular use of the electrode at initial (6 weeks) mic Nucleus Ventro-Postero-Lateralis Inhibits Nucleus Parafas- and long term (>6 weeks) follow-up. Overall, there was cicularis Response to Noxious Stimuli through a Non-Opioid a 61% initial success rate and a 30% long-term success Pathway. Brain Res 280:217Ð231 5. Dellemijn P (1999) Are Opioids Effective in Relieving Neuro- rate.Patientswithnociceptivepainhada56%initialsuc- pathic Pain? Pain 80:453Ð462 cess rate and a 32% long-term success rate, while pa- 6. Gerhart KD, Yezierski RP, Wilcox TK, Willis WD (1984) Inhi- tients with neuropathic pain experienced 20Ð50% suc- bition of Primate Spinothalamic Tract Neurons by Stimulation in cessrates(Levy etal. 1987). Ina thirdstudy,122patients Periaqueductal Gray or Adjacent Midbrain Reticular Formation. J Neurophysiol 51:450Ð466 had thalamic DBSplaced for chronic pain, with68%ini- 7. Hosobuchi Y, Adams JE, Linchitz R (1977) Pain Relief by Elec- tial and 57% long-term success rates (Hosobuchi 1986). trical Stimulation of the Central Gray Matter in Humans and its A meta-analysis of 13 studies (1114 patients) evaluat- Reversal by Naloxone. Science 197:183Ð186 ing DBS for the treatment of chronic pain reported that 8. Hosobuchi Y, Rossier J, Bloom FE, Guillemin R (1979) Stimu- lation of Human Periaqueductal Gray for Pain Relief Increases 50% of all patients experienced long term pain relief. Immunoreactive Beta-Endorphin in Ventricular Fluid. Science Patients with nociceptive pain experienced a 60% long- 203:279Ð281 term relief of pain with PAG stimulation. Patients with 9. Hosobuchi Y (1986) Subcortical Electrical Stimulation for Con- neuropathic pain experienced a 56% long-term success trol of Intractable Pain in Humans. Report of 122 cases (1970- 1984). J Neurosurg 64:543Ð553 rate with Vc stimulation. 10. Lenz FA, Kwan HC, Martin R, Tasker RR, Richardson RT, Dostrovsky JO (1994) Characteristics of somatotopic organi- Complications zation and spontaneous neuronal activity in the region of the human principal sensory nucleus in patients with spinal cord Hemorrhage is the most serious complication of DBS, transection. J Neurophysiol 72:1570-1587 occurring in 14/441 cases and leading to 3 deaths. This 11. Lenz FA, Zirh AT, Garonzik IM, Dougherty PM (1998) Neuronal has been attributed to the design of the electrode, which Activity in the Region of the Principle Sensory Nucleus of Human has since been modified (Levy et al. 1987; Hosobuchi Thalamus (Ventralis Caudalis) in Patients with Pain Following Amputations. Neuroscience 86:1065Ð1081 1986; Young and Rinaldi 1997). Neurologic sequelae 12. Levy RM, Lamb S, Adams JE (1987) Treatment of Chronic Pain of stimulation were reported in 7% of cases, including by Deep Brain Stimulation: Long Term Follow-up and Review diplopia, vertical gaze paresis, blurred vision, oscillop- of the Literature. Neurosurgery 21:885Ð893 sia, hemineglect and hemiparesis. In one study, persis- 13. Maciewicz R, Fields HL (1986) Pain pathways. In: Asbury AK, McKhann GM, McDonald WI (eds) Diseases of the Nervous Sys- tent headache occurred in 50% of cases; however, this tem. Clinical Neurobiology. W.B. Saunders Company, Philadel- was not mentioned in others (Youngand Rinaldi 1997). phia, London, pp 930Ð940 Infections occurred in 5Ð12% of cases (Young and 14. PoolJL, ClarkWK, HudsonP,LombardoM(1956)Hypothalamic- Rinaldi 1997; Levy et al. 1987; Hosobuchi 1986), with Hypophysial Dysfunction in Man. Laboratory and Clinical Assessment. In: Guillemin R, Guillemin R, Carton CA (eds) staphylococcus species being the majority of causative Hypothalamic-Hypophysial Interrelationships. Thomas, Spring- organisms. Stitch and subgaleal infections were most field, pp 114Ð124 Degenerative Joint Disease 531

15. Boivie J (1994) Central pain. In: Wall PD, Melzack R (eds) Text- Definition 1- book of Pain. Churchill Livingston, Edinburgh, pp 87 902 Commonlyaffectsthelowerlegandcanpresentasapain 16. Radhakrishnan V, Tsoukatos J, Davis KD, Tasker RR, Lozano AM, Dostrovsky JO (1999) A Comparison of the Burst Activity of syndrome mimicking sciatica with primarily distal ex- LateralThalamicNeuronsinChronic Pain andNon-PainPatients. tremity pain. Pain 80:567Ð575 Postoperative Pain, Venous Thromboembolism 17. Reynolds DV (1969) Surgery in the Rat During Electrical Anal- gesia Induced by Focal Brain Stimulation. Science 164:444Ð445 Sciatica 18. Richardson DE, Akil H (1977) Pain Reduction by Electrical Brain D Stimulation in Man: Part II: Chronic Self Administration in the Periaqueductal Gray Matter. J Neurosurg 47:184Ð194 19. Tulane University, School of Medicine.Dept.of Psychiatry Default Value and Neurology (1954) Studies in Schizophrenia. A Multi- disciplinary Approach to Mind-Brain Relationships. Harvard Definition University Press, Cambridge 20. Turk DC, Okifuji A (2001) Pain Terms and Taxonomies of Pain. Values attributed to a variable or data as a base value, In: Loeser JD (ed) Bonica’s Management of Pain. Lippincott Williams & Wilkins, Philadelphia, Baltimore, New York, Lon- which remains unless replaced by the user. don, Buenos Aires, Hong Kong, Sydney, Tokyo, pp 17Ð25 Postoperative Pain, Data Gathering and Auditing 21. Vecht ChJ (1989) Nociceptive Nerve Pain and Neuropathic Pain. Pain 39:243Ð244 22. Young RF, Rinaldi PC (1997) Brain stimulation. In: North RB, Levy RM (eds) Neurosurgical management of pain. Springer- Definition of Disability (Adults) Verlag, New York, Berlin, Heidelberg, pp 283Ð301 Definition The inability to engage in any substantial gainful activ- Deep Dysparuenia ity by reason of any medically determinable physical or mental impairment or combination of impairments, which is expected to result in death or that has lasted or Definition can be expected to last for a continuous period of not less Lower abdominal pain exclusively during intercourse. than 12 months. Gynecological Pain and Sexual Functioning Disability Evaluation in the Social Security Admin- istration

Deep Sedation Definition of Disability for Individuals under Age 18 (SSI Program Only) Definition Definition Adrug-induced stateof depressed consciousnessduring A medically determinable physical or mental impair- which patients are not easily aroused and may need air- ment or impairments that result in marked and severe way and ventilatory assistance, although they purpose- functional limitations and that meet the duration re- fully respond to repeated or painful stimulation. quirement. Pain and Sedation of Children in the Emergency Set- Disability Evaluation in the Social Security Admin- ting istration

Deep Somatic Pain Degenerative Disease Deﬁnition Spinal Dorsal Horn Pathways, Muscle and Joint Abiomechanicalandpathologicconditioncausedbyde- generation, inﬂammation, or infection. Chronic Back Pain and Spinal Instability Deep Venous Thrombosis Degenerative Joint Disease Synonyms Blood clot; DVT Arthritis Model, Osteoarthritis 532 Dejerine-Roussy Syndrome

pain. Some controversy exists regarding the relation Dejerine-Roussy Syndrome between maximum voluntary force and symptoms of soreness. Ebbeling and Clarkson suggested that there is Central Pain, Diagnosis no, or very little, relationship between the development of soreness and decrease of muscle strength (Ebbel- ing and Clarkson 1989). Return of maximum muscle Dejerine-Sottas Syndrome (Neuropathy) strength to pre-exercise levels takes between 24 h and 2 weeks. Synonyms Bobbert and co-workers (Bobbert et al. 1986) reported an increase in limb volume 24Ð72 h h after eccentric DSN activity of the calf. Intramuscular edema of the biceps, Definition as verified by magnetic resonance imaging, is maxi- mized at 72 h after eccentric activity. The stiffness and A severe form of inherited neuropathy that is clinically swelling associated with DOMS is probably an effect detected during infancy. due to edema occurring in the perimuscular connective Hereditary Neuropathies tissue. Regardless of whether the swelling is intra- or extra-cellular, an increase in the intramuscular pressure is implicated. In addition to increased tenderness during Delayed Muscle Soreness palpation, the examiner will find prolonged strength loss, a reduced range of motion and elevated levels of Delayed Onset Muscle Soreness creatine kinase in the blood. Frequently, muscle cramps accompany DOMS. DOMS is primarily associated with the eccentric com- ponentofexercise(Asmussen1952)Duringaneccentric Delayed Onset Muscle Soreness action, a contracted muscle is forced to elongate while JAN FRIDÉN producing tension. Its counterpart, concentric action, Department of Hand Surgery, Sahlgrenska University produces tension during muscle shortening. The in- Hospital, Göteborg, Sweden termediate, isometric contraction, produces tension [email protected] while the muscle remains essentially at the same length (Fig. 1). All three actions are common components of Synonyms daily movement. The tensiongeneratedduringeccentric action is higher than that for either of the other actions Delayed Muscle Soreness; Exercise-Induced Muscle (Katz 1939) although fewer motor units are recruited Soreness; DOMS (Bigland-Ritchie 1976). Definition Delayed onset muscle soreness(DOMS) isthe sensation of muscular discomfort and pain during active contractions that occurs 24Ð48 h after strenuous exercise. The initial symptoms are most evident at the muscle tendon junctionandthereafterspreadthroughouttheentiremus- cle. Muscle soreness and injury are associated with intense exercise and are more pronounced if the exercise performed is new to the individual. Characteristics Sore muscles after exercise are stiff, tender and aching, symptoms that are aggravated by active muscle contractions. The symptoms of DOMS develop during the first 24Ð48 h, , peak between 24 and 72 h and usually disappear without intervention within 5Ð7 days (Armstrong 1984; Ebbeling and Clarkson 1989; Fridén 1981). The soreness has been reported by some to be localized at the muscle-tendon junction, while others Delayed Onset Muscle Soreness, Figure 1 Generalized relationship be- describe the pain as being diffusely spread throughout tween muscle length, force and velocity. Note the very high forces occurring the muscle. Regardless of the exact location, palpation, at ”negative” velocities (from Fig. 6, Fridén and Lieber 1992, Med Sci Sports passive stretching and renewed activity aggravate the Exerc 24:521–530). Delayed Onset Muscle Soreness 533

Due to the nature of an eccentric action, the tension gen- tic, destructive changes in muscle ultrastructure may erating mechanism can be expressed in two phases; the occur in response to unusual demands. DOMS and ul- muscle contractsto generate tension and then the muscle trastructural disruptions are selectively associated with is passively stretched by an external force while gener- exercise involving EC (Fridén 1984; Fridén et al. 1981) ating additional tension. and have been reported in both animal and human mod- It is still unknown whether the initial decline of strength els. Such changes may require several weeks to resolve after eccentric contractions (EC) is because of injury and often lead to muscle hypertrophy and strengthening. D or fatigue or a combination of both. Some authors have In previous studies, two pieces of mechanical evidence referred the immediate loss of strength to overstretch of suggested that desmin plays a direct mechanical role sarcomeres resulting in a non-optimal overlap between in the force loss after EC (Fig. 2). Desmin immunostain- actin and myosin filaments. It has been suggested ing was rapidly lost, as fast as 15 min into a single bout that during eccentric exercise some sarcomeres are of EC (Lieber et al. 1996) and a strong linear correla- stretched beyond overlap and thereby injured, while tion was seen between the magnitude of desmin loss and others maintain their length. Despite the great force loss of muscle force generated after EC. Recently, it has loss after eccentric contractions, the resting membrane been hypothesized that there is a relationship between potentials of isolated muscles fatigued by eccentric force loss, desmin immunostaining, transcriptional up- or isometric contractions were similar (Warren et al. regulation and the ultimate increase in desmin content 1993). Since there is no evidence of excitation failure, persarcomere(Barashetal.2002;Petersetal.2003).Di- the ability to produce action potentials is expected to be rect mechanical data demonstrated that reinforced sar- unaffected. Lieber and Fridén showed that it is not high comeres are highly resistant to EC-induced injury. force per se which causes muscle damage following In addition to injuries to muscle fibers, there is evidence eccentric contraction, but the magnitude of the active ofdisturbancetomusclesenseorgansandofpropriocep- strain, i.e. strain during active lengthening (Lieber and tion after eccentric exercise. The peripheralcontribution Fridén 1993). The active strain hypothesis is described to perturbations of force perception after eccentric ex- in terms of the interaction between the myofibrillar ercise is, however, small and the centrally derived sense cytoskeleton, the sarcomere and the sarcolemma. of effort plays the most important role. Proske and Mor- It is generally agreed that the initial force decline is gan made the common observation that a second period due to mechanical injury. A number of mechanical of exercise, for example 1 week after the first, produces factors such as muscle length, force and velocity seem much less damage (Proske and Morgan 2001). One pro- to play roles in the consequences of eccentric contrac- posed mechanism for this adaptation may be an increase tions. Newham and colleagues found more pronounced in sarcomere number in muscle fibers. It is postulated strength loss after eccentric exercise at a long muscle that the adaptation is likely to lead to a secondary shift in length compared to a short muscle length (Newham et the muscle’s optimum length for active tension. The au- al. 1988). Although the nature of morphological injury thors conclude that the ability of muscle to adapt quickly to the muscle has been well documented and reported, after damage from a single boutof eccentric exercise im- the mechanism of the injury is not fully understood. plies the use in clinical applications of mild eccentric Strenuous exercise causes a disturbance of the muscle’s exercise for protecting a muscle against more major in- homeostasis. Although muscle tissue is extremely plas- juries.

Delayed Onset Muscle Soreness, Figure 2 Schematic depiction of eccentric contraction-induced muscle damage. Muscle fiber strain results in disruption of the intermediate filament network. Disruption of the intermediate filaments causes loss of the sarcomere’s structural integrity and misalignment of striated bands. 534 Delayed Severe Respiratory Depression

Nocifensive Behaviors, Muscle and Joint δ Stretching Delta( ) Opioid Receptor(s)

References Synonyms 1. Armstrong RB (1984) Mechanisms of exercise-induced delayed OP1 receptors; DOP onset muscular soreness: a brief review. Med Sci Sports Exerc 16: 529Ð538 Definition 2. Asmussen E (1952) Positive and negative muscular work. Acta Physiol Scand 28:364Ð382. Receptors that preferentially bind enkephalins and 3. Barash IA, Peters D, Fridén J et al. (2002) Desmin cytoskeletal enkephalin-like drugs. It was originally named for its modifications after a bout of eccentric exercise in the rat. Am J discovery in the mouse vas deferens. The receptor was Physiol 283:958Ð563 4. Bigland-Ritchie B, Woods JJ (1976) Integrated electromyogram cloned in 1992. They are present throughout the telen- and oxygen uptake during positive and negative work. J Physiol cephalon and spinal cord. Agonists are associated with 260:267Ð277 spinal analgesia. 5. Bobbert MF, Hollander AP, Huijing PA (1986) Factors in delayed Opiates During Development onset muscular soreness of man. Med Sci Sports Exerc 18:75Ð81 6. Ebbeling CB, Clarkson PM (1989) Exercise-induced muscle Opioid Receptors damage and adaptation. Sports Med 7:207Ð234 Postoperative Pain, Transition from Parenteral toOral 7. Fridén J (1984) Changes in human skeletal muscle induced by long term eccentric exercise. Cell & Tissue Res 236:365Ð372 8. Fridén J, Sjöström M, Ekblom B (1981) A morphological study of delayed muscle soreness. Experientia 37:506Ð507 Delta(δ) Sleep 9. Katz B (1939) The relation between force and speed in muscular contraction. J Physiol 96:45Ð64 10. Lieber RL, Fridén J (1993) Muscle injury is not a function of Definition muscle force but active muscle strain. J Appl Physiol 74:520Ð526 Delta sleep refers to stages 3 and 4 of non-REM (rapid 11. Lieber RL, Thornell LE, Fridén J (1996) Muscle cytoskeletal disruption occurs within the first 15 minutes of cyclic eccentric eye movement) sleep. contraction. J Appl Physiol 80:278Ð284 Fibromyalgia 12. Newham DJ, Jones DA, Ghosh G et al. (1988) Muscle fatigue and pain after eccentric contractions at long and short length. Clin Sci 74:553Ð557 13. Peters D, Barash I, Burdi M et al. (2003) Asynchronous func- Demand Characteristics tional, cellular and transcriptional changes after a bout of eccentric exercise in the rat. J Physiol 553:947Ð957 14. Proske U, Morgan DL (2001) Muscle damage from eccentric Definition exercise: mechanism, mechanical signs, adaptation and clinical Thisterm refersto the demandsof the situation that must applications. J Physiol 537:333Ð345 15. Warren GW, Hayes D, Lowe DA et al. (1993) Mechanical factors beconsideredinthecontextofintroducinghypnosis.Ex- in the initiation of eccentric contraction-induced injury in rat perimental subjects tend to guess at the experimenter’s soleus muscle. J Physiol 464:457Ð475 objectives and then behave accordingly in order to be socially compliant and co-operative. This tendency is clearly important in any therapeutic interaction where Delayed Severe Respiratory Depression the patient may be trying to please the doctor. Therapy of Pain, Hypnosis Definition Severe slowing or arrest of spontaneous breathing, usu- Dementia ally caused by morphine administered close to the spinal cord (epidurally or directly into the cerebrospinal fluid) Definition Postoperative Pain, Acute Pain Team A syndrome characterized by a decline in multiple cognitive functions occurring in clear consciousness. Cancer Pain, Assessment in the Cognitively Impaired Delirium

Deﬁnition Demographic An acuteor subacutesyndromewithwaxingandwaning Deﬁnition levels of consciousness, global cognitive impairment, a reduced ability to focus attention, sustain attention or to Statistical characteristics of populations such as age, ed- shift attention and disorganized wake-sleep cycle. ucational attainment or income. Cancer Pain, Assessment in the Cognitively Impaired Pain in the Workplace, Risk Factors for Chronicity, Cancer Pain Management, Overall Strategy Demographics Demyelination 535

myelinated zones. In particular, demyelination causes a Demyelination striking increase in the axonal membrane capacitance. 1 2 Thus, as electrical signals propagate down an axon, the MATTHEW N. RASBAND ,PETER SHRAGER + 1University of Connecticut Health Center, Farmington, current available to trigger the next group of Na chan- CT, USA nelsisreduced due to capacitativechargingof the axonal 2Department of Neurobiology and Anatomy, University membrane. Demyelination also results in dysregulation of Rochester, Rochester, NY, USA of myelin’s ‘active’ properties. It may be that disruption D [email protected], [email protected] of these ‘active’ properties contributes to the generation of neuropathic pain following demyelination. Definition While alterations to the passive properties of axons af- terdemyelinationarewellunderstood,theconsequences Alargepercentageoftheaxonsinthenervoussystemare for the active properties of myelin are mostly unknown. ensheathed by a lipid rich membranecalled myelin.This As a result, recent work has focused on how myelin- sheath is essential for rapid and efficient conduction of axon interactions regulate the excitable properties of ax- electrical signals along axons. Demyelination is the loss ons. For example, a variety of experimental models have of the myelin sheath and results from disease or injury. been used to investigate the consequences of demyelination and remyelination on Na+ channel clustering and Characteristics expression. Proper nervous system function depends on the transmission of electrical signals ( action potentials) along Acute Demyelination axons and over relatively long distances. In order to Peripheral demyelination has been shown to dramat- facilitate conduction in a rapid and efficient man- ically influence the localization of ion channels. For ner, vertebrates have developed a lipid rich sheath, example, injection of the weak detergent lysolecithin called myelin, which confers several passive elec- into a peripheral nerve causes a transient, focal de- trical properties onto axons. These properties include myelinated lesion about 1 week after the injection. This high membrane resistance and low membrane lesion can be remyelinated by Schwann cells during the capacitance. Myelin also plays several active roles that second and third weeks post-injection. However, the determine axonal excitability. For example, myelin- architecture of this new myelin is somewhat different axon interactions restrict sodium (Na+) channels than before: sheaths are thinner and shorter (Fig. 1b) to regularly spaced gaps in the myelin sheath called (Dugandzija-Novakovic et al. 1995). Therefore, in or- nodes of Ranvier (Fig. 1a, arrow), and compact myelin der to support action potential conduction, new nodes regulates the kinds of Na+ channels expressed in axons of Ranvier with high densities of Na+ channels must (for a more comprehensive review, see Salzer 2003). be formed in regions that were formerly covered by Together, these active and passive properties facilitate compact myelin and characterized by a low density of rapid and efficient action potential conduction by de- channels (Fig. 1b, arrowheads) (Shrager 1989). This creasing loss of electrical charge in regions covered by model has permitted a careful analysis of Na+ channel myelin, and by regenerating the action potential at each localization subsequent to acute demyelination and node of Ranvier. during remyelination (Dugandzija-Novakovic et al. Myelin is made by glial cells: Schwann cells in the 1995). Specifically, regions of demyelinated axon can peripheral nervous system (PNS) and oligodendrocytes be seen to retain Na+ channel clusters. Some of these in the central nervous system (CNS). Demyelination, or clusters even appear indistinguishable from those found loss of the myelin sheath, is most commonly associated in normal axons (Fig. 1c), suggesting that in the ab- with autoimmune diseases (e.g. multiple sclerosis (MS) sence of overlying myelinating Schwann cells, neurons in the CNS and Guillain-Barre syndrome in the PNS) or have intrinsic mechanisms that cause clusters of Na+ traumatic injury (e.g. spinal cord crush), but may also channels to be retained. In other places, Na+ channel be a consequence of mutations in a variety of myelin clusters (Fig. 1d, arrow) can be seen to have a ‘tail’ of proteins (e.g. various types of Charcot-Marie-Tooth immunoreactivity leading away from the main cluster disease). In most cases of demyelination in the PNS, (Fig. 1d, arrowheads). This situation is most often seen Schwann cellsare able to remyelinate axons. In contrast, adjacent to heminodes (where the myelin on one side in the CNS, oligodendrocytes are much less efficient of a node has been lost and the sheath on the other at remyelination. This is thought to be a consequence side remains intact). As remyelination occurs, single of differences between the PNS and CNS extracellular axons can be seen to have multiple Na+ channel clusters environments, as well as intrinsic differences between between remyelinating Schwann cells (Fig. 1e; the two Schwann cells and oligodendrocytes. Na+ channel clusters identified by the arrowheads are Subsequent to demyelination, the passive electrical found in the same axon and are only about 25 μm apart). properties of axons are dramatically altered, resulting As remyelination progresses, these clusters appear to in failure to conduct action potentials through de- be ‘pushed’ ahead of the myelinating Schwann cell 536 Demyelination

Demyelination, Figure 1 Na+ channel clusters in myelinated, demyelinated, and remyelinating peripheral axons. (a) A node of Ranvier (arrow) labeled for Na+ channels. The outline of the myelin sheath can also be seen. (b) Cartoon illustrating that remyelinated axons have shorter and thinner sheaths with new nodes of Ranvier in formerly internodal zones. (c) A Na+ channel cluster in a demyelinated axon. (d) A heminode with a Na+ channel cluster (arrow) and ‘tail’ of Na+ channel immunoreactivity (arrowheads). (e) Two Na+ channel clusters (arrowheads), located on the same remyelinating axon. (f) Two Na+ channel clusters just before they fuse to form a new node of Ranvier. Scalebars = 10 μm. until they finally fuse and form a new node of Ranvier. the consequences of chronic demyelination for Na+ Figure 1f shows two Na+ channel clusters (11 days after channel expression and localization. Some of the first lysolecithin injection) just before they fuse at a nascent experiments relied on mutant dysmyelinating mice to node of Ranvier. assess these characteristics. For example, we showed that the localization of Na+ channels was dramatically Chronic Demyelination disrupted in axons of the hypomyelinated mouse mutant One major difference between lysolecithin mediated Shiverer (Rasband et al. 1999). Further, Westenbroek et demyelination and many forms of disease or injury al. (1992) showed that the expression of one particular related demyelination is that the latter forms are usually type of brain Na+ channel (Nav1.2) was dramatically chronic. As a result, lessons learned from acute de- increased in these mice. However, subsequent studies myelination may not be generally applicable to chronic demonstrated that during normal development, Nav1.2 demyelination. To date, few studies have focused on is found in premyelinated and actively myelinating Dendritic Spines 537 axons (Boiko et al. 2001). Therefore, the differences in Although very little is known about the development of Na+ channel expression and localization seen in Shiv- neuropathic pain asa consequence of demyelination, fu- erer may be related to developmental defects, rather turestudiesdesignedtodeterminethemolecularandcel- than a consequence of demyelination. lular mechanisms underlying control of both Na+ chan- To directly address whether chronic demyelination can nel localization and expression may lead to the ability to influence the kinds of Na+ channels present in CNS directly modulate neuronal activity. However, one thing axons, Craner et al. (2003) examined the localization of is clear: in the arena of neuropathic pain, myelinating D Nav1.2 and Nav1.6 in an inflammatory mouse model cells such as Schwann cells and oligodendrocytes are of CNS demyelination [ experimental allergic en- not simply bystanders, but instead play active roles by cephalitis (EAE)], and Rasband et al. (2003) examined modulating the excitable properties of sensory neurons. localization and expression levels of these same Na+ channels in a genetic, adult onset model of chronic CNS References demyelination. Each of these studies showed essentially 1. Boiko T, Rasband MN, Levinson SR et al. (2001) Compact the same result: that chronic demyelination results in Myelin Dictates the Differential Targeting of Two Sodium a loss of clustered Na+ channels, but a concomitant Channel Isoforms in the Same Axon. Neuron 30:91Ð104 increase in Nav1.2 expression levels. Indeed, Rasband 2. Craner MJ, Lo AC, Black JA et al. (2003) Abnormal Sodium Channel Distribution in Optic Nerve Axons in a Model of In- et al. (2003) showed a 6-fold increase in their model flammatory Demyelination. Brain 126:1552Ð1561 of the amount of Nav1.2 found in chronically demyeli- 3. Dugandzija-Novakovic S, Koszowski AG, Levinson SR et al. nated optic nerve axons. These Nav1.2 channels were (1995) Clustering of Na+ Channels and Node of Ranvier For- found diffusely distributed throughout the axon rather mation in Remyelinating Axons. J Neurosci 15:492Ð503 4. Rasband MN, Kagawa T, Park EW et al. (2003) Dysregulation than in clusters. Together, these studies suggest that, in of Axonal Sodium Channel Isoforms after Adult-Onset Chronic addition to altering the passive electrical properties of Demyelination. J Neurosci Res 73:465Ð470 axons and the active clustering of Na+ channels to nodes 5. Rasband MN, Peles E, Trimmer JS et al. (1999) Dependence of of Ranvier, myelin also regulates the kinds of channels Nodal Sodium Channel Clustering on Paranodal Axoglial Con- tact in the Developing CNS. J Neurosci 19:7516Ð7528 present in CNS axons. The axon-glia signaling that me- 6. Salzer JL (2003) Polarized Domains of Myelinated Axons. Neu- diates this regulation of channel expression, trafficking, ron 40:297Ð318 and/or localization is an active area of investigation. 7. Shrager P (1989) Sodium Channels in Single Demyelinated Mammalian Axons. Brain Res 483:149Ð154 Demyelination and Neuropathic Pain 8. Wallace VC, Cottrell DF, Brophy PJ et al. (2003) Focal Lysolecithin-Induced Demyelination of Peripheral Afferents A very common symptom associated with MS is the Results in Neuropathic Pain Behavior that is Attenuated by presence of acute and/or chronic pain (e.g. trigeminal Cannabinoids. J Neurosci 23:3221Ð3233 9. Westenbroek RE, Noebels JL, Catterall WA (1992) Elevated Ex- neuralgia). Similarly, some forms of Charcot-Marie- + pression of Type II Na Channels in Hypomyelinated Axons of Tooth disease, characterized by segmental demyeli- Shiverer Mouse Brain. J Neurosci 12:2259Ð2267 nation of PNS axons, also have as symptoms the development of hyperalgesia, spontaneous pain, and allodynia. Unfortunately, very little is known about the molecular and cellular mechanisms linking de- Dendrite myelination and neuropathic pain. Since the expression and localization of Na+ channels appears to depend on interactions with myelinating glial cells, and Na+ Definition channels are obvious candidates to modulate neuronal Dendrite refers to the post-synaptic element of a neuron. hyperexcitability, one intriguing possibility is that pain Opioid Receptor Trafficking in Pain States associated with demyelination is a consequence of loss of neuroglial interactions. Recently, Wallace et al. (2003) showed that acute PNS demyelinationbylysolecithinresultsinthedevelopment of both allodynia and hyperalgesia. The development Dendritic Spines of the neuropathic pain coincided with detection of Nav1.3 Na+ channels in formerly myelinated axons Ð a surprising result since Nav1.3 is not normally found in Definition myelinated nerve fibers, or anywhere else in the adult Small protrusions of the dendritic shafts specialized nervous system. Further, spontaneous action potentials at the reception and processing of incoming signals at were measured during the remyelination phase. These synapses. They most often look like pedicled knobs, but results suggest that peripheral demyelination may lead may also assume other configurations such as sessile to aberrant Na+ channel subtype expression and ac- knobs, rose spines, or bunches of knobs connected to a tivity, and the switching of receptor modality from sole pedicle. proprioceptor or mechanoreceptor to nociceptor. Spinothalamic Tract Neurons, Morphology 538 Dendritic Topography

Deﬁnition Dendritic Topography Envelops MD laterally and posteriorly. Its neurons re- semble those of the central lateral nucleus (CL). MDdc Deﬁnition receivesinputfrom many of thesame subcorticalsitesas Spatial distribution of the dendritic tree with respect to CL, and projects to the striatum and to premotor cortical the cell body and gray matter regions located around it. areas. Spinothalamic Tract Neurons, Morphology Spinothalamic Terminations, Core and Matrix

Dendritic Tree Dental Pain, Etiology, Pathogenesis and Management Deﬁnition GRAHAM R. HOLLAND Ensemble of neuronal processes ramifying around the Department of Cariology, Restorative Sciences & cell body and specialized to receive input (chemical or Endodontics, School of Dentistry, University of electrical signals) from other neurons. Michigan, Michigan, MI, USA Spinothalamic Tract Neurons, Morphology [email protected]

Synonyms Dendrogram Toothache; pulpitis; Pulpalgia; dentin sensitivity

Definition Definition A noxious experience that originates or appears to orig- A dendrogram hierarchically organizes stimulus ob- inate from a tooth. jects, subclusters, clusters, etc. on the basis of their relative similarities. Characteristics Multidimensional Scaling and Cluster Analysis Ap- plication for Assessment of Pain Painisnotexperiencedfromanentirelyhealthytoothun- der normal physiological conditions, but can be induced by a cold stimulus at 0ûC or below. It is more readily felt in otherwise normal teeth in which the dentin be- Denervation neath the enamel of the crown or the cementum of the root is exposed. Then hot stimuli may, and osmotic Definition and cold stimuli will, induce pain. This pain is sharp and lasts only for the duration of the stimulus. If the dental Situation where a limb (or an organ or part of it) is ren- pulp, the soft tissue within the dentin and responsible dered insensitive to applied stimuli by severing sensory for its production, is inflamed, the pain to an applied axons that innervate the limb. Sensory endings rapidly stimulus will be strong, dull and throbbing. It may con- degenerate in the process of anterograde (Wallerian) de- tinue beyond the duration of the stimulus and may be generation. present spontaneously. As the majority of nociceptors Anesthesia Dolorosa Model, Autotomy in the uninjured pulp are inactive they can be classified Facet Joint Pain as silent. No sensations other than pain can be experienced from the tooth pulp in response to non-electrical stimuli, a property that has been utilized in a number of Denervation Model of Neuropathic Pain experimental studies. The stimuli capable of inducing pain from inflamed pulps would not be in the noxious Anesthesia Dolorosa Model, Autotomy range when applied to intact, healthy skin. It is difficult to elicit pain from a freshly cut cavity in dentin, but the tooth becomes much more responsive if bacteria are allowed to inhabit the cavity for a week to allow the under- Densocellular Subnucleus of the lying pulp to become inflamed (Anderson et al. 1967). Mediodorsal Nucleus The intensity of pain felt from a tooth with an inflamed pulp is highly variable but it has been ranked using the McGill pain questionnaire as similar to the pain experi- Synonyms enced from arthritis or a bone fracture but substantially MDdc lessthan thatassociated with childbirth (Melzack 1984). Dental Pain, Etiology, Pathogenesis and Management 539

The descriptors most commonly applied to it are throb- undergoes dynamic changes during the inflammation bing, boring, sharp, sickening, annoying, constant and induced by dental caries (Rodd et al. 2000; Bowles et al. rhythmic (Melzack 1975). 2003). The initiation of inflammatory pain in the dental pulp is essentially similar to that elsewhere, as far as is Etiology yet determined, but differs in that it takes place in a rigid Dental caries is the predominantcause of pulpal inflam- non-compliant environment where high extracellular mation and the pain associated with it. Toxins from the tissue fluid pressures prevail. This may contribute to D bacteriacontainedinacariouslesionpermeatethedentin nociceptor activation, given that the pulpal nociceptors and induce inflammation in the pulp long before the bac- are, apparently, exquisitely sensitive to small, localized teriathemselvesinvadethepulp.Somedentalrestorative pressure changes. materialsare potentially irritating but pain from restored The pulpal nociceptors are the terminals of afferent teeth without overt dental caries is often due to the mi- fibers carried in the mandibular and maxillary divisions cro leakage of bacteria beneath the filling and the pene- of the trigeminal nerve with cell bodies in the trigeminal tration of their toxins to the dental pulp. While carious ganglion. They relay at various levels in the trigeminal teeth are commonly painful, in almost a third of cases, nuclear complex and contribute to the central ascending the inflammation may progress to necrosis without the pathways. patient experiencing discomfort (Michaelson and Hol- The variability in the presentation of pulpal pain may, in land 2002). When the dental pulp is heavily inflamed part, be due to variations in the extent of inflammation or becomes necrotic inflammatory mediators as well as but peripheral and central mechanisms of pain suppres- bacteria and toxins may spread into the tissues around sion and hyperalgesia are also involved. For example, the apex of the tooth root. This tissue may be painful es- pulpal inflammation leads to gene product Fos expres- pecially when the tooth is tapped but is often not noticed sion (Chattipakorn et al. 2002) as well as centeral sensi- by the patient. If the inflammation around the tooth apex tization (Chiang et al. 1998) in the trigeminal subnu- progresses to necrosis, abscess formation may oc- cleus caudalis. Opioid peptides and receptors have been cur and this can be acutely painful due to swelling, tissue found in the dental pulp (Jaber et al. 2003). Thepulp also distension and the spread of inflammatory mediators. In has a sympathetic innervation, and activity in this may contrast to pain limited to the pulp, painoriginating from modulate nociceptive output perhaps by effecting neu- the tissue around the tooth is easily localized. ropeptide release (Hargreaves et al. 2003).

Pathogenesis Management The pulp has a dense afferent innervation of Cfibres The diagnosis of dental pain is often complicated by and Aδ fibers, which are a dedicated component of its referral to other teeth and sometimes to extra-oral the pain system with a smaller number of Aβ fibers structures. Central mechanisms and sensitization may that may be recruited during inflammation. The Aδ explain this (Sessle et al. 1986). Conversely pain in fibers may be those which respond to cold stimuli extra-oral structures such as the masticatory apparatus applied to an uninjured tooth. The C fibers may be and boney sinuses may be referred to the teeth. Pain silent and only become active in inflammation, causing of cardiac muscle may sometimes be referred to the the dull throbbing pain characteristic of symptomatic teeth. Thus, the first step in management is to determine pulpitis (Narhi et al. 1992). The stimuli which initiate that the pain is of dental origin and from which tooth dental pain when applied to the dentin, do so mainly it originates. This is done by using cold (ice or solid by causing fluid movement in the narrow (approx. CO2) and sometimes hot stimuli to test all the teeth in 1Ð2 μm in diameter) tubules which make up the tissue both upper and lower arches on the side indicated by the (Matthews et al. 1994). This movement rapidly de- patient. The patient will experience greater pain when forms and activates the exposed axonal membranes of an affected tooth is stimulated. In some circumstances the nociceptors which are abundant in the dental pulp, selective anesthesia of individual teeth may help. If and present to a limited extent within the tubules of serious uncertainty exists, symptoms usually become the dentin. Chemicals may also diffuse more slowly clearer with time. and act directly on the nociceptors (Matthews et al. If a patient reports only occasional brief discomfort 1994). Once inflammation is initiated in the pulp, a to hot and cold drinks and it is determined that the large number of cytokines and inflammatory mediators discomfort is due to exposed dentin in an otherwise are released some of which activate (e.g. bradykinin) healthy tooth, the sensitivity can be reduced or elimi- or sensitize ( prostaglandins) nociceptive terminals. nated by blocking the dentinal tubules. Patent tubules Inflammation also leads to sprouting and increases in are a characteristic of sensitive dentin (Yoshiyama et the neuropeptide content of pulpal nerves (Byers et al. al. 1989). Rubbing the surface with a wood stick cre- 1990). The neuropeptide substance P is found within ates a smeared layer of dentin which occludes many a subpopulation of nociceptive afferent nerve fibers. tubules. Some salt solutions, such as potassium ox- The expression of substance P within pulpal nerves alate and sodium fluoride induce precipitation within 540 Dental Pulp the tubules. These may be applied in a dental office ically to reduce or eliminate central sensitization may setting. Desensitizing toothpastes for home use usu- find application here. ally incorporate fluoride compounds and potassium nitrate. The potassium ions released from these pastes References may permeate the dentin and inactivate nociceptors 1. Anderson DJ, Matthews B (1967) Osmotic Stimulation of Human by altering the ionic composition of the extracellular Dentine and the Distribution of Dental Pain Thresholds. Arch Oral Biol 12:417Ð426 fluid. Sometimes attaching an adhesive restoration to 2. Bowles WR, Withrow JC, Lepinski AM, Hargreaves KM (2003) the surface of the dentin may by occluding the dentinal Tissue Levels of Immunoreactive Substance P are Increased in tubules be successful. Patients with Irreversible Pulpitis. J Endod 29:265Ð267 If the cause of the pain is pulpal inflammation resulting 3. Byers MR, Taylor PE, Khayat BG, Kimberly CL (1990) Effects of Injury and Inflammation on Pulpal and Periapical Nerves. J from dental caries this must be dealt with by removing Endod 16:78Ð84 the infected dentin and replacing it with a filling mate- 4. Chattipakorn SC, Sigurdsson A, Light AR, Narhi M, Maixner W rialthatdoesnotitself induce inflammation, andalso has (2002) Trigeminal c-Fos Expression and Behavioral Responses surface margins that prevent the migration of bacteria to Pulpal Inflammation in Ferrets. Pain 99:61Ð69 5. Chiang CY, Park SJ, Kwan CL, Hu JW, Sessle BJ (1998) NMDA onto the dentinal surface. With the causative factor re- Receptor Mechanisms Contribute to Neuroplasticity Induced in moved, the inflammation in the dental pulp should grad- Caudalis Nociceptive Neurons by Tooth Pulp Stimulation. J Neu- ually subside and the symptoms with it. When the dentin rophysiol 80:2621Ð2631 is severely infected or bacteria themselves rather than 6. Hargreaves KM, Bowles WR, Jackson DL (2003) Intrinsic Reg- ulation of CGRP Release by Dental Pulp Sympathetic Fibers. J just their toxins have reached the pulp the inflammatory Dent Res 82:398Ð401 process may be irreversible and the only solution is to 7. Hu JW, Dostrovsky JO, Lenz YE, Ball GJ, Sessle BJ (1986) Tooth remove the pulp followed by root canal therapy or, al- Pulp Deafferentation is Associated with Functional Alterations in ternatively, to extract the tooth. Unfortunately,it is diffi- the Properties of Neurons in the Trigeminal Spinal Tract Nucleus. J Neurophysiol 56:1650Ð1668 cultto diagnosetheextentof inflammationin anaffected 8. Jaber L, Swaim WD, Dionne RA (2003) Immunohistochemical pulp. No clear correlation has ever been established be- Localization of Mu-opioid Receptors in Human Dental Pulp. J tween symptoms and the inflammatory condition of the Endod 29:108Ð110 9. Matthews B, Vongsavan N (1994) Interactions Between Neural pulp though spontaneously painful teeth usually have and Hydrodynamic Mechanisms in Dentine and Pulp. Arch Oral extensively inflamed pulps. The most consistent find- Biol 39:87SÐ95S ing in examining the pulps that have been removed from 10. Melzack R (1975) The McGill Pain Questionnaire: Major Prop- symptomaticteethisthatsubstancePispresentingreater erties and Scoring Methods. Pain 1:277Ð299 11. Melzack R (1984) The Myth of Painless Childbirth (the John J. amountsin painfulteeth than in normalteeth (Rodd etal. Bonica lecture). Pain 19:321Ð337 2000; Bowles et al. 2003). Currently, the most accepted 12. Michaelson PL, Holland GR (2002) Is Pulpitis Painful? Int Endod standardfordeterminingthepresenceofirreversiblepul- J 35:829Ð832 pal inflammation is the presence of spontaneous pain 13. Narhi M, Jyvasjarvi E, Virtanen A, Huopaniemi T, Ngassapa D, Hirvonen T (1992) Role of Intradental A- and C-type Nerve Fi- or pain that is prolonged well beyond the removal of a bres in Dental Pain Mechanisms. Proc Finn Dent Soc 88:507Ð516 cold stimulus. Convincing evidence supporting this re- 14. Rodd HD, Boissonade FM (2000) Substance P Expression in lationship is meager. In the acute management of den- HumanToothPulpinRelationtoCariesandPainExperience. tal pain, analgesics are of great value in relieving symp- Eur J Oral Sci 108:467Ð474 15. Sessle BJ, Hu JW, Amano N, Zhong G (1986) Convergence of toms. As toothache is predominantly of inflammatory Cutaneous, ToothPulp, Visceral, Neck andMuscle Afferentsonto origin, NSAIDs, Survey are likely to be more effec- Nociceptive and Non-Nociceptive Neurones in Trigeminal Sub- tive than centrally acting analgesics. One presentation nucleus Caudalis (Medullary Dorsal Horn) and its Implications for Referred Pain. Pain 27:219Ð235 of toothache, which provides a special treatment chal- 16. Yoshiyama M, Masada J, Uchida A, Ishida H (1989) Scanning lenge, is a condition often known as hot tooth syn- Electron Microscopic Characterization of Sensitive vs. Insensi- drome. This presents as an intense and spontaneous pain tive Human Radicular Dentin. J Dent Res 68:1498Ð1502 inatoothwhichisdifficulttoanesthetizewithlocalanes- thetics. When other signs of effective local anesthesia are present, the tooth remains painful. Regional block Dental Pulp anesthesia and directlocalinfiltration may prove incom- pletelyeffective.Resolutionisoftenonlyachievedbyre- Definition moving the pulp from the tooth with less than total anesthesia, a trial for both patient and practitioner. In these The dental pulp is a loose connective inside the dentin cases long-standing inflammation and nociceptors stim- of the tooth. It contains a large number of afferent and ulation has led to central sensitization (Hu et al. 1968; sympathetic nerve fibers, an extensive vascular plexus Chiang et al. 1998). The principal features of this are and supportsthecellslining thedentin,theodontoblasts, therecruitmentofAβaxons,hyperalgesia,allodyniaand responsible for its formation and repair. spontaneouspain. A combination of peripherally acting DentalPain, Etiology, Pathogenesisand Management anti-inflammatory drugs and centrally acting analgesics Nociceptors in the Dental Pulp would best control symptoms. Drugs developed specif- Orofacial Pain, Taxonomy/Classification Depression and Pain 541

Dentin Depression

Deﬁnition Deﬁnition Dentin is a mineralized tissue similar in hardness to A state of lowered mood, often accompanied by distur- bone. It forms the bulk of a tooth, but is covered by bances of sleep, energy, appetite, concentration, inter- the harder enamel (that forms the crown and visible ests, and sexual drive. There are also associated depres- D part of the tooth) and the cementum that binds it to the sive thoughts like ideas of hopelessness, worthlessness, bony socket. It is made up of many thousands of small helplessness, low self esteem, and being fed up with life. (1Ð2 μm) tubules running from the dental pulp on its The term depression can be used to denote a mood state, inside to its outer surface in contact with the enamel a symptom or a disorder (Major Depressive Disorder). and cementum. Depression and Pain DentalPain, Etiology, PathogenesisandManagement Pain in the Workplace, Risk Factors for Chronicity, Nociceptors in the Dental Pulp Psychosocial Factors Psychiatric Aspects of the Management of Cancer Pain Dentinal Tubules

Deﬁnition Depression and Pain

Fluid-filled thin tubules (diameter: 1Ð2 μm) in dentin, ROBERT D. KERNS,ALICIA A. HEAPY which extend all the way from the dental pulp to VA Connecticut Healthcare System and Yale the dentin-enamel border. There are 30,000Ð40,000 University, Westhaven, CT, USA tubules/mm2 of dentin. [email protected], [email protected] Nociceptors in the Dental Pulp Synonyms Depression, Major Depressive Disorder Dependence Definition Definition Depression is characterized by sadness and loss of Dependence is a state in which an abstinence syndrome interest or pleasure in previously enjoyed activities. The may occur following abrupt withdrawal, dose reduction term depression can be used to denote a mood state, a or administration of an antagonist. Although usually symptom or a disorder (Major Depressive Disorder). associated with opioids, this is common with many Depression qualifies as a disorder when it is intense, classes of medication including anti-hypertensives and frequent, or enduring enough to result in dysfunction anti-convulsants. It is seen in all subjects chronically and/or concern for the person, his or her significant oth- given a dependence inducing drug. ers, or society, more generally. The formal diagnosis of CRPS, Evidence-Based Treatment Major Depressive Disorder (MDD), as defined by the Opioid Receptors Diagnostic and Statistical Manual of Mental Disorders th Postoperative Pain, Opioids 4 ed. (DSM-IV) (American Psychiatric Association 1994), is the presence of a collection of symptoms that must include depressed mood or loss of interest or pleasure in most activities lasting at least 2 weeks. Depolarisation Additional symptoms include fatigue, feelings of excessive or inappropriate worthlessness or guilt nearly Definition every day, significant weight loss or gain, insomnia or A loss of polarity in general. Depolarisation is a change hypersomnia, diminished concentration or ability to in the electrical charge between the inside and the out- make decisions, frequent thoughts of death, suicidal side of a membrane. Specifically in cells, the response ideation or suicide attempt. In order to meet criteria of a cell membrane to a stimulus, which leads to a loss for MDD, symptoms must cause distress or impair- of the negativity of the membrane potential beyond the ment in functioning. Chronic pain is characterized resting potential, and thereby the generation of an action as non-cancer pain lasting 6 or more months. potential. Characteristics COX-1 and COX-2 in Pain Mechanonociceptors The presence of at least transient experiences of de- Transition from Acute to Chronic Pain pressed mood among persons with chronic pain is 542 Depression and Pain thought to be understandable, and even expected, and the development of depression and the modulation of in fact, a high co-prevalence between the experience pain (Ward et al. 1982). This theory hypothesizes that of chronic pain and depressive symptom severity has depression and pain symptoms both use the descending been noted, both clinically and in formal empirical in- pathways of the central nervous system. Specifically, vestigations for many years. However, estimates of the the periaqueductal gray, the limbic structures and the prevalence of MDD among persons with chronic pain rostral-ventromedial medulla modulate attention and vary widely depending on the manner of assessment, affective response to peripheral pain stimuli, typically population selection, and the definition of depression suppressing these stimuli in favor of attending to outside that is used (Banks and Kerns 1996). MDD may be stimuli. However, in the context of depression and its assessed with varying levels of stringency, and when concomitant depletion of serotonin and epinephrine, standard diagnostic criteria are not used, persons with attention and affective responses to these peripheral significant depressive symptoms, but not MDD, may signals are enhanced, providing a potential explana- be included in the depressed category, thereby pro- tion for the high comorbidity of pain and depression, viding a misleading picture of the true comorbidity and the effectiveness of antidepressant medication for of chronic pain and MDD. Further complicating the chronic pain complaints (Bair et al. 2003). Efforts to picture, several symptoms of MDD and pain overlap fully describe the temporal development of pain and (e.g. sleep disturbance, loss of energy, change in ap- depression have been hampered by lack of longitudinal petite), which may inflate estimates of depression in studies and other methodological shortcomings. The populations with chronic pain. Use of standardized reliability and validity of retrospective patient reports semi-structured interview methods, such as the Struc- of the temporal emergence of pain and depression have tured Clinical Interview for DSM-III-R (SCID, Spitzer been questioned due to the subjective nature of pain and 1992) and DSM-IV criteria, is encouraged to ensure depression, the difficulty identifying the exact onset of reliable and valid diagnosis of MDD in persons with depression, which is usually gradual, and the difficulty chronic pain. When these criteria are used a majority in determining when acute pain can be classified as of studies report point prevalence rates ranging from chronic (Banks and Kerns 1996). 30 % to 54 % (Banks and Kerns 1996). Even when Several theories have been asserted to explain the fre- these criteria are employed, however, MDD appears quent co-occurrence of depression and pain. These to occur more frequently in chronic pain than in other models are variations of major cognitive-behavioral common, chronic medical conditions (Banks and Kerns theories, and hypothesize that an individual’s pattern 1996). Studies also suggest that the presence of chronic of cognitive assessment of pain and pain experience, pain may interfere with the detection of depression in and their behavior in response to pain, contribute to the primary care settings (Bair et al. 2003). Patient empha- development and maintenance of depression. Beck’s sis on somatic complaints in chronic pain conditions, cognitive distortion model (Beck 1976) contends that which may be exacerbated in the context of depression, certain individuals, by virtue of preexisting negative are thought to interfere with physician detection of cognitive schemas, are particularly vulnerable to de- depression, particularly milder cases of depression. veloping depression and depressive symptomatology While depression and pain appear to frequently co- in response to the challenges of living with chronic occur, the temporal association between the two, and pain. Once these negative schemas are activated, they possible causal mechanisms underlying the comorbid- serve to elicit negative thoughts about the self, the ity, have not been identified. Three hypotheses have world and the future. In turn, these negative thoughts been asserted: (1) pain precedes depression, (2) depres- produce negative mood, which in turn leads to other sion precedespain and (3) the two occur simultaneously. symptoms of depression such as decreased activity and Many proponents of the first hypothesis, that pain pre- suicidal ideation. Learned helplessness theory (Selig- cedes depression, argue that depression is largely a man 1975) asserts that when individuals are exposed psychological reaction to pain, mediated by cognitive to uncontrollable negative outcomes like chronic pain, factors, behavioral factors or a combination of both they develop an attitude of helplessness or expectation (e.g. Fordyce 1976; Rudy et al. 1988; Sullivan and that other future outcomes are also uncontrollable. D’Eon 1990). Those that assert that depression pre- These individuals do not attempt to alter future out- cedes pain point to mood-induction studies, that have comes, even when those outcomes are amenable to demonstrated increased self-focus of attention and in- their efforts, due to an erroneous belief in their own creased reports of aches and pain, as well as decreased helplessness, thereby maintaining the circumstances tolerance for laboratory-induced pain in response to that contribute to depression. Behavioral models posit depressed mood (Ingram and Smith 1984, Salovey and that an individual with chronic pain faces greatly re- Birnbaum 1989). Finally, evidence for the simultaneous duced opportunities for rewards and, consequently, is occurrence of depression and pain is rooted in nervous at higher risk of developing depression. Specifically, system biogenic monoamines such as serotonin and persons with chronic pain experience pain as a result of norepinephrine, which have been implicated in both performing previously rewarding activities like work, Dermatomal Level 543 social interactions and physical activity, which leads to References withdrawal from these activities. Additionally, fear of 1. American Psychiatric Association (1994) Diagnostic and Sta- reinjury may also result in a reduction in activities and tistical Manual of Mental Disorders, 4th edn. APA, Washington consequent reinforcement. DC The preceding models, although widely accepted for 2. Bair MJ, Robinson RL, Katon W et al. (2003) Depression and Pain Comorbidity: A Literature Review. Arch Intern Med explaining depression in general,arelessable toaccount 163:2433Ð2455 for the elevated levels of depression found in chronic 3. Banks SM, Kerns RD (1996) Explaining the High Rates of De- D pain compared with other chronic diseases or condi- pression in Chronic Pain: A Diathesis Stress Framework. Psychol tions. The cognitive and behavioral vulnerabilities that Bull 119:95Ð110 4. Beck AT (1976) Cognitive Therapy and the Emotional Disorders. are thought to precipitate depression should be equally International Universities Press, New York distributed across populations with other chronic ill- 5. Fordyce WE (1976) Behavioral Methods for Chronic Pain and nesses, and the presence of a chronic illness could be Illness. Mosby, St. Louis, MO conceptualized as a stressor capable of triggering the 6. Goldman B (1991) Chronic Pain Patients Must Cope with Chronic Lack of Physician Understanding. CMAJ vulnerabilities necessary to set off depression. If these 144:1492Ð1497 models are correct, the prevalence of depression would 7. Haythornthwaite JA, Sieber, WJ, Kerns RD (1991) Depression be approximately equal among persons with various and the Chronic Pain Experience. Pain 46:177Ð184 8. Ingram RE, Smith TS (1984) Depression and Internal versus chronic medical conditions. Banks and Kerns (1996) External Locus of Attention. Cogn Therapy Res 8:139Ð152 have asserted that pain has several unique qualities that 9. Reid J, Ewan C, Lowy E (1991) Pilgrimage of Pain: The Ill- make it a particularly potent stressor. First, chronic pain ness Experience of Women with Repetition Strain Injury and is a symptomatic condition and the symptoms provide the Search for Credibility. Soc Sci Med 32:601Ð612 10. Rudy TE, Kerns RD, Turk DC (1988) Chronic Pain and De- a constant reminder on the condition. Second, pain is pression: Toward a Cognitive-Behavioral Mediation Model. Pain typically a signal of danger and tissue damage and as a 35:129Ð140 result often producesanxiety. Third, pain isoften associ- 11. Salovey P, Birnbaum D (1989) Influence of Mood on Health- ated with a variety of losses resulting in impairment and Relevant Cognitions. J Pers Soc Psychol 57:539Ð551 12. Seligman MEP (1975) Helplessness: On Depression, Develop- disability. Secondary losses are especially prominent. ment, and Death. Freeman, San Francisco Pain can interfere with employment, leisure activities, 13. Spitzer RL (1992) History and Rationale and Development of sexual function, and interpersonal relationships. Finan- SCID for DSM-III-R. Arch Gen Psychiatry 49:624Ð629 cial consequences can include high medical expenses, 14. Sullivan MJL, D’Eon JL (1979) Relation between Catastrophiz- ing and Depression in Chronic Pain Patients. J Abnorm Psychol diminished capacity to work and unemployment. The 99:260Ð263 combination of the many losses experienced by persons 15. Ward NG, Bloom VL, Dworkin S (1982) Psychobiological Mark- with chronic pain can lead to feelings of social isolation, ers in Coexisting Pain and Depression: Toward a Unified Theory. meaninglessness, uncertainty about the future, loss of J Clin Psychiatry 43:32Ð41 self-concept, self-esteem and family role. Finally, due to the frequent discrepancy between structural pathology and pain severity, impairment, and disability, patients may experience a disconnection between their own Depression, Major Depressive Disorder experience and the messages they receive from the health care system. Persons with chronic pain may be Depression and Pain told that there is no medical basis for their pain or that there is a medical basis, but there is nothing more that can be done. The conflicting messages between what a person is told by the health care system and their own Depressive Symptom Severity experience can lead to self-doubt, distrust of healthcare providers, confusion, frustration and affective distress (e.g. Goldman 1991; Reid et al. 1991). Definition Negative mood states, including depressive symptoms Depressive symptom severity refers to the prevalence and MDD, have been shown to hinder pain treatment and intensity of symptoms of depressive disorders. (Haythornthwaite et al. 1991) and exacerbate chronic Depression and Pain pain conditions. Somatic focus and amplification, autonomic arousal and misinterpretation of symptoms are all mechanism through which negative mood states are thought to influence pain experience and outcomes Dermatomal Level (Dersh et al. 2002). The frequent correlation of pain and depression, and the effect of depression on pain Definition treatment, argue for the importance of identification and treatment of depression for improving chronic pain A dermatome is an area on the body supplied by a single treatment outcomes. nerve root. The dermatomal level is used to describe the 544 Dermatomes highest level of anesthesia provided by either a spinal Synonyms or epidural anesthetic. A thoracic 4 level of anesthesia Pain Modulatory Circuitry and Endogenous Pain Con- is typically needed to provide pain relief for cesarean trol; cellular and receptor mechanisms underlying the delivery. development of persistent pain Analgesia During Labor and Delivery Definition In the contextof pain, the descending circuitryrefersto a neural network between the brain stem and spinal cord, Dermatomes which provides supraspinal modulation of nociceptive transmission at the spinal and trigeminal level (Fields and Basbaum 1999, for further details). Plastic changes Definition occur after tissue or nerve injury within the descending Dermatomes are the areas of skin that are innervated by pain modulatory circuitry. Such changes involve tran- single dorsal roots of the spinal cord, or trigeminal nerve scriptional, translational and post-translational modula- in the case of the oral-facial region. Dermatomes are lation of the receptors, lead to enhanced synaptic strength beled by the spinal segment with which they are associ- and altered net descending modulation, and contribute ated, such as C1,C2, (cervical), T1,T2, (thoracic), and to the development of persistent pain. L1,L2 (lumbar). Central Nervous System Stimulation for Pain Characteristics Cervical Transforaminal Injection of Steroids Changing Role of Descending Circuitry after Injury Dorsal Root Ganglionectomy and Dorsal Rhizotomy The potency, efficacy and net effect of the descending Pain in Humans, Psychophysical Law circuitry are subject to modulation by the functional status of the organism. Rats with inflammatory hyperalgesia exhibit an increased sensitivity to opioid analgesics (Neil et al. 1986). Parallel changes in the Dermatomyositis net effect of descending modulation are observed at the spinal level, where an enhanced descending inhibition of spinal nociceptive neurons has been demonstrated Definition in animals with inflammation (Schaible et al. 1991; Immunogenic myositis, mainly with characteristic ad- Ren and Dubner 2002). The source of the increased ditional skin lesions. A paraneoplastic cause should be sensitivity to opioids, and enhanced descending inhi- considered in adult cases. The development of muscle bition after inflammation, can be traced to supraspinal symptoms, especially in proximal muscles, is acute or structures. The antihyperalgesic and analgesic potency subacute. Muscle pain is frequent. Muscle biopsies con- of the mu and delta opioid receptor agonists microin- firm the diagnosis. jected into the rostral ventromedial medulla (RVM), a Myositis pivotal site in the descending pain modulatory circuitry (Fields and Basbaum 1999), is progressively enhanced after adjuvant-induced hindpaw inflammation (Hurley and Hammond 2000). Local anesthesia of the nucleus raphe magnus, leads to a further increase in dorsal Descending Anti-Analgesic Systems horn nociceptive neuronal activity in inflamed, but not noninflamed rats (Ren and Dubner 2002). Focal lesions Descending Circuitry, Opioids of the RVM and locus coeruleus are followed by an in- Descending Facilitatory Systems crease in spinal Fos protein expression and hyperalgesia after inflammation (Tsuruoka and Willis 1996; Ren and Dubner 2002). Stimulation of the periaqueductal gray produces an increased antinociception in the inflamed paw in rats (Morgan et al. 1991). Descending Circuitry, Molecular The descending circuitry can also actively facilitate ab- Mechanisms of Activity-Dependent normal pains. The selective destruction of the nucleus Plasticity reticularis gigantocellularis with a soma-selective neurotoxin, ibotenic acid, leads to an attenuation of hyper- KE REN algesia and a reduction of inflammation-induced spinal Department of Biomedical Sciences, Dental School, Fos expression (Ren and Dubner 2002). There is an en- University of Maryland, Baltimore, MD, USA hancement of the C-fiber wind-up, and the novel A-fiber [email protected] wind-up, during inflammation, which also depends on Descending Circuitry, Molecular Mechanisms of Activity-Dependent Plasticity 545 input from supraspinal circuitry (Herrero and Cervero are NMDA dependent and occur early after inflamma- 1996). A descending facilitatory drive contributes to the tion (Urban and Gebhart 1999; Ren and Dubner 2002). pathogenesisof secondary hyperalgesia and experimen- Higher doses of NMDA at 3 h post-inflammation only tal neuropathic pain (Porreca et al. 2002). The tactile al- produce inhibition. At 24 h post-inflammation, NMDA lodynia after nerve injury is dependent upon a tonic ac- produces only inhibition. Alpha-amino-3-hydroxy-5- tivation of net descending facilitation from supraspinal methyl-4-isoxazole propionic acid (AMPA), a selective sites. Lesions of the RVM inhibit secondary hyperalge- AMPA receptor agonist, produces greater antinocicep- D sia, produced by topical application of mustard oil (Ur- tion at 24 h, as compared to 3 h after inflammation. ban and Gebhart 1999). Hindpaw formalin-induced hy- These findings suggest a change in synaptic strength peralgesia is prevented by RVM lesion (Wiertelak et al. and potency of RVM excitatory amino acid neurotrans- 1997). Spinalization blocks mustard oil-produced sec- mission after inflammation. The increase in potency ondary mechanical allodynia and mechanical hyperex- of NMDA and AMPA receptor agonists parallels the citability of spinal nociceptive neurons (Mansikka and time-dependent enhancement of net descending inhi- Pertovaara 1997). Finally, immune activation produces bition produced by RVM electrical stimulation. Thus, hyperalgesia that depends on a supraspinal facilitatory injury-induced glutamatergic synaptic plasticity may input (Watkins et al. 1995). underlie the mechanisms of time-dependent changes in The injury-induced plasticity in the descending cir- descending modulation. cuitry is dynamic and time-dependent. Following inflammation, brainstem-descending pathways become Activity-Dependent Changes in Gene Expression and Protein progressively more involved in suppressing incoming Phosphorylation in Descending Circuitry nociceptive signals in primary hyperalgesic zones. The The molecular mechanisms of activity-dependent plas- dynamic nature of descending pain modulation after ticity in descending circuitry are largely unknown. inflammation has been examined over time, by moni- Correlate changes in gene transcription and protein toring antinocifensive responses in lightly anesthetized translation have been found in the descending circuitry rats during RVM stimulation (Ren and Dubner 2002). In after injury. Williams and Beitz (1993) have shown these studies, hindpaw inflammation induces temporal that adjuvant-induced hindpaw inflammation increased changes in synaptic activation in the brain stem. Early neurotensin mRNA expression in the periaqueductal (up to 3 h) in the development of inflammation, there gray and the lateral tegmental nuclei, from which is an increased descending facilitation (also see Urban neurotensinergic neurons project to the RVM. The in- and Gebhart 1999), which reduces the net effect of the creased sensitivity of excitatory amino acid receptors inhibition. Over time, the level of descending inhibition in the descending circuitry, during the development of increases, or descending facilitation decreases, lead- inflammatory hyperalgesia, is related to transcriptional ing to a net enhancement of antinociception. In nerve and translational modulation of the receptors (Ren and injured rats, lesions of the dorsolateral fasciculus, Dubner 2002). Examination of the mRNA expression local anesthetic block of the RVM and lesions of RVM of the NR1, NR2A and NR2B subunits of the NMDA mu-opioid receptor expressing cells do not prevent the receptor in the RVM reveals an upregulation that par- onset, but reverse the later maintenance, of tactile and allels the time course of the RVM excitability changes. thermal hypersensitivity (Burgess et al. 2002). This is accompanied by an increase in NMDA receptor protein. Activity-Dependent Synaptic Plasticity in Descending Circuitry AMPA receptor subunits (GluR1-4) exist in the two Synaptic transmission within the descending circuitry ’flip’ and ’flop’ isoforms, which differentially affect the involves multiple neurotransmitters and receptors desensitization properties of the receptor. Reverse tran- (Fields and Basbaum 1999). The role of excitatory scription polymerase chain reaction analysis, indicates amino acid receptors, or glutamate receptors,has that inflammation induces a significant upregulation gained most attention in searching for supraspinal of mRNAs encoding the GluR1-flip (5 hÐ24 h post- mechanisms of persistent pain. Excitatory amino acid inflammation), GluR2-flip (24 h post-inflammation) receptors have been shown to activate pain modulatory and GluR2-flop (24 h post-inflammation) isoforms in neurons in the RVM and mediate morphine analgesia the RVM, whereas the levels of GluR1-1 flop mRNAs (Heinricher et al. 2001). Glutamatergic synapses in do not exhibit significant changes (Guan et al. 2003). descending circuitry also play a critical role in response Western blots demonstrate that the GluR1 protein to injury. N-methyl-D-aspartate ( NMDA), the pro- levels are significantly upregulated at 24 h to 3 days totype NMDA receptor agonist, microinjected into the post-inflammation, compared to that of naive animals. RVM, produceseffectsthatare dependentuponthepost- GluR2 protein levels remain unchanged. Immunohis- inflammatory period. At 3 h post-inflammation, low tochemistry of RVM tissues localizes the increase in doses of NMDA produce facilitation of the response to GluR1 proteins to RVM neurons. The effect of GluR1 noxiousheatoftheinflamedandnon-inflamedhindpaws overexpression in RVM neurons on nocifensive be- and tail, indicating that descending facilitatory effects havior has been examined (Bai et al. 2002). GluR1 546 Descending Circuitry, Molecular Mechanisms of Activity-Dependent Plasticity proteins are introduced into RVM neurons through plasticity at the spinal and brain stem levels share simi- conjugation with green fluorescent protein (GFP), and lar but not identical, and yet to be elucidated, molecular by using sindbis pseudovirus as a vector (sin-GFP- mechanisms. GluR1). Microinjection of sin-GFP-GluR1 into rat RVM results in an overexpression of the GFP-GluR1 References in RVM neurons, as early as 7 h post-injection. The 1. Bai G, Guan Y,Zhuang ZY et al. (2002) Overexpression of GluR1 inflammatory hyperalgesia is significantly attenuated Subunit of AMPA Receptors in the Brain Stem RVM Enhanced in animals receiving sin-GFP-GluR1-flip, but not sin- Descending Inhibition in Rats. Soc Neurosci Abstr 28:351.13 GFP-GluR1-flop. These results suggest that GluR1 2. Burgess SE, Gardell LR, Ossipov MH et al. (2002) Time- Dependent Descending Facilitation from the Rostral Ventro- flip-dominant AMPA receptors ( Flip-flop isoform of medial Medulla Maintains, but Does Not Initiate, Neuropathic AMPA receptors) contribute to descending inhibition Pain. J Neurosci 22:5129Ð5136 of nociception in inflamed animals. 3. Fields HL, Basbaum AI (1999) Central Nervous System Mech- Protein phosphorylation is a major mechanism for regu- anisms of Pain Modulation. In: Wall PD, Melzack R (eds) Text- book of Pain. Churchill Livingstone, Edinburgh, pp 309Ð329 lation of receptor function. The native NMDA receptor 4. Guan Y, Guo W, Zou SP et al. (2003) Inflammation-Induced is a likely tetramer, which consists of two NR1 and two Upregulation of AMPA Receptor Subunit Expression in Brain NR2 subunits. Phosphorylation of multiple sites in the Stem Pain Modulatory Circuitry. Pain 104:401Ð413 cytoplasmicC-terminiof theNR1 and NR2 subunits, in- 5. Heinricher MM, Schouten JC, Jobst EE (2001) Activation of Brainstem N-methyl-D-aspartate Receptors is Required for cludingtyrosine,serineandthreonineresidues,isknown the Analgesic Actions of Morphine Given Systemically. Pain to modulate NMDA receptor activity and affect synap- 92:129Ð138 tic transmission. To examine tyrosine phosphorylation 6. Herrero JF, Cervero F (1996) Supraspinal Influences on the Fa- of the NR2 subunits, protein samples from RVM were cilitation of Rat Nociceptive Reflexes Induced by Carrageenan Monoarthritis. Neurosci Lett 209:21Ð24 first immunoprecipitated with anti-NR2Aor anti-NR2B 7. Hurley RW, Hammond DL (2000) The Analgesic Effects of antibodies. The eluted NR2A or NR2B proteins were Supraspinal Mu and Delta Opioid Receptor Agonists are Poten- then incubated with an anti-phosphotyrosine antibody, tiated During Persistent Inflammation. J Neurosci 20:1249Ð1259 8. Mansikka H, Pertovaara A (1997) Supraspinal Influence on 4G-10.Thetyrosinephosphorylation,asindicatedbythe Hindlimb Withdrawal Thresholds and Mustard Oil-Induced immunoblot against 4G-10, was associated with a band Secondary Allodynia in Rats. Brain Res Bull 42:359Ð365 of 180 kDa in RVM tissues. There was an increase in the 9. Morgan MM, Gold MS, Liebeskind JC et al. (1991) Perique- intensity of the 4G-10 bands after immunoprecipitation ductal Gray Stimulation Produces a Spinally Mediated, Opioid Antinociception for the Inflamed Hindpaw of the Rat. Brain Res with anti-NR2A, but not NR2B antibodies after inflam- 545:17Ð23 mation, as compared to naïve noninflamed rats (Turn- 10. Neil A, Kayser V, Gacel G et al. (1986) Opioid Receptor bach et al. 2003). Interestingly, inflammation induces an Types and Antinociceptive Activity in Chronic Inflammation: increase in NR2B, but not NR2A subunit tyrosine phos- Both Kappa and Mu Opiate Agonistic Effects are Enhanced in Arthritic Rats. Eur J Pharmacol 130:203Ð208 phorylation in thespinalcord. Using an antibody thatse- 11. Porreca F, Ossipov MH, Gebhart GF (2002) Chronic Pain lectively recognizes the phosphoserine residues on the and Medullary Descending Facilitation. Trends Neurosci receptor subunit, a time-dependent increase in NR1 and 25:319Ð325 GluR1 serine phosphorylation has also been identified 12. Ren K, Dubner R (2002) Descending Modulation in Persistent Pain: An update. Pain 100:1Ð6 intheRVMafterhindpawinflammation.Acommonfea- 13. Schaible H-G, Neugebauer V, Cervero F et al. (1991) Changes ture of the changes in glutamate receptor phosphoryla- in Tonic Descending Inhibition of Spinal Neurons with Articular tion is that it occurs rapidly, as early as 10Ð30 min. after Input During the Development of Acute Arthritis in the Cat. J inflammation, and persists for up to a week. The time Neurophysiol 66:1021Ð1032 14. Tsuruoka M, Willis WD (1996) Bilateral Lesions in the Area of courseofchangesinglutamatereceptorphosphorylation the Nucleus Locus Coeruleus Affect the Development of Hyper- in the RVM correlates well with changes in excitability algesia During Carrageenan-Induced Inflammation. Brain Res in descending circuitry after inflammation. 726:233Ð236 15. Turnbach ME, Guo W, Dubner R et al. (2003) Inflammation In- These findings indicate that excitatory amino acid reduces Tyrosine Phosphorylation of the NR2A Subunit and Serine ceptors in the RVM undergo selective transcriptional, Phosphorylation of NR1 Subunits in the Rat Rostral Ventrome- translational and posttranslational modulation fol- dial Medulla. Soc Neurosci Abstr 29 lowing inflammation, and may contribute to activity- 16. Urban MO, Gebhart GF (1999) Supraspinal Contributions to Hy- peralgesia. Proc Natl Acad Sci USA 96:7687Ð7692 dependent plasticity in descending pain modulatory 17. Watkins LR, Maier SF, Goehler LE (1995) Immune Activation: systems after prolonged noxious input. The activity- The Role of Pro-Inflammatory Cytokines in Inflammation, Illness induced plasticity in descending circuitry complements Responses and Pathological Pain States. Pain 63:289Ð302 the activity-dependent neuronal plasticity in ascend- 18. Wiertelak EP, Roemer B, Maier SF et al. (1997) Comparison of the Effects of Nucleus Tractus Solitarius and Ventral Medial ing pain transmission pathways. The spinal and brain Medulla Lesions on Illness-Induced and Subcutaneous Formalin- stem plasticity is dependent upon increased activation Induced Hyperalgesias. Brain Res 748:143Ð150 of nociceptors at the site of injury, and its initiation 19. Williams, FG, Beitz, AJ (1993) Chronic Pain Increases Brain- and maintenance is dependent upon modulation of stem Proneurotensin/Neuromedin-N mRNA Expression: A Hybridization-Histochemical and Immunohistochemical Study glutamatergic, opioidergic, neurotensinergic and pre- using Three Different Rat Models for Chronic Nociception. sumably GABAergic neurons. The activity-dependent Brain Res 611:87Ð102 Descending Circuitry, Opioids 547

tal gray in the midbrain, the locus coeruleus and A7 Descending Circuitry, Opioids catecholamine nuclei in the pons and the hypothalamus and amygdala in the diencephalon are involved DONNA L. HAMMOND,HERBERT K. PROUDFIT Department of Anesthesiology, University of Iowa, in the modulation of nociception and in the produc- Iowa, IA, USA tion of analgesia by opioids. The development of new [email protected],hk-proudfi[email protected] neuroanatomical methods for tracing the efferent projections of neurons subsequently confirmed that many D of these nuclei project either directly or indirectly, Synonyms via other nuclei, to the spinal cord. Hence, the term descending circuitry or bulbospinal pain modulatory Bulbospinal Pathways; Pain Modulatory Pathways pathways was coined as a generic term for a collection of supraspinal neurons that modulate synaptic trans- Definition mission of sensory information in the spinal cord and Descending circuitry is a generic term for neurons in the that are implicated in the production of analgesia by medulla, pons or midbrain that modulate the evoked and opioid receptor agonists. spontaneous activity of neuronsin the dorsal horn of the spinal cord. These neurons may project directly to the Redundant or Complementary Pathways spinal cord or they may project to other brainstem nuclei Neurons in the nucleus raphe magnus and nucleus retic- that in turn project to and terminate in the spinal cord. ularis gigantocellularis pars alpha, which include sero- They are an important component of the neural circuitry tonergic neurons among others, project directly to the by which opioid receptor agonists such as morphine act spinal cord. They also receive direct projections from to produce analgesia or to alleviate hyperalgesia or many other, more rostrally-situated nuclei that are also allodynia. implicated in the modulation of pain sensitivity. Neu- rons in these two midline nuclei therefore comprise a Characteristics final common efferent pathway to the spinal cord and, not surprisingly, have been thesubjectof intense investi- Background gation. However, neurons in the more laterally situated The observation that direct injection of morphine into locus coeruleus and the A7 catecholamine cell group, the cerebral ventricles of rodents produces analgesia which include noradrenergic neurons in the dorsolateral provided some of the earliest evidence that opioid re- pontine tegmentum, also project directly to the spinal ceptor agonists act in the brain to produce analgesia. cord dorsal horn and similarly receive afferent projec- Mapping studies subsequently demonstrated that direct tions from more rostral nuclei implicated in pain modu- injection of small microgram doses of morphine into lation. For reasonsthatremain unclear, these nucleihave many different nuclei in the midbrain, pons or medulla not been as extensively studied as those in the rostral was sufficient to produce analgesia (Yaksh and Rudy ventromedial medulla. Yet, the literature reveals many 1978). Indeed, activation of opioid receptors in any instances in which experimental manipulations that pro- one of these nuclei was sufficient to produce analge- duce analgesia, including local application of opioid re- sia. These findings were further supported by others ceptoragonistsatsupraspinalsites,isattenuatednotonly that determined that the analgesic effects of systemi- by intrathecaladministrationofserotoninreceptoran- cally administered morphine were reduced in rats in tagonists, butalso by noradrenergicreceptor antagonists which specific nuclei had been selectively inactivated (Jensen and Yaksh 1986). Furthermore, coincident re- by chemical or electrolytic lesions or by injection of lease of serotonin and norepinephrinein the spinal cord an opioid receptor antagonist or local anesthetic. These has been documented after microinjection of morphine studieswere undertaken atthe same timeasother studies at supraspinal sites. Thus, there appear to be several ef- that demonstrated that supraspinal nuclei exert strong ferent pain modulatory pathways at which opioid recep- inhibitory and excitatory influences on the synaptic tor agonists can act to produce analgesia. transmission of sensory information in the spinal cord. These bulbospinal pathways may or may not function Indeed, chemical activation or electrical stimulation of in concert, but their presence suggests complementary many of the same nuclei at which morphine acted to and possibly redundant means by which sensitivity to produce analgesia was demonstrated to suppress the painful stimuli can be regulated and by which opioids responses of dorsal horn neurons to noxious stimuli in can produce analgesia. Systemically administered opi- anesthetized animals and to produce analgesia in con- oids like morphine, meperidine or fentanyl that cross scious animals. Collectively, these data indicate that the blood-brain barrier readily distribute throughout neurons in the lateral reticular nucleus in the ventro- the brain and are therefore likely to act at multiple lateral medulla, the nucleus raphe magnus and nucleus supraspinal sites to produce analgesia. Thus, spinally reticularis gigantocellularis pars alpha in the rostral projecting neurons in the rostral ventromedial medulla ventromedial medulla, the ventrolateral periaqueduc- and in the dorsolateral pontine tegmentum could be 548 Descending Circuitry, Opioids recruited independently and possibly in a redundant synaptic transmission of sensory information in the manner. However, it is also highly likely that these spinal cord dorsal horn. For example, microinjection pathways are recruited in a concordant or coordinated of glutamate or electrical stimulation in these same manner. For example, neurons in the periaqueductal nuclei could also produce hyperalgesia, in addition gray, an important site of opioid action, project to to analgesia (Zhuo and Gebhart 1990). This set of neurons in the rostral ventromedial medulla and to findings introduced the concept that brainstem nuclei neurons in the dorsolateral pontine tegmentum. Thus, contain pain facilitatory neurons, as well as pain in- both pathways are recruited by an action of opioids hibitory neurons. Sensitivity to painful stimuli or the limited solely to the periaqueductal gray. Furthermore, analgesic effects of opioid receptor agonists therefore neurons in the rostral ventromedial medulla project reflects the net sum activity in these opposing bul- to and activate neurons in the locus coeruleus and A7 bospinal pathways. Thus, it was proposed that opioid catecholamine cell group. Thus, even though the rostral receptor agonists may not only produce analgesia by ventromedial medulla does not contain noradrenergic disinhibition of pain inhibitory neurons, but also by di- neurons, microinjection of opioid receptor agonists in rect inhibition of bulbospinal pain facilitatory neurons this region produces an analgesia that can be reversed (Marinelli et al. 2002). by intrathecal administration of either serotonergic or noradrenergicreceptor antagonists (Hurley et al. 2003). Evolving Concepts: Bimodal Regulation The latter finding is concordant with a recruitment of Sensitivity to painful stimuli is regulated or maintained spinally projecting noradrenergic neurons in the locus through a process of bimodal regulation. Homeostasis coeruleus or A7 catecholamine cell group. reflects a balance of activity in bulbospinal pain facilitatory and pain inhibitory neurons. The apparent potency Evolving Concepts: Disinhibition and Inhibition and efficacy of opioid receptor agonists is also depen- The finding that local application of glutamate, an exci- dent on this balance of activity. Recent data suggest that tatory amino acid, or electrical stimulation of brainstem opioid receptor agonists may disinhibit pain facilitatory nuclei produced analgesia led to the proposal that anal- and pain inhibitory neurons in concert and that the gesia results from the activation of brainstem neurons analgesia produced by opioids represents the sum of that then inhibit the transmission of sensory infor- that activity. For example, microinjection of morphine mation in the spinal cord. However, opioid receptor in the A7 catecholamine cell group results in analgesia agonists are almost exclusively inhibitory. They sup- that is enhanced by antagonism of spinal α1 noradren- press synaptic transmission by acting at postsynaptic ergic receptors and diminished by antagonism of spinal + receptors to increase K conductance resulting in α2 noradrenergic receptors (Holden et al. 1999). This hyperpolarization or by acting at presynaptic recep- finding requires further elaboration of the concept of tors to decrease Ca++ conductance thereby inhibiting pain inhibitory and pain facilitatory pathways. Neurons neurotransmitter release. At first glance, the inhibitory in the rostral ventromedial medulla and the dorsolateral effects of opioid receptor agonists are difficult to rec- pontine tegmentum can synapse directly on spinoretic- oncile with the data that suggested that activation of ular and spinothalamic tract neurons. In this instance, neurons in brainstem nuclei was necessary for the pro- the functional effect of activation of the bulbospinal duction of analgesia. However, neurons in the rostral projection will be dictated by the postsynaptic receptor. ventromedial medulla and the locus coeruleus and A7 For example, activation of α1 noradrenergic receptors catecholamine cell group express γ-aminobutyric acid depolarizes dorsal horn neurons, whereas activation (GABA)A and GABAB receptors and receive inputs of α2 noradrenergic receptors hyperpolarizes these from local GABAergic interneurons that appear to be neurons. Thus, activation of bulbospinal noradrenergic tonically active. These GABAergic neurons express neurons of the locus coeruleus or the A7 catecholamine opioid receptors. Thus, the idea was put forth that opi- cell group can respectively facilitate or inhibit synaptic oid receptor agonists produced analgesia by a process of transmission of nociceptive information in the spinal disinhibition, rather than by direct excitation. Specif- cord. However, other neurons in these same nuclei ically, it was proposed that opioid receptor agonists synapse on interneurons in the dorsal horn that may inhibited the activity of tonically active GABAergic be excitatory (i.e. contain substance P or glutamate) neurons, thereby releasing spinally projecting neurons or inhibitory (i.e. contain enkephalin, glycine or in the rostral ventromedial medulla or A7 neurons from GABA). In this instance, the identity of the interneu- inhibition, resulting in their excitation. The concept of ron will dictate the functional consequence of activation disinhibition by opioids as a means by which spinally or inhibition of the bulbospinal neuron. For example, projecting brainstem neurons were activated to produce serotonin (5HT)3 receptors are excitatory and cause analgesia dominated the literature for over a decade depolarization of neurons. Serotonergic neurons of the (Fields and Basbaum 1999). rostral ventromedial medulla are postulated to inhibit Careful examination of the literature suggested, how- synaptic transmission and produce analgesia via their ever, that brainstem neurons were also able to facilitate projections to GABAergic interneurons that express Descending Circuitry, Opioids 549 a5HT3 receptor (Alhaider et al. 1991). Excitation of the GABAergic interneuron in turn inhibits the activity of spinothalamic or spinoreticular tract neurons and produces analgesia. However, serotonergic neurons in the rostroventromedial medulla are also proposed to facilitate pain via their direct projections to spinothalamic and spinoreticular neurons that also express the D excitatory 5HT3 receptor (Suzuki et al. 2002).

Evolving Concepts: Plasticity in Opioid Actions The vast majority of studies investigating the brainstem neural circuitry by which opioids modulate nociceptive sensitivity limited their investigation to naïve, uninjured rats and used acute measures of pain. Thus, it was not until very recently that it was understood that the bulbospinal efferent pain modulatory pathways exhibit substantial plasticity in terms of their physiological and pharmacological properties (Ren and Dubner 2002) or that these changes had important ramifications for the actions of opioid receptor agonists. For example, the anti-hyperalgesic and antinociceptive effects of μ and δ opioid receptor agonists applied directly into the rostral ventromedial medulla are enhanced under conditions of persistent inflammatory nociception. In addition, persistent inflammation increases the levels of enkephalins, endogenous opioid peptides that have preferential affinity for δ opioid receptors, in the rostral ventromedial medulla. The enhancement of the antinociceptive effects of μ opioid receptor agonists appears to occur as a consequence of an additive or synergistic interaction of the μ opioid receptor agonist with the enhanced release of enkephalins that act preferentially at δ opioid receptors (Hurley and Hammond 2001). These results suggest that endogenous opioids such as enkephalin can be recruited in persistent inflammatory pain states as part of a compensatory response on the part of brainstem pain modulatory pathways to mitigate the behavioral pain state and enable the organism to derive maximum benefit from systemic opioid pharmacotherapies. Figure 1 summarizes the complementary pain modulatory pathways that arise from neurons in the rostral ventromedial medulla, comprised of the nucleus raphe magnus and nucleus reticularis gigantocellularis pars alpha and the dorsolateral pontine tegmentum, which includes the locus coeruleus and A7 catecholamine cell DescendingCircuitry,Opioids,Figure 1 Schematicillustratingtheinter- group. The strain and stock of Sprague-Dawley rat will connections among nuclei in the midbrain, pons and medulla that mediate determine whether the noradrenergic pathways in the the antinociceptive, anti-allodynic and anti-hyperalgesic effects of opioid dorsolateral pontine tegmentum that modulate noci- receptor agonists such as morphine. Neurons in these nuclei may function ceptive sensitivity arise from the locus coeruleus (e.g. to either facilitate or inhibit (+/–) the synaptic transmission of nociceptive information in the dorsal horn of the spinal cord. Although not illustrated Harlan Sprague-Dawley rats) or the A7 catecholamine for the sake of clarity, more rostrally situated nuclei implicated in opi- cell group (Sasco or Charles River Sprague-Dawley oid mediated antinociception, such as the hypothalamus and amygdala, rat) (Clark and Proudfit 1992). Neurons in the rostral send afferent projections to the periaqueductal gray. PAG, periaqueductal gray; DLPT, dorsolateral pontine tegmentum; RVM, rostral ventromedial ventromedial medulla and in the dorsolateral pontine medulla. tegmentum express several different types of opioid receptor although the μ opioid receptor predominates. Opioid receptor agonists can act directly in each nucleus 550 Descending Circuitry, Opioids to produce analgesia either by disinhibition of spinally ofopioidswillrequireameanstoidentifypaininhibitory projecting pain inhibitory neurons or by direct inhibi- and pain facilitatory neurons on the basis of their neu- tion of pain facilitatory neurons. Figure 1 also illustrates rotransmitter contents and receptor expressions, their the interconnections among these nuclei that can sup- afferent and efferent projections and their responses to port concordant recruitment of these bulbospinal pain a variety of nociceptive stimuli and pharmacological modulatory neurons, even when the action of an opioid agents. Although definition of the neural circuitry that is limited to just one nucleus. Finally, Fig. 1 illustrates regulates pain sensitivity and mediates the actions of the efferent projections of the periaqueductal gray, different drug classes requires a systems-based analysis, which also contains opioid receptors, to neurons in both it is not complete without complementary investiga- the rostral ventromedial medulla and the dorsolateral tions that address these same hypotheses using cellular pontine tegmentum that can also support concordant re- and molecular approaches. Therefore, concordance is cruitment of pain modulatory pathways in these nuclei. required so that classification schemes that are devel- Although not illustrated, more rostrally situated nuclei, oped can be uniformly applied under both in vivo and such as the hypothalamus and amygdala, which are in vitro conditions. implicated in nociception and opioid-mediated analgesia send afferent projections to the periaqueductal gray. References

Current Conundrums and Challenges 1. Alhaider AA, Lei S, Wilcox GL (1991) Spinal 5-HT3 receptor- mediated antinociception: possible release of GABA. J Neurosci Substantial evidence has accrued that the antinocicep- 11:1881Ð1888 tive effects of opioid receptor agonists are mediated 2. Clark FM, Proudfit HK (1992) Anatomical evidence for genetic by the activation of serotonergic bulbospinal neurons differences in the innervation of the rat spinal cord by noradren- in the rostral ventromedial medulla. For example, the ergic locus coeruleus neurons. Brain Res 591:44Ð53 3. Fields H (2004) State-dependent opioid control of pain. Nat Rev antinociceptive effects of opioid receptor agonists can Neurosci 5:565Ð575 bereversedbyintrathecaladministrationofserotonergic 4. Fields HL, Basbaum AI (1999) Central nervous system mech- receptor antagonists and opioid administration results anisms of pain modulation. In: Wall PD, Melzack R (eds) The in an increased release of serotonin in the spinal cord. Textbook of Pain, 4th edn. Churchill Livingstone, Edinburgh, pp 309Ð329 Yet, electrophysiological recordings from serotonergic 5. Gao K, Chen DO, Genzen JR et al. (1998) Activation of seroton- neurons (or neurons categorized as serotonergic based ergic neurons in the raphe magnus is not necessary for morphine on their physiological response properties) in the rostral analgesia. J Neurosci 18:1860Ð1868 ventromedial medulla could document no consistent 6. Holden JE, Schwartz EJ, Proudfit HK (1999) Microinjection of morphine in the A7 catecholamine cell group produces increase or decrease in their firing rate after adminis- opposing effects on nociception that are mediated by α1- and tration of morphine (Gao et al. 1998). These results are α2-adrenoceptors. Neurosci 91:979Ð990 difficult to reconcile with the results of earlier phar- 7. Hurley RW, Hammond DL (2001) Contribution of endogenous μ macological and neurochemical investigations unless enkephalins to the enhanced analgesic effects of supraspinal opioid receptor agonists after inflammatory injury. J Neurosci one proposes that opioids may increase the release of 21:2536Ð2545 serotonin from the spinal terminals of these neurons 8. Hurley RW, Banfor P, Hammond DL (2003) Spinal pharmacol- in the absence of a direct excitation of the neuron or ogy of antinociception produced by microinjection of mu or delta that tonically released serotonin exerts a modulatory opioid receptor agonists in the ventromedial medulla of the rat. Neurosci 118:789Ð796 effect at the spinal terminations of other bulbospinal 9. Jensen TS, Yaksh TL (1986) II. Examination of spinal pathways. monoamine receptors through which brainstem opiate-sensitive A principal challenge at present concerns the develop- systems act in the rat. Brain Res 363:114Ð127 10. Marinelli S, Vaughan CW, Schnell SA et al. (2002) Ros- mentof methodsto reliably identify painfacilitatory and tral ventromedial medulla neurons that project to the spinal pain inhibitory neurons in the unanesthetized, awake cord express multiple opioid receptor phenotypes. J Neurosci behaving animal. Although a classification scheme 22:10847Ð10855 has been developed whereby neurons in the rostral 11. Mason P (2001) Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic ventromedial medulla are characterized as on (pain fa- functions. Annu Rev Neurosci 24:737Ð777 cilitatory), off (pain inhibitory) or neutral (no response) 12. Ren K, Dubner R (2002) Descending modulation in persistent cells based on their response to painful stimulation, the pain: an update. Pain 100:1Ð6 vast majority of this work has been conducted in anes- 13. Suzuki R, Morcuende S, Webber M et al. (2002) Superficial 1- thetized animals. Similar studies in conscious animals NK expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci 5:1319Ð13126 have suggested that this classification scheme and the 14. Yaksh TL, Rudy TA (1978) Narcotic analgetics: CNS sites and function of these neurons may be more tightly linked mechanisms of action as revealed by intracerebral injection tech- to and reflective of behavioral state than originally niques. Pain 4:299Ð359 envisioned (Mason 2001; Fields 2004). Advances in 15. Zhuo M, Gebhart GF (1990) Characterization of descending inhibition and facilitation of spinal nociceptive transmission from understanding the neural circuitry that mediates the the nuclei reticularis gigantocellularis and gigantocellularis pars analgesic, anti-allodynic and anti-hyperalgesic effects alpha in rat. Pain 42:337Ð350 Descending Circuitry, Transmitters and Receptors 551

Since there are multiple pathways that descend from Descending Circuitry, Transmitters and the brain into the spinal cord to modulate incoming no- Receptors ciceptive information, it is not surprising that there are a myriad of neurotransmitters and receptors associated ALVIN J. BEITZ with these pathways. The major descending pathways Department of Veterinary and Biomedical Sciences, and their transmitters and receptors are summarized University of Minnesota, St. Paul, MN, USA in Table 1. This list is by no means definitive, and the [email protected] D reader is referred to the comprehensive review by Mi- lan (2002) for an in-depth summary of these pathways, Synonyms transmitters and receptors. Transmitters in the Descending Circuitry; Receptors in the Descending Circuitry Cortical and Subcortical Pathways The anterior cingulated gyrus, agranular insular cor- Definition tex and the frontal/parietal cortical areas have direct Neurotransmitters can be defined as chemicals re- projections to the spinal cord, but each of these released from nerve cells, which convey information from gions also affects the spinal cord indirectly via relays to one neuron to another or to non-neuronal target cells brainstem nuclei, including the rostroventralmedulla such as muscle. Following their release, transmitters (RVM). All three pathways utilize glutamate as a typically affect postsynaptic neurons by binding to major transmitter, but the anterior cingulated gyrus and specialized proteins located in their neuronal mem- the agranular insular cortex facilitate nociception, while brane called receptors. Once a transmitter binds to its the frontal/parietal cortex inhibits nociception, perhaps receptor, it either facilitates opening of an intrinsic ion by acting on different glutamate receptor subtypes or by channel or activates a second messenger system, such as affecting different brainstem circuits or spinal interneu- cyclic GMP, which ultimately leads to a response in the rons. Based on these differential effects, the cerebral postsynaptic neuron. The descending circuitry associ- cortex has been proposed to modulate pain by acting ated with modulation of spinal nociceptive processing on both pronociceptive and antinociceptive circuits, to utilizes a wide variety of transmitters and receptors. change the set-point of pain threshold (Jasmin et al. 2003). The amygdala is a subcortical structure that Characteristics also projects directly to the spinal cord. It utilizes Descending pain modulatory circuitry can either facil- GABA and several peptides as neurotransmitters, and itate or inhibit nociceptive signaling from the spinal has both an inhibitory and facilitory effect on nocicep- cord to higher brain regions by interacting with the tion at the spinal cord level. The amygdala participates terminals of primary afferent fibers, with projection together with the agranular insular cortex, and other neurons, intrinsic spinal cord interneurons or terminals cortical areas, in setting the pain threshold at the level of of other descending pathways. There is no absolute the spinal cord, and an imbalance in the output from the anatomical separation between brain regions that give cortex and amygdala is likely to underlie some chronic rise to descending pathways that inhibit nociceptive pain states. transmission, versus those that give rise to pathways that facilitate nociceptive transmission. The difference Hypothalamus between whether a pathway facilitates or inhibits spinal The hypothalamushas direct projections to the spinal nociceptive processing is dependent in most cases on cordbutisalsoextensivelylinkedtothe periaqueductal the transmitters and receptors associated with that gray (PAG), nucleus of the solitary tract and RVM, and particular pathway (Milan 2002). For instance, neurons thus can influence spinal cord nociception indirectly. in the rostroventral medulla, includingthe nucleusraphe For example, the paraventricular nucleus (PVN) of the magnus, give rise to descending serotonergic (5-HT) hypothalamus provides the major source of oxytocin- pathways, which can produce inhibition or facilitation and vasopressin-containing axons to the dorsal horn, of spinal cord dorsal horn neurons (Fields and Basbaum and release of these peptides inhibits nociception by ac- 1999; Porreca et al. 2002), based in part on the type of tivation of VP1a and oxytocin receptors on spinal cord 5-HT receptor that is activated upon 5-HT release. Thus inhibitory interneurons. A number of other peptides 5-HT activation of 5-HT1B, 1D, or 3 receptors inhibits and transmitters have been identified in paraventric- dorsal horn nociceptive transmission, while activation ular hypothalamospinal projections, as summarized of 5-HT1A,2A,2C,3,4,or7receptors facilitates nocicep- in Table 1. The posterior periventricular nucleus and tive transmission (Milan 2002). Similarly, descending the tuberomamillary nucleus are the major sources dopaminergic, cholinergic and noradrenergic path- of dopamine and histamine, respectively, to the ways can facilitate or inhibit dorsal horn nociceptive spinal cord. Dopamine acts at spinal cord D2 receptors transmission, by differential actions on dopaminergic, to inhibit nociception and at D1 receptors to facilitate cholinergic or noradrenergic receptor subtypes. nociception, while histamine acts at H1 receptors to fa- 552 Descending Circuitry, Transmitters and Receptors

Descending Circuitry, Transmitters and Receptors, Table 1 Overview of the descending pathways that modulate nociception in the spinal cord dorsal horn Brain Structure Primary Transmitter Other Transmitters Inhibits Nociception Facilitates Nociception

Anterior Cingulate Gyrus Glutamate ? - ++

Frontal/Parietal Glutamate ? ++ -

Amygdala GABA Somatostatin, Neurotensin, ++ + VIP

Paraventricular VasopressinOxytocin- Dynorphin, Enkephalin VP1a/OTCRF1 K-opioid - Nucleus/Hypothalamus CorticotrophinReleasing NeuropeptideFFNitric Oxide Factor

Posterior Peri-ventricular Dopamine RFamide related peptides D2 D1 nucleus (A11)/Hypothalamus CGRP

Tuberomamillary Histamine GABA, Galanin, Enkephalin - H1 Nucleus/Hypothalamus

Arcuate B-endorphinMelanocortin- CART µ-opioidNPY1 MC4 Nucleus/Hypothalamus Neuropeptide Y

Lateral Hypothalamus Orexin DynorphinGlutamate orexin-1 receptor -

Periaqueductal Gray Glutamate, SerotoninNeurotensin- NMDA5-HT3 CCK2/NK1 CCK/Substance P Enkephalin

Parabrachial Nucleus GlutamateAcetylcholine Somatostatin, ++ + EnkephalinGABA

Pedunculopontine Nucleus Acetylcholine Dynorphin,Vasopressin ++ -

A5, A6, A7 Nuclei Noradrenaline GABA, Glutamate, α2A, α2B α1A, α1B Neuropeptide Y

Nucleus Raphe Magnus Serotonin GABA. Glutamate, 5-HT1B,1D,3 5-HT 1A,2A,2C,3,4,7 Enkephalin, Galanin, CCK

RostroVentral Medulla Acetylcholine, GABA Glycine, CCK, Enkephalin MuscarinicNicotinic Nicotinic

Nucleus of the Solitary Tract Glutamate Somatostatin,Orphanin ++ + FQ,CCK

Dorsal Reticular Nucleus Glutamate ? + ++

A summary of the major descending pathways that synapse in the spinal cord dorsal horn and the transmitters and receptors associated with each pathway that inhibit or facilitate nociception. The primary transmitters of each pathway are listed in the second column, while additional transmitters (neuromodulators) are listed in the third column. The identity of other transmitters for corticospinal pathways and some reticulospinal pathways remain to be determined. The specific receptor subtypes involved in antinociceptive or pronociceptive actions are also listed. In cases where the specific receptors that facilitate or inhibit nociception have yet to be identified with certainty, the antinociceptive or pronociceptive effect of stimulating the pathway is indicated by pluses (++). A single “+” indicates that the evidence is controversial and a lack of evidence is indicated by a minus sign. It is important to note that while the structures listed in this table have direct projections to the spinal cord, they may also influence nociception indirectly by activating other brain regions, particularly medullary and pontine nuclei, that in turn project directly to the spinal cord. Receptor Abbreviations: α, Adrenergic; CCK, Cholecystokinin; CRF, corticotropin releasing factor; D, Dopamine; H, Histamine; MC, Melanocortin; NK, Neurokinin; NMDA, N-Methyl-D-Aspartate;OT, oxytocin; 5-HT, serotonergic; VP, Vasopressin cilitate nociception. The hypothalamic arcuate nucleus Brain Stem Nuclei contains a large number of neuroactive peptides, as in- The periaqueductal gray (PAG) is a midbrain structure dicated in table 1, and sends projections directly to the with a vast number of neurotransmitters and neuropep- spinal cord, where these neuroactive peptides are either tides, and has a rich history as a key component in antinociceptive or pronociceptive, depending on the the descending pain modulation system (Beitz 1995). neuropeptide receptors that are activated. Finally, the While glutamate appears to be the key transmitter of de- lateral hypothalamus provides a direct orexin projection scending projections from this region to the spinal cord to the spinal cord, which is thought to play a role in and to other brainstem nuclei (Beitz 1995), a number descending antinociceptive mechanisms, by activating of other transmitters including 5-HT, cholecystokinin, inhibitory interneurons in the spinal cord dorsal horn substance P and neurotensin are present in descending (Grudt et al. 2002). PAG projections (Beitz 1982; Beitz et al. 1987). Neu- Descending Circuitry, Transmitters and Receptors 553 rotensin released from the PAG has a dual effect in the to the spinal cord. This region can inhibit nociception, rostroventral medulla (RVM): facilitation predominates via activation of muscarinic and nicotinic cholinergic at low (picomolar) doses of neurotensin injected into receptors, and can facilitate nociception via activation the RVM, whereas higher doses (nanomolar) produce of nicotinic receptors. Descending projections from the antinociception (Smith et al. 1997). It is also worth not- RVM also contain glycine, CCK, enkephalin and 5-HT ing that stimulation of μ- opioid receptors in the PAG (Milan 2002). These neurotransmitters also appear to with morphine or other μ-opioid receptor agonists modulate spinal nociception, but the precise action of D activates a descending antinociceptive circuit with a each transmitter and the specific receptor subtypes ac- delta-opioid receptor link in the RVM (Hirakawa et al. tivated within the dorsal horn remain to be adequately 1999). While a significant portion of the PAG’s effect defined. The nucleus of the solitary tract (NTS) plays on spinal nociception is mediated via relays in other a crucial role in processing visceral information, and nuclei, like the RVM and A7 nucleus, direct descending like the PBN, it serves as an interface between the au- pathways from this region can inhibit nociception at tonomic and sensory branches of the nervous system. the spinal cord level via actions at NMDA receptors on Stimulation of the NTS has both antinociceptive and spinal interneurons, and facilitate nociception via acti- pronociceptive effects, which appear to be mediated vation of neurokinin and cholecystokinin receptors. The by glutamatergic bulbospinal projections, with contri- pons contains a number of noradrenergic cell groups butions from a peptidergic component consisting of including the locus coeruleus (A6), the A5 group in the somatostatin, CCK and orphanin FQ-containing axons. ventrolateral brainstem and the A7 group, whose axons Since the NTS contains a myriad of neuropeptides and project directly to the spinal cord dorsal horn. The bul- transmitters, it is likely that other NTS neuropeptides bospinal axons arising from these cell groups release and transmitters may also contribute to nociceptive noradrenaline, which inhibits nociception by acting modulation at the spinal level. The dorsal reticular on α2-adrenergic receptors on primary afferent termi- nucleus is located in the dorsal portion of the medulla, nals, to reduce the release of glutamate and substance P, adjacent and lateral to the NTS, and stimulation of this and by increasing the release of inhibitory neurotrans- region has been shown to enhance the responsiveness mitters from lamina II interneurons (Kawasaki et al. of spinal nociceptive neurons to peripheral stimula- 2003). Noradrenaline released from these descending tion (Dugast et al. 2003). Neurons in this region are fibers can also facilitate nociception, by acting at spinal activated by noxious stimuli, contain a high level of cord α1A-andα1B-adrenergic receptors. In addition to GABAB receptors, and send glutamatergic projections these noradrenergic cell groups, the pons provides a ma- to the spinal cord to modulate nociception. jor cholinergic projectionto the spinal cord, arising from Given the information summarized above, it is clear that the pedunculopontine nucleus and the parabrachial nu- there are a large number of transmitters and receptors cleus (PBN), as well as a glutamatergic projection aris- associated with the descending circuitry that modulates ing from the parabrachial nucleus. The pedunculopon- spinal nociceptive processing. An understanding of the tine nucleus inhibits nociception via release of acetyl- rolethateachtransmitterandreceptorplaysinpainmod- choline, dynorphin and vasopressin, while the PBN ulationiscomplicatedbythefactthatasingletransmitter can inhibit nociception via activation of glutamate and even a single receptor class can exert differential ef- receptors located on spinal inhibitory interneurons or fectson nociception, atboth spinalandsupraspinalsites. via the direct release of GABA and enkephalin. Nonetheless, extensive progress has been made in defin- The medulla provides a rich contribution of descending the rolesof many ofthe neuroactive substanceslisted ing projections to the spinal cord, which includes a above, and knowledge of the mechanisms by which de- major source of serotonin, glutamate, GABA and scending pathways modulate nociception has increased neuropeptide input. The 5-HT innervation of the spinal dramatically in recent years, which should lead to im- cord dorsal horn arises in large part from the nucleus proved management of pain. raphe magnus. This descending serotonergic projection References can both inhibit and facilitate nociception via activation 1. Beitz AJ (1982) The Sites of Origin of Brain Stem Neurotensin of different 5-HT receptors, as summarized in table 1. and Serotonin Projections to the Rodent Nucleus Raphe Magnus. It should be noted that descending 5-HT axons also J Neurosci 2:829Ð842 contain a number of other neuropeptides and transmit- 2. Beitz AJ (1995) Periaqueductal Gray. In: Paxinos G (ed) The ters including glutamate (Hokfelt et al. 2000), and thus Rat Nervous System, 2nd end. Academic Press, San Diego, it is likely that additional neuroactive substances are pp 173Ð182 3. Beitz AJ, Clements JR, Ecklund LJ et al. (1987) The Nuclei of co-released with 5-HT in the spinal cord dorsal horn, Origin of Brainstem Enkephalin and Cholecystokinin Projections causing a wide spectrum of post- (and pre-) synaptic to the Spinal Trigeminal Nucleus of the Rat. Neuroscience 1987 action. The rostroventral medulla consists of several 20:409Ð425 subnuclei, including the nucleus gigantocellularis pars 4. Dugast C, Almeida A, Lima D (2003) The Medullary Dorsal Reticular Nucleus Enhances the Responsiveness of Spinal No- alpha and the lateral paragigantocellular nucleus, which ciceptive Neurons to Peripheral Stimulation in the Rat. Eur J provide both a GABAergic and cholinergic projection Neurosci 18:580Ð588 554 Descending Circuits in the Forebrain, Imaging

5. Fields, HL and Basbaum AI (1999) Central Nervous System One pitfall in the interpretation of functional imaging Mechanisms of Pain Modulation. In: Wall PD, Melzac R (eds) data is that increases in the oxygenation level of the Textbook of Pain, 4th edn. Churchill Livingston, Edinburgh, pp 309Ð329 blood (as is commonly measured in fMRI experiments) 6. Grudt TJ, van den Pol AN, Perl ER (2002) Hypocretin-2 (orexin- or metabolism (as measured with PET) can represent B) Modulation of Superficial Dorsal Horn Activity in Rat. J Phys- increased activity in either excitatory or inhibitory neu- iol 538(Pt 2):517Ð525 rons (or both) within the area of interest, making it hard 7. Hirakawa N, Tershner SA and Fields HL (1999) Highly δ Se- lective Antagonists in the RVM Attenuate the Antinociceptive to distinguish the net neurophysiological outcome of Effect of PAG DAMGO. Neuroreport 10:3125Ð3129 the measured activity. A second caution when interpret- 8. Hokfelt T, Arvidsson U, Cullheim et al. (2000) Multiple Messen- ing imaging results involves the distinction between gers in Descending Serotonin Neurons: Localization and Func- changes that occur in each “active” area as a source of tional Implications. J Chem Neuroanat 18:75Ð86 9. Jasmin L, Rabkin SD, Granato A et al. (2003) Analgesia and modulation and changes that occur as a result of such Hyperalgesia from GABA-Mediated Modulation of the Cerebral modulation (through the influence of other brain areas). Cortex. Nature 424:316Ð320 Without supporting research from other methodologies, 10. Kawasaki Y, Kumamoto E, Furue H et al. (2003) Alpha 2 hypotheses based on results from imaging studies alone Adrenoceptor-Mediated Presynaptic Inhibition of Primary Af- ferent Glutamatergic Transmission in Rat Substantia Gelatinosa are speculative. Neurons. Anesthesiology 98:682Ð689 Given these caveats, the great advantage of functional 11. Milan MJ (2002) Descending Control of Pain. Prog Neurobiol brain imaging isthatresponsivenessinanumber ofbrain 66:355Ð474 regions can be looked at simultaneously to examine how 12. Porreca F, Ossipov MH, Gebhart GF (2002) Chronic Pain and Medullary Descending Facilitation. Trends Neurosci these areas are affected by particular manipulations that 25:319Ð325 occur within short experimental sessions and with 13. Smith DJ, Hawranko AA, Monroe PJ et al. (1997) Dose- relatively few subjects. This allows for a comprehen- Dependent Pain-Facilitatory and -Inhibitory Actions of Neu- rotensin are Revealed by SR 48692, a Nonpeptide Neurotensin sive assessment of the areas that may be involved in Antagonist: Influence on the Antinociceptive Effect of Morphine. descending modulation of pain. J Pharmacol Exp Ther 282:899Ð908 The regions most consistently activated by nociceptive stimulation alone, measured with PET and fMRI, have been well studied using various types of peripheral stim- Descending Circuits in the Forebrain, ulation. The recognition that brain imaging techniques could bring special insight regarding which of these ar- Imaging eas exhibited changes in activity that were correlated ELIZABETH ROY FELIX with changes in pain perception measured psychophysi- The Miami Project to Cure Paralysis, University of cally has led to another level of investigation,one which Miami Miller School of Medicine, Miami, FL, USA examines the mechanisms of nociceptive modulation in [email protected] the forebrain. A first approach to understanding the mechanisms of Synonyms pain modulation is the investigation of responsiveness to the presentation of the effective manipulation itself, Functional Imaging of Descending Modulation; Cogni- in the absence of nociceptive stimulation. PET studies tive Modulation of Pain; imaging descending circuits in are especially useful in this regard and have provided a the forebrain starting point for evaluating the possible mechanisms Definition of descending modulation. Manipulations involving suggestions of pain relief ( placebo :Petrovicetal. Functional brain imaging techniques have been used 2002; hypnosis: Faymonville et al. 2000) result in in- as in vivo methods for examining which brain regions creased regional cerebral blood flow (rCBF) in areas of may be involved in or reflective of the modulation the ACC compared to a resting condition. Administra- of pain. Current evidence using positron emission tion of fentanyl (Adler et al. 1997; Casey et al. 2000) or tomography (PET) and functional magnetic reso- remifentanyl(Petrovicetal. 2002),bothopioidagonists, nance imaging (fMRI) methodologies supports roles also results in increased rCBF in the perigenual- and for the perigenual- and mid- anterior cingulate cor- mid-ACC regions. Similarly, increased activations in tices (ACC) and portions of the prefrontal cortex in prefrontal regions during placebo (Petrovic et al. 2002) modulating input from nociceptive afferent pathways or opioid administration (Firestone et al. 1996; Petrovic via descending projections. et al. 2002), support inclusion of prefrontal areas in the circuitry responsible for descending modulation of Characteristics pain. Utilization of brain imaging techniques to study the de- Perhaps a more direct way to implicate regional involve- scending modulation of pain is not straightforward and ment in descending modulation of pain is to examine the thus the results from these studies must be considered nociceptive specific changes that occur in forebrain ac- together with results derived from other methodologies. tivity during manipulations aimed at altering pain per- Descending Circuits in the Forebrain, Imaging 555 ception. Indeed, several cortical and sub-cortical areas Many prefrontal areas have also been implicated as have been shown to modulate their level of responsive- possible sources of descending modulatory control. ness to painful stimuli in the presence of cognitive and Changes similar to those seen in the perigenual/rostral pharmacological manipulations that modify the percep- ACC have been reported in the prefrontal cortex when tionofsuchstimuli.Oneofthemostfrequentlyidentified the subjective perception of a noxious stimulus is de- areas related to this type of modulation in human sub- creased due to distraction or administration of pharma- jects is the ACC. Although the exact location and po- cological agents or when nociceptive specific increases D larity of the changes in activity within the ACC during in activation of prefrontal regions are evident (Adler et cognitive modulation of pain are not in full agreement al. 1997; Bantick et al. 2002; Frankenstein et al. 2001; among all such studies, the most consistent effect in this Petrovic et al. 2000). Administration of opioidergic area suggests that manipulations that cause decreases in agents in the absence of pain stimulation also increases painperception(comparedtoequalintensitystimulipre- activation in prefrontal areas (Firestone et al. 1996; sented outside the cognitive modulation context) result Petrovic et al. 2002), further suggesting that such ac- inincreasedstimulusinducedactivationhere(Banticket tivation may serve to inhibit forthcoming nociceptive al. 2002; Frankenstein et al. 2001; Petrovic et al. 2002). signals. In addition, a study that prompted increased pain per- Experiments involving evoked increases in pain percep- ceptual ratings by increasing the anxiety associated with tion due to increased anticipatory anxiety however, re- an impending noxious stimulus was correlated with de- port positive correlationsbetweenratingsof painandac- creased activation in this area of the ACC (Porro et al. tivity in prefrontal areas (Hsieh et al. 1999; Porro et al. 2002), suggesting that the direction of change in ACC 2002).Theseresultsimplythattheprefrontalcortexmay modulatory activity can be reversed if the situation calls work as a coding mechanism for pain intensity Ð sim- for increased vigilance. ply a reflection of changes in pain perception Ð rather Although the mechanisms underlying the relationship than a source of such modulation. Similarly, peripheral between the modulation of pain and activity in the stimulation with capsaicin, which sets up conditions of perigenual/rostral ACC seen in brain imaging studies allodyniaand secondaryhyperalgesia(mediatedby are far from fully elucidated, the evidence cited above central mechanisms), also results in increases in posi- demonstrates that this area is a likely candidate for the tive correlations between prefrontal activation and mea- modulation of pain in certain contexts. Taken together, sures of pain intensity (Iadorola et al. 1998; Lorenz et these studies suggest that increased activation in this al. 2002). The current evidence regarding the prefrontal area of the ACC serves to suppress incoming nocicep- cortex and its modulatory role in pain perception then, tive information, causing decreases in pain perception. suggests a complex relationship, involving increases in In fact, Petrovic and colleagues (2002) (see Fig. 1) have activation of this area under contexts that cause reduc- shown that, during administration of either remifentanyl tions in pain (during distraction and opioid administra- (an opioid receptor agonist) or placebo (administered tion) and those that cause increases in pain sensitivity with suggestions of pain relief), there is increased cor- (during anxiety and stimulus induced allodynia and hy- relation between activation in rostral ACC and areas of peralgesia). the pons and the periaqueductal gray (PAG) in the The insular cortex is another area that is consistently re- brainstem (when compared with correlated stimulus ported to show changes in its level of stimulus-induced induced activation of these areas in the absence of pain activation under cognitive and pharmacological condi- modulation). A recent fMRI study (Bingel et al. 2006) tions that alter pain sensitivity. Manipulations resulting supports this finding, identifying significant covariation inincreasesinpainresultinincreasesinactivityinthein- of placebo-dependent activation between rostral ACC sula (Hofbauer et al. 2001; Porro et al. 2002) and manip- and the PAG, and between rostral ACC and bilateral ulations that result in decreases in pain perception cor- amygdalae, as well. These results implicate the ACC relate with similar decreases in this area (Brooks et al. as a possible source of cortical nociceptive modulation, 2002; Bantick et al. 2002; Petrovic et al. 2002). To date, exerting control of activity in brainstem areas known there is little evidence from functional imaging studies to be involved in the descending modulation of pain. thattheinsulahasanydirectinfluenceoverincomingno- Despite the differences in the vehicle of modulation ciceptive input. Instead, it may serve as a coding mech- (administration of an opioid agonist or cognitive sug- anism for the level of the sensory experience. Likewise, gestions accompanying placebo administration), both other areas involved in pain processing during baseline means of manipulating pain perception resulted in ac- or control conditions (thalamus, primary and secondary tivation of similar brain circuits, suggesting at least somatosensory cortex) show changes in responsiveness some common mechanisms for modulation of pain at that positively correlate with the direction of the percep- the cortical level. Additionally, fMRI has been used tualchanges(Bantick etal. 2002;Casey etal. 2000;Hof- to further suggest the engagement of the PAG during bauer etal. 2001;Lorenzetal.2003;Petrovicetal. 2000) modulation of pain via attentional mechanisms (Tracey andarenotimplicatedassourcesofthecognitiveorphar- et al. 2002). macological modulation of pain. 556 Descending Circuits in the Forebrain, Imaging

Descending Circuits in the Forebrain, Imaging, Figure 1 Covariation of activity in brainstem regions with activity in the rACC (denoted by the blue sphere) in different pain conditions. (a) Activity in the rostral ACC covaried with activity in the PAG and in the lower pons/medulla during the pain + opioid condition. These covariations were signiﬁcantly greater during the pain + opioid condition compared with the pain alone condition. (b) A similar covariation between the rostral ACC and the lower pons/medulla was observed during the pain + placebo condition. This covariation was signiﬁcantly greater during pain + placebo as compared with pain alone. (c) No such regressions were observed during the pain alone condition. The activations are presented on an SPM99-template and a more detailed image of the brainstem indicating the approximate position of the PAG and the pons. The threshold of activation is at p = 0.005 (from Petrovic et al. 2002).

Although thespatialand temporalresolution ofPET and 3. Bingel U, Lorenz J, Schoell E, Weiller C, Büchel C (2006) Mech- fMRI may not always be fine enough to resolve direct anisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain 120:8Ð15 relationships between different brain structures known 4. Brooks JCW, Nurmikko TJ, Bimson WE et al. (2002) fMRI of toexhibitdescendingpainmodulationdefinitively,these thermal pain: Effects of stimulus laterality and attention. Neu- methods do allow us access to the inter-related nature of roImage 15:293Ð301 the forebrain during such modulation. Functional brain 5. Casey KL, Svensson P, Morrow TJ et al. (2000) Selective opiate modulation of nociceptive processing in the human brain. J imaging in human subjects has allowed the evaluation, Neurophysiol 84:525Ð533 not only of pharmacological effects, but also of complex 6. Faymonville ME, Laureys S, Degueldre C et al. (2000) Neural psychologicalmanipulationson changesin activationof mechanisms of antinociceptive effects of hypnosis. Anesthesi- particular brain areas that correspond with changes in ology 92:1257Ð1267 7. Firestone LL, Gyulai F, Mintun M et al. (1996) Human brain pain perception. Current research, indicating increased activity response to fentanyl imaged by positron emission to- activity levels in the ACC and in prefrontal regions dur- mography. Anesth Analg 82:1247Ð1251 ing decreased pain perception due to experimental ma- 8. Frankenstein UN, Richter W, McIntire MC et al. (2001) Distrac- nipulation,pointstotheseareasasthebestcandidatesfor tion modulates anterior cingulated gyrus activations during the cold pressor test. NeuroImage 14:827Ð836 exerting descending control over nociceptive signaling. 9. Hofbauer RK, Rainville P, Duncan GH et al. (2001) Cortical Many other areas responsive to pain, including the in- representation of the sensory dimension of pain. J Neurophysiol sular cortex, the primary and secondary somatosensory 86:402Ð411 cortices and the thalamus, may also be found to be in- 10. Hsieh J-C, Stone-Elander S, Ingvar M (1999) Anticipatory coping of pain expressed in the human anterior cingulated volved in the descending modulation of pain, but current cortex: a positron emission tomography study. Neurosci Lett functional imaging results do not strongly support such 262:61Ð64 roles. 11. Iadorola MJ, Berman KF, Zeffiro TA et al. (1998) Neural activation during acute capsaicin-evoked pain and allodynia assessed with PET. Brain 121:931Ð947 References 12. Lorenz J, Cross DJ, Minoshima S et al. (2002) A unique representation of heat allodynia in the human brain. Neuron 35:383Ð393 1. Adler LJ, Gyulai FE, Diehl DJ etal. (1997) Regional brain activity 13. Lorenz J, Minoshima S, Casey KL (2003) Keeping pain out of changes associated with fentanyl analgesia elucidated by positron mind: the role of the dorsolateral prefrontal cortex in pain mod- emission tomography. Anesth Analg 84:120Ð126 ulation. Brain 126:1079Ð1091 2. Bantick SJ, Wise RG, Ploghaus A et al. (2002) Imaging how 14. Petrovic P, Petersson KM, Ghatan PH et al. (2000) Pain-related attention modulates pain in humans using functional MRI. Brain cerebral activation is altered by a distracting cognitive task. Pain 125:310Ð319 85:19Ð30 Descending Facilitation and Inhibition in Neuropathic Pain 557

15. Petrovic P, Kalso E, Petersson KM et al. (2002) Placebo and to peripheral nerves. Nerve injury may be due to phys- opioid analgesia Ð imaging a shared neuronal network. Science ical trauma, a consequence of a disease state or a result 295:1737Ð1740 16. Porro CA, Baraldi P, Pagnoni G et al. (2002) Does anticipa- of cancer chemotherapy or other medications. Abnor- tion of pain affect cortical nociceptive systems? J Neurosci mal nerve injury induced pain states are often charac- 22:3206Ð3214 terized by spontaneous burning pain, paroxysmal pain, 17. Tracey I, Ploghaus A, Gati JS et al. (2002) Imaging attentional allodynia and hyperalgesia. Neuropathic pain is resis- modulation of pain in the periaqueductal gray in humans. J Neu- rosci 22:2748Ð2752 tant to common protocols for treatment of chronic pain. D Allodynia refers to the condition when normally non- noxious stimuli are perceived as noxious. Hyperalgesia refers to enhanced perception of and responses to noxious stimuli. Descending Control It is generally accepted that specific regions of the brain exert modulatory control over incoming pain Descending Modulation of Nociceptive Processing signals. As such influences descend from the brain to the spinal cord, this process is referred to as descending modulation. Descending inhibition is the activation of inhibitory systems arising from discrete brain loci and projecting to the dorsal horns of the spinal cord that Descending Control of Hyperalgesia modulate nociceptive inputs at that level (for review see Fields and Basbaum 1999). Accordingly, electrical DescendingModulationofNociceptiveTransmission stimulation of discrete regions of the brain has produced during Persistent Damage to Peripheral Tissues robust antinociception in many species. Although several brain sites have been identified as important in the descending modulation of pain, considerable anatomical evidence indicates that the rostroventromedial medulla (RVM) is an integral relay in the processing Descending Excitatory Modulation of bulbospinal pain modulation (Fields and Basbaum 1978). The RVM includes, but is not limited to, the Descending Facilitatory Systems midline nucleus raphe magnus (NRM). It is defined anatomically as the region of the medulla between the pyramids, from the ventral surface to the top of the facial nucleus and extending rostro-caudally from the caudal aspect of the superior olive to the rostral aspect Descending Facilitation of the inferior olive. Projections from the RVM to the spinal cord course principally along the dorsolateral Descending Facilitatory Systems funiculus (DLF). Descending Modulation of Visceral Pain Characteristics Descending Modulation of Pain Convincing evidence that specific regions of the brain Descending Facilitation and Inhibition in exert a control over incoming pain signals at the level of Neuropathic Pain the spinal cord was first demonstrated when focal electrical stimulation in the midbrain periaqueductal gray MICHAEL H. OSSIPOV,FRANK PORRECA (PAG) of the conscious rat produced a profound analge- Department of Pharmacology, University of Arizona, sia. Electrical stimulation of the PAG has also relieved Health Sciences Center, Tucson, AZ, USA intractable cancer pain in man. Other sites, including the [email protected], [email protected] locus coeruleus and the thalamus, also produce robust antinociception in several species when stimulated (for Synonyms review see Fields and Basbaum 1999). These sites co- incide with those that produce antinociception after the Spinopetal Modulation of Pain; Bulbospinal Modula- microinjectionofmorphine(FieldsandBasbaum1999). tion of Nociceptive Inputs The interpretation that the RVM functions as a critical brainstem relay in the modulation of descending noci- Definitions ceptive controls is supported by observations that inter- Neuropathicpain refersto thesetof behavioralsignsand ruptionoftheactivityoftheRVMbyeitherlidocainemi- symptoms that are associated with pain following injury croinjections or lesions blocked antinociception elicited 558 Descending Facilitation and Inhibition in Neuropathic Pain by stimulation of the PAG (Gebhart et al. 1983). More caine or ibotenic acid also blocked hyperalgesia and recent studies show that the RVM may give rise to a fa- increased WDR cell activity of inflammatory origin cilitatory pathway that promotes pain as well. For ex- (Pertovaara 1998). In the light of these considerations, ample, nociceptive inputs may activate pain facilitatory it is believed that behavioral manifestations of neuro- neurons of the RVM, thus promoting further nocicep- pathic pain result in part from supraspinal neuroplastic tion, setting the stage for the maintenance of a chronic changes in response to abnormal, persistent afferent pain state (Porreca et al. 2002). An illustration of this inputs resulting from the nerve injury. These changes concept is observed when hyperalgesia induced by a va- appear to induce the activation of medullospinal fa- riety of means, including naloxone precipitated opiate cilitatory pathway(s) that result in further increase in withdrawal, inflammation or nerve injury is reversed by afferent input. These changes lead to a self-generating intra-RVM lidocaine or electrolytic lesion (Pertovaara feed forward mechanism that perpetuates sensations 1998). Electrical stimulation of the RVM at low intensi- of neuropathic pain, even after the original injury has ties has facilitated dorsal horn neuronal activity and the been resolved. spinal nociceptive tail flick reflex, further demonstrating The spinopetal projections from the RVM travel along the existence of nociceptive facilitation arising from this the dorsolateral funiculus (DLF) to synapse with either region (Zhuo and Gebhart 1997). interneuronsornerveterminalsofprimaryafferentfibers In order to describe how the RVM may mediate appar- in the dorsal horn of the spinal cord(Fieldsand Basbaum ently physiologically contradictory functions, it should 1999).AblationoftheDLFipsilateraltospinalnervelig- be remembered that the RVM is considered to con- ation abolished injury induced tactile hypersensitivity, tain three types of cells, which have been extensively whereas contralateral DLF lesions or sham DLF lesions characterized by Fields and colleagues (Fields and had no effect on neuropathic pain (Ossipov et al. 2000). Heinricher 1985). Based on response characteristics The maintenance, but not the initiation, of nerve injury to nociception, these cells are described as “on”-cells, induced pain appear to require supraspinal neuroplas- “off”-cells and neutral cells. The physiologic function tic changes that ultimately activate descending facilita- of the neutral cells is undetermined. The off-cells are tion from the RVM. RVM lidocaine, selective lesions of tonically active, pause in their firing immediately before mu-opioid receptor expressing neurons of the RVM and a withdrawal response occurs to noxious stimuli and DLF lesions blocked tactile and thermal hypersensitiv- are believed to be responsible for descending inhibition ity elicited by nerve injury, but only beyond the 3rd day of nociceptive inputs (see Fields and Basbaum 1999). post-injury (Burgess et al. 2002). At day 3, these manip- The on-cells accelerate firing immediately before the ulations were without effect (see below). nociceptive reflex occurs and are likely to be the source The up-regulation of spinal dynorphin may provide a of descending facilitation of nociceptive inputs and means through which enhanced afferent inputs may be thus can mediate hyperalgesia (Fields and Basbaum maintained. Considerable evidence has demonstrated 1999). Accordingly, manipulations that increase noci- that dynorphinis pronociceptiveand tactile and thermal ceptive responsiveness, thus indicating facilitation, also hypersensitivity elicited by nerve injury was reversed increase on-cell activity. Naloxone precipitated opioid by the spinal injection of dynorphin antiserum (Wang withdrawal is associated with hyperalgesia and also et al. 2001). Furthermore, spinal dynorphin content is with increased activity of RVM on-cells, which is in maximally elevated within 10 days after nerve injury, turn blocked by RVM lidocaine (for reviews see Fields although behavioral signs of abnormal pain occur as and Basbaum 1999; Porreca et al. 2002). early as 3 days after the injury (Wang et al. 2001). This It is now generally accepted that a spino-bulbo-spinal observation suggests that spinal dynorphin elevations loop may be important in the development and main- may be a result of neuroplastic changes over a period tenance of exaggerated pain behaviors produced by of several days. This suggestion was supported by the noxious (i.e. hyperalgesia) and non-noxious (i.e. allo- observation that in mice tested within 2 days of SNL, dynia) peripheral stimuli (Fields and Basbaum 1999; tactile hypersensitivity wasreversed by spinalinjections Porreca et al. 2002). Behavioral signs of tactile hyper- of MK-801, but not by antiserum to dynorphin. In con- sensitivity and thermal hyperalgesia were produced by trast, on the 10th day after SNL, both spinal injections CCK injected into the RVM and this effect was blocked of MK-801 and antiserum to dynorphin blocked signs bytheCCK2 receptorantagonistL365,260(Kovelowski of neuropathic pain (Wang et al. 2001). Accordingly, et al. 2000). Furthermore, microinjection of L365,260 spinal dynorphin content was not elevated on the second or of lidocaine into the RVM blocked behavioral signs day, but was elevated on the 10th day (Wang et al. 2001). of neuropathic pain in rats with spinal nerve ligation Furthermore, mice with deletions of the prodynorphin (SNL) (Kovelowski et al. 2000; Pertovaara et al. 1996). gene (dynorphin knockout; KO) developed behavioral Persistent noxious input from an injection of formalin signs of neuropathic pain within 2 days of SNL that into the hind paw has facilitated the nocifensive tail were blocked by MK-801. These signs spontaneously flick reflex through an NMDA-mediated mechanism resolved over a 10 day period, whereas those of the wild within the RVM (Wiertelak et al. 1994). RVM lido- type littermatesdid not (Wang et al. 2001). These studies Descending Facilitatory Systems 559 taken together suggest that elevated spinal dynorphin for the treatment of neuropathic pain states. These may not be critical to the initiation of increased pain, but would include local anesthetic application at the site isanecessary componentfor thelong-termmaintenance of injury, antagonists of excitatory neurotransmitters of abnormal pain after nerve injury. (e.g. CCK antagonists or NMDA antagonists), inter- The precise mechanisms through which elevated spinal ruption of spinal neurotransmitter release or blockade dynorphin promotes neuropathic pain remain to be of the neurotransmitter receptors and prevention of the elucidated. However, there is considerable evidence up-regulation of spinal dynorphin. D that increased spinal dynorphin promotes the further release of excitatory amino acids from primary afferent References neurons, in this way provoking a positive feedback 1. Burgess SE, Gardell LR, Ossipov MH et al. (2002) Time- loop that amplifies further sensory input. Microdialysis dependent descending facilitation from the rostral ventromedial studies have demonstrated localized, dose-dependent medulla maintains, but does not initiate, neuropathic pain. J Neurosci 22:5129Ð36 release of glutamate and aspartate elicited by exogenous 2. Fields HL, Basbaum AI (1978) Brainstem control of spinal pain- dynorphin in the hippocampusand spinal cord (Skilling transmission neurons. Annu Rev Physiol 40:217Ð48 et al. 1992). More recently, it was demonstrated that 3. Fields HL, Basbaum AI (1999) Central nervous system mecha- capsaicin-stimulated release of CGRP was potentiated nisms of pain modulation. In: Wall PD, Melzack R (eds) Textbook of pain. Churchill Livingstone, Edinburgh, pp 309Ð329 by dynorphin in spinal cord slices in vitro (Gardell et al. 4. Fields HL, Heinricher MM (1985) Anatomy and physiology of 2003). In recent studies, spinal cord sections obtained a nociceptive modulatory system. Philos Trans R Soc Lond B from rats with SNL demonstrated elevated capsaicin- Biol Sci 308:361Ð74 induced release of CGRP and this effect was blocked 5. Gardell LR, Vanderah TW, Gardell SE et al. (2003) Enhanced evoked excitatory transmitter release in experimental neuropathy by antiserum to dynorphin (Gardell et al. 2003). Dynor- requires descending facilitation. J Neurosci 23:8370Ð9 phin antiserum did not alter capsaicin-induced release 6. Gebhart GF, Sandkuhler J, Thalhammer JG et al. (1983) Inhi- of CGRP in spinal cord tissue from sham-operated rats bition of spinal nociceptive information by stimulation in mid- (Gardell et al. 2003). These observations are consis- brain of the cat is blocked by lidocaine microinjected in nucleus raphe magnus and medullary reticular formation. J Neurophys- tent with previous reports of dynorphin facilitation of iol 50:1446Ð59 capsaicin-evoked substance P release from trigeminal 7. Kovelowski CJ, Ossipov MH, Sun H et al. (2000) Supraspinal nuclear slices, an effect blocked by MK-801, but not cholecystokinin may drive tonic descending facilitation mecha- by opioid antagonists (see Gardell et al. 2003). Thus, nisms to maintain neuropathic pain in the rat. Pain 87:265Ð73 8. Ossipov MH, Hong Sun T, Malan P Jr et al. (2000) Mediation of dynorphin may contribute to amplification of nocicep- spinal nerve injury induced tactile allodynia by descending fa- tive input at the level of the spinal cord by promoting cilitatory pathways in the dorsolateral funiculus in rats. Neurosci NMDA-mediated sensory input. Initial afferent dis- Lett 290:129Ð32 9. Pertovaara A (1998) A neuronal correlate of secondary hyper- charges lead to release of excitatory neurotransmitters algesia in the rat spinal dorsal horn is submodality selective and and activation of descending facilitation. Constant fa- facilitated by supraspinal influence. Exp Neurol 149:193Ð202 cilitation results in neuroplastic changes, including 10. Pertovaara A, Wei H, Hamalainen MM (1996) Lidocaine increased dynorphin release. In turn, spinal dynorphin in the rostroventromedial medulla and the periaqueductal gray attenuates allodynia in neuropathic rats. Neuroscience promotes further release of excitatory neurotransmitters Letters 218:127Ð30 in the spinal cord. In this way, dynorphin may maintain 11. Porreca F, Ossipov MH, Gebhart GF (2002) Chronic pain and a facilitated pain state initiated by the original increased medullary descending facilitation. Trends Neurosci 25:319Ð25 discharge of the injured nerve and promoted by this 12. Skilling SR, Sun X, Kurtz HJ et al. (1992) Selective potentiation of NMDA-induced activity and release of excitatory amino acids feed forward mechanism. by dynorphin: possible roles in paralysis and neurotoxicity. Brain In summary, initial nerve injury may result in increased Res 575:272Ð8 neuronal hyperexcitability, predominantly of large di- 13. Wang Z, Gardell LR, Ossipov MH et al. (2001) Pronociceptive ameter Aβ afferent fibers. This excitation results in actions of dynorphin maintain chronic neuropathic pain. J Neu- rosci 21:1779Ð86 supraspinal neuroplastic changes, ultimately leading 14. Wiertelak EP, Furness LE, Horan R et al. (1994) Subcutaneous to the development of descending facilitation arising formalin produces centrifugal hyperalgesia at a non- injected site from the RVM. Furthermore, this underlying abnormal via the NMDA-nitric oxide cascade. Brain Res 649:19Ð26 15. Zhuo M, Gebhart GF (1997) Biphasic modulation of spinal no- pain state may be the reason why opioid requirements ciceptive transmission from the medullary raphe nuclei in the to produce a consistent level of analgesia increase after rat. J Neurophysiol 78:746Ð58 nerve injury. Finally, it is proposed that these neuroplastic changes lead to elevations in spinal dynorphin expression and that these pathologically elevated levels exhibit a pronociceptive effect. Consequently, elevated Descending Facilitatory Systems spinal dynorphin further promotes nociceptive input and contributes to a positive feed forward cycle that MIN ZHUO serves to maintain an abnormally sensitized pain state. Department of Physiology, University of Toronto, Manipulations that interrupt this self-perpetuating cycle Toronto, ONT, Canada may be exploited as targets for rational novel therapies [email protected] 560 Descending Facilitatory Systems

Synonyms 4. Theyhavelongerlatenciesfortheonsetofdescending Descending Excitatory Modulation; Descending Anti- facilitatory systems as compared to that of descend- Analgesic Systems ing inhibitory systems. Descending inhibition from the RVM has a latency of 90 ms, while facilitation is 232 msec. Definition Descending facilitation systems are the descending pro- Descending facilitatory systems affect animals’ behav- jection functional neuronal networks originating from ioral withdrawal reflexive responses to noxious stimuli supraspinal structures to the spinal cord. Activation of (Zhuo and Gebhart 1990; Zhuo and Gebhart 2002; Zhuo these systems enhances or increases evoked responses and Gebhart 1991). In the spinal nociceptive tail-flick of spinal sensory neurons to peripheral sensory stim- reflex, activation of descending facilitatory systems ulation, including noxious and non-noxious stimuli. reduces the response latency to noxious heating of the Reduction in the neuronal threshold to sensory stimuli tail. In visceromotor responses to colorectal distention contributes to the facilitatory effects. These systems (noxious visceral stimuli), descending facilitatory sys- are likely to be active in physiological conditions, to tems enhance responses to noxious visceral stimuli. enhance the detection, localization and reaction to po- These results consistently indicate that facilitation of tentially dangerous or noxious stimuli. In pathological spinal sensory neurons’ responses lead to changes in conditions,activationofdescendingfacilitatorysystems behavioral reflexive responses in intact animals. Most contributes to persistent pain related to inflammation 5-HT-containing nerve fibers in the spinal cord orig- or nerve injury. inate from the RVM. Pharmacological studies, using intrathecal drug administration, found that spinal 5-HT Characteristics receptors mediate descending facilitatory modulation (Zhuo and Gebhart 1991). It is likely that certain brain Brain activity is able to affect sensory transmission in activity leads to the release of 5-HT at the level of the the spinal cord through descending modulatory systems spinal cord, 5-HT binds to postsynaptic and presynap- (Basbaum and Fields 1984). Descending modulation is tic 5-HT receptors, and enhances responses of spinal biphasic, including descending inhibitory and facilita- sensory neurons to peripheral sensory (noxious and tory systems. Descending projection pathways derive non-noxious) stimuli. The enhanced neuronal activities directly or indirectly from central nuclei, including in spinal dorsal horn neurons, also contribute to the the anterior cingulate cortex (ACC), periaqueductal shortening of behavioral withdrawal response latencies gray (PAG), and brainstem rostroventral medulla by reducing the threshold. (RVM). As the last step of relay nuclei, neurons in the It is important to point out that, in the case of cutaneous RVM play important roles in descending inhibition and sensory transmission, descending facilitation is often facilitation of spinal sensory transmission. Biphasic small or difficult to elicit. This is because spinal sen- modulation of spinal nociceptive transmission from the sory transmission receives tonic descending inhibitory RVM offers fine regulation of spinal sensory thresholds modulation under normal physiological conditions. and responses. Removal of tonic descending inhibition (e. g. by le- Integrative approaches have been used to investigate the sioning the dorsolateral funiculi) often increases the mechanisms for descending facilitation, including elec- chance of observing descending facilitation (Zhuo and trophysiological, pharmacological, behavioral, and bio- Gebhart 1991). Recent studies from the ACC show that chemicalstudies.Thekeyevidencefordescendingfacil- descending facilitation may have stronger influences in itation is from electrophysiological recording of spinal pain perception at cortical levels. Activation of neurons sensory dorsal horn neurons (Zhuo and Gebhart 1991; in the ACC, leads to pure facilitation of the spinal no- ZhuoandGebhart1997;Zhuoetal.2002;ZhuoandGeb- ciceptive tail-flick reflex in adult animals, without any hart2003). Through focallydelivered electricalstimula- significant inhibition (Calejesan et al. 2000). tion or glutamate into brain regions, it has been shown The cellular mechanism for descending facilitation is thatresponsesofspinaldorsalhornneuronstoperipheral provided by in vitro spinal cord slice studies. Applica- sensory stimulation are enhanced or increased. No sig- tion of a low dose of 5-HT, or a selective 5-HT receptor nificanteffectson spontaneousactivity of spinalsensory 2 agonist, induces facilitation of fast EPSCs in the lum- neurons have been found. There are four major charac- bar spinal cord (Li and Zhuo 1998). 5-HT at low doses teristics of descending facilitatory systems: could facilitate fast EPSCs in the presence of an NMDA 1. Theyaffectspinalsensorytransmissionfrombothcu- receptor antagonist AP-5, indicating that the facilitatory taneous and visceral inputs effect is NMDA receptor independent. Furthermore, the 2. They reduce the neuronal threshold to nociceptive facilitatory effect induced by 5-HT at low doses persists stimulation during the washout of 5-HT. While the activation of 5- 3. They are intensity-dependent, and stimulation at HT receptors is important for the induction of the facil- lower intensities usually leads to facilitation itation, continuous activation of these receptors is not Descending Facilitatory Systems 561 necessary for the expression of the facilitation. Appli- experiments with BAPTA (1,2-bis-(o-aminophenoxy) cation of methysergide after the 5-HT receptor agonist ethane-N,N,N’,N’-tetracetic acid) in the pipette so- DOI fails to reverse the facilitatory effect (Li and Zhuo lution, the facilitatory effect of 5-HT is abolished, 1998). indicating that an increase in postsynaptic Ca2+ is re- One synaptic mechanism for the 5-HT produced facil- quired. Additional evidence against a mechanism of itation is due to the recruitment of silent glutamatergic 5-HT-induced synaptic facilitation, involving modula- synapses. Application of 5-HT (5 μM) causes typi- tion of presynaptic glutamate release, comes from the D cally fast EPSCs to appear at synapses initially lacking observation that while 5-HT application clearly causes AMPA/kainate receptor-mediated responses. 5-HT AMPA receptor mediated EPSCs, NMDA receptor may affect spinal sensory transmission, by acting on mediated EPSCs are significantly decreased by 5-HT in presynaptic or postsynaptic receptors. Postsynaptic ap- the same neurons (Li and Zhuo 1998). This result sug- plication of G protein inhibitors, introduced through the gests that postsynaptic enhancement of AMPA receptor recording pipette, abolish the effect of 5-HT to facili- mediated currents by 5-HT are selective. tate synaptic transmission, suggesting that postsynaptic One possible mechanism for the recruitment of silent 5-HT receptors are critical for the facilitatory effect. synapsesistheinteractionofglutamateAMPAreceptors In support of this notion, postsynaptic Ca2+-dependent and proteins containing postsynaptic density-95/Discs processes are required for 5-HT-induced facilitation. In large/zona occludens-1 (PDZ) domains. GluR2 and

Descending Facilitatory Systems, Figure 1 Descending Facilitatory Systems. (a) Example of facilitation of spinal visceral transmission produced by electrical stimulation and glutamate in the nucleus raphe magnus (NRM). Peristimulus time histograms (1−s binwidth) and corresponding ocillographic records, in the absence (top histograms) and presence (bottom histograms) of, electrical stimulation (25 μA) and glutamate (5 nmoles) given in the same site in NRM. The intensity and duration of colorectal distension is illustrated below; the period of electrical stimulation (25 s) is indicated by the arrows. (b) Model of intensity-dependent biphasic modulation of spinal nociceptive transmission. (c) Model of different effects of facilitatory vs. inhibitory modulation on the SRFs of spinal dorsal horn neurons. (d) Model of the latency for descending facilitatory vs. inhibitory effects from the RVM. (e) Model of electrical stimulation in the RVM on the latenies of cardiovascular vs. neuronal effects. 562 Descending Facilitatory Systems

-3 are widely expressed in sensory neurons in the su- does not significantly affect synaptic responses induced perficial dorsal horn of the spinal cord. Glutamate by dorsal root stimulation. However, Co-application of receptor-interacting protein (GRIP), a protein with 7 5-HT and forskolin produces long-lasting facilitation PDZ domains that bind specifically to the C-terminus of synaptic responses. Possible contributors to the in- of GluR2/3, is also expressed in spinal dorsal horn creases in the cAMP levels are the calcium-sensitive neurons. A synthetic peptide corresponding to the adenylyl cyclases. The facilitatory effect induced by last 10 amino acids of GluR2 (“GluR2-SVKI”: NVY- 5-HT and forskolin is completely blocked in mice lack- GIESVKI), which disrupts binding of GluR2 to GRIP ing AC1or AC8 (Wang and Zhuo 2002). One possible (Li et al. 1999) blocks the facilitatory effect of 5-HT.Ex- scenario for regulation of two different signaling path- periments with different control peptides consistently ways, under physiological or pathological conditions, is indicate that the interaction between the c-terminus of that postsynaptic increases in cAMP levels by sensory GluR2/3 and GRIP/ABP (or called GRIP1 and GRIP2) transmitters may favor 5-HT-induced facilitation. is important for 5-HT induced facilitation. Descending facilitatory systems play important roles Possible developmental factors have been raised, be- in physiological and pathological conditions. One cause silent experiments require a good space clamp in important physiological function for descending facil- neurons, thus, most are performed in young neurons. itation is that the activation of descending facilitatory In adult mouse spinal cord dorsal horn, some synaptic systems increases the input of sensory information responses (26.3 % of a total of 38 experiments) be- to enhance the detection, localization and reaction tween primary afferent fibers and dorsal horn neurons to potentially dangerous or noxious stimuli. Imbal- are almost completely mediated by NMDA receptors ance between the descending facilitatory systems and (Wang and Zhuo 2002). Dorsal root stimulation does the inhibitory systems contribute to chronic pain in not elicit any detectable AMPA/kainate receptor medi- pathological conditions. The recruitment of silent or ated responses in these synapses. Unlike young spinal ineffective synapses could significantly enhance spinal cord, 5-HT alone does not produce any long-lasting sensory transmission, including nociceptive transmis- synaptic enhancement in adult spinal dorsal horn neu- sion. AMPA receptors are expressed in the dorsal rons. Activation of adenylyl cyclases by forskolin also horn neurons both at synapses receiving high- and low-

Descending Facilitatory Systems, Figure 2 Cellular Model for Descending Facilitation at the Spinal Cord Dorsal Horn. Peripheral tissue injury activates nociceptors and causes the release of glutamate (filled circles) as well as substance P, CGRP and other putative transmitters (not shown) from the central terminals in the spinal dorsal horn. Serotonin released from descending projection terminals binds to its receptors and activates protein kinase C (PKC) by G-protein coupled receptors. Activation of PKC activated a series of intracellular signaling pathways and caused long-term facilitation of AMPA receptor mediated responses. The interaction between AMPA receptors and the PDZ protein glutamate receptor-interacting protein (GRIP) are likely to contribute to the recruitment of functional AMPA responses. In adult dorsal horn neurons, the activity of adenylyl cyclase subtype 1 and 8 is required for 5-HT produced facilitatory effects. Abbreviations: Glu: glutamate; AMPARs: α-amino-3-hydroxy-5-methyl-4-isoxalepropionate receptors; 5-HT: serotonin; GRIP: glutamate receptor interacting protein; AC1 and AC8: adenylyl cyclase subtype 1 and 8. Descending Inhibition/Facilitation 563 threshold inputs. Activation of silent synapses with 10. Zhuo M, Gebhart GF (1997) Biphasic Modulation of Spinal No- low-threshold afferents might cause the dorsal horn ciceptive Transmission from the Medullary Raphe Nuclei in the Rat. J Neurophysiol 78:746Ð758 neurons to exhibit an increased firing rate in response to 11. Zhuo M, Sengupta JN, Gebhart GF (2002) Biphasic Modulation non-noxious stimuli. Increases in postsynaptic AMPA of Spinal Visceral Nociceptive Transmission from the Rostro- receptor density and activation of silent synapses, could ventral Medial Medulla in the Rat. J Neurophysiol 87:2225Ð2236 contribute to plastic changes in the electrophysiological 12. Zhuo M, Gebhart GF (2003) Modulation of Noxious and Non- Noxious Spinal Mechanical Transmission from the Rostroventral properties of dorsal horn sensory neurons, including as- Medial Medulla in the Rat. J Neurophysiol 88:2928Ð2941 D cending spinothalamic tract projecting neurons. These 13. Zhuo M, Gebhart GF (1990) Characterization of Descending include increased receptive fields, enhanced responses Inhibition and Facilitation from the Nuclei Reticularis Gigan- to noxious and non-noxious stimuli, decreased firing tocellularis and Gigantocellularis Pars Alpha in the Rat. Pain 42:337Ð350 thresholds, and increased background activity. There 14. Zhuo M, Gebhart GF (2002) Biphasic Modulation of a Visceral are two pieces of evidence that indirectly support the Nociceptive Reflex from the Rostroventral Medial Medulla in notion that alterations to descending serotonergic in- the Rat. Gastroenterology 122:1007Ð1019 fluences and spinal glutamate AMPA receptors may 15. Zhuo M, Gebhart GF (1991) Spinal Serotonin Receptors Mediate Descending Facilitation of a Nociceptive Reflex from the Nuclei contribute to persistent pain: first, descending seroton- Reticularis Gigantocellularis and Gigantocellularis Pars Alpha ergic systems from the RVM to the spinal cord have in the Rat. Brain Res 550:35Ð48 been implicated in different types of hyperalgesia after tissue injury (Calejesan et al. 1998; Urban and Gebhart 1999). Second, formalin-induced inflammation causes increases in activity of 5-HT containing neurons in Descending Inhibition the RVM for up to two hours (Robinson et al. 2002). Third, changes in the expression of AMPA receptors on spinal dorsal horn neurons after tissue injury has Definition been reported. Therefore, activation of silent synapses There are three types of opioid receptors, μ, δ,and could serve as an important cellular mechanism un- κ.These are located peripherally, in the spinal cord and derlying two features of chronic pain: hyperalgesia, in areas involved in descending inhibition, including where the intensity of responses to noxious stimuli the nucleus raphe magnus in the rostral ventral medulla is increased over baseline; and allodynia, where the (RVM) and the periaqueductal gray (PAG). The PAG nociceptive threshold is decreased, and a normally sends projection to the RVM, which in turn sends pro- non-noxious stimulus, such a gentle touch, can induce jections to the spinal dorsal horn . Stimulation of the pain. PAG or the RVM produces inhibition of dorsal horn neurons including spinothalamic tract cells. It is commonly accepted that opioid mediated inhibition produces its References effects through activation of the PAG-RVM pathway. 1. Basbaum AI, Fields HL (1984) Endogenous Pain Control Sys- Further, the RVM pathway utilizes serotonin as a neu- tems: Brainstem Spinal Pathways and Endorphin Circuitry. Annu rotransmitter. Another common inhibitory pathway is Rev Neurosci 7:309Ð338 from the pontine noradrenergic cells groups, A6 (locus 2. Calejesan AA, Ch’ang MHC, Zhuo M (1998) Spinal Seroton- ergic Receptors Mediate Facilitation of a Nociceptive Reflex by coeruleus) and A7 (locus subcoeruleus). These pontine Subcutaneous Formalin Injection into the Hindpaw in Rats. Brain neurons utilize the neurotransmitter noradrenaline and Res 798:46Ð54 activate αÐ2 receptors spinally to produce inhibition of 3. Calejesan AA, Kim SJ, Zhuo M (2000) Descending Facilitatory dorsal horn neurons. Modulation of a Behavioral Nociceptive Response by Stimu- lation in the Adult Rat Anterior Cingulate Cortex. Eur J Pain Descending Modulation of Visceral Pain 4:83Ð96 TENS, Mechanisms of Action 4. Li P, Zhuo M (1998) Silent Glutamatergic Synapses and Noci- ception in Mammalian Spinal Cord. Nature 393:695Ð698 5. Li P et al. (1999) AMPA Receptor-PDZ Interactions in Facili- tation of Spinal Sensory Synapses. Nat Neurosci 2:972Ð977 6. Robinson DA, Calejesan AA, Zhuo M (2002) Long-Lasting Changes in Rostral Ventral Medulla Neuronal Activity Following Descending Inhibition/Facilitation Inflammation in the Adult Rat. J Pain 3:292Ð300 7. Urban MO, Gebhart GF (1999) Supraspinal Contributions to Hy- peralgesia. Proc Natl Acad Sci USA 96:7687Ð7692 Definition 8. Wang GD, Zhuo M (2002) Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin Refers to the ability of certain brain areas to inhibit dor- in Adult Mouse Spinal Dorsal Horn Neurons. J Neurophysiol sal horn neuronal responses to nociceptive stimuli and 87:732Ð739 to inhibit the sensation of pain. Descending facilitation 9. Zhuo M, Gebhart GF (1991) Characterization of Descending Fa- referstotheabilityofbrainareastoproduceaheightened cilitation and Inhibition of Spinal Nociceptive Transmission from the Nuclei Reticularis Gigantocellularis and Gigantocellularis sensation of pain. Pars Alpha in the Rat. J Neurophysiol 67:1599Ð1614 Forebrain Modulation of the Periaqueductal Gray 564 Descending Inhibitory Fibers

Descending Inhibitory Fibers Descending Modulation and Persistent Pain Definition ANTTI PERTOVAARA These fibers comprise of descending tracts in the dor- Department of Physiology, University of Helsinki, solateral funiculus (DLF) from cell bodies located in Helsinki, Finland brain stem nuclei, including the nucleus raphe magnus antti.pertovaara@helsinki.fi and adjacent reticular formation, but other brain stem nuclei are also responsible for tonic descending inhibition. The fibers from these descending tracts synapse Synonyms onto nociceptive neurons in the dorsal horn of the spinal Persistent Pain and Descending Modulation cord, and inhibit their responses to noxious stimuli. The main neurotransmitter involved in this process is sero- Definition tonin. Although the growth of descending inhibitory projections to the dorsal horn is well-advanced com- Ascending nociceptive pathways carry information paratively early in development, physiologicalmaturity about potentially harmful peripheral events from the occurs some time later, possibly due to insufficient spinal cord to the brain, and these ascending signals levels of serotonin or other neurochemicals in DLF may eventually evoke the sensation of pain. The mag- axon terminals, or delayed maturation of dorsal horn nitude of the ascending nociceptive signal and the interneurons involved in this pathway. This functional consequent pain sensation can be greatly influenced immaturity appears to be one of the reasons for much by descending pathways originating in the brainstem lower reflex thresholds in the infant as compared to the and terminating in the spinal cord. In conditions that older child and adult. cause persistent pain, such as inflammation or injury, Descending Modulation and Persistent Pain the function of descending pathways may change. This Descending Modulation of Nociceptive Processing change may contribute to suppression or facilitation Infant Pain Mechanisms of pain sensitivity, depending among other things on the pathophysiological condition, the brainstem-spinal pathway, time course of the injury, and the type of pain. Descending Inhibitory Mechanisms and GABA Mechanisms Characteristics Multiple descending pathways originate in several Descending Modulation and Persistent Pain different brainstem nuclei, release different neurotrans- Descending Modulation of Nociceptive Processing mitters from their axonal endings at the spinal cord, GABA Mechanisms and Descending Inhibitory and have different functional characteristics. Those Mechanisms descending pathways that terminate in the spinal dorsal horn, a critical relay for ascending nociceptive signals, contribute to pain modulation (Fields and Basbaum 1999). Descending pain modulatory pathways are in- Descending Inhibitory Noradrenergic volved in mediating the top-down and feedback Pathways control of pain. This includes the optimal setting of gain for ascending signals according to various behav- Definition ioral needs. In healthy animals, descending pathways predominantly suppress pain, as shown by increased Pathways originating from noradrenergic nuclei in the spinal responses to noxious heat following inactiva- brainstemtomodulate(inhibit)incoming(painful)stim- tion of descending pathways, e.g. by a cold block at a uli in the spinal cord. midthoracic level (Fields and Basbaum 1999). How- α Alpha( ) 2-Adrenergic Agonists in Pain Treatment ever, descending pathways may also facilitate pain, and the same brainstem site may be a source of descending facilitation as well as inhibition. This was shown by the Descending Inhibitory Pathway for Pain finding that a low concentration of glutamate, or low electrical stimulus intensity in the rostroventromedial medulla (RVM), produced facilitation of spinal noci- Definition ception in healthy animals, whereas a high glutamate A pain modulating pathway originating in the forebrain concentration or high electrical stimulus intensity in and terminating in the dorsal horn of the spinal cord. the same brainstem site suppressed spinal nociception Alternative Medicine in Neuropathic Pain (Urban and Gebhart 1999). Descending Modulation and Persistent Pain 565

Enhanced Inhibitory Controls descending facilitation was the net effect in experiments In conditions causing persistent pain, such as following in which secondary hyperalgesia was studied (Perto- injury or inflammation, the function of descending vaara 1998; Urban et al. 1996; Wiertelak et al. 1994). pathways may change. The first observations on the The net effect of descending controls may also depend pathophysiologicalfunction of descending pain control on the sub-modality of pain, since it was reported that systems indicated that the inhibitory effect of descend- particularly mechanical and cold hypersensitivity were ing pathways on responses of spinal pain-relay neurons dependent on intact medullospinal pathways (Kauppila D was stronger in animals with experimental arthritis et al. 1998). Furthermore, the net effect of descending than in controls (Schaible et al. 1991). Enhanced de- controls may vary from facilitation to inhibition as time scending inhibitory controls have been observed in progresses from the start of the injury (Ren and Dubner not only experimental arthritis, but also following paw 2002). inflammation or formalin-treatment of the skin (Ren NeurocircuitryandNeurochemistryUnderlyingDescendingFa- and Dubner 2002). The enhanced inhibitory controls cilitation required a few days to develop in inflamed animals. It was accompanied by an increased inhibitory efficacy of The dorsal column is at least partly involved in carrying glutamate, via action on medial medullary N-methyl- the ascending injury signal to the brainstem level that D-aspartate (NMDA) and alpha-amino-3-hydroxy-5- maintains the descending facilitation, since a lesion of methyl-4-isoxazole propionic acid (AMPA) receptors, this ascending pathway selectively attenuated hyper- and by a phenotypic switch in the response profile of sensitivity in neuropathic animals (Porreca et al. 2002). RVM neurons (Ren and Dubner 2002). These results The RVM, an important relay for many descending in- suggest that following inflammation, the RVM and hibitory pathways, is also a major link for mediating the its glutamatergic receptors exhibit activity-dependent facilitatory effect to the spinal cord level. Attenuation plasticity leading to enhanced inhibitory controls. Ad- of hypersensitivity following micro-administration of ditionally, the noradrenergic locus coeruleus nucleus a local anesthetic into the RVM or following a lesion of in the pontomesencephalic junction has an important the dorsolateral funiculus, a major conduit of descend- role in the enhanced inhibition, as shown by a stronger ing projections from the RVM (Urban and Gebhart inflammation-induced decrease of a heat-evoked spinal 1999) demonstrates this. Glutamatergic NMDA, neu- withdrawal latency in animals with a bilateral lesion rotensin and cholecystokinin B (CCK-B) receptors in of the locus coeruleus than in sham-operated animals the RVM are involved in the maintenance of descending (Tsuruoka and Willis 1996). Enhanced descending inhi- facilitation, since micro-administrations of antagonists bition provides a feedback control of pain, which helps of these receptors into the RVM reduced hypersensi- to maintain the capacity to use an injured and painful tivity induced by neurogenic inflammation or nerve body part for fight or flight in case of emergency, giving injury (Porreca et al. 2002). The finding that a single potential evolutionary benefits dose of an NMDA receptor antagonist microinjected into the RVM, prior to but not after a nerve injury, Enhanced Facilitatory Controls delayed the development of hypersensitivity, suggests An opposite effect to the enhanced descending inthat medullary NMDA receptors trigger central changes hibitory controls has also been described in conditions that contribute to descending facilitation (Pertovaara causing persistent pain. Namely, hypersensitivity in- 2000). However, attenuation of neuropathic symptoms duced by inflammation or nerve injury was attenuated by local anesthesia near the injury site indicates that following brainstem lesions or a blockade of descend- central changes alone are not sufficient to maintain ing pathways (Herrero and Cervero 1996; Pertovaara hypersensitivity, but continuous injury discharge from et al. 1996; Urban et al. 1996; Wiertelak et al. 1994). the periphery is of critical importance for the sustained This finding indicates that descending spinal pathways facilitatory action of medullo-spinal pathways (Porreca may contribute to hypersensitivity by facilitating noci- et al. 2002). From the RVM, the facilitatory action ception at the spinal cord level. Thus, persistent pain may be mediated downwards by a class of mu-opioid may induce not only enhanced inhibitory controls, but receptor-expressing neurons called ON-cells, which also enhanced facilitatory controls, or concurrently typically discharge prior to a noxious stimulus - both. There is evidence suggesting that the net ef- induced withdrawal, and are considered to have a role fect of descending controls may critically depend on in the induction of protective (pain) reflexes. This is whether nociceptive signals originate in the site of suggested by the finding that immunocytochemical injury ( primary hyperalgesia predominantly due to destruction of these RVM neurons reduced hypersensi- peripheral mechanisms), or adjacent to it ( secondary tivity,andattenuatedspinalupregulationofdynorphin,a hyperalgesia predominantly dueto centralmechanisms) pronociceptive substance, in neuropathic animals (Por- (Urban and Gebhart 1999). Enhanced inhibitory con- reca et al. 2002). The contribution of increased ON-cell trols were reported in experiments in which primary discharge to hypersensitivity is further supported by hyperalgesia wasstudied (Schaible etal. 1991), whereas the finding that, neurogenic inflammation-induced hy- 566 Descending Modulation and Persistent Pain perreflexia was accompanied by an increase of ON-cell may induce significant hyperalgesia following inflam- activity in the RVM, and these effects were reversed in mation or injury. From the evolutional point of view, parallel by an NMDA receptor antagonist (Heinricher enhanced facilitation of pain might help the healing et al. 2003). Unexpectedly, the response properties of process by promoting immobilization and protection medullary ON-neurons were not markedly changed of the injured region. However, under human clini- in animals with a fully developed neuropathy (Per- cal conditions this type of pain-enhancing loop may tovaara et al. 2001). However, a lack of change in contribute to chronic hypersensitivity and persistent response properties of medullary ON-neurons during pain that serves no useful purpose. Further character- the chronic phase of neuropathy, does not exclude the ization of the neurochemical basis of this facilitatory possibility that the afferent barrage at the time of nerve circuitry may provide novel targets for selective sup- injury would have caused long-term changes in the pression of chronic hyperalgesia, without influence on synaptic efficacy of the spinal terminals of the RVM the physiological pain mechanisms that help to protect neurons. This spinal change would not be revealed by tissues. characterization of neuronal response properties at the medullary level. The finding that intrathecal adminis- References tration of a serotonin receptor antagonist (Pertovaara et al. 2001), a CCK-B receptor antagonist (Urban et 1. Fields HL, Basbaum AI (1999) Central Nervous System Mech- anisms of Pain Modulation. In: Wall PD, Melzack R (eds) Text- al. 1996), an NMDA receptor antagonist and a ni- book of Pain, 4th edn. Churchill Livingstone, Hong Kong, pp tric oxide synthesis inhibitor (Wiertelak et al. 1994) 309Ð329 selectively attenuated hypersensitivity suggests that 2. Heinricher MM, Pertovaara A, Ossipov MH (2003) Descending serotonin, CCK, glutamate through action on NMDA Modulation after Injury. Prog Pain Res Manag 24:251Ð260 3. Herrero JF, Cervero F (1996) Supraspinal Influences on the Fa- receptors, and nitric oxide are involved in mediating cilitation of Rat Nociceptive Reflexes Induced by Carrageenan the descending facilitatory action on spinal nociceptive Monoarthritis. Neurosci Lett 209:21Ð24 neurons. Following a block of descending pathways, 4. Kauppila T, Kontinen VK, Pertovaara A (1998) Influence of Spinalization on Spinal Withdrawal Reflex Responses Varies hypersensitivity in nociceptive spinal neurons was at- Depending on the Submodality of the Test Stimulus and tenuated, but still significant (Pertovaara 1998). This the Experimental Pathophysiological Condition. Brain Res finding indicates that medullary descending facilitation 797:234Ð242 augments spinal segmental mechanisms, which alone 5. Pertovaara A (1998) A Neuronal Correlate of Secondary Hyperalgesia in the Rat Spinal Dorsal Horn is Submodality Selective and Facilitated by Supraspinal Influence. Exp Neurol 149:193Ð202 6. Pertovaara A (2000) Plasticity in Descending Pain Modulatory Systems. Prog Brain Res 129:231Ð242 7. Pertovaara A, Wei H, Hämäläinen MM (1996) Lidocaine in the Rostroventromedial Medulla and the Periaqueductal Gray Attenuates Allodynia in Neuropathic Rats. Neurosci Lett 218:127Ð130 8. Pertovaara A, Keski-Vakkuri U, Kalmari J et al. (2001) Response Properties of Neurons in the Rostroventromedial Medulla of Neuropathic Rats: Attempted Modulation of Responses by [1DMe]NPYF, a Neuropeptide FF Analogue. Neuroscience 105:457Ð468 9. Porreca F, Ossipov MH, Gebhart GF (2002) Chronic Pain and Medullary Descending Facilitation. Trends Neurosci 25:319Ð325 10. Ren K, Dubner R (2002) Descending Modulation in Persistent Pain: An Update. Pain 100:1Ð6 11. Schaible HG, Neugebauer V, Cervero F et al. (1991) Changes in Tonic Descending Inhibition of Spinal Neurons with Articular Input during the Development of Acute Arthritis in the Cat. J Neurophysiol 66:1021Ð1032 12. Tsuruoka M, Willis WD (1996) Bilateral Lesions in the Area of the Nucleus Locus Coeruleus Affect the Development of Hy- peralgesia during Carrageenan-Induced Inflammation. Brain Res 726:233Ð236 13. Urban MO, Gebhart GF (1999) Supraspinal Contributions to Hy- Descending Modulation and Persistent Pain, Figure 1 A schematic di- peralgesia. Proc Nat Acad Sci USA 96:7687Ð7692 agram showing one example of enhanced descending inhibitory controls 14. Urban MO, Jiang MC, Gebhart GF (1996) Participation of and one of enhanced descending facilitatory controls in inflamed and/or Central Descending Nociceptive Facilitatory Systems in Sec- nerve-injured conditions. LC: noradrenergic locus coeruleus nucleus in the ondary Hyperalgesia Produced by Mustard Oil. Brain Res pons. RVM: rostroventromedial medulla. - indicates inhibitory and + a fa- 737:83Ð91 cilitatory effect. NA, noradrenaline; EAA, excitatory amino acid; CCK, chole- 15. Wiertelak EP, Furness LE, Horan R et al. (1994) Subcu- cystokinin; NT, neurotensin; 5-HT, serotonin; NO, nitric oxide. It should be taneous Formalin Produces Centrifugal Hyperalgesia at a noted that the RVM is also an important source of descending inhibitory Non-Injected Site via the NMDA-Nitric Oxide Cascade. Brain controls. Res 649:19Ð26 Descending Modulation of Nociceptive Processing 567

of seizure activity and animalswere still capable of eat- Descending Modulation of Nociceptive ing. The analgesia produced by electrical stimulation Processing of the PAG was of rapid onset and as potent as high doses of morphine Ð completely inhibiting withdrawal RONALD DUBNER responses to even the most severe noxious stimuli. University of Maryland, Department of Biomedical An important final common descending modulatory Sciences, Baltimore, MD, USA site in the brain stem is the RVM or rostral ven- D [email protected] tromedial medulla, whose major component is the nucleus raphe magnus (NRM). The RVM receives Synonyms signals directly from the PAG and indirectly from Pain Modulation; Descending Control; pain inhibitory forebrain sites such as the prefrontal cortex, the systems; pain facilitatory systems; endogenous anal- amygdalaandtheanteriorcingulategyrus(Bandlerand gesia systems; Supraspinal Pain Control Systems; de- Shipley 1994). The descending PAG-RVM circuit is scending pain modulation involved in the emotional, motivational and cognitive factors that modulate the sensation of pain. Numer- Definition ousanatomicalstudieshave demonstratedthatPAGaf- Information about the condition of injured peripheral ferents arise predominantly in the forebrain. PAG re- tissuesentersthe spinalcord and thenascendstohigher ceives significant innervation from a number of corti- centers in the brain stem, thalamus and cerebral caland subcorticalsitesinvolved in nociception. These cortex, ultimately being elaborated as a complex sen- forebrain projections terminate with a high degree of sory experience. What we perceive depends not only topographical specificity, forming sets of longitudinal on the features of the stimulus, but is also related to input columns extending focally throughout the ros- its meaning, based on previous exposure to pain, its trocaudal extent of PAG. Several of these same fore- influence on our emotional state and its relevance to brain structures send parallel projections to the RVM. our survival. Descending modulation of pain refers These sites include the medial preoptic area (MPO), to how the pain experience is modified at supraspinal central nucleusof the amygdala (CNA)and certainme- sites in the brainstem and forebrain. It is an important dial prefrontal cortical fields. Thus the PAG is ideally componentof the sensory processing ofpain because it positioned to integrate information from sensory sys- provides the neural networks by which attention, mo- tems in the brainstem / spinal cord with information tivation and cognition modulate what we perceive. from higher processing in the forebrain and is thought to modulate a number of homeostatic processes in- Characteristics cluding fear, anxiety, cardiovascular tone and vocal- Our knowledge of the existence of endogenous de- ization. The descending nociceptive modulation from scending pain modulatory systems (see Pain Mod- PAG appears to be normally under tonic Gamma(γ)- ulatory Systems, History of Discovery)spans at least Aminobutyric Acid (GABA) inhibitory control. En- three decades (for comprehensive reviews, see Fields dogenousandexogenousopiatesactingwithinthePAG and Basbaum 1999; Millan 2002). The first line of probably produceanalgesia via inhibition ofinhibitory evidence to support endogenous pain control came GABA containing interneurons and thereby activate from the study of Reynolds (1969) who demonstrated (disinhibit) PAG output neurons. that focal brain stimulation of the periaqueductal Besson and colleagues were the first to show that gray (PAG) produced sufficient analgesia to permit electrical stimulation of the nucleus raphe magnus in abdominal surgery. Liebeskind and colleagues con- the RVM suppressed behavioral responses to a strong firmed this finding and concluded that stimulation of pinch of the tail or the limbs as well as modifying the PAG activated a normal function of the brain, pain the threshold of the jaw opening reflex (Oliveras et al. inhibition (Mayer et al. 1971; Mayer and Liebeskind 1975). Perhaps the most important finding concerning 1974). They labeled the phenomenon, stimulation- SPA was that analgesia induced by brain stimulation produced analgesia (SPA). These early studies found shared several characteristics with analgesia from opi- SPA to be specifically antinociceptive Ð producing ate drugs. Areas of the brain from which SPA could no generalized sensory, attentional, emotional or mo- be elicited were rich in opiate receptors and microin- toric deficits. They also showed that SPA could outlast jection of morphine into these brain regions produced the period of brain stimulation and that it occurred in analgesia, indicating that common brain sites support a restricted peripheral field, such that noxious stimuli both SPA and opiate analgesia. Tsou and Jang (1964) applied outside that field elicited normal defensive re- discoveredthatthemostsensitivesitesfortheanalgesic actions. They reported that during stimulation the sen- action of morphine were located in the PAG and the sation of light touch was intact, there was no indication adjacent hypothalamic periventricular area. This led 568 Descending Modulation of Nociceptive Processing

to the hypothesis that opiate drugs like morphine acted glutamate or neurotensin produce facilitation of be- by binding to a receptor in the brain (Pert and Snyder havioral and spinal dorsal horn neuronal responses to 1973)andthattherewereprobablyendogenousligands noxious stimulation (Thomas et al. 1995; Urban and or chemical mediators whose actions were mimicked Gebhart 1999; Zhou et al. 2002; Zhuo and Gebhart by opiates. These findings led to the discovery of the 1992). RVM neurons may exert bi-directional con- endogenous opioid peptides (Goldstein et al. 1979; trol of nociception through descending serotoninergic Hughes et al. 1975) and subsequently to the cloning pathways and descending noradrenergic pathways of the three major subtypes of opioid receptors,mu, (Holdenetal.1999;ZhuoandGebhart1991).Descend- delta and kappa (Chen et al. 1993; Evans et al. 1992; ing inhibitory influences from the RVM travel mainly Kieffer et al. 1992; Thompson et al. 1993). in the dorsolateral funiculus whereas descending facil- Electric shock, restraint, rotation, forced swim and in- itatory effects reach the spinal cord via the ventral and truder threat can all produce analgesia in laboratory ventrolateral funiculi (Zhuo et al. 2002). animals without producing identifiable tissue damage (Hayes et al. 1978). Since the same environmental in- Descending Modulation of Visceral Pain fluences are known to produce stress and activate the Descending modulation of visceral pain processing at hypothalamic-pituitary-adrenal (HPA) axis, this has the spinal level is also under the control of both facili- been called “ stress-induced analgesia (SIA). Tim- tatory and inhibitory influences.Activation of neurons ing, severity and location of a single stressor were in the RVM attenuates responses to inflammation of all eventually reported to differentially produce opi- the viscera (Coutinho et al. 1998; Urban et al. 1999). oid and nonopioid SIA (Terman et al. 1984). Some Electrical stimulation or glutamate microinjection into forms of opioid SIA, although depending on descend- the PAG, RVM or the NGC inhibits the activity of dor- ingpaininhibitorypathways, appeartobeactivateden- sal horn neurons responsive to visceral afferent fiber tirely by the physical properties of the stressor and can stimulation or noxious colorectal distension (CRD) be elicited even in the surgically anesthetized animal (Ammonetal.1984;Cerveroetal.1985;NessandGeb- (Terman et al. 1984). On the other hand, other forms hart 1987). Other studies have shown that spinal vis- of opioid SIA depend on learning mechanisms and can ceral input is subject to facilitation from descending be blocked by decerebration, muscarinic antagonists, brain stem sites (Zhou et al. 2002). These descending amygdala lesions and pentobarbital anesthesia. Plac- effects are intensity dependent with facilitation pro- ing rats in a cage where foot shock was previously reduced by the lowest levels of electrical stimulation or ceived, but is not currently administered, can also elicit drug doses and higher levels of stimulation account- analgesia(" conditionedanalgesia").Evidently,ani- ing for descending inhibition at RVM and PAG sites. malscan not only activate their intrinsic paininhibitory In addition, multiple transmitters may exert different systemsinthepresenceofstress, buttheycanalsolearn actions depending on the type of neurons stimulated to activate them in anticipation of such stimuli. Uncon- and the receptors activated (Park and Al-Chaer 2002). ditioned expectations also appear capable of activating In addition, stimulus dependent vagal afferent stimu- opioiddescendingpaininhibitorysubstrates.Thescent lation has also been shown to produce facilitation and of an animal’s natural predator for instance can induce inhibition of the nociceptive tail flick reflex as well as analgesia. dorsalhorn nociceptiveneuronalactivity(Randichand Bidirectional Descending Control Gebhart 1992). Vagal afferents transmit signals from Early studies established the presence of a descend- the esophagus, lower airways, heart, gastrointestinal ing inhibitory pain modulatory circuit linking the brain tract,liver,gallbladderandpancreastothenucleustrac- stem PAG and RVM with the spinal cord (see Bas- tus solitarius in the medulla oblongata. Pharmacolog- baumandFields1984;FieldsandBasbaum1999;Geb- ical activation of vagal afferents with intravenous ad- hart1986;Millan2002,forreviews).However,wenow ministration of serotonin or low dose opioids also in- know that there are parallel descending facilitatory hibits spinal nociceptive reflexes and the response of mechanisms(seeGebhart2004;RenandDubner2002, spinothalamic neurons to noxious stimuli. for reviews). Brain stem descending pathways also facilitate nociceptive transmission at the spinal cord Functional Properties of RVM Neurons level. Excitation and inhibition of dorsal horn neurons In the RVM, two types of cells have been identified can be produced by stimulation of the dorsolateral by Fields and colleagues (Fields et al. 1991) as pain funiculusof thespinalcord (Dubuissonand Wall1979; modulatory neurons. On-cells are characterized by McMahon and Wall1988), NRM (Dubuisson and Wall a sudden increase in activity before the initiation of a 1980) and nucleus reticularis gigantocellularis (NGC) nocifensive behavior, in this case, a tail flick to a tran- (Haber et al. 1980). In the NGC, low intensity elec- sientnoxiousheatstimulus. Off-cellsexhibitapause trical stimulation or microinjection of a low dose of in activity just prior to the initiation of the tail flick. Descending Modulation of Nociceptive Processing 569

While off-cells are usually associated with the inhibi- There is evidence of enhanced net descending inhibition of nocifensive behavior, on-cells are correlated tion after inflammation at sites of primary hyperal- with a facilitation of nocifensive behavior. A third type gesia. Primary hyperalgesia involves increased sensi- of cell, the neutral cell, was also identified but its ac- tivityofprimaryafferentneurons(peripheralsensitiza- tivity was not correlated with nocifensive behavior in tion) as well as central sensitization. Descending inhi- response to transient stimuli. bition is greater in neurons with input from an inflamed The RVM also contains serotonergic cell types. Sero- knee as compared to a non-inflamed knee (Schaible et D tonergic cells comprise about 15% of the cells in RVM. al. 1991). In rats with hind paw inflammation, spinal Most serotonergic RVM cells send unmyelinated ax- cord lidocaine block leads to an enhanced activity of ons through the dorsolateral funiculus into the spinal dorsal horn nociceptive neurons that is greater in in- cord. Most serotonergic cells contain at least one and flamed than that in non-inflamed rats (Ren and Dub- often several co-transmitters, including excitatory and ner 1996). Similar findings are found using Fos pro- inhibitory amino acids and a plethora of neuropeptides tein expression (see c-Fos) as a marker of neuronal (Bowker et al. 1982). Since decreasing the availabil- activation. There are more inflammation induced Fos- ity of serotonin or antagonizing the activation of sero- immunoreactive neurons in the dorsal horn in spinally tonergic receptors strongly attenuates antinociception, transected or dorsolateral funiculus lesioned rats as serotonergic RVM cells were originally thought to be compared to sham-operated inflamed rats (Ren and the antinociceptive output cell of the RVM. However, Ruda 1996; Wei et al. 1998). Kauppila et al. (1998) serotonergic RVM cells are not activated by midbrain showedthatthermalbutnotmechanicalnociceptivere- periaqueductal gray stimulation or opioid administra- sponses were further enhanced in hind paw inflamed tion that evokes analgesia. Further, supraspinal opioid and spinal nerve ligated rats after midthoracic spinal- administration that causes analgesia does not consis- ization. Finally, hyperalgesia is intensified in rats with tently evoke serotonin release in the spinal cord. Sero- lesions of the dorsal lateral quadrant of the spinal cord tonergic RVM cells fire at their highest rates when an after inflammation or formalin injection (Abbott et al. animal is active and moving about, fire progressively 1996; Ren and Dubner 1996). These studies reveal the moreslowlyasananimalproceedsfromdrowsytoslow net descending inhibitory effects of activation of mul- wave sleep and are silent during rapid eye movement tiple supraspinal sites. The findings suggest that injury sleep. Within the dorsal horn, serotonin is likely to pri- induced dorsal horn hyperexcitability and primary hy- marily function by presynaptically modulating the re- peralgesia are dampened by descending pathways, due lease of glutamate and other transmitters (Li and Zhuo to enhancement of descending net inhibitory effects. 1998). The source of the enhanced net inhibition can be found A second neurochemically distinct monoamine de- in the brain stem. Local anesthesia of the RVM re- scending system involves noradrenergic neurons sults in a further increase in dorsal horn nociceptive whose cell bodies are in A5, A6 and A7 cell groups in neuronal activity in hind paw inflamed rats (Ren and the brainstem. Several studies indicate that a descend- Dubner 1996). Focal lesions of the RVM and locus ing norepinephrine (NE) system can mediate analgesia coeruleus produce an increase in spinal Fos expres- and dorsal horn inhibition and that the NE descending sion and hyperalgesia after inflammation (Tsuruoka system is critical for opiate induced analgesia. Block- andWillis1996a;TsuruokaandWillis1996b;Weietal. ade of PAG SPA by intrathecal α2 adrenergic antago- 1999b). It appears that both RVM and locus coeruleus nists (Graham et al. 1997) emphasizes the importance descending pathways are major sources of enhanced of noradrenergic systems in descending nociceptive net inhibition in inflamed animals. modulation. After inflammation, descending facilitation parallels inhibition but can also dominate it, resulting in a net Persistent Pain and Descending Modulation enhancement of activity or hyperalgesia. The selective Earlier studies of descending modulation mainly fo- destruction of the NGC with a soma selective neuro- cused on responses to acute or transient stimuli. In toxin, ibotenic acid, leads to an attenuation of hyperal- contrast, recent studies have examined the effects of gesia and a reduction of inflammation induced spinal persistent pain on descending modulation following Fos expression (Wei et al. 1999a). A descending facil- tissue damage or nerve injury. These persistent, or itatory effect may also originate from the medullary chronic, pain conditions are associated with prolonged dorsal reticular nucleus (Lima and Almeida 2002) and functional changes in the nervous system, evidenced other brain sites such as the anterior cingulate cortex by the development of dorsal horn hyperexcitability (Calejesan et al. 2000). and activity dependentplasticity,alsocommonlyre- A descending facilitatory drive contributes to the ferred to as spinal central sensitization (for reviews pathogenesis of certain types of persistent pain, partic- see Dubner and Ruda 1992; Woolf and Salter 2000). ularly those associated with secondary hyperalgesia 570 Descending Modulation of Nociceptive Processing

or nerve injury (Porreca et al. 2002; Ren and Dubner inhibitory control of descending inputs as suggested 2002). Spinalization blocks mustard oil produced sec- by a clear contralateral increase in Fos-positive cells ondary mechanical allodynia and mechanical hyper- in transected rats after inflammation (Ren and Ruda excitability of spinal nociceptive neurons (Mansikka 1996). It appears that following inflammation, brain- and Pertovaara 1997). Hind paw formalin induced hy- stemdescendingpathwaysbecomeprogressivelymore peralgesia is prevented by RVM lesions (Wiertelak et involved in suppressing incoming nociceptive signals al. 1997). RVM lesions inhibit secondary hyperalge- in primary hyperalgesic zones. Injury related primary sia produced by topical application of mustard oil (Ur- afferentinputisprobablyresponsiblefortriggeringthis ban and Gebhart 1999). The same phenomenon occurs ascending-descending feedback circuit. This enhance- in models of neuropathic pain. The tactile allody- ment of descending inhibition appears to be present nia after nerve injury is dependent upon a tonic acti- when the animal is subject to continuous, persistent vation of net descending facilitation from supraspinal noxious stimulation. sites(Ossipov etal. 2000). In nerveinjuredrats, lesions Persistent inflammation induces dramatic changes in of the dorsolateral funiculus, local anesthetic block of the excitability of RVM pain modulatingcircuitry, sug- the RVM and lesions of RVM mu-opioid receptor ex- gesting that there are dynamic temporal changes in pressing cells do not prevent the onset, but reverse the synaptic activation in the brain stem after inflamma- later maintenance of tactile and thermal hyperalgesia tion (Guan et al. 2002; Terayama et al. 2000). Early (Burgess et al. 2002; Porreca et al. 2001). These obser- (up to 3 h) in the development of inflammation there vations point to an ascending-descending loop that is is an increased descending facilitation as shown previ- activated in response to prolonged stimulation and re- ously(UrbanandGebhart1999),whichreducesthenet sulting in facilitation at the spinal level. Although most effectof the inhibition. Over time, the levelofdescend- of the above studies have concluded that the hyperalge- ing inhibition increases, or descending facilitation de- sia is dependent completely on facilitatory influences creases, leading to a net enhancement of antinocifen- from the brain stem, it should be noted that the same sive behavior. Direct stimulation of the dorsolateral fu- effectscanbeproducedbyareductionindescendingfa- niculus that bypasses brain stem synaptic mechanisms cilitation leading to a dominance of descending inhibi- does not produce a dynamic change in excitability, in- tion. Thus, inflammatory secondary hyperalgesia and dicating that the changes are due to supraspinal mech- neuropathic hyperalgesia may be dependent on a net anisms at the level of the RVM or higher. descending facilitatory effect. Both facilitatory and in- What are the cellular mechanisms that underlie these hibitory circuitry may be activated by ascending input changes? Excitatory amino acids (EAAs) have pre- after injury (Gozariu et al. 1998; Herrero and Cervero viously been shown to mediate descending modula- 1996; Terayama et al. 2000). There is an increase in tion in response to transient noxious stimulation and on- and off-cell activity after inflammation (Miki et al. early inflammation (Heinricher et al. 1999; Urban and 2002). What appears to be important then is the bal- Gebhart 1999 for review;) and they appear to be in- ance between synaptic excitation and inhibition under volved in the development of RVM excitability asso- different conditions. It has been shown previously that ciated with inflammation and persistent pain (Guan et the NGC plays a role in descending facilitation of no- al. 2002; Miki et al. 2002; Terayama et al. 2000). At 3 h ciceptive transmission after transient noxious stimuli post-inflammation, low doses of NMDA, a prototype (ZhuoandGebhart1992).LesionsoftheNGCproduce NMDA receptor agonist, microinjected into the RVM an attenuation of hyperalgesia and spinal Fos expres- produces facilitation of the response to noxious heat sion after inflammation (Wei et al. 1999). However, of the inflamed hind paw, supporting previous findings combined NGC and NRM lesions reverse the oppo- (Urban and Gebhart 1999). Higher doses of NMDA site NGC or NRM lesion induced effects. It appears at 3 h post-inflammation only produce inhibition. At that severe persistent pain may be enhanced when the 24 h post-inflammation, NMDA produces only inhi- descending facilitatory drive overrides the descending bition. All of these effects are blocked by administra- inhibitory drive. tion of NMDA receptor antagonists. AMPA, a selective AMPA receptor agonist, producesdose- and time- Dynamic Shifts in Descending Modulation after Injury dependent inhibition at 3 and 24 h post-inflammation Studies indicate that the enhancement of descending that is blocked by an AMPA receptor antagonist. The inhibition in response to tissue injury appears to build above findings indicate that there is an increase in the up gradually (Danziger et al. 1999; Dubner and Ren potency of the dose-response curves of NMDA- and 1999; Hurley and Hammond 2000; Ren and Dubner AMPA-produced inhibition at 24 h post-inflammation 1996; Ren and Ruda 1996; Schaible et al. 1991). An as compared to 3 h. The leftward shift of the dose- effect of Freund’s adjuvant on the spinal cord con- response curves of EAA receptor agonists parallels tralateral to tissue injury may also be subject to the the time dependent enhancement of net descending Descending Modulation of Nociceptive Processing 571 inhibition produced by RVM electrical stimulation. and protein expression and increased phosphorylation The results suggest that the time dependent functional of these receptors. changesin descending modulation are mediated inpart This activity induced plasticity in pain modulating cir- by enhanced EAA neurotransmission. cuitry after inflammation complements the activity de- Rats with inflammatory hyperalgesia exhibit an in- pendentneuronalplasticityinascendingpaintransmis- creased sensitivity to opioid analgesics (Neiletal. sion pathways (Dubner and Ruda 1992; Ren and Dub- 1986). Typically, there is a leftward shift of the dose- ner 2002). Inflammation leads to peripheral sensiti- D response curve for opioids from the inflamed hyper- zation of nociceptors and central sensitization or activ- algesic paw when compared to the non-inflamed paw ity dependent plasticity of spinal nociceptive neurons. (Hylden et al. 1991). Kayser et al. (1991) suggesting The increased neuronal barrage at the spinal level ac- that this increased opioid sensitivity in inflamed ani- tivates spinal projection neurons, which leads to acti- mals is related to a peripheral mechanism, as it is sig- vation of glutamatergic, opioidergic and GABAergic nificantly attenuated after local injections of very low neurons at the brain stem level and a similar, but not doses (0.5Ð1 μg) of naloxone. Recent observations in- identical, form of activity dependent plasticity. dicate thatthe increased opioid sensitivity after inflammation may also reflect changes in central pain modu- Phenotypic Changes in the RVM after Inflammation lating pathways. Hurley and Hammond (2000, 2001) The time dependent plasticity in descending pain mod- have demonstrated enhancement and plasticity of the ulatory circuitry also involves changes in the response descending inhibitory effects of mu and delta-2 opi- profiles of RVM neurons. Miki et al. (2002) used paw oid receptor agonists microinjected into the RVM dur- withdrawal latency as a behavioral correlate to as- ing the development and maintenance of inflammatory sessthe relationship between nocifensive behavior and hyperalgesia. It is likely that opioid peptide activation RVM neural activity after inflammation.Similar to the or GABA disinhibition (Fields and Basbaum 1999) findings of Fields et al. (1991), who correlated tail flick are also important in the initiation and maintenance of responses to RVM neural activity after transient nox- RVM plasticity. ious thermal stimuli, Miki et al. (2002) observed on- like, off-like and neutral-like cells based on the rela- Molecular Mechanisms of Plasticity in the RVM tionship of their responses to paw withdrawal behavior What are the molecular and cellular mechanisms of during the development of inflammation. They found this increased potency leading to enhanced synaptic thatsomeneutral-likecellschangedtheirresponsepro- activity and increases in descending net inhibition as- file and were reclassified as on- or off-like cells during sociated with primary hyperalgesia? Recent studies continuous recordings of 5 h or more. The change in have examined whether transcriptional, translational the response profile of RVM neurons correlated with and posttranslational changes occur in the RVM after the temporal changes in excitability in the RVM af- inflammation and may underlie thechangesin EAAre- ter inflammation (Terayama et al. 2000). This pheno- ceptorsensitivityobserved.ExaminationofthemRNA typic switch of RVM neurons was verified in a popu- expression of the NR1, NR2A and NR2B subunits lation study which showed that there was a significant of the NMDA receptor in the RVM revealed an up- increase in the percentage of on-like and off-like cells, regulation that parallels the time course of the RVM and a decrease in the neutral-like cell population 24 h excitability changes (Miki et al. 2002). This is ac- after inflammation. There was also a greater increase companied by an increase in NMDA receptor pro- in the magnitude of the responses of on-like cells af- tein. There is also an increase in receptor phospho- ter inflammation as compared to on-like responses in rylation of the NR2A subunit of the NMDA recep- naïve controls, suggesting an increase in facilitatory tor in the RVM after inflammation (Turnbach et al. drive in the RVM. In contrast, off-like responses were 2003). Western blot analysis revealed a time depen- reduced after inflammation, suggesting an increase in dentincreaseintheAMPAreceptorGluR1subunitlev- inhibitory descending activity originating in the RVM. els in the RVM at 5 h and 24 h post-inflammation as However, it is difficult to predict the net effect of de- compared to naïve animals (Guan et al. 2004). West- scending facilitation and inhibition from changes in ern blots also demonstrated that GluR1 phosphopro- single neuronal activity without recording from very tein levels were increased as early as 30 min and were large populations of neurons. time dependent, suggesting that posttranslational re- Although the on and off cell classification system ex- ceptor phosphorylation may also contribute to the en- plains much of the existing data, a number of unan- hanced AMPA transmission (Guan et al. 2004). These sweredquestionsremain.Forinstance,cellsthatareex- findings support the hypothesis that activity dependent cited by noxious stimulation are not inhibited by mor- plasticity takes place at the RVM level and involves phine in the conscious animal (Martin et al. 1992). Af- both changes in excitatory amino acid receptor gene ter inflammation, some cells have different response 572 Descending Modulation of Nociceptive Processing

properties depending upon the site of peripheral stim- underlying hypnotic analgesia are poorly understood ulation (Ren and Dubner, unpublished). In conscious thoughitisthoughtthatbothascendinganddescending animals, the function of these neurons may be more nociceptive pathways are involved. tightly linked to behavioral state than other aspects of the stimulus conditions (Fields 2004). RVM neurons Clinical Implications clearly participate in a number of processes in addition Descending modulation and activity dependent plas- topainmodulation.HowindividualRVMneuronscon- ticity are normal functions of the brain and presum- tribute to multiple modulatory functions is part of the ably are activated to protect the organism from fur- future challenge in this field. ther environmentalinjury.Ren andDubner (2002)pro- pose that after inflammatory primary hyperalgesia, the Placebo Analgesia and Hypnosis: Role of Descending Effects early facilitation may function to enhance nocifensive Placebo analgesia is that component of the reduc- escape behavior, whereas the dominant late inhibition tion of pain due to an inert treatment (or the nonactive may provide a mechanism by which movement of the component of an active treatment) administered to a injured site is suppressed or reduced to aid in healing subject who expects that it will reduce pain. Thus, the and recuperation. In contrast, Gebhart (2004) provides context in which a placebo is administered and the ex- an anthropomorphic explanation in which the need to pectation of the subject influence the level of analge- escape from a predator requires enhanced control of sia produced. Conditioning stimulation can also influ- painandthusmoredescendinginhibition(e.g.thefoot- ence the level of analgesia, but such conditioning ef- ball player who breaks an ankle but continues to run fects appear to involve cognitive functions and are in order to score a touchdown). The Gebhart proposal notmerelyreflexeffects.Theneuralmechanismsofthe is supported by opioid and nonopioid mechanisms of placebo effect are unclear. There are numerous stud- stress induced analgesia seen in animals (Hayes et al. ies that suggest that the placebo effect, in part, involves 1978), butisnotconsistentwith theenhanceddescend- endogenousopioidpathwaysanddescendingmodu- ing facilitation found at sites of secondary hyperal- lation. Studies using positron emission tomography gesia. Gebhart hypothesizes that descending facilita- (PET) have shown that the brain regions in the cerebral tion is necessary to maintain secondary hyperalgesia cortexandinthebrainsteminfluencedbyaplaceboma- as the tissue heals and to protect the injured tissue from nipulation are also those activated by opioids, suggest- further insult. It is clear that enhanced modulation in- ing similar mechanisms in placebo induced and opi- cludes shifts in the balance between inhibitory and fa- oid induced analgesias (Petrovic et al. 2002). The ar- cilitatory components. Recuperationfromaninjuryin- eas activated include the rostral anterior cingulate cor- volves the need for this balance, which may shift de- tex, the orbitofrontalcortex and the brainstem. In addi- pending upon the behavioral state of the animal, which tion, there are several pharmacological studies which has other survival needs besides the control of pain. show that placebo analgesia is attenuated or reversed Present evidence suggests that there is a different bal- by the opioid receptor antagonist naloxone (Amanzio ance in neural networks receiving input from zones of and Benedetti 1999; Grevert et al. 1983; Levine et al. secondary hyperalgesia where there is no primary in- 1978, Levine and Gordon 1984), providing further ev- jury. The balance towards facilitatory influences ap- idence for the involvement of opioid mechanisms. It pears to be maintained for longer periods after per- is important to note that placebo analgesia can also be manent types of nerve injury. Activation of these sites insensitive to opioid receptor antagonists, suggesting would lead to an enhancement of movement behavior that chemical mediators other than opioids may be inthat could also be protective. volved (Amanzio and Benedetti 1999; Gracely et al. The imbalance between these modulatory pathways 1983). may also be one mechanism underlying variability in Hypnotically induced reductions in pain are induced other persistent or chronic pain conditions, espe- by suggestions and facilitated by alterations of con- cially those involving deep tissues such as muscle and sciousness (Hilgard and Hilgard 1983; Price and Bar- viscera. Inputs from deep tissues produce more robust rell 1990; Raineville and Price 2003). Hypnosis can dorsal horn hyperexcitability and plasticity than inputs alterthesensorydiscriminativecomponentofpain(see from cutaneous tissues. Primary afferent and spinal Pain in Humans, Sensory-Discriminative Aspects) neurons originating from muscle and viscera are of- as well as the affective dimension. The efficacy of ten multimodal and responsive to innocuous as well hypnotic analgesia depends on several factors in- as noxious stimuli. An imbalance of descending mod- cluding the pain dimension that is measured, baseline ulatory systems in which there is an increase in en- pain intensity, the maintained presence of the hypno- dogenousfacilitation could lead to innocuousinputbe- tist or hypnotic suggestions and finally hypnotic abil- ing perceived as painful. For patients suffering from ity (Price and Barber 1987). The neural mechanisms deep pains, such as temporomandibular disorders, Descending Modulation of Nociceptive Processing 573

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Brain Res 58:850Ð865 726:233Ð236 56. Oliveras JL, Redjemi F, Guilbaud G et al. (1975) Analgesia in- 78. Tsuruoka M, Willis WD (1996b) Descending modulation from duced by electrical stimulation of the inferior centralis nucleus the region of the locus coeruleus or nociceptive sensitiv- of the raphe in the cat. Pain 1:139Ð145 ity in a rat model of inflammatory hyperalgesia. Brain Res 57. Ossipov MH, Hong Sun T, Malan P Jr et al. (2000) Mediation 743:86Ð92 of spinal nerve injury induced tactile allodynia by descend- 79. Turnbach ME, Guo W, Dubner R et al. (2003) Inflammation ing facilitatory pathways in the dorsolateral funiculus in rats. induces tyrosine phosphorylation of the NR2A subunit and ser- Neurosci Lett 290:129Ð132 ine phosphorylation of the NR1 subunits in the rat rostral ven- 58. Park Y, Al-Chaer ED (2002) Thalamic stimulation differen- tromedial medulla. Society for Neuroscience Abstracts 2003, tially modifies spinal neuronal responses to colorectal disten- vol 29:695.13 sion in rats with chronic visceral pain. J Pain 3:31; American 80. Urban MO, Gebhart GF (1999) Supraspinal contributions to Pain Society Abstract 722 hyperalgesia. Proc Natl Acad Sci USA 96:7687Ð7692 59. Pert CB, Snyder SH (1973) Opiate receptor: demonstration in 81. Urban MO, Coutinho SV, Gebhart GF (1999) Biphasic modu- nervous tissue. Science 179:1011Ð1014 lation of visceral nociception by neurotensin in rat rostral ven- 60. Petrovic P, Kalso E, Petersson KM et al. (2002) Placebo and tromedial medulla. J Pharmacol Exp Ther 290:207Ð213 opioid analgesia ÐImaging a shared neuronal network. Science 82. Wei F, Ren K, Dubner R (1998) Inflammation-induced Fos 295:1737Ð1740 protein expression in the rat spinal cord is enhanced follow- 61. Porreca F, Burgess SE, Gardell LR et al. (2001) Inhibi- ing dorsolateral or ventrolateral funiculus lesions. 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84. Wei F, Dubner R, Ren K (1999b) Laminar-selective noradrener- nuclei reticularis gigantocellularis and gigantocellularis pars gic and serotoninergic modulation includes spinoparabrachial alpha in the rat. Brain Res 550:35Ð48 cells after inﬂammation. NeuroReport 10:1757Ð1761 88. Zhuo M, Gebhart (1992) Characterization of descending facili- 85. Wiertelak EP, Roemer B, Maier SF et al. (1997) Comparison tation and inhibition of spinal nociceptive transmission from the of the effects of nucleus tractus solitarius and ventral medial nuclei reticularis gigantocellularis and gigantocellularis pars medulla lesions on illness-induced and subcutaneous formalin- alpha in the rat. J Neurophysiol 67:1599Ð1614 induced hyperalgesias. Brain Res 748:143Ð150 89. Zhuo M, Sengupta JN, Gebhart GF (2002) Biphasic mod- 86. Woolf CJ, Salter MW (2000) Neuronal plasticity: Increasing ulation of spinal visceral nociceptive transmission from the D the gain in pain. Science 288:1765Ð1768 rostroventral medial medulla in the rat. J Neurophysiol 87. Zhuo M, Gebhart GF (1991) Spinal serotonin receptors me- 87:2225Ð2236 diate descending facilitation of a nociceptive reﬂex from the

The descending pain-controlsystem is modified by, and Descending Modulation of Nociceptive in turn modifies, persistent nociception caused by in- Transmission during Persistent Damage flammation or nerve damage. In animal models of these to Peripheral Tissues two types of chronic pain, application of noxious stimuli to the affected body part elicits exaggerated nocicep- HORACIO VANEGAS tiveresponses( primaryhyperalgesia),andevenprevi- Istituto Venezolano de Investigaciones Cientificas ouslyinnocuousstimulicanelicitsuchversiveresponses (IVIC), Caracas, Venezuela (primary allodynia). In addition, healthy body parts [email protected] near the affected areas may also show hyperexcitability ( secondary hyperalgesia and allodynia). Synonyms Inflammation of Peripheral Tissues Descending Pain Control; Descending Control of Hy- peralgesia One model of inflammatory pain in rats involves the in- jectionofanantigenicsubstance,likecompleteFreund’s Definition adjuvantor carrageenan, intoa hindpaworarticularcav- ity.Anothermodelconsistsofapplyingmustardoiltothe Inhibitory or facilitatory influences which brain stem skin of a hind leg; this excites C-fibers and thus mimics structures exert upon the spinal transmission of pain persistent peripheral damage. messages that arise from inflamed peripheral tissues or Normally there is a tonic descending inhibition of damaged peripheral nerves. Animal models show that spinal nociceptive transmission. When inflammation persistent nociception induces changes in the activity of peripheral tissues begins, an increased impulse flow of brain stem structures, and these in turn facilitate or reaches the spinal cord (Schaible and Grubb 1993). inhibit spinal circuits responsible for hyperalgesia Here the (primary) neuronal pool that receives these and allodynia. impulses relays, in turn, an elevated number of impulses towards supraspinal, including brainstem, targets. At Characteristics the same time, the primary neuronal pool becomes Transmissionofpainmessagesinthespinalcordismod- hyperexcitable. Primary hyperalgesia thus sets in. The ulated by the descending pain-control system (Fields normal tonic descending inhibition may hinder the and Basbaum 1999). In its simplest form this system is development of primary hyperalgesia (Ren and Dub- pictured as follows: The gray matter around the sylvian ner 2002). Additionally, the hyperexcitable neuronal aqueduct (periaqueductal gray, PAG) is connected to the pool becomes more sensitive to descending noradren- rostral ventromedial medulla (RVM), which contains ergic and local opioidergic inhibition (Hylden et al. the nucleus raphe magnus and other reticular nuclei. 1991, Stanfa and Dickenson 1994). Both factors tend Neurons in RVM in turn send their axons to the spinal to dampen the ensuing hyperalgesia. The increased dorsal horn, where they increase or decrease trans- flow of ascending nociceptive impulses induces time- mission of nociceptive messages along spinal reflex dependent changes in the inhibitory and facilitatory circuits, as well as along pathways that ascend towards influences which simultaneously descend from RVM. the brain stem, the thalamus and the cerebral cortex. In primary hyperalgesia, descendinginhibition predom- PAG and RVM receive messages from vast areas of inates over facilitation, so that the resulting pain is not as the central nervous system, which thereby can influ- intense as it could be (Ren and Dubner 2002, Schaible ence nociceptive transmission. Importantly, exogenous et al. 1991). This is due to an increase in enkephalin opiate and non-opiate analgesic drugs act upon PAG synthesis in RVM and PAG, as well as an increase in and RVM by imitating, or interacting with, endogenous the expression of both NMDA and AMPA receptors opioids, and this contributes to their analgesic action. in RVM, which results in an elevated opioidergic and 576 Descending Modulation of Pain glutamatergic drive on descending inhibitory mecha- References nisms (Hurley and Hammond 2001; Ren and Dubner 1. Burgess SE, Gardell LR, Ossipov MH, Malan TP, Vanderah TW, 2002). Simultaneously, an increase in the activation Lai J, Porreca F (2002) Time-Dependent Descending Facilitation of NMDA, AMPA, neurotensin and cholecystokinin from the Rostral Ventromedial Medulla Maintains, but Does Not Initiate, Neuropathic Pain. J Neurosci 22:5129-5136 (CCK) receptors in RVM, causes descending facili- 2. Fields HL, Basbaum AI (1999) Central Nervous System Mech- tation of secondary hyperalgesia (Urban and Gebhart anisms of Pain Modulation. In: Wall PD, Melzack R (eds) Text- 1999). book of Pain. Churchill Livingstone, London, pp 309-329 3. Hurley RW, Hammond DL (2001) Contribution of Endogenous Damage to Peripheral Nerves Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ- Opioid Receptor Agonists after Inflammatory Injury. J Neurosci The role of the descending pain-control system has also 21:2536-2545 been studied in animal models of nerve damage. These 4. Hylden JLK, Thomas DA, Iadarola MJ, Nahin RL, Dubner R include partial lesion of the sciatic nerve or ligation of (1991) Spinal Opioid Analgesic Effects are Enhanced in a Model of Unilateral Inflammation/Hyperalgesia: Possible Involvement spinal nerves L5 and L6, which cause hyperalgesia and of Noradrenergic Mechanisms. Eur J Pharmacol 194:135-143 allodynia of the corresponding hind leg, and ligation of 5. Kovelowski CJ, Ossipov MH, Sun H, Lai J, Malan TP, Porreca F spinal nerves S1ÐS3, which causes allodynia of the tail. (2000) Supraspinal Cholecystokinin May Drive Tonic Descend- During the first few days after nerve damage, plastic- ing Facilitation Mechanisms to Maintain Neuropathic Pain in the Rat. Pain 87:265-273 ity at both the damaged and neighboring nerve fibers, 6. Monhemius R, Green DL, Roberts MHT, Azami J (2001) Peri- as well as at the spinal cord, trigger the development of aqueductal Grey Mediated Inhibition of Responses to Noxious primary hyperalgesia and allodynia. Potentially, these Stimulation is Dynamically Activated in a Rat Model of Neu- ropathic Pain. Neurosci Lett 298:70-74 disturbances may subside after a few days, but descend- 7. Porreca F, Burgess SE, Gardell LR, Vanderah TW, Malan TP, ing influences from RVM maintain the neuropathic syn- Ossipov MH, Lappi DA, Lai J (2001) Inhibition of Neuropathic drome for several weeks (Burgess et al. 2002). Indeed, Pain by Selective Ablation of Brainstem Medullary Cells Ex- the primary neuronal pool at the spinal dorsal horn is un- pressing the μ -Opioid Receptor. J Neurosci 21:5281-5288 8. Ren K, Dubner R (2002) Descending Modulation in Persistent der abnormal bombardment from peripheral fibers, and Pain: An Update. Pain 100:1-6 sends exaggerated ascending impulses that eventually 9. Schaible H-G, Neugebauer V, Cervero F, Schmidt RF (1991) induce changes in RVM. Among these changes is an ac- Changes in Tonic Descending Inhibition of Spinal Neurons with tivation of CCK receptors (Kovelowski et al. 2000). The Articular Input During the Development of Acute Arthritis in the Cat. J Neurophysiol 66:1021-1032 so-called “on-cells” of RVM are then thought to convey 10. Schaible H-G, Grubb BD (1993) Afferent and Spinal Mecha- facilitatory influences onto the spinal dorsal horn, and nisms of Joint Pain. Pain 55:5-54 thus close a positive feedback circuit that goes from the 11. Stanfa LC, Dickenson AH (1994) Enhanced Alpha-2 Adrenergic primary neuronal pool to RVM and back to this pool. Controls and Spinal Morphine Potency in Inflammation. Neu- roReport 5:469-472 This circuit is broken, and hyperalgesia and allodynia 12. Urban MO, Gebhart GF (1999) Supraspinal Contributions to Hy- thus disappear, if RVMis anesthetized with lidocaine, or peralgesia. Proc Nat Acad Sci USA 96:7687Ð7692 its CCK receptors are blocked with an antagonist, or the on-cells are destroyed with a neurotoxin (Kovelowski et al. 2000; Porreca et al. 2001). Together with descending facilitation of the primary Descending Modulation of Pain neuronal pool, peripheral nerve damage triggers descending influences from PAG, which hinder nocicep- Definition tive responses to stimulation of healthy areas around the neuropathic zone (Monhemius et al. 2001). Whether Noradrenergic and serotonergic fibers descending from these PAG influences are channeled through RVM is supraspinal loci may act to reduce nociceptive transmis- still unknown. sion atthelevelof thedorsalhorn. Thisprocessistermed “inhibitory descending modulation”. Descending mod- Conclusion ulatory pathways may also act to enhance nociceptive PAG and RVM are modified due to peripheral tissue transmission “facilitatory descending modulation”. Descending Modulation and Persistent Pain damage. During inflammation, both inhibitory and facilitatory influences descend from RVM. However, Encoding of Noxious Information in the Spinal Cord inhibition predominates at the primary neuronal pool, Somatic Pain thus attenuating primary hyperalgesia, while facilitation predominates at the secondary neuronal pool, thus exaggerating secondary hyperalgesia. During the Descending Modulation of Visceral Pain neuropathic syndrome, descending facilitation is also accompanied by inhibition, but facilitation affects the ELIE D. AL-CHAER primary neuronal pool and is essential for primary hy- Center for Pain Research (CPR), University of peralgesia and allodynia, whereas inhibition attenuates Arkansas for Medical Sciences, Little Rock, AR, USA nociception at secondary neuronal pools. [email protected] Descending Modulation of Visceral Pain 577

Synonyms be context-specific. For example, in chronically sensi- Descending inhibition; Descending Facilitation; Irrita- tized adult rats that received neonatal colon irritation, ble Bowel Syndrome; IBS; Functional Abdominal Pain; thalamic stimulation caused a facilitationofneuronalre- Visceral Hyperalgesia; visceral hypersensitivity sponses to colorectal distension in more than 60% of the neurons isolated. This facilitation was observed regard- Definition less of the intensity of electrical stimulation, and was facilitated by DC input. Inhibition in response to thala- D Spinal visceral nociceptive transmission is subject to mic stimulation was seen in less than 40% of the neurons descending modulatory influences from supraspinal in chronically sensitized rats. This inhibition appeared structures (e.g. periaqueductal gray [PAG], nucleus to be controlled by DC input. This goes to show that de- raphe magnus [NRM], nuclei reticularis gigantocel- scending pathways do not exclusively exert inhibitory lularis [NGC], and the ventrobasal complex of the actions in the dorsal horn. Indeed, individual transmit- thalamus [VBC]). This descending modulation can ters may exert multiple actions in the dorsal horn as a be either inhibitory, facilitatory or both, depending on function of the type of neuron targeted and the receptor the context of the visceral stimulus or the intensity activated (Park and Al-Chaer 2002, Saab et al. 2004). of the descending stimulation. The descending path- Nevertheless, studies have revealed evidence of tonic ways originating in the brainstem and other cerebral descending inhibition under normal circumstances, structures play an important role in the modulation and whose removal produced increases in spontaneous ac- integration of visceroceptive messages in the dorsal tivity and/or responses of spinal neurons to visceral horn. Serotonergic, noradrenergic and to a lesser extent stimuli. For example, reversible cold block of the cer- dopaminergic networks comprise of major components vical spinal cord revealed that spinal viscerosomatic of these descending mechanisms. neurons are under tonic descending inhibitory influences from supraspinal structures (Akeyson et al. 1990, Characteristics Cervero 1983, Tattersall et al. 1986). Descending modulation of spinal visceral nocicep- On the other hand, a number of studies have shown that tive processing is tonically active, and includes both spinalvisceralinputissubjecttofacilitatorymodulation, inhibitory and facilitatory influences. Correlative be- providing the basis of a mechanism that could enhance havioral and neuronal studies have demonstrated that visceral perceptions in the absence of noxious visceral descending modulation influences both behavior and stimulation, which would explain in part the visceral hy- neuronal activity at spinal cord levels in acute and persensitivity, often observed in cases of functional persistent pain; this modulation includes descending boweldisordersand irritablebowelsyndrome. Tonicde- facilitatory as well as inhibitory influences that may im- scending facilitatory influences have been documented. pact on pain of visceral origin (Dubner and Ren 1999). For example, 44% of viscerosomatic neurons, recorded Electrical stimulation or chemical activation of a num- from thoracic segments of the cat spinal cord, gave no berofsupraspinalcenterscanmodulatetheneuronaland responses to splanchnic nerve stimulation during cervi- behavioral responses to visceral stimuli. For example, cal cold block (Tattersall et al. 1986). Electrical stimula- responses to an intraperitoneal injection of hypertonic tion in the RVM produced intensity-dependentbiphasic saline in rats are attenuated by electrical stimulation modulation (intensity-dependent inhibition, or facilita- in the PAG (Giesler and Liebskind 1976). Chemical tion) of the visceromotor response (VMR) to colorectal activation of cell bodies in the rostroventral medulla distention. Activation of glutamatergic receptors in the (RVM) attenuated responses to visceral stimulation RVM also facilitated or inhibited the VMR to colorec- (Coutinho et al. 1998, Urban et al. 1999). Electrical tal distention. The descending facilitatory effects were stimulation or glutamate microinjection into the PAG, shown to be primarily mediated by pathways traveling NRM, or NGC inhibit spinal dorsal horn neuron re- in the ventral/ventrolateral spinal cord. Importantly, de- sponses (including spinoreticular and spinothalamic scending modulation, whether inhibitory or facilitatory, tract neurons) to visceral afferent fiber stimulation or was shown to be linked to the stimulus; resting EMG ac- noxious colorectal distension (CRD) (Ammons et tivity was unaffected by either electrical stimulation or al. 1984, Cervero et al. 1985, Ness and Gebhart 1987). glutamate microinjection in the RVM (Zhuo and Geb- The descending inhibitory effects from the RVM have hart 2002). been shown to be primarily mediated by pathways traveling in the dorsolateral spinal cord (Zhuo and Gebhart 2002). References Similarly, electrical stimulation of the ventrobasal com- 1. Akeyson EW, Kneupfer MM, Schramm LP (1990) Splanchnic plexofthethalamus(VBC)inhibitstheresponsesofdor- Input to Thoracic Spinal Neurons and its Supraspinal Modulation in the Rat. Brain Res 536:30Ð40 sal horn neurons to colorectal distension in normal rats, 2. Ammons WS, Blair RW, Foreman RD (1984) Raphe Magnus In- an effect attenuated in part by dorsal column (DC) inhibition of Primate T1-T2 Spinothalamic Cells with Cardiopul- put. However, thalamic descending inhibition proved to monary Visceral Input. Pain 20:247Ð260 578 Descending Noradrenergic Pathways

3. Cervero F (1983) Supraspinal Connections of Neurons in the Thoracic Spinal Cord of the Cat: Ascending Projections and Ef- Desensitization fects of Descending Impulses. Brain Res 275:251Ð261 4. Cervero F, Lumb BM, Tattersall JEH (1985) Supraspinal Loops that Mediate Visceral Inputs to Thoracic Spinal Cord Neurons in Definition the Cat: Involvement of Descending Pathways from Raphe and Non-operative therapy designed to treat pain is termed Reticular Formation. Neurosci Lett 56:189Ð194 5. Coutinho SV, Urban MO, Gebhart GF (1998) Role of Glutamate desensitization. This therapy produces a stream of new Receptors and Nitric Oxide in the Rostral Ventromedial Medulla neural impulses that permits cortical remapping, and in Visceral Hyperalgesia. Pain 78:59Ð69 represents sensory re-education of the C-fibers and 6. Dubner R, Ren K (1999) Endogenous Mechanisms of Sensory Modulation. Pain: 45Ð53 A-delta fibers. It is used in neuropathic pain conditions 7. Giesler GJ, Liebskind JC (1976) Inhibition of Visceral Pain by to help re-program the nerves in the affected area by Electrical Stimulation in the Periaqueductal Gray Matter. Pain touching the painful area. Simulation by an agonist that 2:43Ð48 leads from unresponsiveness to further stimulation is 8. Ness TJ, Gebhart GF (1987) Quantitative Comparison of Inhi- bition of Visceral and Cutaneous Spinal Nociceptive Transmis- also sometimes called desensitization. sion from the Midbrain and Medulla in the Rat. J Neurophysiol Complex Chronic Pain in Children, Interdisciplinary 58:850Ð865 Treatment 9. Park YC, Al-Chaer ED (2002) Thalamic Stimulation Differen- Nociceptor, Fatigue tially Modifies Spinal Neuronal Responses to Colorectal Disten- sion in Rats with Chronic Visceral Pain. J Pain 3 Suppl 1:31 Opioid Receptor Trafficking in Pain States 10. Saab CY,Park YC, Al-Chaer ED (2004) Thalamic modulation of Painful Scars visceral nociceptive processing in adult rats with neonatal colon Psychology of Pain, Sensitisation, Habituation and irritation. Brain Res 1008:186Ð192 Pain 11. Tattersall JEH, Cervero F, Lumb BM (1986) Effects of Reversible Spinalization on the Visceral input to Viscerosomatic Neurons in the Lower Thoracic Spinal Cord of the Cat. J Neurophysiol 56:785Ð796 12. Urban MO, Coutinho SV, Gebhart GF (1999) Biphasic Mod- Desensitizing Toothpastes ulation of Visceral Nociception by Neurotensin in Rat Rostral Ventromedial Medulla. J Pharmacol Exp Ther 290:207Ð213 13. Zhuo M, Gebhart GF (2002) Facilitation and Attenuation of a Definition Visceral Nociceptive Reflex from the Rostroventral Medulla in Desensitizing toothpastes apply medicaments to dentin the Rat. Gastroenterology 122:1007Ð1019 that has become exposed and block fluid flow through the dentinal tubules and/or allow the diffuse of salts into the dental pulp that reduce the sensitivity of nociceptors. Descending Noradrenergic Pathways DentalPain, Etiology, Pathogenesisand Management

Definition Serotonergic and noradrenergic projections originate Desmin from pontine and medullary neurons, and descend into the spinal cord to modulate pain by inhibiting nocicep- Definition tive transmission in the dorsal horn of the spinal cord. In some psychological disorders, these pathways may The intermediate filament system (mainly desmin) of become dysfunctional and cause physical symptoms of skeletal muscle is believed to be responsible for the me- pain that are unrelated to the mental state. chanical integration of the myofibrillarlattice in boththe Nitrous Oxide Antinociception and Opioid Receptors longitudinal and radial directions. Delayed Onset Muscle Soreness

Descending Pain Control Detection Threshold Descending Modulation of Nociceptive Processing DescendingModulationofNociceptiveTransmission Deﬁnition during Persistent Damage to Peripheral Tissues The minimum amount of stimulus energy necessary to elicit a sensory response, deﬁned as the lowest current amplitude perceived by the subject. Descending Pain Modulatory Pathways, Hyperaesthesia, Assessment Sex Differences Hyperpathia, Assessment Hypoesthesia, Assessment SexDifferencesinDescendingPainModulatoryPath- Pain in Humans, Electrical Stimulation (Skin, Muscle ways and Viscera) Diabetic Neuropathies 579

Developmental Level Diabetic Amyotrophy

Deﬁnition Diabetic Neuropathies Aperiodorphaseinthelifespan.Inchildren,fociinclude the development of cognition, language, affect, and motor skills. D Cancer Pain, Assessment in Children Diabetic Autonomic Polyneuropathy

Diabetic Neuropathies Dexamethasone

Deﬁnition Thelong-actingparenteralororallyadministeredsteroid Diabetic Cranial Mononeuropathy dexamethasone prevents the increased expression of COXÐ2, which is stimulated by bacterial lipopolysac- Diabetic Neuropathies charide, cytokines or growth factors. Acute Pain in Children, Post-Operative Cyclooxygenases in Biology and Disease Diabetic Mononeuritis

Diabetes Mellitus Diabetic Neuropathies

Definition The disease due to inadequate secretion of a pancreatic hormone (insulin) resulting in hyperglycemia (abnor- Diabetic Neuropathies mally high glucose level in blood). ANNE LOUISE OAKLANDER Toxic Neuropathies Nerve Injury Unit, Departments of Anesthesiology, Neurology and Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Diabetes Mellitus Type I MA, USA [email protected] Definition Synonyms Diabetes brought on by an autoimmune attack on the insulin-producing beta cells of the pancreas. It is more Acute Painful Diabetic Neuropathy; burning feet common in the young, and onset of symptoms is usu- syndrome; diabetic amyotrophy; diabetic autonomic ally abrupt. Patients are treated with a lifetime regimen polyneuropathy;diabetic cranial mononeuropathy;dia- of exogenous insulin. betic mononeuritis;diabetic sensorimotor polyneuropa- Diabetic Neuropathies thy; diabetic sensory neuropathy; diabetic amyotrophy; diabetic symmetrical proximal neuropathy; DSPN; diabetic truncal mononeuropathy; hyperglycemic neuropathy; Insulin Neuropathy; mixed forms of diabetic Diabetes Mellitus Type II neuropathy; proximal diabetic neuropathy; vasculitic neuropathy Definition Definition Diabetes in which cells develop difficulty uptaking in- sulinfromtheblood.Alsoknownasadult-onsetdiabetes Focal or generalized damage to the peripheral nerves is (it is more common in older individuals), type II is the common with diabetes mellitus type I or II. Various most common type of diabetes in the Western world. patternsofneuralinjuryhavebeendescribed.Themech- Obesity is a major risk factor, and onset of symptoms anisms underlying them are poorly understood. Other is gradual. metabolic derangements can also cause similar nerve Diabetic Neuropathies damage, especially renal failure or hypothyroidism. 580 Diabetic Neuropathies

Characteristics able to entrapment, whose effects can be additive to the Epidemiology underlying neuropathy. In such cases, surgical decompression (e.g., at the tarsal tunnel of the ankle) may be Diabetesandrelatedmetabolicdisturbancesarethemost therapeutic (Aszmann et al. 2000). Electrophysiologic common cause of peripheral neuropathies in Western study has demonstrated central neural damage from dia- countries. Demographic trends, including aging of the betes as well (Comi 1997), which can contribute to pain population and increasing obesity, suggest that inci- and other neural abnormalities common in diabetes. Of dence will increase. Diabetic neuropathies had been course, diabetes is a major risk factor for stroke, usu- estimated to affect about one-third of diabetics (Dyck et ally because of accelerated atherosclerosis and vascular al. 1991), but this figure is being revised upward as more disease. sensitive tests for early diabetes and glucose intoler- Generalized polyneuropathy affecting autonomic neu- ance are developed, and as almost half of patients with rons is common and can cause difficulty with sexual so-called idiopathic small-fiber neuropathy are found function, gastric motility, or sweating. Dysfunction to have subtle abnormalities of glucose handling, which of autonomic innervation of the heart may contribute do not qualify as fully-fledged diabetes according to to excess cardiac disease in diabetics. Patients with the current criteria (Singleton et al. 2001). diabetic autonomic nerve damage may no longer develop the symptoms of hypoglycemia (e.g., tachycardia, Clinical Spectrum of Diabetic Nerve Damage sweating), and thus experience clinically inapparent The mildest and most easily reversed types of diabetes- hypoglycemia that goes uncorrected until severe conse- associated nerve damage are transient abnormalitiesdue quencesdevelop.Similarly,lossofperceptionofanginal to either transient hyper- or hypoglycemia; these are as- chest pain can lead to “silent” myocardial infarctions sociated with changes in ionic concentrations and fluid in diabetics. balances around axons that can temporarily disturb ax- onalconduction(AleyandLevine2001).Ithasalsobeen Diabetic Sensory Polyneuropathy (DSPN) suggested that norepinephrine released into the blood- By far the most common form of diabetic neuropathy stream during glucose excursions has the ability to acti- is a distal, symmetric, predominantly sensory, painful, vate nociceptive axons (and cause pain) with abnormal small-fiber polyneuropathy (DSPN) (Dyck et al. 1991). properties from earlier diabetic damage. DSPN patients usually complain of burning bilateral Several types of longer-lasting but still reversible focal foot pain, which over time can spread upward along the neuropathies, which affect one or a few discrete nerves, legs, involving the arms and torso as it becomes more are common in diabetics. Such mononeuropathies can severe. DSPN is a major contributor to infection and affect the cranial nerves (especially cranial nerve amputation in diabetics, as well as to other major com- III, which usually causes double vision), or nerves or plications of diabetes, including sexual dysfunction, but nerve roots that innervate the torso. Truncal diabetic it is the least understood of the common complications radiculopathy typically presents as a band of pain along of diabetes. one side of the thorax or abdomen, in the territory of one or a few sensory segments. Damage to truncal Pathophysiology nerve roots or intercostal nerves can cause bulging of Several biochemical abnormalities have been described the abdomen (due to muscle weakness) as well. This in diabetic nerves, although their relative clinical impor- is rarely clinically significant but can provide a clue tance remains unknown. Increased activity of aldose re- for diagnosis. Proximal diabetic amyotrophy, which ductase leads to accumulation of fructose and sorbitol, usually causes pain and weakness of the thighs, is due and depletion of NADPH (nicotinamide adenine dinu- to similar focal damage to the nerves innervating the cleotide phosphate). Loss of NADPH limits removal of thighs. These diabetic neuropathies are usually due to toxic molecules, such as free radicals, that can damage underlying focal vasculitis, and resulting ischemia neurons. Hyperglycemia produces pathologic glycation and infarction within individual nerves or roots. They of a wide variety of molecules, and the products of this present with the sudden onset of focal neurologic glycation reaction also cause free-radical damage. In- deficit (usually pain, weakness, and muscle atrophy), creased activity of aldose reductase elevates activity of due to impaired function of the damaged nerve. These protein kinase C (PKC); this is associated with constric- vasculitic mononeuropathies tend to improve if the tion of vasa nervori and possibly nerve ischemia. Im- damaged axons can regenerate (Lauria et al. 1998). muneabnormalities,suchasautoantibodiesoractivation If vasculitis is severe or present in multiple locations of T lymphocytes, have also been detected; these may (mononeuritis multiplex), immunosuppression with play a role in the vasculitic diabetic mononeuropathies. corticosteroids and cyclophosphamide, or intravenous immunoglobulin may be indicated. Diagnosis Nervesaffectedbydiabeticperipheralneuropathycanbe Diagnosis of early DSPN is easy when the patient swollen and compromised, and therefore more vulner- complains of the typical “burning” foot pain. These Diabetic Neuropathies 581 neuropathic pains are usually most severe at night, is that central pain-processing neurons fire, even in the when there is nothing to distract attention away from absence of incoming pain signals, producing ongoing them. Nocturnal exacerbation provides a valuable clue pain. Cross-connections between touch (low threshold) to diagnosis, because most pains from orthopedic or neurons and nociceptive neurons, at some point in the vascular causes typically worsen with activity and im- pathway, can render even the lightest touch painful prove with rest. The major problem with diagnosis is (allodynia). Surviving neurons are left in an abnormal that objective confirmation can be difficult to obtain on environment, because nearly all tissue contacted by D examination or through lab testing, since the axons most axons (e.g., Schwann cells, muscle cells, keratinocytes) vulnerable to diabetic damage are the small-diameter, dramatically change their gene expression when axonal thinly myelinated (A-delta) or unmyelinated (C-fiber) contact is lost. It is not clear how many of these changes axons that subserve pain and autonomicfunction. Dam- are potentially reversible if diabetic control is main- age to these types of neurons does not cause overt signs tained. Some patients experience periods of remission on exam (e.g., weakness, muscle atrophy, or loss of from pain, but the mechanisms are unknown. reflexes), and is not “captured” by electromyography and nerve conduction studies, the standard tests for Treatment Options diagnosing neuropathy. Damage to large myelinated Two categories of treatment for DSPN exist. Of greatest axons, detectable as slowing and reduced amplitude of potential importance are those that improve the under- sensory nerve action potentials, does not often develop lying diabetes (disease-modifying treatments). Weight until the neuropathy is advanced and has spread to af- lossisprobablythesinglemostimportantandsafestther- fect large-diameter axons as well. Lack of a marker for apy for those with type II diabetes. The secondisoptimal early DSPN may have contributed to negative results in control of hyperglycemia,which has been convincingly clinical trials of potential treatments (Apfel et al. 1998). demonstratedtodelaytheonsetandslowtheprogression An early marker might also make presymptomatic di- of diabetic neuropathy (The Diabetes Control and Com- agnosis - as well as therapies that slow or prevent onset plications Trial Research Group 1993). A trial of nerve of clinical symptoms - possible. growth factor (NGF), with the goal of increasing axonal regeneration in DSPN, failed to show efficacy (Apfel Neuropathology et al. 1998). That trial has been criticized for method- Severalmethodshavedocumentedanatomicalandfunc- ological difficulties, and the efficacy of growth factors tional loss of primary sensory axons in DSPN. Until re- isfarfromdisproven.Trialsofdietarysupplements(e.g., cently, suralnervebiopsy wasthe“gold”standard, but myoinositol, alpha-lipoic acid, and aldose-reductase in- it is invasive and cannot be repeated to monitor disease hibitors) have been more helpful in animal models than progress or the effects of therapy. It leaves about half of in humans. Physical therapy to encourage motility and diabeticswithpersistentpainandsensoryabnormalities. weight loss, as well as meticulous podiatric care to pre- Examination and quantitation of nerve endings within vent and treat foot infections can go far in treating the punch skin biopsies is an easier, safer, and more sen- underlying disease, as well as minimizing its compli- sitive diagnostic alternative; like sural nerve biopsy, it cations. Decompressive neurosurgery is indicated only is only available at specialized centers (Kennedy et al. if entrapment contributes to clinically significant symp- 1996). DSPN is a central-peripheral-distal axonopathy, toms. with damage evident to the central as well as peripheral Symptomatic or palliative treatment is also commonly axons of primary afferent neurons. used for patients with moderate or severe symptoms, usually pain. For pain, randomized, controlled clinical Pain Mechanisms trials have established efficacy and safety for several Various mechanisms contribute to pain in diabetic classes of medications, including the noradrenergi- neuropathies. Early in vasculitic neuropathies, tissue cally active tricyclic antidepressants (Max et al. 1987). hypoxia, acidosis, and abnormalities characteristic of Nortriptyline and desipramine have fewer side effects acute inflammation are present. The nervi nervorum than amitriptyline. There are data supporting the use of can be affected by all of the above, not to mention by anticonvulsants, especially gabapentin and diphenylhy- intrafascicular edema, even well proximal to the distal dantoin (Chadda and Mathur 1978), and several trials end of the nerve. Early hyperexcitability of periph- documenting safety and efficacy of opioid medications eral nerves can be followed by a more chronic picture (Harati et al. 2000). There are preliminary data support- of Wallerian degeneration, with atrophy and scarring ing use of topical local anesthetics applied to painful within affected nerves. Many primary afferents will lose feet (Dworkin et al. 2003). contact with their central post-synaptic targets, either from distal axonopathy or frank cell death, if damage is Animal Models severe. Loss of enough primary afferents leads to bio- Animal models of DSPN are used to study disease chemical and anatomical changes within the dorsal root pathophysiology and to screen potential treatments. ganglia, dorsal horn and higher centers. The net result There are two major types: animals with genetic muta- 582 Diabetic Neuropathies

Diabetic Neuropathies, Figure 1 PGP9.5-immunolabeled sensory nerve endings within punch skin biopsies. Representative labeled vertical skin-biopsy sections from subjects with and without diabetic neuropathy reveal distal loss of sensory nociceptive nerve endings. Both punches are from the standard biopsy site (10 cm above the lateral malleolus) used to diagnose peripheral neuropathy. (a) Skin biopsy from a normal subject is densely innervated, with a total of 320 epidermal neurites/mm2 skin surface area; (b) biopsy from a patient with painful diabetic neuropathy shows near-total loss of innervation (2 epidermal neurites/mm2 skin surface area). Immunohistochemistry and photography by Li Zheng. tions that predispose them to diabetes, and those whose 2. Aley KO, Levine JD (2001) Rapid Onset Pain Induced by In- diabetes is experimentally induced. Induction of dia- travenous Streptozotocin in the Rat. J Pain 2:146Ð150 3. Apfel SC, Kessler JA, Adornato BT, Litchy WJ, Sanders C, Rask betes offers the advantage of not having to wait until CA (1998) Recombinant Human Nerve Growth Factor in the diabetic complications develop as the animal ages. In Treatment of Diabetic Polyneuropathy. Neurology 51:695Ð702 rodents, a single systemic injection of streptozoticin 4. Aszmann OC, Kress KM, Dellon AL (2000) Results of De- (STZ), a pancreatic beta cell toxin, induces diabetes. compression of Peripheral Nerves in Diabetics: A Prospective, Blinded Study. Plast Reconstr Surg 106:816Ð822 Treated animals develop most symptoms characteristic 5. Chadda VS, Mathur MS (1978) Double Blind Study of the Effects of human DSPN, including mechanical hyperalge- of Diphenylhydantoin Sodium on Diabetic Neuropathy. J Assoc sia (Ahlgren and Levine 1993). These abnormalities Physicians India 26:403Ð406 develop within 1 to 2 weeks, are due to insulin defi- 6. Comi G (1997) Evoked Potentials in Diabetes Mellitus. Clin Neu- rosci 4:374Ð379 ciency and/or hyperglycemia (they resolve with insulin 7. Dworkin RH, Hart-Gouleau S, Galer BS, Gammaitoni AR, treatment) (Sima et al. 1988), and persist indefinitely. Domingos J (2003) Effectiveness and Impact on Quality of Neuropathologic evaluation has shown that diabetic rats Life of the Lidocaine Patch 5% in Painful Diabetic Neuropathy develop similar structural lesions to diabetic humans Patients With or Without Allodynia (abstract). Abstracts: Poster Session, APS 22nd Annual Meeting, American Pain Society, (e. g., central peripheral distal axonopathy [CPDA] Chicago with degeneration of the central and peripheral axons of 8. Dyck PJ, Kratz KM, Lehman KA, Karnes JL, Melton LJ, O’Brien their primary sensory neurons). Early changes include PC, Litchy WJ, Windebank AJ, Smith BE, Low PA, Service FJ, axonal swelling and paranodal demyelination, followed Rizza RA, Zimmerman BR (1991) The Rochester Diabetic Neu- ropathy Study: Design, Criteria for Types of Neuropathy, Selec- by remyelination, axon degeneration and regeneration, tion Bias, and Reproducibility of Neuropathic Tests. Neurology and ultimately Wallerian degeneration of axons (Sima 41:799Ð807 et al. 1988). On the other hand, STZ, a nitrosourea 9. Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M (2000) Mainte- chemotherapeutic agent, also is directly neurotoxic nance of the Long-Term Effectiveness of Tramadol in Treatment Other causes of metabolic neuropathy are considerably of the Pain of Diabetic Neuropathy. J Diabetes Complications less common in Western cultures. They include neu- 14:65Ð70 ropathy associated with chronic renal failure from any 10. Kennedy WR, Wendelschafer-Crabb G, Johnson T (1996) Quan- titation of Epidermal Nerves in Diabetic Neuropathy. Neurology cause. Renal neuropathy typically presents differently 47:1042Ð1048 from DSPN, as painless ataxia, because it prefer- 11. Lauria G, McArthur JC, Hauer PE, Griffin JW, Cornblath DR entially damages the large-diameter myelinated fibers (1998) Neuropathological Alterations in Diabetic Truncal Neu- that mediate touch, vibration, and joint position sense ropathy: Evaluation by Skin Biopsy. J Neurol Neurosurg Psy- chiatry 65:762Ð766 among others. Hypothyroidism cancause a nonselective 12. Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, axonal loss that can produce pain as well as sensory loss Smoller B, Dubner R (1987) Amitriptyline Relieves Diabetic and ataxia. Testing kidney and thyroid function should Neuropathy Pain in Patients with Normal or Depressed Mood. be included in the evaluation of peripheral neuropathy. Neurology 37:589Ð596 13. Sima AA, Zhang WX, Tze WJ, Tai J, Nathaniel V (1988) Di- NeuropathicPainModel,DiabeticNeuropathyModel abetic Neuropathy in STZ-Induced Diabetic Rat and Effect of Toxic Neuropathies Allogeneic Islet Cell Transplantation. Morphometric analysis. Ulceration, Prevention by Nerve Decompression Diabetes 37:1129Ð1136 14. Singleton JR, Smith AG, Bromberg MB (2001) Painful Sensory References Polyneuropathy Associated with Impaired Glucose Tolerance. Muscle Nerve 24:1225Ð1228 1. Ahlgren SC, Levine JD (1993) Mechanical Hyperalgesia in 15. The Diabetes Control and Complications Trial Research Group Streptozotocin-Diabetic Rats. Neuroscience 52:1049Ð1055 (1993) The Effect of Intensive Treatment of Diabetes on Diabetic Neuropathy, Treatment 583

the Development and Progression of Long-Term Complica- Treatment of DSPN tions in Insulin-Dependent Diabetes Mellitus. N Engl J Med 329:977Ð986 The treatmentcan be divided intotreatmentoftheunder- lying disease, treatment of neuropathic pain, protection from painless injuries, and currently topical unproved therapies. Diabetic Neuropathy, Treatment

1 2 Treatment of the Underlying Disease D ANNE KJ¯RSVIK BERTELSEN ,JOHN W. GRIFFIN 1Department of Neurology, Haukeland University The unequivocal message of large-scale, prospective, Hospital, Bergen, Norway controlled studies is that tight glycemic control im- 2Department of Neurology and Departments of proves the prognosis for neuropathy (DCCT Research Neuroscience and Pathology, Johns Hopkins University Group 1988). A decade ago this was a controversial School of Medicine, The Johns Hopkins Hospital, point, and it is of fundamental significance in planning Baltimore, MD, USA diabetic care. This concept can now be extended to an [email protected], jgriffi@jhmi.edu important group of individuals with impaired glucose tolerance but without frank diabetes. Such individu- Synonyms als, identified by glucose tolerance tests (GTT), are at substantial risk to progress to diabetes within a few Symmetric diabetic neuropathy; diabetic polyneuropa- years (Tuomilehto et al.2001). Prospective studies have thy shown that progression to diabetes can be deferred or prevented by weight loss and exercise. This issue is Definition relevant to neuropathy, because it has recently been Focal or generalized damage to the peripheral nerves is proved that a subgroup of individuals with impaired common with diabetes mellitus type I or II. GTT develop painful neuropathies before frank diabetes (Singleton et al. 2001; Sumner et al. 2003), and Characteristics because there is evidence of peripheral nerve damage Most patients with diabetic neuropathy have the type in others who are asymptomatic (Smith et al. 2001). designated diabetic sensory polyneuropathy (DSPN), and this section focuses on this form, emphasizing the Treatment of Neuropathic Pain aspects relevant to pain. The manifestations can include Education regarding the physiologic basis and meaning neuropathicpain, hypalgesia with lossof protective of neuropathic pain is an essential first step; to the ex- sensibility and a predilection for painless injuries, and tent patients understand that the pain sensation does not autonomic dysfunction (Dyck and Dyck 1999). The au- reflect ongoing damage to the feet or the tissues, they tonomic manifestationscan include cardiovascular(loss are better able to objectify the pain. Taking advantage of of heart period variability, loss of Valsalva response, their observations about factors that exacerbate or im- orthostatic hypotension), genitourinary (impotence, prove pain is useful. For example, if they have cold al- retrograde ejaculation, incontinence), gastrointestinal lodynia they may prefer to keep the feet warm. In con- (constipation, diarrhea, fecal incontinence), and sudo- trast, many individuals are more comfortable with the motor (loss of sweating) abnormalities. The hypalgesia feet cool, and prefer to sleep without covers over the is typically greatest in the feet, and can contribute to the feet. Similarly, if there is mechanical hyperalgesia the development of skin ulcers, painless fractures and joint bed sheets are often painful at night; use of a foot cradle damage (Charcot feet), and ultimately amputations. can eliminate that pain. Neuropathic pain is prevalent in diabetics, reaching Drug treatments are adjuncts in management and are 16.9% of the diabetic population in a recent study, and detailed below. The available agents include anticon- is underreported to physicians (Daousi et al. 2004). vulsants (gabapentin, pregabalin and newer analogues), Spontaneous pain can occur even in individuals with antidepressants including SNRI, tricyclic, and proba- profound hypalgesia. The pain is usually greatest in bly SSRI representatives (Sindrup and Jensen 2000; the toes and feet. With progression it moves into the Sindrup et al. 2003), some non-opiate analgesics such fingers and can involve a “shield” over the sternum and as tramadol, and if needed, opiates. There are special parasternal areas, representing the most distal regions considerations in choice of agents in diabetics. Due to of innervation of the intercostals nerves. Patients use the frequent association with atherosclerotic cardiovas- many descriptors for their pain, including “burning” cular disease and autonomic insufficiency, tricyclics “squeezing” and “throbbing” The particular adjective require special caution. Also, due to gastrointestinal that they use does not have clinical or prognostic cor- motility disturbances, the opiates, and even tramadol, relates. Sudden stabbing lightning pains are frequent. may cause severe constipation. Some data supports The clinical manifestations conform to those described the use of α-lipoic acid, an antioxidant (Ametov et al. in small fiber polyneuropathies. 2003), and adverse reactions have not been recognized. 584 Diabetic Neuropathy, Treatment

Antiepileptic Drugs tidepressants in that they selectively block serotonin Gabapentin has been demonstrated in two large clini- reuptake. In clinical trials, SSRIs have shown to reduce cal trials to result in significant pain relief in patients the pain of diabetic neuropathy better than placebo, but with painful DSPN (Backonja et al. 1998; Morello et not as effectively as tricyclic antidepressants. al. 1999). Compared with amitriptyline, gabapentin has been shown to have equal efficacy; however, the Topical Analgetics side-effect profile of gabapentin has been shown to be Lidocaine is an amide-type local anesthetic that stabi- more favorable, although dizziness and sedation are lizesneuralmembranesbymodulatingvoltage-sensitive frequently reported (Dallocchio et al. 2000). The doses sodium channels. It is the most frequently used local should therefore be titrated slowly to the maximum anesthetic in the treatment of neuropathic pain, and has dose. It is recommended to start at 300 mg/d on day 1, been shown to produce moderate reduction in pain in increasing by 300 mg every day in three days to achieve patients with diabetic neuropathy. a dose of 900 mg/d by day 3. Then further dose increases Capsaicin cream, (Zostrix) the active component in hot by 300 mg/day up to 1800 mg/d by day 14. Once this chili peppers, applied topically four to five times per day dose level is achieved, gabapentin can be titrated up for 4 weeks is effective in treating painful diabetic pe- to 3600 mg/d as required over the following weeks to ripheral neuropathy. However, initial burning of the skin achieve a maximal response with good tolerability or upon application is an unpleasant side effect that leads until intolerable side effects occur. to treatment discontinuation among more than 30% of Pregabalin is a follow-up drug to gabapentin, which also patients. Capsaicin is thought to affect pain transmis- binds to the alpha2delta subunit of voltage-dependent sion by depleting the neural stores of substance P, a calcium channels, but has a more linear bioavailability pain-modulating substance, in epidermal nerve fibers than gabapentin. Lower doses are therefore needed than and temporary decrease in numbers of epidermal nerve for gabapentin, and the efficacy is more predictable. fibers in treated regions. The capsaicin cream contains The therapeutic dose range for pregabalin is between 0.025% to 0.075% capsaicin and should be applied 150Ð600 mg/d divided into two or three doses. to intact skin only. Patients should wash their hands Oxcarbamazepine may be effective in treating painful thoroughly after applying capsaicin cream in order to DSPN. Data from an open-label prospective study indi- prevent inadvertent contact with other areas. cate that oxcarbazepine (mean effective dose 814 mg/d, range 150Ð1200 mg/d) may significantly improve pain Opioid Analgesics and Opioid-Like Drugs scores in patients with painful diabetic peripheral neuropathy. Although opioids are considered a last resort for chronic Lamotrigine, a phenyltriazine derivate, inhibits the neuropathic pain control, limited data suggest efficacy release of glutamate, possibly by stabilizing the neural and tolerability of oxycodone and other opioids for membrane through blocking activation of voltage- painful diabetic peripheral neuropathy. Tramadol, a dependent sodium channels, and thus suppressing centrally acting analgesic chemically unrelated to the μ abnormal ectopic discharges. To avoid side effects such opiates, has a low binding affinity at -opioid receptors as skin-rash the doses should be titrated slowly to the and weak inhibition of norepinephrine and serotonin re- therapeutic dose. It is recommended to start at 25 mg/d uptake. However, its precise mechanism is not known, on day 1, increasing the dose by 25 mg every 14 days since the analgesic effect is only partially antagonized until a dose of 400Ð600 mg/d divided on two doses has by the opioid antagonist naloxone. Tramadol causes been achieved. significantly less respiratory depression than morphine and, in contrast to morphine, does not stimulate the Antidepressant Drugs release of histamine. Tramadol does produce μ-opioid Tricyclic antidepressants, like amitriptyline, doxepin type dependence like codeine or dextropropoxyphene; and desipramine, are strong sodium channel modula- however, there appears to be little potential for tolerance tors in addition to their well-known effect on reuptake developmentor abuse. Tramadol is thus a useful drug in of serotonin and noradrenaline. The sodium channel- the treatment of painful diabetic peripheral neuropathy, blocking effect is presumed to be the pain-relieving and in particular effective to treat the nociceptive com- mechanism of these drugs in cases of painful diabetic ponent of axonal pain such as that caused by ischemia. neuropathy. The cumulative efficacy reported from Its use is however limited in elderly patients or those trials with subjects with diabetic neuropathy, suggests with impaired hepatic and renal function, and it should that about one third of patients will achieve a 50 percent be used with caution by patients taking other psychoac- reduction in neuropathic pain; however, the benefits are tive drugs. The dose of tramadol should be in the range often outweighed by side effects, especially among the of between 200Ð400 mg/d. As pain treatment in dia- elderly. betic neuropathy is a long-term undertaking, beginning Selective Serotonin-Reuptake Inhibitors (SSRIs), like with monotherapy and evaluating progress with a daily paroxitine and citalopram, differ from tricyclic an- visual analog scale log can simplify decisions. Diabetic Polyneuropathy 585

Protection from Painless Injuries References The problem of insensitive or anesthetic feet requires 1. Ametov AS, Barinov A, Dyck PJ et al. (2003) The Sen- the individual to be constantly vigilant so that injuries sory Symptoms of Diabetic Polyneuropathy are Improved with Alpha-Lipoic Acid: The SYDNEY Trial. Diabetes Care to the feet can be prevented. It is particularly important 26:770Ð776 to recognize early foot injuries and to treat all injuries 2. Aszmann O, Tassler PL, Dellon AL (2004) Changing the Natural promptly. Among the indications of failed foot care are History of Diabetic Neuropathy: Incidence of Ulcer/Amputation ulcers in the skin and bony sequelae (Charcot joints) that in the Contralateral Limb of Patients with a Unilateral Nerve D Decompression Procedure. Ann Plast Surg 53:517Ð522 result from unfelt injuries. In severe cases, amputation 3. Daousi C, MacFarlane IA, Woodward A et al. (2004) Chronic of digits, the foot, or even the lower leg may eventu- Painful Peripheral Neuropathy in an Urban Community: A Con- ally be required. Repeated tiny injuries to the skin and trolled Comparison of People With and Without Diabetes. Diabet bones of the feet, caused by loss of pain sensibility and Med 21:976Ð982 4. DCCT Research Group (1988) Factors in Development of Dia- lossof position sense, can be overcome by continualvig- betic Neuropathy: Baseline Analysis of Neuropathy in Feasibil- ilance. Warning signs of danger are localized redness ity Phase of Diabetes Control and Complications Trial (DCCT). (erythema) or blisters on the feet, breaks in the skin, or Diabetes 37:476Ð481 5. Dyck PJB, Dyck PJ (1999) Diabetic Polyneuropathy. In: Dyck PJ, hot points over the skin. The keystone is regular careful Thomas PK (eds) Diabetic Neuropathy. WB Saunders Company, examination of the feet. Philadelphia, pp 255Ð278 Shoes that fit well are essential. Callouses are a sign of 6. Lee CH, Dellon AL (2004) Prognostic Ability of Tinel Sign in longstandingexcessivepressureontheskinandthussig- Determining Outcome for Decompression Surgery in Diabetic and Nondiabetic Neuropathy. Ann Plast Surg 53:523Ð527 nal badly fitting shoes. Callouses are usually found on 7. Sindrup SH, Bach FW, Madsen C et al. (2003) Venlafaxine ver- the balls of the feet, the sides of the feet, or the tops of sus Imipramine in Painful Polyneuropathy: A Randomized, Con- the toes. A persistent or growing callous needs to be ex- trolled Trial. Neurology 60:1284Ð1289 amined and treated by a medical professional. 8. Sindrup SH, Jensen TS (2000) Pharmacologic Treatment of Pain in Polyneuropathy. Neurology 55:915Ð920 Individuals with insensitive feet should not walk bare- 9. Singleton JR, Smith AG, Bromberg MB (2001) Painful Sensory footed, as minor inadvertent injuries can cause major Polyneuropathy Associated with Impaired Glucose Tolerance. long-term problems. The feet should be bathed in luke- Muscle Nerve 24:1225Ð1228 warm water, and the water temperature should be tested 10. Smith AG, Ramachandran P, Tripp S et al. (2001) Epidermal Nerve Innervation in Impaired Glucose Tolerance and Diabetes- with a sensitive part of the body (the elbow or upper arm Associated Neuropathy. Neurology 57:1701Ð1704 if the hands or wrists are insensitive). For some patients, 11. Sumner CJ, Sheth S, Griffin JW et al. (2003) The Spectrum of heat feels good on the feet, but under no circumstances Neuropathy in Diabetes and Impaired Glucose Tolerance. Neu- rology 60:108Ð111 should a heating pad or hot water bottle be used, because 12. Tuomilehto J, Lindstrom J, Eriksson JG et al. (2001) Prevention of the potential for painless thermal injury. Insensitive of Type 2 Diabetes Mellitus by Changes in Lifestyle among fingers can be burned painlessly by smoking or during Subjects with Impaired Glucose Tolerance. N Engl J Med cooking. Gas ranges are preferable to electric ranges be- 344:1343Ð1350 13. Backonja M, Beydoun A, Edwards KR et al. (1998) Gabapentin cause it is apparent when they are “on”. for the Symptomatic Treatment of Painful Neuropathy in Patients with Diabetes Mellitus: A Randomized Controlled Trial. JAMA 280:1831Ð1836 Unproved Therapies 14. Dallocchio C, Buffa C, Mazzarello P et al. (2000) Gabapentin vs. Patients can find a variety of devices that are advocated Amitriptyline in Painful Diabetic Neuropathy: An Open-Label Pilot Study. J Pain Symptom Manage 20:280Ð285 to provide relief in painful diabetic neuropathy, and the 15. Morello CM, Leckband SG, Stoner CP et al. (1999) Randomized internet provides a marketplace for such devices. Tran- Double-Blind Study Comparing the Efficacy of Gabapentin with scutaneous nerve stimulators are widely used and it is Amitriptyline on Diabetic Peripheral Neuropathy Pain. Arch In- reasonable to view their efficacy in terms of their effec- tern Med 159:1931Ð1937 tiveness in other pain disorders. At present, no device specifically claimed to improve nerve function has been proved to be of value. Such claims have been made for a variety of bracelets, electrical devices, etc. Another unproved therapy is surgical release of putative nerve Diabetic Polyneuropathy entrapments. Claims have been made that surgical release of multiple nerves in the legs and arms relieves pain and improves the neuropathicprognosis, including Definition preventing ulcers, even in individuals in whom the only Diabetic polyneuropathyrefers to pathological changes evidence of possible entrapment is a Tinel’s sign to per- to nerve function due to diabetes mellitus. This usually cussion over possible entrapment sites (Aszmann et al. manifests as loss of sensation and burning pain, s. also 2004; Lee and Dellon 2004). Diabetics are at increased Diabetic Neuropathy. risk for nerve entrapments. In individuals with physio- Diabetic Neuropathies logic and clinical evidence of entrapment, surgical cor- Diabetic Neuropathy, Treatment rection should be considered. Opioids in Geriatric Application 586 Diagnosis

Characteristics Diagnosis Clinical Characteristics There is no major distinction between pain following a Definition central or a peripheral nervous lesion. Chronic neuro- The term Ð diagnosis, is derived from the Greek words: pathic pain in general may be stimulus-independent δια (dia) meaning between, and γνoσι (gnosis) mean- (spontaneous) or stimulus-dependent (evoked). The ingknowing.WhenusedasaverbÐtodiagnose,itmeans spontaneous pain may be ongoing and / or paroxysmal. to determine which of two or more possible causes of The quality of the pain may be described in many terms, a complaint is actually the cause, e.g. “the doctor will such as burning, pricking, stinging, aching, lancinating, diagnose the cause of your chest pain”. When used as throbbing, pressing (or a large variety of other adjec- an abstract noun, diagnosis means the act or process of tives) and many patients will experience two to four determining the cause, e.g. “the patient was admitted to pain qualities. There is no single pain descriptor that hospital for diagnosis of her chest pain”. When used as a characterizes the qualities of central pain. The onset of common noun, diagnosismeanswhatisfound asaresult pain may be immediate or with a delay. Post-stroke pain of that process, and is a generic term for the name of the was found to be delayed for at least 1 month in 37% condition that is the cause of the complaint, e.g. “on the of the patients (Andersen et al. 1995). Similar results basis of the test results, the doctor provided a diagnosis have been reported by Leijon et al. (1989). Of a total of the patient’s chest pain”. of 591 patients with pain and or dysesthesia following Classically, diagnosis requires establishing the pathol- SCI, the onset of pain was within the first year in 58% ogy that is responsible for a patient’s symptoms, on the of the cases and pain was immediate from the moment grounds that if the pathology is found, it can be recti- of injury in 34% of the cases (Störmer et al. 1997). The fied, and the patient’s symptoms thereby relieved. In location of pain will depend upon which parts of the Pain Medicine, this may not always be possible. Some central nervous system are injured, but some general sources of pain cannot be detected using currently distinctions between pain of different etiologies exist. available techniques of investigation. One example is post-stroke pain, where 75% of the In that event, physicians are nevertheless able to formu- patients will suffer from a hemipain, situated con- late an assessment of the patient and their problems. tralateral to the lesion, while hemipain seldom occurs The assessment is not the same as a diagnosis, foracause in MS (Boivie 2003). Ninety percent of MS patients of the pain is not established. Nevertheless, the assess- will suffer from pain in the lower extremities and 36% ment may provide a sufficient basis for instituting treat- in the upper extremities (Boivie 2003). Neuropathic mentthatmayhelpthepatienttoreduceoreliminatetheir pain following SCI may occur in segments above, at or pain and associated problems. below the level of injury and may be caused by factors Taxonomy other than the spinal cord lesion, such as compressive mononeuropathiesand nerve root compression (Siddall et al. 1997; Siddall et al. 2000). There is no correlation between the size of the lesion and the risk of developing Diagnosis and Assessment of Clinical central pain (Boivie 2003). The location of the lesion, however, plays a crucial part in the developmentof pain Characteristics of Central Pain and of special importance is whether the spinothalamic ELLEN J¯RUM tract system is involved in the lesion. The laboratory of clinical neurophysiology, Rikshospitalet University Hospital, Oslo, Norway Clinical Diagnosis of Central Pain [email protected] The diagnosis of central pain is based on a thorough clinical and neurological examination of the patient. Synonyms A thorough interview with the patient is mandatory, including detailed questions about spontaneous pain, Central Pain, Diagnosis and Assessment of Clinical both ongoing and paroxysmal as well as questions about Characteristics stimulus-evoked pain. Pain drawingsare recommended. But it is emphasized that a correct diagnosis cannot be Definition made on evaluation of pain and sensory abnormalities Central pain is defined as “pain initiated or caused alone. The investigation has to include examination of by a primary lesion or dysfunction in the central ner- the motor system, reflexes, brainstem and cerebellar vous system” (Merskey and Bogduk 1994). Some com- functions in order to be able to pinpoint the extent and mon causes of central pain are spinal cord injury (SCI), level of the central lesion. In patients with central pain, vascular brain lesions, arteriovenous malformations, sy- there will be a large variation in the presence of other ringomyelia and multiple sclerosis (MS). neurological symptoms. No major difficulty will be en- Diagnosis and Assessment of Clinical Characteristics of Central Pain 587 countered in making a diagnosis of a spinal cord injury tients with below-level pain following SCI by Beric et or a vascular brain lesion, but the complete extent of al. (1988), 10 patients had absence of sensibility to ther- neurological deficits needs to be evaluated. Typically, mal stimulation measured by QST, while the sensation central pain is characterized by sensory abnormalities, of vibration and light touch was present, but reduced. such as a possible combination of hypoesthesia and These results suggest a relative preservation of dorsal allodynia / hyperalgesia (or other combinations). column function with an abolition of spinothalamic sys- Lesions involving the spinothalamic-thalamocortical tem function. Resultsof such studiesshowhowQST can D projection system seem to be crucial for the develop- help in differentiating between sensibility changes due ment of central pain. The sensory abnormalities may to dorsal column and spinothalamic tract functions. No be evaluated by simple means, such as cotton (for the other method than QST will accurately assess an even- evaluation of light touch), pins for pinprick and pain tual allodynia and hyperalgesia to thermal stimuli, but sensation and warm and cold water for the evaluation of thermal allodynia has scarcely been reported in patients the spinothalamic tract system. One should be aware, with central pain (Boivie et al. 1989), mainly because of however, that in many cases, hypoesthesia to light touch a substantial loss of thermal sensibility in patients with maybemaskedbyaconcomitantallodyniatolighttouch central pain. Since evoked pain is an important feature and that a reduced sensitivity to painful pinprick may be in central pain, diagnostic tools should include tests of masked by a hyperalgesia to pinprick. For the detection central hyperexcitability. of sensory deficits in such cases, more sophisticated tools may be needed. The detailed sensory examination Evaluation of Allodynia and Hyperalgesia by quantitative sensory testing (QST) developed by Patients with central pain may, like all patients with Ulf Lindblom and colleagues has major advantages for neuropathic pain, complain of evoked pain, pain that is the detailed examination of sensorydeficits, but isnot, in evoked by stimulation of painful skin area. There are general, crucial for making a diagnosis of central pain. two types of allodynia / hyperalgesia to tactile stimuli, one to light touch and one to punctate stimuli (the static Quantitative Sensory Testing (QST) type). Although both are caused by central sensitization QST is used to measure the intensity of stimuli needed mechanisms, they are mediated by different peripheral to produce specific sensory perceptions. Tests are de- nerve fibers; allodynia to light touch is mediated by A veloped to determine sensory thresholds for tactile, β fibers, whereas the punctate type is mediated by A δ vibratory, pressure and temperature stimulation. All fibers. Mapping of the area may be recommended for quantitative sensory tests are psychophysical tests re- both types. Punctate hyperalgesia may be mapped by quiring awake and alert patients who fully understand the use of von Frey hairs, while dynamic allodynia is the instructions given and who are fully capable of usually mapped by lightly brushing the skin. cooperating. QST methods have been mainly used for research purposes for the classification of neuropathic Abnormal Temporal Summation pain, in studies of pathophysiological mechanisms Temporal summation of neural impulses in nociceptive and in pharmacological trials. For a purely clinical nerve fibers is a physiologically important mechanism evaluation of the individual patient, the diagnosis of that can intensify the sensation of pain. Repetitive stim- neuropathic pain may be made without using these ulation of a painful skin area in a patient suffering from time-consuming methods. The testing is restricted to a neuropathic pain may produce an intense and long- few laboratories and needs specially trained personnel. lasting pain in a phenomenon referred to as abnormal Through the use of QST, it has become evident that all temporal summation (or “wind-up-like pain"). The patients with central post-stroke pain have lesions in the abnormal temporal summation seen in patients may be spinothalamic-cortical pathways, as seen by abnormal assessed roughly by repetitive skin stimulation with sensitivity to temperature and pain (Boivie et al. 1989). the frequency of 2Ð3 Hz with a von Frey hair for up to A high proportion of these patients (80%) did not feel 20Ð30 s. If temporal summation is abnormal, the patient any temperature between 0û and 50ûC, indicating the will report a sudden intense pain in the stimulated area, severity of the sensory deficit. Many of these patients often occurring within a few seconds, with aftersensa- also had large deficits in the sensibility to touch and tion and radiation. An abnormal increase in temporal vibration, indicative of a disturbed function in the dor- summation may be regarded as a sign of central hyper- sal column-medial lemniscal pathway but, on the other excitability and can be quantified by measuring latency, hand, other patients had no sensory deficit related to duration of aftersensation and area of radiation. thesepathways.Similarresultsareobtainedfromstudies of patientswith MS, showing reduced sensibility to tem- Evidence of Central Hyperexcitability in Central Pain perature and pain, but less prominent findings compared Following SCI to patients with central post-stroke pain (Boivie 2003). In a study of 16 patients with traumatic SCI and below- In studies of central pain following spinal cord injury, level pain, somatosensory abnormalities in painful den- similar results have been obtained. In a study of 13 pa- ervated skin areas below the level of the lesion as well as 588 Diagnosis of Pain, Epidural Blocks in non-painful denervated skin areas at the level of the 7. Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A et al. lesion were compared (Eide et al. 1996). In the painful (2003) Sensory function in spinal cord injury patients with and without central pain. Brain 126:57Ð70 denervated area, a highly significant reduction in sen- 8. Garcia-LarreaL, Convers P,Magnin M et al. (2002) Laser-evoked sibility to heat and cold, indicating reduced function in potential abnormalities in central pain patients: the influence of thespinothalamictractsystemandsupportingtheresults spontaneous and provoked pain. Brain 125:2766Ð2781 of Beric et al. was found. An important observation was 9. Leijon G, Boivie J, Johansson I (1989) Central post-stroke pain Ðneurological symptoms and pain characteristics. Pain thattherewasnosignificantdifferenceinsensorythresh- 36:13Ð25 olds in the painful denervated skin areas compared with 10. Merskey H, Bogduk N (1994) Classification of chronic pain: the nonpainful denervated skin areas. Thus, in these pa- descriptions of chronic pain syndromes and definitions of pain. tients, deafferentation of spinothalamic pathways was IASP Press, Seattle 11. Siddall PJ, Taylor DA, Cousins MJ (1997) Classification of pain not a sufficient condition for the development of cen- following spinal cord injury. Spinal Cord 35:69Ð75 tral neuropathic pain. One of the main findings was the 12. Siddall PJ, Yezierski RP, Loeser JD (2000) Pain following spinal demonstration of evoked pain, both allodynia to brush cord injury: clinical features, prevalence and taxonomy. IASP andanabnormaltemporalsummationinthepainfulden- Newsletter 3:3Ð7 13. Störmer S, Gerner HJ, Grüninger W et al. (1997) Chronic ervated area alone. These data show that sensory loss pain / dysesthesia in spinal cord injury patients: results of a must be coupled with abnormal pain responsiveness to multicentre study. Spinal Cord 35:446Ð455 reach a diagnosis of central neuropathic pain (Eide et al. 1996). Similar findings have more recently been reported by others (Finnerup et al. 2003). The main finding of their study was a higher intensity of brush-evoked Diagnosis of Pain, Epidural Blocks dysesthesia and pinprick hyperalgesia at the lesion level NIKOLAI BOGDUK in SCI patients with central pain as opposed to SCI pa- University of Newcastle, Department of Clinical tients without below level pain, despite a similar degree Research, Royal Newcastle Hospital, Newcastle, of lostsomatosensory function inthetwogroups. Brush- NSW, Australia evokedpainordysesthesiahavealsobeenreportedtooc- [email protected] cur in patients with post-stroke pain (Boivie et al. 1989; Leijon et al. 1989; Andersen et al. 1995). Synonyms Supplementary Investigations Epidural Diagnostic Blocks Supplementary investigations such as CT (computer tomography), MRI (magnetic resonance imaging ) Definition and electrodiagnostic evaluations can be performed Epidural blocks are a diagnostic test, in which a local to visualize and functionally assess the central le- anaesthetic (or another drug) isinjected into the epidural sions. In clinical neurophysiology, measurement of space, in order to obtain information about a patient’s somatosensory evoked potentials to electrical stimu- pain. lation is routinely performed for investigating deficits in sensory pathways. It is important to be aware that Characteristics electrical stimuli activate the dorsal column-lemniscal Diagnostic epidural blocks should not be confused with systems and that no information is obtained from the epiduralinjectionsfortherapeuticpurposes.Classically, pain and temperature mediating spinothalamic tract epidural injections of local anaesthetic have been used system. Laser-evoked late potentials, on the other hand, to provide analgesia for childbirth and for certain opera- may evaluate function in the spinothalamic tract system, tive procedures. Epidural injections of local anaesthetic, but few results have so far been published on central morphine, clonidine, corticosteroids, and other agents, pain (Garcia-Larrea et al. 2002). have been used to provide relief of pain for a variety of conditionssuch asCRPS, cancer pain, neuropathic pain, References radicularpain,andbackpainthathasfailedtoberelieved 1. Andersen G, Vestergaard K, Ingeman-Nielsen M et al. (1995) by surgery. In these instances, epidural injections have Incidence of central post-stroke pain. Pain 61:187Ð193 2. Beric A, Dimitrijevic MR, Lindblom U (1988) Central dyses- been used to provide sustained relief of pain, as a treat- thesia syndrome in spinal cord injury patients. Pain 34:109Ð116 ment. 3. Boivie J (1989) On central pain and central pain mechanisms. When used for diagnostic purposes, epidural blocks are Pain 38:121Ð122 used to obtain information. Relief of pain may or may 4. Boivie J (2003) Central pain and the role of quantitative sensory testing (QST) in research and diagnosis. Eur J Pain 7:339Ð343 not occur, but relief of pain is not the objective; it is one 5. Boivie J, Leijon G, Johansson I (1989) Central post-stroke pain Ða of the possible results of the test. study of the mechanisms through analyses of the sensory abnor- Since they block multiple nerves, epidural blocks do malities. Pain 37:173Ð185 not provide information about the location of a patient’s 6. Eide PK, J¿rum E, Stenehjem AE (1996) Somatosensory findings in patients with spinal cord injury and central dysesthesia pain. pain. Instead, they provide information about the nature J Neurol Neurosurg Psychiatry 60:411Ð415 of the patient’s pain. Diagnosis and General Pain Management 589

tific scrutiny, they have been shown to lack any greater Diagnosis and General Pain Management degree of validity. NIKOLAI BOGDUK The next level of validity is content validity. This re- Department of Clinical Research, Royal Newcastle quires that the test be defined with strict criteria that Hospital Newcastle, University of Newcastle, mustbesatisfied beforetheresultof thetestcan becon- Newcastle, NSW, Australia sidered positive. Having content validity ensures that D [email protected] physicians use the test consistently, and do not differ from patient to patient in what they consider to constitute a positive result. In one sense, content validity Patients with pain look to physicians for treatment to serves to secure reliability in applying the test, but it stop that pain; but before treatment can be sensibly ini- also serves to ensure that the test is properly defined so tiated, the physician needs to determine what is caus- as to identify specifically the particular condition that ing the pain. The process of finding that cause is called it is supposed to detect and not some other condition. making a diagnosis and the name of the cause is also Howwellatestactuallydiscriminatesbetweenapartic- referred to as the diagnosis. ular condition and some other condition or conditions definesitsconstructvalidity.Justbecausetheresultofa Diagnosis testispositivedoesnotnecessarilymeanthatthecondi- At their disposal, physicians have a variety of tools by tion sought for is present. Other conditions might also which to pursue a diagnosis. These include taking a causetheresulttobepositive.Suchresultsarefalsepos- history (see medical history), performing a physi- itive results. Similarly, test results may be negative, but cal examination (see musculoskeletal examination). the condition is nevertheless present. Such results are Depending on the nature of the complaint, the physi- false negative. Construct validity is the measure of the cian will use these tools to various extents. However, extent to which a test is compromised by false positive for the subsequent treatment to be effective the diag- and false negative results. The greater the incidence of nosis must be correct and that requires that the tools false results, the less accurate, and less useful the test. used to make the diagnosis are both reliable and valid. The cardinal measures of the validity of a diagnostic Without these features the diagnosis that is made will test are its sensitivity, specificity, and likelihood be false. ratios. The sensitivity isthe extent to which the test cor- Reliability is the extent to which two observers, who rectly detects the presence of a condition. The speci- usethesametestonthesamegroupofpatients,agreeon ficity is the extent to which the test correctly detects the results of the test. If the agreement is high, when the the absence of the condition. The likelihood ratios in- test is positive, it is highly likely that the patient truly dicate the extent to which a positive result is likely to has the abnormality that has been detected. However, be true positive and to which a negative result is likely if the agreement is low, neither observer, nor the pa- to be true negative. tient, can be certain whether or not the patient has the One of the means by which the reliability and valid- abnormality. ity of diagnosis in pain medicine is enhanced is by the Validity is the measure of the extent to which a test use of taxonomies. A taxonomy is a catalogue that lists actually detects the presence and absence of the con- the conditions that can be a cause of pain and which dition that it is designed to detect. Whereas reliability stipulates for each condition the criteria that must be measures the ability of observers to perform the test satisfied before the condition can be diagnosed. If the correctly, validity measures the intrinsic ability of the criteriaaresatisfiedtheconditioncanbelegitimatelybe test to detect what it is supposed to detect, when it is diagnosed. If the criteria are not satisfied, the condition performed correctly. cannot be diagnosed as the cause of pain, irrespective Various sub-types of validity can apply. The most ele- of the intuition or conviction of the physician that it is mentary is concept validity, which is no more than the cause. Taxonomies serve to prevent physicians ar- a statement of the purported, theoretical basis for the bitrarily and incorrectly making diagnoses that may be test. A test is considered to have concept validity if, wrong. in principle, it sounds as if it should work. All tests in The International Association for the Study of Pain pain medicine have concept validity. They do sound as (IASP) has produced a taxonomy that lists the possible if they should work; but having only concept validity causes of chronic pain (Merskey and Bogduk 1994). does not guarantee, in a scientific sense, that the test The IASP taxonomy catalogues these conditions in does indeed work. Unfortunately, too many tests that terms of the region of the body affected by the pain, have been used in pain medicine are based solely on the anatomical location of its source (if known), and conceptvalidity. They have notbeenshown tohave any its pathology (if known). A similar taxonomy has been greater degree of validity or when subjected to scien- developedforheadache,bytheInternationalHeadache 590 Diagnosis and General Pain Management

Society (IHS) (1988). The IHS taxonomy lists the • Relieving Factors criteria that must be satisfied before particular types • Associated Features of headache can be diagnosed. The American Psychi- By taking a comprehensive history,a physician will of- atric Association has produced the fourth edition of ten be able to establish the nature of the pain and at least its taxonomy for psychiatric disorders, known as the its possible causes. Most forms of headache can be Diagnostic and Statistical Manual of Mental Disor- diagnosed from the history alone. ders ( DSM-IV) (American Psychiatric Association Physical examination complements the history. By ex- 1994). For certain conditions that may be associated amining the patient, the physician looks for abnor- with pain, the DSM-IV prescribesthe criteria that must malities of structure or function that can be detected be satisfied before a patient can be considered to have by inspection, palpation, movement or the applica- a condition in which pain is due to or associated with tion of simple tools at the bedside, such as a stetho- a significant psychological disorder. scope or a patellar hammer and other neurological Despite the availability of taxonomies to assist diag- instruments. The examination can address particular nosis, it is often not possible to make a distinct, patho- body parts or body systems. A neurological exam- anatomicorevenpsychologicaldiagnosisofapatient’s ination (see Diagnosis of Pain, Neurological Ex- pain. In such cases, the physician can formulate an amination) tests the integrity of the nervous system. assessment, instead of a diagnosis. The assessment A musculoskeletal examination tests the status and typically describes the location and nature of the pa- functionofthemuscles,bonesandjoints.Otherpartsof tient’s pain, the associated psychological distress that the body can be examined according to the complaint the patient expresses and the disabilities that both of with which the patient presents. These might include these features seem to produce. Such a formulation al- an examination of the ear, nose and throator themouth, lows the physician to treat various components of the teeth and jaws or the chest, abdomen, pelvis or per- patient’s problems when they do not have access to the ineum. root cause of the pain. Diagnosis and assessment dif- However,whereasphysicalexaminationhasbeenatra- fer only with respect to the end point that is achieved. ditional component of medical diagnosis, its reliability Theformerdefinesthecauseofthesymptoms;thelatter and validity is variable. Most reliable and valid is neu- carefully defines the symptoms when the cause cannot rological examination. Any two observers will usually be found. Both processes rely on the same tools. agree reasonably well on whether a patient has numb- The pain history is a catalogue of all the features of ness or weakness; and the presence of such features ac- the pain that a patient can describe. The catalogue is curately indicates particular causes. The same does not produced by the patient responding to enquiries from apply to musculoskeletal examination. Research stud- thephysicianintopossiblefeaturesthatmayormaynot ieshaveshownthatobservershavedifficultiesagreeing be present. A comprehensive pain history is obtained on the extent to which the patient has tenderness, stiff- by enquiry into a set of prescribed domains (see be- ness, spasm or impaired movement.Furthermore, even low). These domains are based on traditional wisdom iftheobserverscanagreeonthepresenceofsuchabnor- expressed by experts experienced in assessing patients malities, data are missing as to what these abnormali- with pain. Not all domains of enquiry will necessarily tiesactuallyimplyaboutthepossiblecauseofpain.The be relevant or fruitful in every patient, but the set of reliability and validity of other forms of examination domains covers all possibilities. Following the set en- are not known, in the context of pain. sures that the physician does not neglect or forget do- Because of these limitations, physical examination has mains that may be relevant. The domains of enquiry limited utility in allowing a patho-anatomic diagnosis for a comprehensive pain history are: to be made. Nevertheless, it does serve as a screening • Length of illness test to exclude obvious and major abnormalities; and • Aetiology it serves for descriptive purposes to define the nature • Site and extentof the physicalabnormalitiesthatthe patient • Extent or Spread exhibits. In conjunction with the history, the results of • Intensity the physical examination may serve to indicate what • Quality investigations may or may not be required. • Frequency Having obtained a history and having performed a • Duration physical examination, a physician should be able • Time of Onset to establish, in broad terms, the nature of the pa- • Mode of Onset tient’s pain. The major types of pain are neuropathic • Precipitating Factors pain, central pain, radicular pain, neuralgia, • Aggravating Factors somatic pain and Visceral Nociception and Pain. Diagnosis and General Pain Management 591

Somatic pain and visceral pain may be associated with carpal tunnel syndrome, the utility of electrophysio- referred pain. Because the latter can be mistaken for logical testing has been questioned because of the very radicular pain, recognition of its features is important. high false positive rate (Hadler 1997; Atroshi et al. Failure to distinguish the two conditions will lead to 1999). inappropriate investigations and possibly inappropri- Similarly, thermography has been advocated as a ate treatment. Recognition of these broad categories of test for pain due to radiculopathy and to assess sym- pain is not tantamount to having made a diagnosis. In- pathetic function in Complex Regional Pain Syn- D vestigations may be required to establish the cause or dromes, General Aspects. For radiculopathy, however, source of pain or to define more precisely its mecha- thermography is essentially superfluous or redundant nisms. because the diagnosis can be made clinically and be- The investigations used in the assessment of patients cause other tests such as MRI establish the actual with pain include, but are not necessarily limited to, cause of the problem. Thermographymay corroborate blood tests, electrophysiological tests and medical a diagnosis of complex regional pain syndrome but the imaging. These tests, however, typically do not detect operational criteria for this condition do not require the pain but are designed to detect conditions that may thermography. be responsible for the pain. Their use is, therefore, in- The mainstay of diagnosis in pain medicine is med- dicated not by the presence of pain, but by features ob- ical imaging. This may involve plain radiography, tained by the history or examination that suggest the i.e. X-rays, CT scanning, ultrasound, magnetic possibility of a particular cause. resonance imaging,i.e.MRI, bone scan or single Blood tests can be diagnostic for conditions such as photon emission tomography,i.e. SPECT. Because acute intermittent porphyria and systemic infection. of its limited sensitivity and specificity for disorders The erythrocyte sedimentation rate is an important and other than fractures, plain radiography is not suitable inexpensive screening test for conditionssuchasinfec- either as a diagnostic tool or a screening toolin patients tion and cancer. A raised sedimentation rate calls for with pain. It neither detects nor excludes serious dis- furtherinvestigationofapossibleseriouscauseofpain. orders that are not otherwise manifest. Meanwhile, tu- A normal sedimentation rate is essentially reassuring mours and infections are demonstrated with far greater insofarasfurtherpursuitofseriousconditionsisnotin- sensitivity and specificity by other tests, such as MRI. dicated unless and until other clinical features sugges- For conditions such as rheumatoid arthritis, plain ra- tiveofapossibleseriousillnessaremanifest.Inpatients diography can demonstrate the state of a joint, but is with features of a visceral disorder, specific blood tests not one of the diagnostic criteria for this condition. In may be obtained, such as serum amylase for suspected patients with suspected osteoarthritis, features seen on pancreatitisand prostate specific antigen levelsforsus- plain radiography are barely more than coincidentally pected prostatic cancer. Serum calcium levels and al- associated with pain. The indications for plain radiog- kaline phosphatase levels can be tested in patients with raphy are features possibly suggestive of fracture, viz. suspected osseousmetastasesor hyperparathyroidism. major trauma or minor trauma in elderly patients with Catecholamine levels will be diagnostic of headache osteoporosis, in patients on corticosteroids or with a caused by phaeochromocytoma. Serological tests can risk factor for pathological fracture. It is also an appro- be used to confirm rheumatoid arthritis and related in- priate screening test for patients suspected of having flammatory disorders. Serological tests are appropri- Paget’s disease. ate in patients with spinal pain in whom myeloma is a CT scanning is not an appropriate screening test for pa- possibility. tients with pain. It is indicated only if clinical features, In some circles, electromyography,i.e.EMGandre- or other tests, implicate a serious disorder. In that con- lated electrophysiological tests such as conduction text, CT is used to define better a lesion that has already velocities are used in the assessment of patients with been detected. Ultrasound can be used to demonstrate pain. Despite this practice however, the evidence chal- lesions in soft tissues. It is strongly diagnostic of vis- lenges and even refutes their utility. Electrophysiolog- ceral disorders that cause cystic lesions or abnormal- ical tests do not detect pain. They only show abnormalities in hollow organs. For musculoskeletal disorders, ities in motor fibres and large diameter sensory fibres. its utility is questionable. Although it can show lesions Suchabnormalitiescorrelatepoorlywithpain.System- such as tears in tendons, there is no evidence that these atic reviews and consensus statements have found no lesions are indeed the cause of the patient’s pain. justification for electrophysiological tests for radicu- Ofallmedicalimagingtests,MRIhasthehighestsensi- lar pain that is otherwise clinically apparent (Anders- tivity and highest specificity. It can detect lesions such son et al. 1996; Dvorak 1996, 1998). Only rarely might as tumours, infections and osteonecrosis, early in their they be justified if the clinical features suggest periph- evolution, and can allowthese lesionsto be specifically eral neuropathy rather than radicular pain. Even for identified. No other imaging test has these properties. 592 Diagnosis and General Pain Management

It defines soft tissue lesions as clearly as, or better than, nervous system that is responsible for the pain. Local ultrasound. However, specific lesions are uncommon anaesthetic agents and other drugs can be infused into in patients with pain. The utility of MRI is not so much the epidural or intrathecal space, as a diagnostic test. to bediagnostic, butto detector excludeoccultor cryp- Epidural Diagnostic Blocks can be used when the tic lesions that do not manifest distinctive clinical fea- actual source of pain is not evident. Relief of pain im- tures. Bone scan does not demonstrate specific lesions. plies that the source lies somewhere in the periphery It shows only hyperaemia when this is a response to and that the pain is not central pain. Conversely, failure a lesion such as a stress, a fracture, an infection or a to relieve pain with an epidural block indicates that the tumour. Although classically used to detect such le- source is not peripheral and strongly implicates some sions, bone scan is largely being replaced by MRI be- form of central cause. cause of its greater specificity in diagnosing these dis- For thediagnosisof spinalpain, diagnosticblockshave orders. been refined to target particular and often small struc- SPECT scanning combines the virtues of bone scan- tures. They are performed under fluoroscopic control ning and CT. Its utility in pain medicine has not inordertodelivertinyamountsoflocalanaestheticinto been established. For classical disorders of the mus- small joints of the spine or onto small nerves that inner- culoskeletal system it does not reveal anything that vate these joints. These procedures include cervical is not otherwise evident on MRI. SPECT is used by medial branch blocks for the investigations of neck some physicians to corroborate a diagnosis of com- pain, lumbar medial branch blocks and sacroiliac plex regional pain syndrome, but it lacks sensitivity joint blocks for the investigation of low back pain, and specificity in this regard. Moreover, the diagnosis Spinal Nerve Block for the investigation of lumbar can be made clinically without recourse to tests such radicular pain, thoracic medial branch blocks and as SPECT. intra-articular blocks for the investigation of thoracic Morethananyotherbranchofmedicine,painmedicine spinal pain, and thoracic spinal nerve blocks for the in- is characterised by the use of diagnostic blocks.In- vestigation of thoracic radicular pain. jections of local anaesthetics or other agents can be Analogous procedures do not involve the injection of used to determine either the mechanism of pain or its local anaesthetic agents to relieve pain, but instead source. In patients with neuropathic pain, diagnostic involve the injection of contrast medium to provoke blockscanbeusedtodeterminewhetherornotapartic- the target structure with the objective of determining ular nerve is involved in mediating the patient’s symp- whether or not the patient’s accustomed pain is repro- toms. In patients with somatic pain, diagnostic blocks duced or not. The singular examples of this form of test can be used to locate the structure from which the pain are cervicaldiscographyand lumbardiscography. seems to arise. In patients with complex regional pain An important requirement for any invasive test, be it syndromes, diagnosticblockscan beused todetermine a diagnostic block or a provocation test, is that the if the pain is sympathetically maintained. test must be controlled. Without some form of con- Diagnostic blocks can be performed by injecting small trol observation, a positive response to the test is not amounts of local anaesthetic onto peripheral nerves, compelling. A patient may report relief of pain for in order to block conduction along that nerve. Re- reasons other than the action of the local anaesthetic lief of pain constitutes prima facie evidence that the injected. Such responses are known as placebo re- nerve is responsible for mediating the pain, and that sponses. Similarly, a patient may report provocation of the source of pain lies somewhere in the territory sup- their pain, not because the target structure is the source plied by the nerve. Diagnostic blockscanbe performed of their pain but because anything or everything in the as intravenous infusions. If a particular region of the targetregionhurts.Suchfalsepositiveresponsesrender body is infused with a local anaesthetic, relief of pain the diagnosis incorrect. Performing control tests mili- implies that the source of pain or its mechanism lies tates against false positive responses and incorrect di- in the region infused. If a particular region is infused agnosis. with a drug other than a local anaesthetic agent, relief For diagnostic blocks, control tests can be performed of pain implies a mechanism for pain that involves a using an inert agent or an active agent with a differ- processthatisblocked by theagentused. Inthatregard, ent duration of action. If an inert agent is used, the pa- sympathoplegicagentsmaybeinfusedtodetermineifa tient should report no relief of pain. If an alternative patient’s pain involves activity of the sympathetic ner- agent is used, the patient should report relief that lasts vous system. for the expected duration of action of the agent used. Local anaesthetic agents may also be infused system- For provocation tests, structures other to the target one ically. Systemic infusions are used to test if the pa- shouldalsobetested.Thetargetstructurecanbeheldto tient has central pain. It is believed that systemic in- be symptomatic only if stimulating adjacent structures fusions suppress spontaneous activity in the central does not reproduce the pain. Diagnosis of Pain, Epidural Blocks 593

Treatment transcutaneous electrical nerve stimulation.Apart Having made a diagnosis or having formulated an as- from formal psychological interventions, the patient sessment of the patient’s pain, a physician can imple- may be treated holistically with assurance and activa- menttreatmentforit.Thistreatmentmaybehighlyspe- tion, coupled with patient education. cific,ifthecauseofpainisknownandcanberesolvedor Specific entities may be treated with conventional removed. The treatment may be target specific but not or traditional neurosurgical procedures that include D curative, if the pain from a particular structure can be destructive and augmentative therapies. Certain stopped, but without resolving or removing its cause. forms of pain can be relieved by techniques using Or the treatment may be palliative, in that the pain can radiofrequency neurotomy. These include: trigem- be reduced, while the cause of pain takes its natural inal neurotomy, lumbar medial branch neurotomy, course. In addition, other dimensions of the patient’s cervical medial branch neurotomy, dorsal root gan- problem can be managed, without focusing or while glion lesioning and sacroiliac neurotomy. focusing on their pain. Their distress can be managed Critical to the selection of any intervention from this using psychological interventions. Their disability can armamentarium is whether or not the treatment works be managed using rehabilitation techniques. and if it has any attributable effect beyond that of For the relief of pain, physicians have at their disposal placebo. For this reason, physicians should be aware of a wide variety of tools, from which they can select of the data concerning the efficacy and effectiveness ones that are appropriate for the patient’s condition. of any procedure that they select and its effect size, These include pharmacotherapy,inwhichthephysi- or number needed to treat (NNT). Not all the treat- cian may use analgesics, compound analgesics, ments available to physicians work as well as their nonsteroidal anti-inflammatory drugs (NSAIDS), reputations pretend. Systematic reviews have brought opioids, tricyclic antidepressants or muscle re- into question many hallowed interventions. Increas- laxants as systemic agents to relieve pain irrespective ingly,throughpublicationsandtheInternet,consumers of its cause or source. They may use topical NSAIDS, are becoming aware of these data, allowing them to topical local anaesthetics or topical capsaicin (see demand access to treatments that have been shown Topical Drug Therapy) to relieve pain in particu- to work and to question those treatments that do lar regions. Agents known as nutraceuticals,which not. are naturally occurring substances that can be used as drugs, are increasingly available. They are used to References treat pain from joints. These include glucosamine, 1. American Psychiatric Association (2000) DSM-IV-TR. Diag- chondroitin,and avocado-soya bean unsaponifi- nostic and Statistical Manual of Mental Disorders, 4th edn. Text ables. There is emerging evidence that certain vita- Revision, Washington DC mins are effective for joint pain. There is evidence that 2. Andersson GBJ, Brown MD, Dvorak J et al. (1996) Consen- sus summary on the diagnosis and treatment of lumbar disc bisphosphonatesmayrelievecomplexregionalpain. herniation. Spine 21:75Ð78 For focal sources of pain, injection therapy may be 3. Dvorak J (1996) Neurophysiologic tests in diagnosis of nerve indicated. Tender areas in muscles might be treated root compression caused by disc herniation. Spine 21:39Ð44 with local anaesthetic injections, steroid injections, 4. Dvorak J (1998) Epidemiology, physical examination and neu- rodiagnostics. Spine 23:2663Ð2673 botulinum toxin,or prolotherapy. Radicular pain 5. Hadler NM (1997) Carpal tunnel syndrome diagnostic conun- may be treated with epidural steroids,or lumbar drum. J Rheumatol 24:417Ð418 transforaminal steroids or cervical transforaminal 6. Headache Classification Committee of the International steroids. Jointpain can be treated with intra-articular Headache Society (1988) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial steroids or hyaluronan. pain. Cephalalgia 8:1Ð96 Regional pain problems might be treated with ex- 7. Merskey H, Bogduk N (eds) (1994) Classification of Chronic ercises, traction, manipulation, passive mobiliza- Pain. Descriptions of Chronic Pain Syndromes and Definition tion, massage, various physiotherapy modalities, such of Pain Terms, 2nd edn. IASP Press, Seattle 8. Atroshi I, Gummeson C, Johnsson R, Ornstein E, Ranstam J, as Shortwave Diathermy, therapeutic ultrasound, Rosen I (1999) Prevalence of carpal tunnel syndrome in a gen- or interferential therapy or with acupuncture or eral population. JAMA 282:153-158

Technique tube isused to administer any of a selection of agents. A needle is inserted into the epidural space, usually at a A typical regimen requires the serial administration of mid-lumbar or low-lumbar level, using an interlaminar normal saline, fentanyl, naloxone, and local anaesthetic. approach. Through the needle, a plastic tube is threaded After each drug is administered the patient reports the into the epiduralspace, and the needle iswithdrawn. The intensity of their pain. 594 Diagnosis of Pain, Neurological Examination

Application 2. Sorensen J, Kalman S, Tropp H et al. (1996) Can a Pharmaco- logical Pain Analysis be Used in the Assessment of Chronic Low Epidural blocks can be used to determine the nature of Back Pain? Eur Spine J 5: 236Ð242 a patient’s pain, if this cannot be determined from the medicalhistoryorothertests.Inparticular,theycanbe usedtodistinguishnociceptivepain(i.e. somaticpain) form neuropathic pain or central pain. Epidural in- Diagnosis of Pain, Neurological jection of a local anaesthetic should relieve nociceptive Examination pain, but will have a variable effect on neuropathicpain, NIKOLAI BOGDUK and no effect on central pain. University of Newcastle, Department of Clinical If a patient genuinely has nociceptive pain, they would Research, Royal Newcastle Hospital, Newcastle, obtain no relief on each occasion that normal saline is NSW, Australia administered. Fentanyl should relieve their pain, but [email protected] naloxone will subsequently reverse that effect. Finally, local anaesthetic will relieve their pain. Thus, if a patient Definition exhibits this pattern of response, under controlled conditions, the interpretation is that they have a peripheral Neurological examination is a process in which the source for their pain. physician assesses the integrity of the nervous sys- If they do not obtain relief, some other explanation is tem by testing at the bedside, using hands and simple required. It may be that they have neuropathic pain, or instruments, but not involving special devices. central pain. That diagnosis might be pursued using Characteristics intravenous infusions. If the patient has inconsistent or paradoxical responses, Principles such as relief after normal saline, or relief after nalox- Neurological examination involves testing the function onebutnotafterfentanyl,theresponsesuggeststhatpsy- of either individual nerves, or of large parts or entire di- chologicalfactors,ratherthannociceptiveprocesses,are visions of the nervous system, such as the spinal cord, or the major determinantsofthepatient’scomplaint. Inthat thesympatheticnervoussystem.Abnormalityisdeemed event, treatment can be focused on behavioural factors. to be present if the normal function that is expected is Utility absent or reduced. Disorders of sensory fibres in peripheral nerves, or of Diagnostic epidural blocks appear attractive in princi- sensory tracts in the spinal cord, are indicated by loss ple, as a means to not just distinguish between central of sensation from skin, muscles, bones or joints. Disor- and nociceptive pain, but also to distinguish patients in ders of motor nerves or of motor tracts are indicated by whom nociception or psychological factors are the prin- paralysis or weakness of movements. Disorders of the cipal determinantsof their presentation. Evidencein this sympathetic nervous system are indicated by changes in regard, however, is meagre. The application of epidural temperature of the skin, discoloration, swelling, sweat- blocks has been described only in case series that illus- ing, and by trophic changes in skin, muscles and joints. trate their application. In certain neurological disorders, amplified or altered Theoriginalseriesdescribedseveralpatientswhohadin- sensations can occur, when normal functions are disin- consistent or paradoxical responses (Cherry et al 1985). hibited by injury to nearby or overlapping nerves. Hy- These patients responded to behavioural therapy. Other peraesthesia is a sensation of exaggerated touch. Hyper- patients had a clearly nociceptive response, but a cause algesia isan increased sensation of pain. Allodynia isthe for their pain was not evident on first assessment. The perception of pain in response to a stimulus that would response to the epidural block prompted further inves- normally produce a sensation of touch or brush. tigation. In one patient, a previously unrecognized neoplasm was detected. Other patients responded well to Practice spinal cord stimulation. Sensory function is tested by determining if the patient The second series reported how 40 patients with back can feelselected stimuli, such astouch, brush, pin-prick, pain could be classified into those who had a nocicep- cold,orheat,whenappliedtoselectedareasofskin.Posi- tive response; those who had neuropathic pain; and oth- tion sensation is tested by asking if the patient can detect ers who were non-responders (Sorensen et al 1996). The movements passively applied to selected joints. Other authorsarguedthatestablishingthesedistinctionsserves sensory functionscan be testedby elicitingreflexesfrom to channel patients appropriately into pharmacological, tendons, muscles, the skin, or from the cornea. behavioural, or surgical treatment regimens. Motor function is tested by having the patient execute References movements, with and without resistance, to determine how strongly they can activate the muscles responsible 1. Cherry DA, Gourlay GK, McLachlan M et al. (1985) Diagnostic Epidural Opioid Blockade and Chronic Pain: Preliminary Report. for that movement. Motor function can also be tested Pain 21: 143Ð152 indirectly by eliciting reflexes to selected muscles. Diagnostic and Statistical Manual of Mental Disorders 595

Function of sympathetic nerves are tested indirectly, by disorder that, on the one hand causes pain, and on the examining for features of increased or decreased func- other hand causes the neurological features. tion in the form of temperature changes, discoloration, Some intrinsically painful neurological disorders lack swelling in the skin, wasting of muscles, or stiffening any features detectable by neurological examination. of joints. For more direct testing of the sympathetic Such disorders include migraine and trigeminal nervous system, laboratory tests are required, in which neuralgia. Other intrinsically painful neurological dis- the responses of tissues are measured when sympathetic orders are consistently associated with signs of reduced D nerves are artificially stimulated or anaesthetised. or exaggerated function. These include post-herpetic Parasympathetic nerves are difficult to test directly, neuralgia, peripheral neuropathies, syringomyelia, and but disturbed function of parasympathetic nerves is some spinal cord tumours. inferred when features of that disturbance are evident. Some painful disorders do not arise in the nervous Typically, this occurs in the form of facial flushing or system, but affect nearby nerves secondarily, usually salivation in the case of cranial parasympathetic nerves, by pressing on them. Such disorders include tumours, or bladder and ejaculatory dysfunction in the case of cysts, and infections of the vertebral column, and inter- pelvic parasympathetic nerves. vertebral disc herniations. In such cases, neurological examination does not establish the cause of pain, but Interpretation does point to its location. By combining and correlating all the abnormalities de- When peripheral nerves have been injured, injury is the tected in a neurological examination, a physician will obviouscauseof abnormalities. In such cases, neurolog- usuallybeabletodeterminewhereinthenervoussystem ical examination is not required to establish the cause, an injury or disorder is located. When a peripheral nerve but it serves to establish the nature and extent of altered is affected, the abnormalities will all fall in the distribu- functions. tion of that nerve. When the disorder affects the spinal Neurological examination is also used to determine the cord, the abnormalities will be distributed across greater accuracyofdiagnosticblocksthatmightbeperformedin or lesser regions of the body, according to which parts thecourseofmanagingapainfuldisorder.Whensomatic of the spinal cord are affected. nerves are blocked, finding numbness in the appropriate Reliability territory indicates that the block has been delivered correctly to the target nerve. Similarly, when sympathetic Since it is a long-established, traditional part of medical nerves are blocked, finding increased temperature or a practice, neurological examination at large has been as- Horner’s syndrome, indicates that the target nerve has sumed to be reliable. Consequently, it has not often been been successfully blocked. subject to formal study. When studied, however, it has typically been found to be reasonably reliable (Viikari- References Juntura 1987; Waddell et al 1982; McCombe et al 1989; 1. McCombe PF, Fairbank JCT, Cockersole BC et al. (1989) Repro- Nelson et al 1979). ducibility of Physical Signs in Low-Back Pain. Spine 14:908Ð918 Validity 2. Nelson MA, Allen P, Clamp SE et al. (1979) Reliability and Reproducibility of Clinical Findings in Low-Back Pain. Spine Neurological examination serves well to establish the 4:97Ð101 location of a neurological disorder. In that regard, it 3. Viikari-Juntura E (1987) Interexaminer Reliability of Obser- vations in Physical Examinations of the Neck. Phys Ther 67: is considered to be valid. However, neurological ex- 1526Ð1532 amination does not usually establish the cause of the 4. Waddell G, Main CJ, Morris EW et al. (1982) Normality abnormality. It is not designed to do so. If an injury and Reliability in the Clinical Assessment of Backache. BMJ has occurred, that should be evident from the patient’s 284:1519Ð1523 history (see medical history). Otherwise, the actual cause typically requires special investigations, such as electrodiagnostic testing or medical imaging. Diagnostic and Statistical Manual of Relevance to Pain Medicine Mental Disorders Only a minority of patients with pain has a neurological NIKOLAI BOGDUK disorder or a neurological cause for their pain. Conse- University of Newcastle, Department of Clinical quently, neurological examination is not relevant for Research, Royal Newcastle Hospital, Newcastle, most patients with pain, other than perhaps to establish NSW, Australia that there is no abnormal neurological function and, [email protected] therefore, no neurological disorder. Neurologicalexaminationisspecificallyindicatedwhen Synonyms patients report neurological symptoms in association with their pain. They may have a neurological disorder DSM, DSM-IV,DSM-IVR;DSM-IV;DSM-IVR;Men- that is responsible for their pain, or they may have a tal Disorders, Diagnostics and Statistics 596 Diagnostic and Statistical Manual of Mental Disorders

Definition Hypochondriasis The DSM is a taxonomy and schedule designed to se- Thediagnosticcriteriaforhypochondriasisstipulatethat cure the accurate and reliable use of diagnostic terms for the patient has a preoccupation with fears of having a se- mental disorders. rious disease. Although patients with chronic pain may DevelopedbytheAmericanPsychiatricAssociation,the appear preoccupied with their pain, to the extent of seek- manual has appeared in several editions, the latest being relief, this differs from having a preoccupation with ing the fourth (DSM-IV) (American Psychiatric Asso- a fear of having pain, or fear of a serious disorder. ciation 1994), and a revised (DSM-IV-TR) (American Somatisation Disorder Psychiatric Association 2000) edition. When an organic explanation cannot be found for a pa- Characteristics tient’s pain, physicians are often attracted to attributing the pain to a psychological origin. Somatisation Disor- The DSM consists of two principal parts. A general sec- der is one of the available rubrics that they might invoke. tion outlines how the assessment and description of pa- The diagnostic criteria for this condition, however, stip- tientswithmentaldisordersshouldbeconductedaccord- ulatethatthepatientmusthavepaininatleastfourdiffer- ing to five axes. These are: Clinical Disorders, Personal- ent sites, as well as two gastrointestinal symptoms, one ity Disorders, General Medical Conditions, Psychoso- sexualsymptom,andonepseudoneurologicalsymptom, cial and Environmental Problems, and Global Assess- the latter not limited to pain. Furthermore,the symptoms ment of Functioning. The remainder of the manual sys- are not intentional. These criteria specify a complex dis- tematically lists and numbers all psychiatric disorders; order,thatsomepatientswithchronicpainmayhave;but provides descriptions of each; and specifies criteria that by definition, the criteria do not apply to patients with must be satisfied before a particular diagnosis can be ac- pain in a single region, such as back pain, abdominal corded. It is this latter section that potentially pertains pain, or neck pain. to pain. Undifferentiated Somatoform Disorder Relevance to Pain The diagnostic criteria for this disorder are more lib- Paincanbeafeatureofcertainpsychiatricorbehavioural eral than those for Somatisation Disorder, and some disorders. The DSM indicates under which conditions a physicians may be attracted to attributing undiagnosed psychiatric diagnosis might be applied to a patient with chronic pain to this disorder. The notes for this disorder, pain. The Handbook of Differential Diagnosis (First et however, specify fatigue, loss of appetite, gastroin- al. 2002), which accompanies the Manual, recommends testinal, or urinary symptoms. Pain is conspicuously the algorithm depicted in Fig. 1 for classifying patients not mentioned, which suggests that this rubric was not with pain. designed to accommodate patients with pain for which Thealgorithmprimarilyinvitesthedecisionthatthepain there is no explanation. is no more than a symptom of a medical condition, and requiresnopsychiatricdiagnosis.Forapsychiatricdiag- Factitious Disorder nosis to apply, the DSM prescribes explicit criteria that This condition is characterized by the intentional pro- must be satisfied. duction or feigning of physical or psychological signs or symptoms in order to assume a sick role, but where Other Mental Disorder external incentives for the behaviour are absent. A fur- The critical criterion for determining a mental disorder ther qualification is that individuals with factitious dis- is that pain is not the focus of attention. By definition, order present their history with dramatic flair, but are such patients, who present with features of the mental extremely vague and inconsistent when questioned in disorder, may admit pain as a symptom, but it is neither greater detail. their primary concern nor the cardinal cause of disabil- Pain may be the symptom produced, and distinction be- ity. Most patients with chronic pain would not qualify tween a genuine and fabricated complaint may be dif- for this diagnosis, as pain is their primary complaint and ficult. Lack of external incentives distinguishes Facti- primary concern. tious Disorder from Malingering; and a patient who is consistent and lacks dramatic flair when describing their Conversion Disorder symptoms is unlikely to qualify as having a factitious Patients with pain are sometimes, if not commonly, re- disorder. garded as having a conversion disorder. The essence of For a physician to apply a diagnosis of Factitious Dis- this diagnosis, however, is that the patient has a loss of order they would need to be certain that the patient is motor or sensory function, such as paralysis, blindness, intentionally complaining of a false symptom. This con- or numbness. The notes and diagnostic criteria for this viction should be based on objective evidence. It should rubric specifically preclude its use if pain is the sole not be a reflection of the physician’s lack of knowledge symptom. about unusual or unfamiliar pain problems. Diagnostic and Statistical Manual of Mental Disorders 597

Diagnostic and Statistical Manual of Mental Disorders, Figure 1 Decision tree for the psychiatric diagnosis of pain.

Malingering incriminating. The criterion for medicolegal context Malingering is not a formal psychiatric diagnosis, and pertains to overt, and deliberate compensation-seeking the DSM does not provide diagnostic criteria for it. It behaviour. It does not apply to injured patients cov- states only that Malingering should be strongly sus- ered by workers compensation who cannot avoid a pected if any combination is noted of medicolegal con- medicolegal context. Some causes of pain may lack text of presentation, marked discrepancy between the objective findings. In other instances, physical findings person’s claimed distress or disability and the objective on musculoskeletal examination lack reliability and findings, lack of cooperation during the diagnostic eval- validity. Therefore, physicians will naturally fail to uation and in complying with the prescribed treatment find a correlation between findings ands symptoms. regimen, and the presence of Antisocial Personality They should not misrepresent this natural feature of the Disorder. disorder as malingering. For many patients with chronic pain, some of these fea- A systematic review found little scientific evidence tures must be carefully interpreted lest they be unjustly to justify malingering as a diagnosis in patients with 598 Diagnostic Block chronic pain (Fishbain et al. 1999; Osterwels 1987). Ex- The pivotal weakness of the DSM is that ‘judgment’ is pert opinion considers it to be a rare condition (Fishbain required to determine whether or not psychological facet al. 1999; Osterwels 1987). tors are associated with the disorder. This is a vexatious issue, and may be more a measure of the physician’s per- Adjustment Disorder sonal beliefs than a diagnosis of the patient. The essential feature for this diagnosis is a psychologi- References cal response to an identifiable stressor that results in the development of clinically significant emotional or be- 1. American Psychiatric Association (1994) DSM-IV. Diagnostic th havioural symptoms. Examples of stressors include ter- and Statistical Manual of Mental Disorders, 4 edn. Washington DC mination of a relationship, business difficulties, living 2. American Psychiatric Association (2000) DSM-IV-TR. Diagnos- in a crime-ridden neighbourhood, and natural disasters. tic and Statistical Manual of Mental Disorders, 4th edn, Text Although pain is listed as a symptom by the Handbook, Revision. Washington DC it is conspicuously not mentioned by theManual. Rather 3. First MB, Frances A, Pincus HA (2002) DSM-IV-TR Hand- the Manual emphasizes behavioural symptoms such as book of Differential Diagnosis. American Psychiatric Associ- ation, Washington DC anxiety and depression. 4. Fishbain DA, Cutler R, Rosomoff HL et al. (1999) Chronic Pain The use of this rubric may not be valid if the physician Disability Exaggeration/Malingering and Submaximal Effort attributespaintoastressorbecausesuperficiallyitiscon- Research. Clin J Pain 5:244Ð274 5. Osterwels R, Kleinman A, Mechanic D (1987) Institute of venienttodoso,insteadofpursuingadiagnosisinamore Medicine Committee on Pain, Disability, and Chronic Illness rigorous manner. Behavior: Pain and Disability, Clinical Behavioral and Public Policy Perspectives. National Academy Press, Washington DC, Pain Disorder p 171 The DSM provides an entry that explicitly accommo- dates patients with chronic pain. It provides three subtypes: Diagnostic Block • Pain Disorder Associated with PsychologicalFactors • Pain Disorder Associated with Both Psychological Definition Factors and a General Medical Condition Relief of pain with local anesthetic injection. • Pain Disorder Associated with a General Medical Chronic Low Back Pain, Definitions and Diagnosis Condition Pain Treatment, Spinal Nerve Blocks For the first two subtypes, the critical criterion is that Peripheral Nerve Blocks “psychological factors are judged to have an important role in the onset, severity, exacerbation, or maintenance of the pain”. What the DSM does not provide are guide- Diaphragmatic Breathing lines by which this judgment is to be made. Therefore, the judgment becomes a matter of the physician’s opinion. For these rubrics to apply, psychological factors Definition must overtly be responsible for the onset, severity, A type of relaxation training in which the individual is exacerbation, or maintenance of the pain. This is not taught to monitor his or her respiration and to take deep the same as finding that patients have psychological breaths using the muscles of the diaphragm. This tech- features that are secondary to the persistence of pain. nique is associated with increased oxygen perfusion and The third subtype is not specified as a mental disorder. reduction in muscle tension. Having pain, for which psychological factors are judged Coping and Pain not to be important, is no more than a medical condition. Psychological Treatment in Acute Pain Unless there is explicit evidence to the contrary, most Relaxation in the Treatment of Pain patients with chronic pain should fall into this category. It is this category that would accommodate patients with psychological features that are caused by the pain, not vice-versa. Diaries

Utility Definition The cardinal utility of the DSM is that it stipulates rig- Diaries are self-report devices that involve the collec- orous criteria that must be satisfied before a psychiatric tionofinformationaboutvariablesovertimecapture(i.e. diagnosis can be applied to a patient with pain. Unless when it occurs, such as a rating of pain at a specific pre- those criteria are expressly satisfied, a psychiatric diag- designated interval, or whenever medication is taken), nosis cannot be justified. or gathering of information in relatively close proximity Diathesis-Stress Model of Chronic Pain 599 to an event of interest, rather than relying on retrospec- Characteristics tive reporting of an extended time period such as weeks or months (e.g. pain over the past month). Several authors (e.g. Feuerstein et al. 1987; Flor et al. Multiaxial Assessment of Pain 1990; Flor and Turk 2006; Traue 1989) have formulated biobehavioral conceptualizations of chronic pain states that incorporate a multifactorial dynamic view of chronic pain with a mutual interrelationship of phys- D Diathermy iological and psychological factors and the change in these interrelationships over time. The diathesis-stress Definition model views pain as a response with physiological, Literally ãheating through“. Originally the term was behavioral and subjective components, that may or may used to describe the deep heating effects of ultrasound, not have an underlying organic-pathological basis in shortwaves and microwaves. This usage remains cor- the sense of a structural change, but that will always rect, but the word is now often broadened to include the have physiological antecedents and consequences. putative non-thermal effects of these agents as well. That is, behavior is also physiological and physiologi- Therapeutic Heat, Microwaves and Cold cal processes have behavioral expressions. Thus, these three interrelated levels are incorporated in one model. The physiological level is comprised of ascending and descending neuronal connections, supraspinal and cor- Diathesis tical mechanisms, as well as biochemical processes on all levels. The verbal-subjective modality consists of thoughts, feelings and images. The behavioral-motor Definition level takes into consideration pain behaviors ranging Underlying constitutional factors, which are the biolog- from medication intake to grimacing, limping and use ical and psychological make-up of the individual. of the health care system. Interactions between the Pain as a Cause of Psychiatric Illness levels are continuous Ðlearning occurs in physiological mechanisms and physiological mechanisms are modified by behavioral and subjective changes. Thus, pain behaviors may be motivated by physiological, cognitive Diathesis Stress and behavioral antecedents and consequences, all of which need to be considered in the analysis of pain. Definition This view is consistent with the IASP definition that, to reiterate, views pain as an “unpleasant sensory and Diathesis stress is an understanding of the relationship emotional experience associated with actual or potential between a stressor and an individual’s response. tissue damage, or described in terms of such damage” Psychiatric Aspects of Pain and Dentistry (Merskey 1986, p 217) but in addition, emphasizes cognitive and learning parameters as integral to the experience of pain as a dynamic process. Diathesis-Stress Model of Chronic Pain Although everyoneexperiences acute pain, only a small percentage of people develop chronic pain syndromes. HERTA FLOR These preconditions include predisposing factors, pre- Department of Clinical and Cognitive Neuroscience cipitating stimuli, precipitating responses and maintain- at the University of Heidelberg, Central Institute of ing factors (Fig. 1). Mental Health, Mannheim, Germany The existence of a physiological predisposition or fl[email protected] diathesis involving a specific body system is the first component of the diathesis stress model. This predis- Synonyms position consists of a reduced threshold for nociceptive activation that may be related to genetic variables, pre- Biobehavioral Model; Multidimensional Model; Psy- vious trauma, or social learning experiences and results chobiological Model; biopsychosocial model in a physiological response stereotypy of the specific body system. The existence of persistent aversive exter- Definition nal or internal stimuli (pain-related or other stressors) The diathesis-stress model views pain as a result of the with negative meaning activate the sympathetic nervous interaction of predisposing and stress-related factors system and muscular processes (e.g. various aversive and assumes that social, psychological and physiolog- emotional stimuli such as familial conflicts or pres- ical factors are equally important in the understanding sures related to employment) as unconditioned and of chronic pain states. conditioned stimuli and motivate avoidance responses. 600 Diathesis-Stress Model of Chronic Pain

Diathesis-Stress Model of Chronic Pain, Figure 1 A diathesis-stress model delineating the main factors contributing to the development and maintenance of chronic pain.

Aversive stimuli may be characterized by “exces- for the site of pain and manifest themselves in an en- sive” intensity, duration, or frequency of an external larged representation of the pain-affected body part in or internal stimulus. “Inadequate” or “maladaptive” central structures. This type of implicit pain memory behavioral, cognitive or physiological repertoires of is outside the patient’s conscious awareness, but will the individual to reduce the impact of these aversive lead to enhanced responsivity to stimuli that originate environmental or internal stimuli are among the pre- in the affected body region. It has also been shown that cipitating responses. Operant and respondent learning the explicit recall of a pain-related episode leads to the of behavioral, verbal-subjective and physiological pain activation of a large cortical network subserving pain as responses may maintain the pain experiences. shown by the enhanced dimensional complexity of the An important role is played by the cognitive process- EEG in chronic pain patients. Thus learnt pain mem- ing of external or internal stimuli related to the experi- ories (i.e. psychological processes) directly influence ence of stress and pain, for example, increased percep- the physiological processing of pain (cf. Flor 2000; tion, preoccupation and over-interpretation of physical Sandkühler 2000). symptoms or inadequate perception of internal stimuli In short, a diathesis-stress model places greatest empha- such as muscle tension levels. Moreover, the nature of sis on the role of learning factors in the onset, exacer- the coping response Ð active avoidance, passive toler- bation and maintenance of pain for those patients with ance or depressive withdrawal Ð may determine the type persistentpain problems. Itwassuggestedthatarangeof of problem that develops as well as the course of the ill- factors predispose individuals to develop chronic or re- ness. Subsequentmaladaptivephysiologicalresponding current acute pain, however, the predisposition is neces- suchasincreasedandpersistentsympatheticarousaland sary but not sufficient. In addition to anticipation, avoid- increased and persistent muscular reactivity as well as ance and contingencies of reinforcement, cognitive fac- sensitization of central structures including the cortex tors, in particular expectations, are also of centralimpor- may induce or exacerbate pain episodes. Thus, learning tance in a diathesis-stress model of chronic pain. Condi- processes in the form of respondent conditioning of fear tioned reactions are viewed as self-activated on the basis of activity (including social, motor and cognitive activ- of learned expectations as well as automatically evoked. ities), social learning and operant learning of pain be- The critical factor of this model, therefore, is not that haviors Ð but also operant conditioning of pain-related eventsoccurtogetherintime,butthatpeoplelearntopre- covert and physiological responses as described above Ð dict them and to summon appropriate reactions (Turk et make a contribution to the chronicity of pain. al.1983).Itistheindividualpatient’sprocessingofinfor- It is important to note that these learning processes lead mation that resultsin anticipatory anxiety and avoidance to both implicit and explicit memories for pain that behaviors. subsequently guide the patient’s behavior and deter- The primary focus of a diathesis-stress model is thus mine his or her pain perception. For example, it has on the patient, rather than symptoms and pathophysiol- been shown that chronic pain leads to the formation ogy. In this model, we emphasize the patient’s explicit of somatosensory pain memories that are specific thoughts and feelings in addition to implicit condi- Diencephalic Mast Cells 601 tioning factors, as these will all influence behavior. amnesia, anxiolysis and (central) muscle relaxation and From this perspective, assessment and treatment of the acts as an anticonvulsant. patient with persistent pain requires a broader strategy GABA and Glycine in Spinal Nociceptive Processing than those based on the previous dichotomous models described, that examines and addresses the entire range of psychosocial and behavioral factors, in addition to biomedical ones. D Thediathesis-stressperspectiveonpainmanagementfo- Dictionary of Occupational Titles cuses on providing the patient with techniques to gain a senseofcontrolovertheeffectsofpainonhisorherlifeas Synonyms wellasactuallymodifyingtheaffective,behavioral,cog- nitiveandsensoryfacetsoftheexperience(TurkandFlor DOT 2006). Behavioralexperienceshelpto showpatientsthat they are capable of more than they assumed, increasing Definition their sense of personal competence. Cognitive techniques help to place affective, behavioral, cognitive and The U.S. Department of Labor provides definitions of sensory responses under the patient’s control. Our as- contents and demands (qualitative and quantitative) sumption is that long-term maintenance of behavioral of occupations in order properly to match jobs and changes will occur only if the patient has learned to at- workers. These definitions are identified by electronic tribute success to his or her own efforts. There are sug- sources from the Occupational Information Network at gestions that these treatments can result in changes of (http://www.oalj.dol.gov/publicgov/public/dot/refrne/ beliefs about pain, coping style and reported pain sever- how2find.htm), or in Jist’s Enhanced Dictionary of Oc- ity,aswellasdirectbehaviorchanges.Further,treatment cupational Titles S 2000. The dictionary is organized that results in increases in perceived control over pain under the headings: and decreased catastrophizing are also associated with Nine-digit Occupational Code identifying: (a) a particu- decreases in pain severity ratings and functional disabil- lar occupational group; (b) worker functions concerning ity. data, people and things, and (c) differences between occupations. References Occupational title Industry designation 1. Feuerstein M, Papciak AS, Hoon PE (1987) Biobehavioral mechanisms of chronic low back pain. Clin Psychol Rev 7:243Ð273 The body of the occupational definition state 2. Flor H (2000) The functional organization of the brain in pain. Worker actions, their purpose, machines, tools, equip- Prog Brain Res 129:313Ð322 ment, or work aids used by the worker, material used, 3. Flor H, Turk D C (in press) A biobehavioral perspective of chronic productsmade,subjectmatterdealtwith,orservicesren- pain and its management. APA Press, Washington DC 4. Flor H, Birbaumer N, Turk DC (1990) The psychobiology of dered, instructions followed or judgments made. chronic pain. Advances in Behaviour Res Ther 12:47Ð84 The definition trailer presents worker traits, i.e. selected 5. Merskey H (1986) Classification of chronic pain: Descriptions occupational characteristics on a General Educational of chronic pain syndromes and definitions of pain terms. Pain 1:225 DevelopmentScale,whereasReasoning,Mathematical, 6. Sandkühler J (2000) Learning and memory in pain pathways. and Language Development Scales and the Specific Vo- Pain 88:113Ð118 cational Preparation Scale determine the requirements 7. TraueHC(1989)Gefühlsausdruck, HemmungenundMuskelspan- of a specific occupation. nung unter sozialem Stress: Verhaltensmedizin myogener Kopfschmerzen [Emotional expression, inhibition, and muscle Vocational Counselling tension during social stress: Social-psychophysiological studies of myogenic headache]. Hogrefe, Göttingen 8. Turk DC, Flor H (2006) Cognitive-behavioral approach to pain management. In McMahon S, Koltzenburg M (eds) Wall and Melzack’s textbook of pain, 5th edn. Elsevier, London, pp 241Ð258 Diencephalic Mast Cells 9. Turk DC, Meichenbaum DH, Genes M (1983) Pain and behavioral medicine: A cognitive-behavioral approach. Guilford, New DANIEL MENÉTREY York CNRS, Université René Descartes, Biomédicale, Paris, France [email protected] Diazepam Definition Definition Paracrine immune cells as part of the neuroimmune Diazepam is a classical benzodiazepine facilitating the axis making a contribution to developing, mature and effect of GABA at GABAA receptors. Itcausessedation, degenerating nervous system. 602 Diencephalic Nociceptive Neurons in the Human

Characteristics cells. Mast cells release histamine by degranulation and may account for up to 50% of this mediator in the adult Mast cells are immune system elements, mostly found rat brain (Sugimoto et al. 1995). Unlike dura mater cells, at host-environment interfaces such as skin, gastroin- diencephalic mast cells store serotonin and heparin in testinal and respiratory tracts. They are known to derive different granules. Intravascular serotoninergic cells from the bone marrow and enter the tissues as im- having mast cell features but lacking heparin also exist mature or precursor cells which then mature under (Menétrey and Dubayle 2003). microenvironmental conditions (Metcalfe 1997). Mast Diencephalic mast cell functions still remain to be de- cells are routinely identified by their proteoglycan termined. It has been hypothesized that they could play contents, mostly heparin and chondroitin sulfate. Two a role in maintaining the normal physiology of vessel main types of cells have been recognized, connec- walls or local hemodynamics by regulating the opening tive and mucosal cells, which can be distinguished by of the blood-brain barrier (Zhuang et al. 1996; Esposito their proteolytic enzyme contents, proteases I and II, et al. 2001). A detoxifying action has also been envis- respectively. Several lines of evidence indicate that aged since excessive numbers are often associated with the functions of mast cells are linked to their capacity infectious or degenerative processes. Their preferential to respond to a broad array of mediators (neuropep- functionalrelationshipswith astrocytesand their abil- tides, chemokines,...) and their ability to synthesize and ity to provide delivery of neuromodulatorsto specific re- release potent bioactive and vasoactive molecules (his- gions of the brain suggest neural-endocrineinteractions tamine, heparin, cytokines, nerve growth factor, nitric at central level and the existence of a neuroimmune axis oxide, serotonin, ...(Gordon 1990)). In addition to its an- based on the cross-talk between mast cells, astrocytes ticoagulant properties, heparin is related to regulation of and neurons (Purcell and Atterwill 1995). angiogenesis, suppression of delayed hypersensitivity and binding of proteins. Bioactive substances are stored References in intracellular granules and released by extrusion. Mast 1. Esposito P, Gheorghe D, Kandere K et al. (2001) Acute stress cell activation may correspond to either intragranular increases permeability of the blood-brain-barrier through acti- changes accompanied with differential release of me- vation of brain mast cells. Brain Res 888:117Ð127 diators or massive granule compound exocytosis 2. Gordon JR, Burd PR, Galli SJ (1990) Mast cells as a source of multifunctional cytokines. Immunol Today 11:458Ð464 (degranulation) as in anaphylactic reactions.Mast 3. Metcalfe DD, Baram D, Mekori YA (1997) Mast cells. Physiol cells have been demonstrated to be fundamental cellular Rev 77:1033Ð1079 elements in the development of allergic reactions and 4. Menétrey D, Dubayle D (2003) A one-step dual-labeling inflammation (Wasserman 1979). method for antigen detection in mast cells. Histochem Cell Biol 120:435Ð442 Mast cells also exist within the brain of several species, 5. Olsson Y (1968) Mast cells in the nervous system. Intern Rev includingmammalsandhumans(Olsson1968;Persinger Cytol 24:27Ð70 1977; Silver et al. 1996; Silverman et al, 2000). These 6. Persinger MA (1977) Mast cells in the brain: possibilities for physiological psychology. Physiol Psychol 5:166Ð176 include mast cells in dura mater, leptomeninges 7. Purcell WM, Atterwill CK (1995) Mast cells in neuroimmune and central nervous system (CNS), the last being ex- function: neurotoxicological and neuropharmacological perspec- clusively located within the diencephalon. Evidence tives. Neurochem Res 20:521Ð532 has been given that the diencephalic homing of mast 8. Silver R, Silverman A-J, Vitkovic L et al. (1996) Mast cells in the brain: evidence and functional significance. TINS 19:25Ð31 cells can be triggered behaviorally and be influenced 9. Silverman A-J, Sutherland AK, Wilhelm M et al. (2000) Mast by physiological parameters (Theoharides 1990). The cells migrate from blood to brain. J Neurosci 20:401Ð408 prevalent location of CNS mast cells within the dorsal 10. Sugimoto K, Maeyama K, Alam K et al. (1995) Brain histamin- thalamus, including nuclei with cortical projections, ergic system in mast cell-deficient (Ws/Ws) rats: histamine content, histidine decarboxylase activity, and effects of (S) alpha- and their ability to react to physiological conditions fluoromethylhistidine. J Neurochem 6:791Ð797 raise the question of a potential role in sensory integra- 11. Theoharides TC (1990) Mast cells: the immune gate to the brain. tive processes. Diencephalic mast cell numbers vary Life Sci 4:607Ð617 with age, sex and physiologicalstate, as well as with en- 12. Wasserman SI (1979) The mast cell and the inflammatory response. In: Pepys J, Edwards AM (eds), The mast cell - Its role vironmental and hormonal factors. In small mammals, in health and disease. Pitman Medical, Turnbridge Wells, pp 9Ð20 they increase in situations such as hibernation, exposure 13. Zhuang X, Silverman A-J, Silver R (1996) Brain mast cell degran- to cold or magnetic fields, fostering, parturition, estrus ulation regulates blood-brain barrier. J Neurobiol 31:393Ð403 phase, subordination stress and pharmacologicalinsult. However, they decrease during social isolation or with daily handling. Diencephalic mast cells are more numerous in females than in males and show a left-sided Diencephalic Nociceptive Neurons in the predominance, especially in females. In doves, their Human number increases in aggressively behaving males and courted females as well as with steroid treatments. In all species, younger animals have more diencephalic mast Human Thalamic Nociceptive Neurons Dietary Variables in Neuropathic Pain 603

activation of protein kinase C (PKC). These changes in Dietary Variables in Neuropathic Pain turn promote neuronal dysfunction (e.g. decreased 1 1 nerve blood flow resulting in neural hypoxia). Vegan JASENKA BORZAN ,SRINIVASA N. RAJA , 2 diet combined with exercise has been reported to effec- YORAM SHIR 1Department of Anesthesiology and Critical Care tively reduce symptoms of painful diabetic neuropathy, Medicine, Johns Hopkins University, Baltimore, MD, supposedly by helping to regulate blood viscosity and USA filterability above and beyond glycemic control (Mc- D 2Pain Centre, Department of Anesthesia, McGill Carty 2002). Dietary supplements such as evening University Health Centre, Montreal General Hospital, primrose oil, alpha-lipoic acid and capsaicin might also Montreal, QC, Canada have some role in decreasing pain symptoms in painful [email protected], [email protected], diabetic neuropathy, without directly affecting blood [email protected] glucose (Halat and Dennehy 2003). Chronic alcohol abuse may result in a peripheral neu- Definition ropathy in the lower extremities due to direct degenerative effects on both myelinated and unmyelinated nerve Foods and beverages are composed of various sub- fibers, disruption of axonal transport and enhance- stances that can be helpful or harmful to human health. ment of glutamate neurotoxicity in neurons (Koike However, data on a possible analgesic role of dietary et al. 2001). constituents in acute and chronic pain states are still Only a small number of dietary constituents have been limited. Recent in vitro and in vivo animal studies have shown to possess analgesic properties in animal models indicated that dietary amino acids, proteins and oils of neuropathic pain. Diets enriched with the amino acids can be beneficial in neuropathic conditions. Most of the tryptophan(AbbottandYoung1991)andtaurine(Belfer published human studies lack proper control groups, et al. 1998), and diets based on casein protein (Shir et al. but the results corroborate the idea that specific dietary 1997), have been shown to suppress autotomy (self choices or supplements have the potential to alleviate mutilation) levels in a rat model of deafferentation chronic neuropathic pain. These beneficial effects prob- pain, produced by total peripheral neurectomy. Trypto- ably depend on both genetic factors and the specific type phan, a precursor of serotonin, could exert its analgesic of the neuropathic condition. Conversely, carbohydrate effects by activating spinal and supraspinal serotonergic consumption among untreated diabetics or chronic al- antinociceptive mechanisms. In a placebo controlled cohol abuse can lead to painful neuropathic conditions. study, tryptophan supplements have been shown to A large number of dietary constituents have yet to be reduce neuropathic pain in humans (as discussed in explored for their potential benefits in the treatment of Abbott and Young 1991). Taurine, an inhibitory amino neuropathic pain. acid found abundantly in the CNS, is bioavailable primarily through ingestion of seafood and meat. Rats with Characteristics a genetic tendency to develop high levels of autotomy Many peptides derived from foods have been identified (HA rats) expressed reduced levels of self mutilation to have opioid-like properties, and hence have been following total hind limb denervation when consuming named exorphins (in contrast to endogenous opi- taurine enriched water, either pre- or post-nerve injury oid peptides-endorphins). As exorphins show opioid (Belfer et al. 1998). These authors argued that taurine receptor agonist or antagonist properties, they are an might protect the inhibitory neurons in the central ner- indication that diet selection is of potential importance vous system from the damaging excitotoxic barrage in neuropathic as well as other painful conditions (for that accompanies nerve injury. review of bioactive proteins and peptides including The most comprehensive evidence for the analgesic ef- exorphins, see Kitts and Weiler 2003). fect of diet in neuropathic pain models derives from the Chronic neuropathic pain conditions in humans have a studies on the effect of soy protein on the development variety of etiologies, making the association between of chronic neuropathic pain behavior in rats undergoing dietary constituents and neuropathic pain very complex. partial sciatic nerve ligation injury (PSL model) (see The majority of the clinical data available to date on the Neuropathic Pain Model, Partial Sciatic Nerve Liga- effects of dietary components on neuropathic pain exist tion Model). In these studies, tactile (Fig. 1a) and heat in diabetic patients and alcohol abusers with painful (Fig. 1b) allodynia and hyperalgesia were signifi- peripheral neuropathy. People with hyperglycemia, if cantly attenuated in rats fed soy-rich diets, compared untreated, often develop a painful neuropathic condi- to rats fed soy deficient diets (Shir et al. 1998; 2001a). tion most commonly affecting the extremities (Duby et It was further established that the analgesic effects of al. 2004). A diet high in carbohydrates can contribute soy was fairly short lasting, because discontinuation to high intracellular glucose levels that can lead to of a soy diet 15 h prior to nerve injury resulted in lack pathological changes such as vasoconstriction and en- of analgesic effects (Shir et al. 2001b). In contrast to dothelial hyperplasia, increased oxidative stress and its prophylactic effect, palliative consumption of a soy 604 Dietary Variables in Neuropathic Pain

Since highly variable levels of neuropathic pain among rats undergoing nerve injury were also attributed to genetic factors, the interaction between genetic anddietary factors was studied in PSL-injured rats. Levels of heat hyperalgesia were highly variable across eight different rat strains fed seven different diets suggesting that genetic factors may influence the effects of diet on neuropathic pain (Shir and Seltzer 2001c). Polyunsaturatedfattyacids(PUFA),mainlytheessential fatty acids linoleic acid (omega-6) and alpha-linolenic acid (omega-3), are another dietary group with biological activities that could be relevant to the suppression of chronicneuropathicpain(e.g.inhibitionofvoltagegated sodium and calcium channels; inhibition of several protein kinases) (Shapiro 2003). Perez et al. (2004) have tested the role of dietary fat and the fat/protein interactions in the development of tactile allodynia and heat hyperalgesia in PSL-injured rats. These experiments have shown that dietary fat is a significant independent predictor of levels of neuropathic pain in rats, and that this effect could be accentuated by dietary protein (Perez et al. 2004). Dietary Variables in Neuropathic Pain, Figure 1 The effect of bread It is reasonable to assume that multiple dietary con- and cucumber (BC), casein rich (CAS), or soy rich (SOY) diet on average stituents have biologically significant consequences, mechanical (a) and heat (b) paw withdrawal thresholds before and 14 days some of which are directly related to neuropathic after partial sciatic nerve ligation. Animals were fed one of the diets for 28 days (left panels: intact), or 14 days before and after the nerve injury pain suppression. However, the identification of pro- (right panels: post-PSL). After PSL injury, rats fed soy rich diet displayed analgesic nutrients has only recently started to emerge significantly less mechanical and heat allodynia than BC or CAS fed rats in preclinical and clinical research. Future investiga- (p = 0.04 and p = 0.001 for mechanical, and p = 0.0002 and p = 0.0006 tions identifying new relevant dietary constituents and for thermal responses respectively). (Modified from Shir et al. 2001a). describing their underlying mechanisms in pain processing may provide novel therapeutic strategies in the treatment of neuropathic pain. diet following injury did not attenuate neuropathic pain behavior. Soy diet can affect the consequences of References partial nerve ligation only within a few hours of the 1. Abbott FV, Young SN (1991) The Effect of Tryptophan Sup- injury. Thus, it is reasonable to assume that the chronic plementation on Autotomy Induced by Nerve Lesions in Rats. pain resulting from PSL is triggered by pathological Pharmacol Biochem Behav 40:301Ð304 processes occurring relatively shortly after the injury 2. Belfer I, Davidson E, Ratner A et al. (1998) Dietary Supple- (Shir et al. 2001b). mentation with the Inhibitory Amino Acid Taurine Suppresses Autotomy in HA rats. Neuroreport 9:3103Ð3107 What is the active antinociceptive ingredient of soy? 3. Duby JJ, Campbell RK, Setter SM et al. (2004) Diabetic Neuropa- Phytoestrogens, abundantly found in soy products, thy: An Intensive Review. Am J Health-Syst Pharm 61:160Ð176 were tested because they possess biological activities 4. Halat KM, Dennehy CE (2003) Botanicals and Dietary Supple- ments in Diabetic Peripheral Neuropathy. J Am Board Fam Pract that could be relevant to pain (e.g. alteration of steroid 16:47Ð57 hormone metabolis, inhibition of various protein-kinase 5. Kitts DD, Weiler K (2003) Bioactive Proteins and Peptides from enzymes, antioxidative properties) (Shir et al. 2002). Food Sources. Applications of Bioprocesses Used in Isolation In this study, rats were fed one of 5 diets containing and Recovery. Curr Pharm Des 9:1309Ð1323 6. Koike H, Mori K, Misu K et al. (2001) Painful Alcoholic Polyneu- different phytoestrogenlevels for 2 weeks prior to and 2 ropathy with Predominant Small-Fiber Loss and Normal Thi- weeks following PSL injury. At certain concentrations, amine Status. Neurology 56:1727Ð1732 phytoestrogens were associated with reduced neuro- 7. McCarty MF (2002) Favorable Impact of a Vegan Diet with Ex- pathic pain in rats. Average plasma concentrations of ercise on Hemorheology: Implications for Control of Diabetic Neuropathy. Med Hypotheses 58:476Ð486 phytoestrogens (approximately 400Ð900 nmol/l) were 8. Pérez J, Ware MA, Chevalier S, Gougeon R, Bennett GJ, Shir Y associated with reduced levels of tactile allodynia and (2004) Dietary fat and protein interact in suppressing neuropathic mechanical hyperalgesia, but not with reduced heat pain-related disorders following partial sciatic ligation injury in allodynia. Low and high plasma phytoestrogen levels, rats. Pain 111:297Ð305 9. Shapiro H (2003) Could n-3 Polyunsaturated Fatty Acids Reduce however, were not analgesic in these tests (Shir et al. Pathological Pain by Direct Actions on the Nervous System? 2002). Prostaglandins Leukot Essent Fatty Acids 68:219Ð224 Dimethylsulfoxide 605

10. Shir Y, Campbell JN, Raja SN et al. (2002) The Correlation be- Acupuncture Mechanisms tween Dietary Soy Phystoestrogens and Neuropathic Pain Behav- Opiates During Development ior in Rats after Partial Denervation. Anesth Analg 94:421Ð426 11. Shir Y, Ratner A, Raja SN et al. (1998) Neuropathic Pain follow- Pain Modulatory Systems, History of Discovery ing Partial Nerve Injury in Rats is Suppressed by Dietary Soy. Tourniquet Test Neurosci Lett 240:73Ð76 12. Shir Y, Ratner A, Seltzer Z (1997) Diet can Modify Autotomy Behavior in Rats following Peripheral Neurectomy. Neurosci Lett 236:71Ð74 Diffusion D 13. Shir Y, Raja SN, Weissman CS et al. (2001b) Consumption of Soy Diet before Nerve Injury Preempts the Development of Neu- ropathic Pain in Rats. Anesthesiology 95:1238Ð1244 Deﬁnition 14. Shir Y, Seltzer Z (2001c) Heat Hyperalgesia following Partial Sciatic Nerve Ligation in Rats: Interacting Nature and Nurture. The diffusion describes the effect of movement of par- NeuroReport 12:809Ð813 ticles from a region of higher concentration to a region 15. Shir Y, Sheth R, Campbell JN et al. (2001a) Soy-Containing of lower concentration. Diet Suppresses Chronic Neuropathic Sensory Disorders in Rats. NSAIDs, Pharmacokinetics Anesth Analg 92:1029Ð1034

Diffusion Tensor Imaging Differentiation Synonyms Definition DTI The process cells undergo as they mature into normal cells. Differentiated cells have distinctive characteris- Definition tics different from undifferentiated cells, perform spe- Allows the mapping of white matter tracts in vivo. cific functions and are less likely to divide than undif- Human Thalamic Response to Experimental Pain ferentiated cells. (Neuroimaging) Cell Therapy in the Treatment of Central Pain

Digital Nerve Blocks Difficulty to Disengage Definition Definition Local anesthetic blockade of the finger or toe. Difficulty in switching attention towards neutral infor- Acute Pain in Children, Post-Operative mation once a threat stimulus has been detected and is being processed. Hypervigilance and Attention to Pain Digital Radiography

Plain Radiography Diffuse Noxious Inhibitory Controls

Synonyms Dimension DNIC Definition Definition A dimension serves to define a point by its coordinates. The theoretical basis for understanding the inhibitory Multidimensional Scaling and Cluster Analysis Ap- controls activated by noxious stimuli hypothesizes that plication for Assessment of Pain noxiousstimuliactivateasurroundinhibitionthatsharp- Pain Measurement by Questionnaires, Psychophysi- ens contrast between the stimulus zone and adjacent ar- cal Procedures and Multivariate Analysis eas. This sharpened contrast would actually have a net enhancingeffectontheperceivedintensityofthepainful stimuli and an analgesic effect outside the stimulated Dimethylsulfoxide zone, i.e. inhibition within the spinal cord by noxious stimulation of one part of the body, inhibits nociception in another part of the body. This surround analgesia may Synonyms explain counterirritation and acupuncture analgesia. DMSO 606 Diohypogastric Nerve Block

Deﬁnition Disability and Health (ICF) Dimethylsulfoxide is a substance that has been used for pain treatment. It selectively sensitizes Aδ nociceptors and desensitizes C nociceptors. WHO System on Impairment and Disability Opioid Modulation of Nociceptive Afferents In Vivo

Disability and Impairment Definitions Diohypogastric Nerve Block GEROLD STUCKI,THOMAS EWERT Dioinguinal and Diohypogastric Nerve Block Department of Physical Medicine and Rehabilitation, Ludwig-Maximilians University, Munich, Germany [email protected] Dioinguinal and Diohypogastric Nerve Synonyms Block Functioning; Functional Health; Handicap Definition Definition Blockade of sensory innervation to the groin and scrotal sac on the ipsilateral side by infiltration of the abdomi- Impairment is a loss or abnormality in body structure nal wall in the region of the superior anterior iliac spine, or physiological function (including mental functions). or fanshaped injection of 3-5 ml local anesthetic just be- Here, abnormality is used strictly to refer to a significant neath the internaI oblique fascia. variation from established statistical norms (i.e. as a de- Acute Pain in Children, Post-Operative viation from a population mean within measured standard norms), and should be used only in this sense. Disability is an umbrella term for impairments, activity limitations and participation restrictions. Direct Suggestion It denotes the negative aspects of the interaction between an individual (with a health condition) and that Definition individual’s contextual factors (environmental and Direct suggestion in the context of hypnosis refers to a personal factors). Disability is characterized as the suggestion that directly indicates what experience or be- outcome or result of a complex relationship between an haviorwilloccur(e.g.“Yourhandwillfeelprogressively individual’s health condition and personal factors, and number and less painful” ) of the external factors that represent the circumstances Hypnotic Analgesia in which the individual lives. The positive expression for disability is functioning.

Characteristics Disability The current framework of disability and impairment is the WHO International Classification of Functioning, Definition Disability and Health ( ICF) (WHO 2001). Histori- According to the WHO International Classification of cally, there have been two major conceptual frameworks Impairments, Disabilities and Handicaps (ICIDH) it is in the field of disability: the International Classification defined as “any restriction or lack of ability to perform ofImpairment,DisabilityandHandicap(ICIDH),which an activity in a manor or within the range considered is the precursor to the ICF (WHO 1980), and the “func- normal for a human being”. All in all the term disabil- tional limitation”, or Nagi, framework (Nagi 1964). In ity serves as an umbrella term for impairments, activity the ICIDH, the four concepts were disease, impairment, limitationsandparticipationrestrictions.Itcantherefore disability and handicap. In the Nagi framework, the four be seen as the negative term of functioning. The inter- concepts are pathology, impairment, functional limita- action of disability and health condition works in both tion, and disability. Different from the ICIDH, the Nagi directions, because the presence of disability may even framework was not accompanied by a classification. modify the health condition. Building on the conceptual frameworks of the ICIDH Disability and Impairment Definitions and Nagi, the US Committee on a National Agenda Disability, Upper Extremity for the Prevention of Disabilities developed a model Impairment, Pain-Related emphasizing the interaction between the disabling pro- Oswestry Disability Index cess, quality of life and individual risk factors (Pope Pain as a Cause of Psychiatric Illness and Tarlov 1991). Disability and Impairment Definitions 607

The ICF,the current framework of disability, attempts to Problems an individual may experience in involvement achieve a synthesis, thereby providing a coherent view in life situations are participation restrictions. Limita- of different perspectives of health from a biological, in- tions and restrictions are assessed against a generally dividual and social perspective. It emphasizes “building accepted population standard. It records discordance blocks” to form specific models, focusing on more de- between the observed and the expected performance. tailed aspects. The ICF has addressed many of the criti- The expected performance is the population norm, cisms of prior conceptual frameworks, and has been de- which represents the experience of people without the D veloped in a worldwide comprehensive consensus pro- specific health condition (e.g. restrictions in community cess over the few last years. For all these reasons, the life, recreation and leisure, but maybe in walking too, ICF is likely to become the generally accepted concep- if walking is an aspect of participation in terms of life tual framework and classification to describe a persons’ situation). However, disability serves as an umbrella level of function and health. term for impairments, activity limitations and partic- It is important to recognize that the ICF is a common ipation restrictions. So it can be seen as the negative language (Stucki et al. 2002): The texts that can be term of functioning. The interaction of disability and created with it depend on the users, their creativity and health condition works in both directions, because their scientific orientation. The understanding of inter- the presence of disability may even modify the health actions between the components of the ICF is shown in condition. Fig. 1. A person’s functioning and disability is conceived as Health condition refers to any kind of disorder or dis- a dynamic interaction between health conditions (disease. It may include information about pathogeneses eases, disorders, injuries, traumas, etc.) and contextual and/or etiology. There are (possible) interactions with factors. Likewise, there are (possible) interactions with all components of functioning: Body functions and all components of functioning and contextual factors. structures, activity and participation. Contextualfactorsarefactorsthattogetherconstitutethe Body functions are the physiological (and psycholog- completecontextofanindividual’slife,andinparticular, ical) functions of body systems. Body structures are the backgrounds against which health states are classi- anatomicalpartsofthebody.Problemsinbothconstructs fiedinICF.Therearetwocomponents: Environmental are impairments, which are defined as a significant de- factors and personal factors. viation or loss (e.g. deformity) of structures (e.g. joints) Environmentalfactors refer to all aspects of the external and/or functions (e.g. reduced range of motion (ROM), or extrinsic world that form the context of an individ- muscle weakness, pain and fatigue). The levels of ref- ual’s life and, as such, have an impact on that person’s erence are body systems; accordingly, body structures functioning. Environmental factors include the physical are not considered as organs. world and its features, the human-made physical world, Activity is described as the execution of a task or ac- otherpeopleindifferentrelationshipsandroles,attitudes tion by an individual. It represents the individual‘s per- and values, social systems and services, and policies, spective of functioning. Difficulties an individual may rules and laws. have in executing activities are activity limitations (e.g. Personal factors are contextual factors that relate to the limitations in mobility such as walking, climbing steps, individual such as age, gender, social status, life experi- grasping or carrying). ences and so on. Risk factors could be described under Participation is described as involvement in a life situa- both personal factors (e.g. lifestyle, genetic kit) and en- tion.Itrepresentsthesocietalperspectiveoffunctioning. vironmental factors (e.g. living and work conditions, ar- chitectural barriers) that are associated with conditions such as pain. Risk factors are not only associated with the onset, but interact with the disabling process at each stage. Bidirectional arrows in Figure 1 indicate the possibility of ‘feedback’. Risk factors also affect the progression of disability and may include, depending on the stage,treatment,rehabilitation,ageofonset,financialre- sources, expectations and environmental barriers. Per- sonal factors are included in the ICF model of functioning and health, but not classified. The components of functioning and disability are distinct, but they are related. All kinds of loss in body- structures and functions, activities and participation are described with disability. Several health states can be mentioned, with (in particular) independent involve- Disability and Impairment Definitions, Figure 1 Interactions between ment of the components of functioning. For example, the components of ICF. one may: 608 Disability and Impairment Definitions

Disability and Impairment Deﬁnitions, Table 1 ICF Categories of the ICF Core Set for Chronic Widespread Pain ICF Code ICF Category Title

categories of the component ‘body functions’

b122 Global psychosocial functions

b130 Energy and drive functions

b134 Sleep functions

b140 Attention functions

b147 Psychomotor functions

b152 Emotional functions

b1602 Content of thought

b164 Higher-level cognitive functions

b180 Experience of self and time function

b260 Proprioceptive function

b265 Touch function

b270 Sensory function related to temperature and other stimuli

b280 Sensation of pain

b455 Exercise tolerance functions

b640 Sexual functions

b710 Mobility of joint functions

b730 Muscle power functions

b735 Muscle tone functions

b740 Muscle endurance functions

b760 Control of voluntary movement functions

b780 Sensations related to muscles and movement functions

category of the component ‘body structures’

s770 Additional musculoskeletal structures related to movement

categories of the component ‘activities and participation’

d160 Focusing attention

d175 Solving problems

d220 Undertaking multiple tasks

d230 Carrying out daily routine

d240 Handling stress and other psychological demands

d410 Changing basic body position

d415 Maintaining a body position

d430 Lifting and carrying objects

d450 Walking

d455 Moving around

d470 Using transportation

d475 Driving Disability and Impairment Deﬁnitions 609

Disability and Impairment Deﬁnitions, Table 1 (continued) ICF Code ICF Category Title

d510 Washing oneself

d540 Dressing d570 Looking after one’s health D d620 Acquisition of goods and services

d640 Doing housework

d650 Caring for household objects

d660 Assisting others

d720 Complex interpersonal interactions

d760 Family relationships

d770 Intimate relationships

d850 Remunerative employment

d855 Non-remunerative employment

d910 Community life

d920 Recreation and leisure

categories of the component ‘environmental factors’

e1101 Drugs

e310 Immediate family

e325 Acquaintances, peers, colleagues, neighbors and community members

e355 Health professionals

e410 Individual attitudes of immediate family members

e420 Individual attitudes of friends

e425 Individual attitudes of acquaintances, peers, colleagues, neighbors and community members

e430 Individual attitudes of people in positions of authority

e450 Individual attitudes of health professionals

e455 Attitudes of Other Professionals

e460 Societal attitudes

e465 Social norms, practices and ideologies

e570 Social security services, systems and policies

e575 General social support services, systems and policies

e580 Health services, systems and policies

e590 Labor and employment services, systems and policies

Havelimitationsinactivitywithoutevidentimpairments The ICF is intended for use in multiple sectors that in- (e.g. phantom pain or reduced performance in daily ac- clude, besideshealth, education, insurance, labor,health tivities associated with many diseases) and disability policy, statistics, etc. In the clinical con- Have participation restrictions without having impair- text, it is intended for use in needs assessment, match- ments or activity limitations (e.g. an individual with mi- ing interventions to specific health states, rehabilitation graine, not actually having any pain, but avoiding some and outcome evaluation. However, the ICF needs to be situations like, for example, meeting friends in a pub) tailored in order to suit these specific uses. Firstly, the 610 Disability and Impairment Definitions

Disability and Impairment Deﬁnitions, Figure 2 Illustration of how the ICF components can be used to structure patient problems (listed in the upper section “patient perspective”) as well as ﬁndings, and observations by the rehabilitation team (listed in the lower section “health professional perspective”). Lines between the selected target problems from the patient’s perspective (circled in the upper section), impaired body functions and structures as well as the given personal and environmental factors (circled in the lower section) denote their hypothesized relationship. Please note that the wording denotes patient’s words or special medical terms and not text from ICF categories.

joint use of the ICF and the International Classification information about quality of life. Quality of life refers of Diseases ICDÐ10 needs to be addressed when apply- to total well-being, encompassing both physical and ing the ICF to medicine. WHO considers the ICF and psychosocial determinants. Quality of life is affected the ICDÐ10 to be distinct but complementary classifi- by each stage of the disabling process (e.g. in patients cations. According to this view, patient functioning and with scleroderma the quality of life may be decreased health are associated with, but are not merely a conse- due to structure of the skin disease, pain, restricted grip quence of, a conditionordisease.Forpractical purposes, function and consequently inability to shop). Within lists of ICF categories called ICF Core Sets have been the disabling process, each stage affects an individual’s developed for a number of conditions with a high bur- quality of life; it is not a finite endpoint, but an integral den of disease, including chronic widespread pain and part of the disabling process. low back pain (Stucki et al. 2002). Table 1 shows the The close relation of the ICF to quality of life ap- ICF Core Set for chronic widespread pain (Cieza et al. plies accordingly to measures of quality of life, in- 2003). The brief ICF Core Set, marked in bold, includes cluding measures of health related quality of life or the categories to be assessed in every clinical study and generic measures, condition specific measures e.g. clinical encounter to allow for a meaningful description for low back pain, and dimension specific measures of a patients functioning and health. The comprehensive e.g. for pain and depression. The concepts contained ICF Core Set includes the categories considered rele- in such measures can be linked to the ICF using de- vant for a comprehensive multidisciplinary assessment. fined linkage rules (Cieza et al. 2002). It seems that A practical possibility of how to use the ICF is shown the concepts contained in these measures are gener- in Fig. 2. ally represented in the ICF (Weigl et al. 2003; Cieza Since the new ICF defines components of health and and Stucki 2003). It is important to recognize that some health-related components of well-being (such different measures address different components of as education and labor), it could also be used to obtain the ICF. Condition specific measures typically fo- Disability Assessment, Psychological / Psychiatric Evaluation 611 cus on body functions and activities, whilst generic measures tend to cover activities and participation in- Disability Assessment, Psychological / cluding aspects of physical, mental and social health. Psychiatric Evaluation Contextual factors are hardly covered by any of these ROBERT J. GATCHEL instruments. Nonetheless, there is a need to address all Department of Psychiatry, The University of Texas components when assessing functioning and health Southwestern Medical Center at Dallas, Dallas, TX, in patients with chronic conditions (Ewert et al. USA D 2004). [email protected] Finally, it is important to note, that the perspective of functioning, disability and health is different when viewedfromamoremedicalversusfunctioningoriented Synonyms perspective e.g. in rehabilitation. From the medical per- Psychological Evaluation; Psychiatric Evaluation spective, functioning and health are seen primarily as a consequence of a disease or condition. Accord- ingly, medical interventions are targeted towards the Characteristics disease process. The measurement of functioning, The fundamental goal of the disability evaluation proce- disability and health is required to evaluate the patient- dure is usually to ascertain whether a patient can or can- relevant outcomes of an intervention. Instead, from not work. However, such a determination is quite diffi- a functioning-oriented or rehabilitation perspective cult in evaluating painful conditions because of the mis- represented in the ICF, patients functioning and health guided assumption that impairment can be precisely and are associated with, but not merely a consequence of, objectively measured and is closely linked to “mechan- a condition or disease. Furthermore, functioning and ical failure” of an organ or body part. Often however, health are not only seen in association with a condition, chronic pain patients will report activity restrictions that but also in association with personal and contextual cannot be fully understood in terms of a specific “me- factors. Therefore, the measurement of functioning, chanical failure.” There is often a low concordance be- disability and health is not only relevant to evaluate tweensubjectivereportsofpainandobjectivedataofim- intervention outcomes but for the diagnosis (assess- pairment. Thus, this will introduce vagaries into the dis- ment) and interventional management, as well. For the ability evaluation process. One disability evaluator may management of most patients with pain conditions, the tend to ignore the patient’s subjective reports of pain and latter perspective is more relevant. disability and rely more heavily on any objective evidence of mechanical dysfunction that is available. An- References other evaluator may rely more exclusively onthe subjec- 1. Cieza A, Brockow T, Ewert T et al. (2002) Linking Health-Status tive appraisals and activity restrictions reported by the Measurements to the International Classification of Functioning, patient, regardless of whether they can be objectively Disability and Health. J Rehab Med 34:205Ð210 quantified in terms of any measurable mechanical fail- 2. Cieza A, Stucki G (2005) Content Comparison of Health Related ure or dysfunction. Still another evaluator may attempt Quality of Life (HRQOL) Instruments Based on the International Classification of Functioning, Disability and Health (ICF). Qual to develop a composite of both the subjective and objec- Life Res 14:1225Ð37 tivemeasures.Unfortunately,thereiscurrentlynototally 3. Cieza A, Stucki G, Weigl M et al. (2003) ICF Core Sets for agreedupondisabilityevaluationsystemthatcanbeused chronic widespread pain. J Rehab Med 44 Suppl:63Ð68 (Dembe 2000; Robinson 2001). 4. EwertT, Fuessl M, CiezaAetal. (2004) Identificationofthe Most Common Patient Problems in Patients with Chronic Conditions A“ stepwise approach” should be used in the psycho- using the ICF Checklist. J Rehab Med 36:186Ð188 logical / psychiatric evaluation process (Gatchel 2000). 5. Nagi SZ (1964) A study in the Evaluation of Disability and Re- This is because most clinicians are under various time habilitation Potential: Concepts, Methods, and Procedures. Am J Pub Health 54:1568Ð1579 constraints, as well as billing constraints imposed by 6. Pope AM, Tarlov AR (1991) Disability in America: Toward a third-party payers, when considering the best method National Agenda for Prevention National Academy Press, Wash- of evaluating possible disability in their patients with ington pain. Therefore, a frequently asked question is, “If I 7. Stucki G, Ewert T, Cieza A (2002) Value and Application of the ICF in Rehabilitation Medicine. Disabil Rehabil 24:932Ð938 were to choose the most time- and cost-efficient assess- 8. Stucki G, Ewert T, Cieza A et al. (2002) Application of the In- ment method, which one should I select?” However, ternational Classification of Functioning, Disability and Health one must not make the assumption that there is a sin- (ICF) in Clinical Practice. Disabil Rehabil 24:281Ð282 gle instrument that can serve as the best assessment. 9. Weigl M, Cieza A, Harder M et al. (2003) Linking Osteoarthritis Specific Health Status Measures to the International Classifica- For many patients, several methods and measures will tion of Functioning, Disability and Health (ICF). Osteoarthritis be needed. Rather than asking which instrument and Cartilage 11:1Ð5 approach should be used, a better question is, “What 10. WHO (2001) International Classification of Functioning, Dis- sequence of testing should I consider to develop the ability and Health: ICF. WHO, Geneva 11. WHO (1980) ICIDH. International Classification of Impair- best understanding of potential disability problems that ments, Disabilities and Handicaps. WHO, Geneva might be encountered with this patient with reports 612 Disability Assessment, Psychological / Psychiatric Evaluation of pain?” Therefore, psychosocial evaluation should applied in the clinical setting. Basically, it is answering be viewed as a stepwise process, proceeding from the question of test validity by addressing the “valid global indices of emotional distress and disturbance for what purpose?” issue. Assessment methods may to more detailed evaluations of specific diagnoses of be valid for measuring specific biological states but psychopathology. Thus, for example, an initial evalu- have no validity in predicting, for example, disability or ation of disability may involve the administration of activities of daily living. Finally, it must be kept in mind specific assessment tools that have been developed for that, when embracing a comprehensive biopsychosocial this purpose, such as the Million visual analog scale evaluation (see biopsychosocial perspective) model (Million et al. 1982) or the Roland and Morris disability (Turk and Monarch 2002), it is important to consider questionnaire (Roland and Morris 1983). A compre- each successive assessment measure in context with hensive review of many of these instruments is provided the other measures to be integrated. This will lead to by Gatchel (2001) and Turk and Melzack (2001). In the most comprehensive disability assessment of a addition to one of these instruments, an initial screening patient that will then significantly contribute to the de- process that can be done efficiently to flag obvious psy- velopment of the most effective treatment regimen for chosocial distress might consist of the administration dealing with the disability problem. A “step-wise ap- of the SF-36 (Ware et al. 1993), the SCL-90 (Derogatis proach” to assessment is recommended (Gatchel 2000), 1983, pp 115Ð132) and the Beck depression inventory which proceeds from global indices of biopsychosocial (BDI; Beck et al. 1961). Any pronounced scale ele- concomitants of pain to more detailed evaluations of vations on these instruments would alert clinical staff specific diagnoses. to the degree of emotional distress or dysfunction in a pain patient and would indicate the need for a more thorough evaluation. This may then lead to the admin- References istration of the MMPI-2 (Keller and Butcher 1991) or a structured interview to develop official American 1. Beck AT, Ward CH, Mendelson MM et al. (1961) An inven- Psychiatric Association’s Diagnostic and Statistical tory for measuring depression. Archives of General Psychiatry th 4:561Ð571 Manual, 4 edition, DSM-IV-based diagnoses of an 2. Dembe AE (2000) Pain, function, impairment and disability: Im- Axis I or Axis II disorder (First et al. 1995). The final plications for workers’ compensation and other disability insur- step would be the administration of a psychosocial ance systems. In: Mayer TG, Gatchel J, Polatin PB (eds) Oc- cupational Musculoskeletal Disorders: Function, Outcomes and clinical interview, which is one of the most powerful Evidence. Lippincott Williams and Wilkins, Philadelphia assessment tools of the clinician. In addition to the 3. Derogatis L (1983) The SCL90-R Manual-II: Administration, traditional areas explored in a clinical history, there Scoring and Procedures. Clinical Psychometric Research, Bal- are other areas that would be explored that may pose timore 4. First MB, Spitzer RL, Gibbon M et al. (1995) Structured Clini- potential barriers to recovery and could affect response cal Interview for DSM-IV Axis I Disorders-Nonpatient Edition to treatment. Some of these topics include history of (SCID-I / NP, Version 2.0). New York State Psychiatric Institute, head injury, convulsions or impairment of function, any New York stressful changes in lifestyle or marital status before or 5. Gatchel RJ (2000) How practitioners should evaluate personality to help manage patients with chronic pain. In: Gatchel RJ, since the injury that precipitated the pain, any litiga- Weisberg JN (eds) Personality Characteristics of Patients with tion pending for the patient’s current medical or pain Pain. American Psychological Association, Washington problem and a work history, including explanation of 6. Gatchel RJ (2001) A Compendium of Outcome Instruments for job losses, changes and dissatisfaction. The interview Assessment and Research of Spinal Disorders. North American Spine Society, LaGrange allows the clinician to contrast the patient’s current 7. Keller LS, Butcher JN (1991) Assessment of Chronic Pain Pa- psychosocial functioning with past functioning and tients with the MMPI-2. University of Minnesota Press, Min- to compare the testing data with the interview data. neapolis 8. Million S, Hall W, Haavik NK et al. (1982) 1981 Volvo Award The clinician can then estimate the degree of disability in Clinical Science: Assessment of the progress of the back-pain reported by the patient and the potential for getting the patient. Spine 7:204Ð212 patient to change behavior and possibly work toward 9. Robinson RC (2001) Disability evaluation in painful conditions. rehabilitation. In: Turk DC, Melzack R (eds) Handbook of Pain Assessment, 2nd edn. Guilford, New York Of course, the common denominator of all assessment 10. Roland M, Morris R (1983) A study of the natural history of back methods is the qualities of validity, reliability (repro- pain. Part I: Development of a reliable and sensitive measure of ducibility) and predictive value. However, there often disability and low back pain. Spine 8:141Ð144 remain frequent misunderstandings over the appropri- 11. Turk DC, Melzack R (2001) Handbook of Pain Assessment, 2nd edn. Guilford, New York ate use of assessments based upon the generalizability 12. Turk D, Monarch ES (2002) Biopsychosocial perspective on of the scientific reports of validity to the circumstances chronic pain. In: Turk DC, Gatchel RJ (eds) Psychological in which the health care professional is using the as- Approaches to Pain Management: A Practitioner’s Handbook, sessment method. Such ambiguities can be minimized 2nd edn. Guilford, New York 13. Ware JE, Snow KK, Kosinski M et al. (1993) SF-36 Health Sur- by examining the match between the clinical context in vey: Manual and Interpretation Guide. The Health Institute, New which a test is evaluated and the patient to whom it is England Medical Center, Boston Disability, Effect of Physician Communication 613

relevant psychosocial factors are diverse. They include Disability Determination pre-injury problems such as substance abuse or major depression. However, there is also abundant evidence Disability Evaluation in the Social Security Admin- that workers’ responses to low back injuries are affected istration by a variety of factors that become evident only after injury, and are more appropriately viewed as expected reactions to injury than as mental disorders. In particular, D Disability, Effect of Physician recentresearch indicatesfear of painand/orreinjuryacts Communication as a major impediment to return to normal activities for individuals who have sustained back injuries (Vlaeyen JAMES P. ROBINSON and Linton 2000). University of Washington Pain Center, University of Research suggests that various kinds of psycholog- Washington, Seattle, WA, USA ical interventions can lead to reductions in patients’ [email protected] fears regarding their pain conditions, and that clinical improvement following therapies is mediated by Synonyms reductions in fear (Boersma et al. 2000; Burns et al. Secondary Prevention; Disability Management 2003; Woby et al. 2004). This literature supports the conclusion that low back pain patients benefit from Definition interventions that reduce their fears, but it has only Physicians engage in a wide range of behaviors to indirect relevance to the issue of whether communica- help injured workers return to work. The most obvi- tions by physicians allay patients’ fears and/or increase ous interventions are medical or surgical treatments their likelihood of returning to work. While expert that promote an injured worker’s recovery from injury. opinion supports the conclusion that communication Physicians also perform activities that facilitate return by MDs can influence patients’ recoveries (Anema et to work without directly altering the biology of an al. 2002; Deyo 1988; Pransky et al. 2004), method- injury. These activities can collectively be called dis- ologic issues make it difficult to study the nuances of ability management activities. They include interacting physician-patientcommunicationempirically.Somere- with a worker’s employer or workers’ compensation search supports the proposition that communications by claims manager (Pransky et al. 2004). They also include physicians can promote return to work following work communication with a patient about the significance of injuries (Catchlove and Cohen 1982; Hall et al. 1994), his or her injury, and, in particular, its implications for but the findings of other studies have been negative or the patient’s ability to work. equivocal (Dasinger et al. 2001; Hazard et al. 1997). In essence, it is not possible to derive any definite con- Characteristics clusions about how physicians should communicate Extensive research demonstrates that the manner in with injured workers from research findings to date. which physicians communicate with patients affects However, informal experience and expert opinion sug- encounters between them. Effective communication by gest several common concerns among injured workers physicians promotes more open disclosure by patients, with back problems, and messages from physicians that increased patient satisfaction with their medical en- might allay these concerns. counters, and increased patient adherence with medical Concern #1 Ð “Low back injuries are disabling, and po- regimens (Teutsch 2003). Much of the research in this tentially catastrophic. I might end up in a wheelchair.” area has addressed how physicians communicate with Response:Thephysiciancanappropriatelypointoutthat patients. In contrast, this essay is focused on the content LBP is an extremely common problem in modern soci- of what physicians communicate to patients with work eties, that it usually occurs in self-limited episodes, and injuries. In particular, it will focus on communication that it only rarely causes protracted disability. Thus, al- that addresses common fears among patients who have though the severity of pain associated with acute LBP is sustained work-related low back injuries. The essay as- often distressing, evidence about the natural history of sumes that a physician is communicating with a worker LBP provides ground for optimism that the symptoms who has localized back pain from a relatively minor will subside (Cheadle et al. 1994). work injury. That is, it assumes that the worker has not Concern #2 Ð “I should reduce my activity to avoid pain sustained major trauma such as a spinal fracture, does in my back, because pain indicates that I am reinjuring not have a lumbar radiculopathy, and does not have any myself.” “red flags” suggestive of non-mechanical sources of low Response: Patients with acute LBP often have enough back pain (LBP) such as neoplasm (Bigos et al. 1994). pain, so that they have little choice but to reduce their ac- Abundantliterature supportsthe conclusionthatthe out- tivitylevelsforashortperiodoftime.Itisunderstandable comes of work injuries are affected by psychosocial fac- that when people experience significant pain when they tors as well as biomedical ones (Turner et al. 2000). The try to return to normal activities, they become concerned 614 Disability, Effect of Physician Communication that they are making their problem worse. However, re- a bad disk, they can’t possibly recover unless the disk search supports the conclusion that pain associated with is fixed. Patients with this perspective need to real- moderate activity is unlikely to make a back problem ize that research demonstrates that MRI findings in worse. That is, the “hurt” that patients may feel during non-radicular LBP tend to be non-specific Ð e.g. that activityusuallydoesnotmeanthattheyareharmingtheir abnormalities such as bulging disks are commonly back, or delaying their recovery. Moreover, prolonged found among individuals with no current back pain or inactivity can create new problems, because patients be- history of back pain (Boos et. al. 2000). come deconditioned.In general,researchsupportsthe strategy of early activation (Hagen et al. 2004), and in- Barriers to Effective Communication dicates that even fairly vigorous exercise is more likely Physicians who attempt to allay the fears of their pa- to facilitate recovery than to impede it (Rainville 2004). tients, to motivate them to take a vigorous role in reha- Concern #3 Ð “I need to let my back heal. I should not re- bilitating their backs, and to encourage them to return to turn to work or to normal activities until then.” It makes normal activities soon after injury, face an uphill battle sense for patients with acute LBP to reduce their activity for many reasons. One is that a rehabilitative approach for a short period of time, but it is unrealistic and usu- ( rehabilitation) that makes heavy demands on the pa- ally counterproductive for people to restrict their activ- tientconflictswithprevalentmythsinadvancedsocieties ities severely until all their symptoms are gone. Most about the magical power of medical/surgical treatment, people return to normal activity Ð and in particular, to and the sense that patients are entitled to rapid, effortless work Ð before their pain has resolved completely (Von relief of suffering. Second, a physician who attempts to Korff M and Saunders 1996). Conversely, people who steerpatientsawayfrominvasivetherapiesandpromotes takethepositionthattheymustremaininactiveuntilthey rapid return to work may be viewed as an agent of the are completely free of symptoms run the risk of adverse employer or insurance company. Third, there are ongo- effects of deconditioning. ing differences of opinion among spine physicians and Concern #4 Ð “My pain implies that I have an injury that surgeons about the benefits of alternatives to a rehabili- needs to be fixed. I expect doctors to find the specific tative approach that places a great deal of responsibility cause of my pain (the pain generator), and to fix the onpatients.Claimsaboutnew interventionaltherapies problem. Only treatment by a skilled doctor will allow create ambiguity in the medical community about how me to recover from my back injury Ð there is nothing that to approach patients with LBP. Moreover, regardless of I can do about the problem.” their benefits as demonstrated in well controlled clinical Response:Thisperspectiverestsontheassumptionsthat trials, interventional therapies have the allure of promis- back pain is a result of a specific structural lesion,that ing patients a “fix” for their problem based on the magic physicians have the skill to identify and fix the lesion, of modern technology. In comparison to new interven- and that it is essentially impossible for an individual to tionaltherapies,recommendationsforself-management return to normal functioning until the lesion has been and return to activities in the absence of a total cure may fixed. All of these assumptions are incorrect for most be perceived by patients as outdated and unimaginative. patients with non-radicular LBP. In addressing this belief system, it is important to note that physicians are Summary often unable to identify a precise pain generator for pa- Research to date suggests that physicians can influence tientswithnon-radicularLBP(WhiteandGordon1982), the course of recovery following work-related back in- and that it is often doubtful that a single pain generator juriesbytheircommunicationswithinjuredworkersand even exists (Robinson et al. 2005). Perhaps because of with other interested parties (e.g. employers) (Pransky the difficulty in determining the anatomic basis of LBP, al. 2004). This essay has focused on a specific area of definitive interventions to “fix” the back are often only physician communication Ð messages that address the modestly helpful. Conversely, the vast majority of peo- belief systems and fears that patients frequently harbor ple who hurt their backs rely on self-management, and regarding their back injuries. Expert opinion and a lim- recover with only minimal professional help. Thus, pa- ited body of research support the conclusion that physi- tients’ interests are best served by taking an active role cians can promote return to normal activity in injured in managing their problem, rather than by waiting for a workers with LBP by addressing these concerns. professional to fix it. Concern #5 Ð “My MRI scan shows a bulging disk. I am References convinced that it is the cause of my pain, and that I won’t 1. Anema JR, Van Der Giezen AM, Buijs PC et al. (2002) Ineffective get better until someone fixes my disk.” Disability Management by Doctors is an Obstacle for Return- Response: This is a variant of the conceptual model to-Work: A Cohort Study on Low Back Pain Patients Sicklisted outlined in #4 above. It embodies the enormous signifi- for 3Ð4 Months. Occup Environ Med 59:729Ð733 cance that LBP patients tend to place on imaging studies 2. Bigos S et al. (1994) Acute Low Back Problems in Adults (AHCPR publication #95-0642). U.S. Department of Health that demonstrate anatomic abnormalities (Rhodes et and Human Services, Public Health Service, Agency for Health al. 1999). Many patients conclude that since they have Care Policy and Research, Rockville, MD Disability Evaluation in the Social Security Administration 615

3. Boersma K, Linton S, Overmeer T et al. (2000) Lowering Fear- Synonyms Avoidance and Enhancing Function through Exposure In Vivo. A Multiple Baseline Study Across Six Patients with Back Pain. Eligibility; Disability Determination; social security Pain 108:8Ð16 disability insurance; Supplemental Security Income 4. Boos N, Semmer N, Elfering A et. al. (2000) Natural History of Individuals with Asymptomatic Disc Abnormalities in Magnetic Definition Resonance Imaging. Spine 25:1482Ð1492 5. Burns JW, Glenn B, Bruehl S et al. (2003) Cognitive Factors Disability is the inability to engage in any substantial D Influence Outcome Following Multidisciplinary Chronic Pain gainful activity by reason of anymedically determinable Treatment: A Replication and Extension of a Cross-Lagged Panel Analysis. Behav Res Ther 41:1163Ð1182 physical or mental impairment that can be expected to 6. Catchlove R, Cohen K (1982) Effects of a Directive Return to result in death or that has lasted or can be expected to Work Approach in the Treatment of Workman’s Compensation last for a continuous period of not less than 12 months. Patients with Chronic Pain. Pain 14:181Ð191 7. Cheadle A, Franklin G, Wolfhagen C et al. (1994) Factors Influ- encing the Duration of Work-Related Disability: A Population- Characteristics Based Study of Washington State Workers’ Compensation. Am The Social Security Administration (SSA) has respon- J Public Health 84:190Ð196 8. Dasinger LK, Krause N, Thompson PJ et al. (2001) Doctor sibility for the administration of the Social Security Proactive Communication, Return-to-Work Recommendation, Disability Insurance (SSDI) program provided for un- and Duration of Disability after a Workers’ Compensation Low der title II of the Social Security Act (the Act) and the Back Injury. J Occup Environ Med 43:515Ð525 Supplemental Security Income (SSI) disability pro- 9. Deyo RA (1988) The Role of the Primary Care Physician in Reducing Work Absenteeism and Costs Due to Back Pain. Occup gram provided for under title XVI of the Act. The SSDI Med 3:17Ð30 program providesdisability benefitsto disabledworkers 10. Hagen KB, Hilde G, Jamtvedt G et al. (2004) Bed Rest for insured under the Act, children of insured workers who Acute Low-Back Pain and Sciatica (Cochrane Review). In: The Cochrane Library, Issue 3. John Wiley & Sons, Ltd, Chichester, become disabled before age 22 and to disabled widows UK or widowers and certain surviving divorced spouses of 11. Hall H, McIntosh G, Melles T et al. (1994) Effect of Discharge insuredworkers.TheSSIprogramisameans-testedpro- Recommendations on Outcome. Spine 15;19:2033Ð2037 gram that provides monthly payments to needy disabled 12. Hazard RG, Haugh LD, Reid S et al. (1997) Early Physician Notification of Patient Disability Risk and Clinical Guidelines adults and disabled children (individuals under age 18). after Low Back Injury: A Randomized, Controlled Trial. Spine Bothdisabilityprogramsarenationalprograms,withthe 22:2951Ð2958 same definition of disability for adults regardless of 13. Pransky GS, Shaw WS, Franche R et al. (2004) Disability Pre- the city or State in which a person lives or where the vention and Communication Among Workers, Physicians, Em- ployers, and Insurers Ð Current Models and Opportunities for disability determination is made. For adults, “disabil- Improvement. Disab Rehabil 26:625Ð634 ity” is defined as the inability to engage in any substan- 14. Rainville J (2004) Exercise as a Treatment for Chronic Low Back tial gainful activity by reason of any medically deter- Pain. Spine Journal 4:106Ð115 minable physical or mental impairment or combination 15. Rhodes LA, McPhillips-Tangum CA, Markham C et al. (1999) The Power of the Visible: The Meaning of Diagnostic Tests in of impairments that is expected to result in death or that Chronic Back Pain. Soc Sci Med. 48):1189Ð1203 has lasted or can be expected to last for a continuous pe- 16. Robinson JP, Ricketts D, Hanscom DA (2005) Musculoskeletal riod of not less than 12 months (1). Under SSI, “disabil- Pain: 1975Ð2005. (in press) 17. Teutsch C (2003) Patient-Doctor Communication. Med Clin ity” for an individual under age 18 means a medically North 87:1115Ð1145 determinable physical or mental impairment or impair- 18. Turner JA, Franklin G, Turk DC (2000) Predictors of Chronic ments that results in marked and severe functional lim- Disability in Injured Workers: A Systematic Literature Synthesis. itations and that meets the duration requirement (2). Am J Ind Med 38:707Ð722 19. Vlaeyen JW, Linton SJ (2000) Review. Fear-Avoidance and its For all individuals, a “medically determinable physical Consequences in Chronic Musculoskeletal Pain: A State of the ormentalimpairment”isanimpairmentthatresultsfrom Art. Pain 85:317Ð332 anatomical, physiological, or psychological abnormal- 20. Von Korff M, Saunders K (1996) The Course of Back Pain in ities which can be shown by medically acceptable clini- Primary Care. Spine 21:2833Ð2837 21. White AA, Gordon SL (1982) Symposium on Idiopathic Low cal and laboratory diagnostic techniques. Likewise, the Back Pain. Mosby, St. Louis rules for considering symptoms,suchas pain,in 22. Woby SR, Watson PJ, Roach NK et al. (2004) Are Changes in determining disability are essentially the same for both Fear-Avoidance Beliefs, Catastrophizing, and Appraisals of Con- adults and children. trol, Predictive of Changes in Chronic Low Back Pain and Dis- ability? Eur J Pain 8:201Ð210 The SSA’s policy for the evaluation of pain and other symptoms is set forth in regulations (3) and further clar- ified in agency instructions called Social Security Rul- Disability Evaluation in the Social Security ings (SSRs), SSR 96-3p (4), SSR 96-4p (5), and SSR 96- Administration 7p (6). A symptom, whether pain, fatigue, shortness of breath, nervousness, or anyother symptom,isnotamed- VICTORIA DORF icallydeterminableimpairment(5).Rather,SSAdefines Social Security Administration, Baltimore, MD, USA asymptomasaperson’sownperceptionordescriptionof [email protected] the impactof hisor her physicalormentalimpairment(s) 616 Disability Evaluation in the Social Security Administration

(7). Neither are symptoms alone enough to establish the mation provided by physicians and psychologists who existence of a physical or mental impairment (7) or to have treated or examined the person, and others about establish disability. This is so regardless of how many the person’s symptoms and how they affect the person, symptoms the person alleges or how genuine the per- and any other relevant evidence in the case record. The son’s complaints may appear to be (5, 6). There must be person’s pain or other symptoms will be found to dimin- an underlying impairment(s), shown by medically ac- ish his or her capacity to do basic work activities to the ceptable clinical and laboratory diagnostic techniques extent that the alleged symptom-related functional lim- (8), which could reasonably be expected to produce the itations and restrictions can reasonably be accepted as symptom(s) (3). consistentwith the objective medicalevidence andother To evaluate a person’s symptoms the SSA first deter- evidence. mines if there is a medically determinable physical or A credibility finding is straightforward if the person’s mental impairment that could reasonably be expected statements are consistent with what would be expected to produce the pain or other symptom(s) that the person on the basis of the objective medical evidence. But the alleges (3, 6). Thus, for example, an impairment of the SSA does not require objective medical evidence to lumbar spine could reasonably be expected to produce establish a direct cause and effect relationship between lowbackpainorpainradiatingintoalowerextremity,but the impairment and the alleged intensity, persistence, could not reasonably be expected to produce arm pain. or functional effects of the symptom(s). Rather, the The threshold for finding that there is a medical basis for SSA recognizes that even people with the same impair- the alleged symptom(s) is low and does not involve a de- ment may experience symptoms differently (10), that termination as to the intensity, persistence, or function- some people who experience pain may also report other ally limiting effects of the symptom(s), only whether the symptoms related to the pain (11), and that a person’s impairment(s)couldreasonablybeexpectedtocausethe statements about symptoms may not always be consis- kind of symptom(s) the person alleges (3). If there is no tent with what can be expected solely on the basis of the medically determinable physical or mental impairment, objective medical evidence and may, in fact, indicate a or if there isa medically determinable physical or mental greater severity of impairment than suggested by that impairment(s) but the impairment(s) could not reason- evidence. ably be expected to produce the person’s pain or other Because of this, the SSA’s adjudicators do not disregard symptoms, the symptom(s) cannot be found to affect the the person’s statements about his or her symptoms and person’s ability to do basic work activities (6). Basic their functional effects solely because the statements workactivitiesaretheabilitiesandaptitudesnecessaryto are not fully corroborated by the objective medical do most jobs. Examples of such activities include phys- evidence. Rather, if the information in the case record ical functions such as walking, standing, sitting, lifting, is insufficient to assess the credibility of the person’s pushing, pulling, reaching, carrying or handling the ca- statements, the SSA’s adjudicators must make every pacitiesfor seeing, hearing and speaking; and the mental reasonable effort to obtain additional information that abilities for understanding, carrying out and remember- could shed light on the credibility of the statements. ing simple instructions, use of judgment, responding ap- In assessing the credibility of the person’s statements propriately to supervision, co-workers, and usual work about his or her symptoms, the objective medical evi- situations; and dealing with changes in a routine work dence must always be considered. While the SSA does setting (9). If there is a medically determinable impair- notrequireobjectivemedicalevidencetocorroboratethe ment that could reasonably be expected to produce the person’sstatementsabouthisorhersymptoms, theclini- types of symptoms a person reports, the SSA goes on caland laboratoryfindingscannotbeignored,whether to consider the person’s statements about the intensity, those findings are positive or negative. However, adju- persistence, and functionally limiting effects of his or dicators are aware that the objective medical evidence is her impairment-related symptoms, unless a fully favor- only one of many medical and nonmedical factors that able determination can be made solely on the basisof the must be considered. objective medicalevidence. If theperson’sstatements SSA needs evidence from acceptable medical sources about the intensity, persistence, or functionally limiting to establish the existence of a medically determinable effects of symptoms are not substantiated by the objec- impairment (12). Once the existence of a medically tive medical evidence, the adjudicator must consider all determinable physical or mental impairment(s) is es- of the evidence in the case record and make a finding as tablished, the SSA considers information from all med- to the credibility of the person’s statements. ical sources Ð not just physicians or psychologists, but This credibility finding is a determination as to the de- also other medical sources, such as physical therapists, gree to which the person’s statements about his or her nurse practitioners, audiologists and chiropractors Ð symptomscan be believed and accepted astrue. Tomake about the severity of the impairment(s) and how it af- the credibility finding, consideration is given to the ob- fects the person’s ability to work. Other sources, such jective medical evidence, the person’s own statements as educational personnel and public and private social about his or her symptoms, statements and other infor- welfare agency personnel, can also provide information Disability, Fear of Movement 617 about the person and how his or her impairment(s) 3. Title20oftheCode of Federal Regulations(CFR), Parts404.1529 affects function. And, evidence from relatives, friends, and 416.929; Evaluation of Symptoms, Including Pain, 56 Fed- eral Register (FR) 57941 and 56 FR 57944, effective November neighbors, co-workers, clergy, and others can provide 14, 1991; www.gpoaccess.gov/nara ("GPO Access"). Accessed valuable information about the person’s functioning on February 2006 a day-to-day basis -information about what the person 4. SSR 96-3p, “Titles II and XVI: Considering Allegations of Pain does and how well he or she does these things now and and Other Symptoms in Determining Whether a Medically De- terminable Impairment is Severe,” 61 FR 34468 (July 2, 1996); how the person functions now compared to how the http://www.socialsecurity.gov, under “Our Program Rules.” Ac- D person functioned in the past. cessed February 2006 The SSA also considers the person’s longitudinal med- 5. SSR 96-4p “Titles II and XVI: Symptoms, Medically De- ical history. Repeated attempts to seek or try medical terminable Physical and Mental Impairments, and Exertional and Nonexertional Limitations” 61 FR 34488 (July 2, 1996); treatment tend to lend credibility to the person’s state- http://www.socialsecurity.gov, under “Our Program Rules.” ments,butthefailuretopursueregularmedicaltreatment Accessed February 2006 does not necessarily mean the person’s statements about 6. SSR 96-7p, “Titles II and XVI: Evaluation of Symptoms in Dis- the intensity, persistence, and functionally limiting ef- ability Claims” 61 FR 34483 (July 2, 1996) http://www.socialsecurity.gov, under “Our Program Rules.” Accessed February 2006 fects of symptoms are not credible without first consid- 7. 20 CFR 404.1528(a), 404.1529, 416.928(a) and 416.929; ering any explanations that he or she may provide and http://www.socialsecurity.gov, under “Our Program Rules.” any other information in the case record that may ex- Accessed February 2006 plain infrequent or irregular medical visits or the failure 8. Sections 223(d)(3) [42 U.S.C. 423] and 1614(a)(3)(D) [42 U.S.C. 1382c] of the Social Security Ac, as amended; to seek medical treatment. http://www.socialsecurity.gov, under “Our Program Rules.” The adjudicator does not have to totally accept or to- Accessed February 2006 tally reject the person’s statements. Rather, in any given 9. 20 CFR 404.1521(b) and 416.921(b); http://www.socialsecurity. gov, under “Our Program Rules.” Accessed February 2006 case, the adjudicator may determine that the evidence 10. 20 CFR 404.1545(e) and 416.945(e); http://www.socialsecurity. supports a finding that all of the person’s statements are gov, under “Our Program Rules.” Accessed February 2006 believable, that only some of those statements are be- 11. Pain and Disability, Clinical, Behavioral and Public Policy Per- lievable, or that none of the statements are believable. spectives (1987) In: Osterweis M, Kleinman A, Mechanic D (eds) Institute of Medicine, p 116 Or some of the statements may be believable, but only 12. 20 CFR 404.1513(a) and 416.913(a); http://www.socialsecurity. to a certain degree. gov, under “Our Program Rules.” Accessed February 2006 Once the adjudicator has arrived at a credibility finding, he or she must provide specific reasons for the finding, supportedbytheevidenceinthecaserecord.Thereasons mustbesufficientlyspecifictomakecleartheweightthat Disability, Fear of Movement 1 2 was given to the person’s statements and the reasons for MAAIKE LEEUW ,JOHAN W. S. VLAEYEN , 2 that weight. GEERT CROMBEZ While the credibility finding is important in draw- 1Department of Medical, Clinical and Experimental ing conclusions as to the extent to which the person’s Psychology, Maastricht University, Maastricht, The symptoms affect his or her ability to perform basic Netherlands work activities, it is not a determination as to whether 2Department of Experimental Clinical and Health the person is or is not disabled. Thus, a finding that Psychology, Ghent University, Ghent, Belgium all of the person’s statements about the functionally [email protected], limiting effects of pain or other symptoms are credible [email protected] does not automatically mean that the person will be found disabled. Nor does a finding that only some or Synonyms even none of the person’s statements about pain or other symptoms are credible mean that the claim will Kinesiophobia; Fear-avoidance; Pain-related fear; Fear be denied. Rather, the adjudicator must consider all of of pain the evidence in the case record before a conclusion can Definition be made about disability. Fear of movement/(re)injury is a specific form of References pain-related fear, and refers to the fear that certain 1. Sections 223(d)(1)(A) and (2)(A) [42 U.S.C. 423] and movements and physical activities will cause (re)injury. 1614(a)(3)(A) and (B) [42 U.S.C. 1382c] of the Social Se- It is especially prominent in patients with (chronic) low curity Act, as amended. Compilation of the Social Security Laws, U.S. Government Printing Office, Washington D.C. back pain. (2005); http://www.socialsecurity.gov under “Our Program Kinesiophobia is defined as ‘an excessive, irrational, Rules.” Accessed February 2006 and debilitating fear of physical movement and activ- 2. Section 1614(a)(3)(C) [42 U.S.C. 1382c] of the Social Security ity resulting from a feeling of vulnerability to painful Act, as amended. Compilation of the Social Security Laws, U.S. GPO, Washington D.C. (2005); http://www.socialsecurity.gov injury or (re)injury’ (Kori et al. 1990). It is associated under “Our Program Rules.” Accessed February 2006 with avoidance of fear-eliciting activities. Both fear of 618 Disability, Fear of Movement movement/(re)injury and avoidance behaviour are A Cognitive Behavioural Model of Chronic Low Back Pain postulated to significantly contribute tothedevelopment Building upon the work of Lethem et al. (1983), and maintenance of chronic low back pain (e.g. Kori the cognitive-behavioural model of fear of move- et al. 1990; Vlaeyen et al. 1995; Vlaeyen and Linton ment/(re)injury was developed to make sense of the 2000). development of chronic suffering in non-specific low Characteristics back pain (Vlaeyen et al 1995). According to the model, two opposing behavioural responses may occur in re- The experience of pain can be characterized by psy- sponse to acute pain: ‘confrontation’ and ‘avoidance’. chophysiological (e.g. muscle activity), cognitive (e.g. A gradual confrontation and resumption of daily activi- anticipation), and behavioural (e.g. escape and avoid- ties despite pain is considered an adaptive response that ance)responses.Theroleoffearofmovement/(re)injury eventually leads to the reduction of fear, the encourage- in the transition from acute to chronic low back pain, ment of physical recovery and functional rehabilitation. and in the maintenance of chronic low back, has been In contrast, a catastrophic interpretation of pain is well documented. In other pain syndromes, such as considered a maladaptive response, which initiates a chronic fatigue syndrome, whiplash, headache, and vicious circle in which fear of movement/(re)injury, fibromyalgia, the evidence on the importance of fear of and the subsequent avoidance of activities, augment movement/(re)injury in the process of chronicity is still functional disability and the pain experience by means preliminary. Fear of movement/(re)injury is strongly of hypervigilance, depression, and disuse (Fig. 1). related to escape and avoidance behaviours. Some This cognitive-behaviouralmodel has several presump- CLBP patients believe that performance of certain actions (Vlaeyen and Linton 2000): tivities may promote pain and (re)injury. This belief leads to fear of movement/(re)injury and consequently 1. Pain catastrophizing, an exaggerated negative to the avoidance of these activities, although there are orientation towards actual or anticipated pain expe- no medical explanations for this behavioural pattern riences, is assumed to be a precursor of pain-related of avoidance. In most instances, these fear-avoidance fear (Vlaeyen and Crombez 1999; Vlaeyen and beliefs take the form of erroneous ‘if ...... then’ cog- Linton 2000). Studies have indeed found a strong nitions, for example, “If I lift this shopping bag, I will association between fear of pain and catastrophizing damage a nerve and end up paralysed”. in chronic pain patients, although most research is Despite the fact that in acute pain the avoidance of daily cross-correlational in nature. For example, chronic activities may be adaptive in facilitating healing and pain patients who catastrophized reported higher recovery, in chronic pain avoidance behaviour is no pain intensities, felt more disabled, and experienced longer necessary for recovery. The long-term mainte- more psychological distress (Vlaeyen et al. 2002). nance and enhancement of avoidance behaviour can Laboratory and longitudinal studies allow investi- be established by the short-term effect of reduced suf- gation as to whether catastrophizing may actually fering as proposed by Fordyce (1982), and by certain precede pain-related fear. For example, pain-free beliefs and expectations that confrontation with par- individuals who catastrophized about pain became ticular activities will promote pain and (re)injury (e.g. more fearful when threatened with an intense pain Asmundson et al. 1999; Kori et al. 1990; Philips 1987; experience than did students who reported low catas- Vlaeyen et al. 1995; Vlaeyen and Linton 2000). trophizing (Crombez et al. 1998). Furthermore, pain Several studies have shown that fear of movement/ catastrophizing appeared to be the most powerful (re)injury is associated with poor physical performance predictor of back pain chronicity one year after the on behavioural tasks (Crombez et al.1999; Vlaeyen and acute onset (Burton et al. 1995). Both studies in- Crombez 1999).The effect of pain-related fear on phys- dicate that catastrophizing is a precursor of fear of ical performance also seems to generalize to daily life movement/(re)injury. situations. For example, fear-avoidance beliefs about 2. Fear is characterized by escape and avoidance be- work are strongly related to disability of daily living and haviours,leadingtoanimpairedabilitytoaccomplish work lost in the previous year, even more so than pain daily living tasks and subsequent functional disabil- severity or other pain variables (Waddell et al. 1993). ity. Several studies have shown that patients with Moreover, self-reported fear of movement/(re)injury chronic low back pain, who associate pain with is a better predictor of self-reported disability than damage, tend to avoid activities that they assume biomedical symptoms and pain severity (Crombez et will promote pain (Asmundson et al. 1999; Kori al. 1999; Vlaeyen et al. 1995; Vlaeyen and Crombez et al.1990; Philips 1987; Vlaeyen and Crombez 1999; Waddell et al. 1993; Vlaeyen et al. 2004). As 1999; Vlaeyen and Linton 2000). Avoidance be- fear of movement/(re)injury and avoidance behaviour haviours can occur as early in the anticipation of are important determinants of disability, Waddell et al. pain rather than as a response to pain. Therefore, (1993) concluded that ‘fear of pain and what we do opportunities are excluded for correction of (erro- about it may be more disabling than pain itself’. neous) catastrophic cognitions and beliefs about the Disability, Fear of Movement 619

Disability, Fear of Movement, Figure 1 A cognitive behavioural model of pain-related fear. From: Vlaeyen, J.W.S. (2002). Fear in musculoskeletal pain. In J.O. Dostrovsky, D.B. Carr and M. Koltzenburg (eds), Proceedings of the 10th World Congress on Pain: 631–650, Seattle, IASP press. Reprinted with permission.

consequencesof activities. By this means, avoidance caused by the experimental setting resulted in mus- is likely to expand and become more persistent. cular reactivity, to which non-fearful patients readily 3. Excessive and long-lasting avoidance of physical habituated over time, while fearful patients did not activities may have detrimental physical and psy- (Vlaeyen et al. 1999). chological consequences. A decrease of mobility, Thereissubstantialsupportforthecognitive-behavioural decreased muscle strength, and loss of fitness can model in explaining the development of chronic non- occur, possibly resulting in a ‘ disuse syndrome’. specific low back pain. Additionally, there is increasing Avoidance can also result in loss of self-esteem, de- support for the idea that fear of movement/(re)injury privation of reinforcers, depression, and worrying. can be initiated or stirred up by beliefs and attitudes Both disuse and depression are known to decrease of health care providers. Besides the fact that health pain tolerance, and can thereby augment the pain care providers on average hold beliefs that are con- experience (Crombez et al. 1999). sistent with current evidence, many would still advise 4. In accordance with other forms of fear, pain-related patients to avoid painful movements. Others still be- fear interferes with cognitive functioning, such as lieve that pain-reduction is a necessary requirement attention (Eccleston and Crombez 1999; Vlaeyen for returning to work, or that sick-leave is an adequate and Linton 2000). Pain patients who report fear of treatment for back pain. The fear-avoidance beliefs of movement/(re)injury may show hypervigilance to certain practitioners can, therefore, reinforce the beliefs pain, which is the increased attention to pain, poten- and avoidance behaviours of patients (Linton et al. tial signals of pain and possible other somatosensory 2002). signals. Using attention-demanding tasks, studies demonstrated that chronic pain patients showed significant impairments in attentional performance. For Cognitive Behavioural Therapy with Exposure In Vivo instance, high-intensity pain appeared to be more Evidence is accumulating that the advice to restrict ac- disruptive than low-intensity pain. Furthermore, in- tivity or to rest in case of back pain is counterproduc- terruption by pain seemed to be mediated by threat. tive, delays recovery, and may lead to chronic disabil- When threatened with intense pain, interruption ity and complicated rehabilitation. Substantial evidence of attention was strengthened for those who catas- favours the recommendation to stay active and continue trophized and interpreted pain-related stimuli as usual daily activities (e.g. Waddell 1998). threatening. In addition, patients with high somatic One of the clinical implications of the idea that chronic awareness suffered from inflated disruption of at- suffering and disability is caused by fear of movement tention. This hypervigilance in fearful chronic pain andavoidance,isthattreatmentofCLBPpatientsshould patients appears at the expense of other tasks, such directly target these perpetuating and exacerbating fac- as everyday activities or pain coping strategies. tors. Therefore, in analogy with phobia and anxiety dis- 5. Pain-related fear is associated with increased psy- orders, exposure in vivo has been proposed as a poten- chophysiological reactivity when the individual tially effective treatment (Kori et al. 1990; Philips 1987; is confronted with situations that are evaluated as Vlaeyen et al. 2002A). Philips (1987) was the first to ar- ‘dangerous’. Results showed that contextual fear gue that graded exposure should be systematically ap- 620 Disability, Fear of Movement plied, to realize disconfirmations between the erroneous the effectiveness of exposure in vivo, which demon- expectationsofharm,painorotherconsequencesandthe strated generalization to other therapists and treatment actual pain of patients who are fearful of movement. settings, adding support for the external validity of Exposure in vivo does not aim to reduce pain lev- the treatment. Taken together, although results on the els, but to restore the functional abilities despite pain. effectiveness of cognitive behavioural treatments with The treatment is embedded in a cognitive-behavioural exposure in vivo should be interpreted as preliminary, treatment approach and is comprised of three stages the results are quite promising. (e.g. Vlaeyen et al. 2004). The treatment starts with a cognitive-behavioural assessment, consisting of an ex- References tensive interview regarding cognitive, behavioural, and 1. Asmundson GJG, Norton PJ, Norton GR (1999) Beyond Pain: psychophysiological aspects of the symptoms, and to The Role of Fear and Avoidance in Chronicity. Clin Psychol estimate the magnitude of the influence of pain-related Rev19:97Ð119 fear on the pain problem. An indication of the level of 2. Butron AK, Tillotson KM, Main CJ, Hollis S (1995) Psychosocial predictors of outcome in acute and subchronic low back trouble. fear of movement can be obtained, for example, by the Spine 20:722Ð728 Tampa Scale for Kinesiophobia (For an overview 3. Boersma K, Linton SJ, Overmeer T, Jansson M, Vlaeyen JWS, de of measures for fear of movement/(re)injury see e.g. Jong JR (2004) Lowering fear-avoidance and enhancing function Vlaeyen et al. 2002a; McCracken et al. 1996). Further- through exposure in vivo: a multiple baseline study across six patients with back pain. Pain 108:8Ð16 more, insight is gained into avoidance behaviour and 4. Crombez G, Eccleston C, Baeyens F, Elen P (1998) When somatic catastrophizing cognitions concerning the relationship information threatens, catastrohic thinking enhances attentional betweenactivitiesandpainand(re)injury.Besidesdefin- interference. Pain 75:187Ð198 ing feasible treatment goals, the cognitive-behavioural 5. Crombez G, Vlaeyen JWS, Heuts PHTG, Lysens R (1999) Pain- Related Fear is More Disabling than Pain Itself: Evidence on the assessment is concluded with the establishment of a Role of Pain-Related Fear in Chronic Back Pain Disability. Pain personal graded hierarchy of activities that the person 80:329Ð339 is actually afraid of, starting with activities that produce 6. Eccleston C, Crombez G (1999) Pain Demands Attention: A Cognitive-Affective Model of Interruptive Function of Pain. Psy- only slight distress and concluding with activities that chol Bull 3:356Ð366 are beyond the present capabilities of the patient. Fol- 7. Fordyce WE, Shelton JL, Dundore DE (1982) The Modifica- lowing this first stage of exposure in vivo, education is tion of Avoidance Learning in Pain Behaviors. J Behav Med provided, aimed to motivate the patient to participate 5:405Ð414 8. Kori SH, Miller RP, Todd DD (1990) Kinisophobia: A New View in previously avoided fear-provoking activities. Dur- of Chronic Pain Behavior. Pain Manage Jan/Feb: 35Ð43 ing education, the pain problem is conceptualised as 9. Lethem J, Slade PD, Troup JD, Bentley G (1983) Outline of a a common condition that can be self-managed, rather Fear-Avoidance Model of Exaggerated Pain Perception: I. Behav than a serious disease that needs careful protection. Res Ther 21:401Ð408 10. Linton SJ, Overmeer T, Janson M, Vlaeyden JWS, de Jong JR Additionally, a careful explanation of the cognitive- (2002) Graded in vivo expsure treatment for fear-avoidant pain behavioural model is provided, in which the patients’ patients with functional disability: a case study. Cognitive Be- idiosyncratic symptoms, cognitions, and behaviours haviour Therapy 31:49Ð58 are discussed. The third stage of the treatment proceeds 11. Linton SJ, Vlaeyen JWS, Ostelo RW (2002) The Back Pain Be- liefs of Health Care Providers: Are We Fear-Avoidant? J Occup with the implementation of behavioural experiments, Rehab 12:223Ð232 during which the patient is systematically exposed to 12. McCracken LM, Gross RT, Aikens J, Carnrike CLM jr (1996) fear-provoking activities, leading to disconfirmation of The Assessment of Anxiety and Fear in Persons with Chronic harm beliefs and reduction of fear, thereby promoting Pain: A Comparison of Instruments. Behav Res Ther 34:927Ð933 13. Philips HC (1987) Avoidance Behaviour and it’s Role in Sus- recovery of activities and functional abilities (Vlaeyen taining Chronic Pain. Behav Res Ther 25:273Ð279 et al. 2004). 14. Vlaeyen JWS, Crombez G (1999) Fear of Movement/(Re)Injury, Avoidance and Pain Disability in Chronic Low Back Pain Pa- Effectiveness of Cognitive Behavioural Therapy with Exposure tients. Man Ther 4:187Ð195 In Vivo 15. Vlaeyen JWS, de Jong JR, Sieben JM, Crombez G (2002A) Graded Exposure In Vivo for Pain-Related Fear. In: Turk DC, At present, the effectiveness of graded exposure in vivo Gatchel RJ (eds) Psychological Approaches to Pain Manage- has only been investigated in single case experimental ment: A Practitioner’s Handbook. The Guilford Press, New York, pp 210Ð233 designs, in which exposure in vivo is compared to usual 16. Vlaeyen JWS, de Jong JR, Geilen M, Heuts PHTG, van Beukelen graded activity in reducing pain-related fear, catastro- G (2002B) The Treatment of Fear of movement/ /re) injury in phizing and disability in CLBP patients reporting fear chronic lowback pain: further evidence on the effectiveness of of movement/(re)injury(Vlaeyen et al. 2002B). Results exposure in vivo. Clin J Pain 18: 251Ð261 17. Vlaeyen JWS, de Jong JR, Leeuw M, Crombez G (2004) Fear show that remarkable improvements were observed on Reduction in Chronic Pain: Graded Exposure In Vivo with Behav- self-report measures of pain-related fear, catastrophiz- ioral Experiments. In: Asmundson GJG, Vlaeyen JWS, Crombez ing, and disability, and in objective physical activity G (eds) Understanding and Treating Fear of Pain. Oxford Uni- measurements whenever exposure in vivo was initiated. versity Press 18. Vlaeyen JWS, Kole-Snijders, AMJ, Rotteveel AM, Ruesink R, In addition, two Swedish single case studies (Boersma Heuts PHTG (1995) The Role of Fear of Movement/(Re)injury et al. 2004, Linton et al. 2002) also found evidence for in Pain Disability. J Occup Rehab 5:235Ð252 Disability, Functional Capacity Evaluations 621

19. Vlaeyen JWS, Linton SJ (2000) Fear-Avoidance and its Conse- Functional capacity evaluations (FCE) are frequently quences in Chronic Musculoskeletal Pain: A State of the Art. relied on for assessing readiness for ‘safe’ return to Pain 85:317Ð332 20. Vlaeyen JWS, Seelen HAM, Peters M, de Jong P, Aretz E, work, particularly for workers’ compensation and other Beisiegel E, Weber W (1999). Fear of movement/ (re)injury insurance systems. The term “functional capacity eval- and muscular reactivity in chronic low back pain patients: an uation” was coined by rehabilitation professionals, experimental investigation. Pain 82:297Ð304 whose goals typically focus on assisting injured or ill 21. Waddell G (1998) The Back Pain Revolution. Churchill Living- stone, London individuals to optimize their ability to perform desired D 22. Waddell G, Newton M, Henderson I, Somerville D, Main CJ work and leisure activities, and assessing such capaci- (1993) A Fear Avoidance Beliefs Questionnaire (FABQ) and the ties. The goal of functional capacity testing is to directly Role of Fear-Avoidance Beliefs in Chronic Low Back Pain and measure capacity for specific tasks, often in relation to Disability. Pain 52:157Ð168 the required physical demands of a particular activity. As mentioned, FCEs are frequently used to assess readiness to return to work following injury, they are Disability, Functional Capacity also used to guide other clinical decisions (King et al. Evaluations 1998; Lechner et al. 1991). They are sometimes used to establish baseline performance levels, to assist MICHELE C. BATTIÉ,DOUGLAS P. G ROSS in planning functional restoration and work harden- Department of Physical Therapy, University of ing programs and to measure program outcomes. In Alberta, Edmonton, AB, Canada addition, FCEs are used to guide retraining programs [email protected], and vocational planning following disabling injuries. [email protected] Another suggested application, is in assessing the extent of disability, to assist in permanent impairment judg- Synonyms ments and determination of wage-earning potential in Functional capacity evaluation; Functional Abilities litigation cases. Evaluation; Functional Capacity Assessment; Func- Types of Functional Capacity Evaluations tional Capacity Battery; Physical Capacity Evaluation; work capacity evaluation; work performance evalua- Some controversy exists over just what should be mea- tion; Job Capacity Evaluation; Occupational Capacity sured during functional capacity testing. In some cases, Evaluation; work-related assessment; Vocational As- functional testing has been limited to specific body sessment; work sample systems or tissue function, while others aim to measure ability for real-life physical tasks (Isernhagen 1992; Definition Takala and Viikari-Juntura 2000). This has resulted in numerous testing methods reportedly measuring func- Functional capacity examinations or evaluations are tional capacity, including tests of joint mobility, muscle standardized test batteries, aimed at determining an strength, general physical fitness, self-report ratings of individual’s capacity or tolerance for work or other ability and entire batteries of such tests (Deyo 1988; activities (Abdel-Moty et al. 1993). They commonly Waddell et al. 1992). However, in the case of injuries rely on physiological, functional or performance-based leading to work disability, FCEs are commonly used to measures, and are often used to assess readiness to assist in case managementand return to work decisions. return to work following injury. Typically required work tasks are identified and then Characteristics compared to performance on related functional tests. These tests often simulate to some degree work tasks of Context and Uses of Functional Capacity Evaluation interest. Many FCEs incorporate the 20 physical work Two of the most sought after pieces of information from functions described in the U.S. Department of Labor’s health care providers in cases of work-related injury Selected Characteristics of Occupations as Defined in claims resulting in work absence are whether or not the the Revised Dictionary of Occupational Titles (DOT) injured worker is ready to return to regular work duties (Gibson and Strong 1997). These tests often include and, if not, what physical restrictions are required. The the evaluation of performance of materials handling, answers to these questions have significant implications ambulation, and sustained postures and positioning. for injured workers and their families, employers, in- Due to the important decisions made based on FCE surance carriers and society as a whole. Yet, few health results and the major implications arising from such care providers are confident in making such judgments. decisions, essential FCE measurement properties for These determinations are further complicated when appropriate, ethical use include adequate reliability, applied to ill defined musculoskeletal pain complaints, or test consistency, and validity. Validity refers to the sometimes referred to as soft tissue injuries, which extent to which a test measures what it is purported now constitute the majority of workers’ compensation to measure, and includes various forms with the most claims and costs in many jurisdictions. important deemed construct, concurrent, and predic- 622 Disability, Functional Capacity Evaluations tive validity. In terms of functional capacity testing, environmental context (Gross and Battié 2005; Rudy little rigorous research has been performed evaluating 1996). these various basic measurement properties, as judged through recent comprehensive literature reviews (Gross Summary 2004; Innes and Straker 1999; Innes and Straker 1999). The use of FCE isbecoming increasinglycommon inoc- No information has been published on FCE responsive- cupationalrehabilitation,andfunctionalorperformance- ness, or the ability of such measures to detect important based tests are being relied upon more frequently for functional change over time or as a result of treatment. making return to work and related decisions. However, The few studies that have been published seem to in- the validity of FCE has not been adequately evaluated dicate that FCEs are reliable measures of functional and, the evidence that does exist makes the usefulness of ability. However, their adequacy in meeting the primary complex functional testing protocols appear limited in objective for their use, accurately identifying safe abil- cases of pain-mediated disability. Given the important ity to return to work, is questionable (Gross and Battié influence of psychological and other contextual factors 2004). The relationship between demonstrated perfor- on subject performance during FCE, these tests may mance on FCE and future return to work appears weak, be more accurately viewed as behavioral assessments and lower in magnitude than the relationship between rather than evaluations of maximum physical ability. recovery outcomes and other personal and contextual Accordingly, FCE results must be interpreted within factors. This appears to be the case especially in situa- each subject’s unique personal and environmental con- tions of pain-mediated disability such as low back pain text, when return to work or related decisions are being (Gross et al. 2004; Matheson et al. 2002; Fishbain et al. made. 1999).

FCE in Persons with Pain-Mediated Disability Conditions References Considering the context in which FCEs are often per- 1. Abdel-Moty E, Fishbain DA, Khalil TM, Sadek S, Cutler R, Ro- somoff RS, Rosomoff HL (1993) Functional Capacity and Resid- formed, and the fact that many of the individuals un- ual Functional Capacity and their Utility in Measuring Work Ca- dergoing testing have pain-mediated or non-specific pacity. Clin J Pain 9:168Ð173 disabilityconditions,questionshavearisenastowhether 2. Deyo RA (1988) Measuring the Functional Status of Patients functional capacity testing is measuring true physical with Low Back Pain. Arch Phys Med Rehabil 69:1044Ð1053 3. Fishbain DA, Cutler RB, Rosomoff H, Khalil T, Abdel-Moty E, capacity or other constructs. Performance during FCE Steele-Rosomoff R (1999) Validity of the Dictionary of Occu- or on any physical test can be influenced by multiple pational Titles Residual Functional Capacity Battery. Clin J Pain factors including, but not limited to, physiological lim- 15:102Ð110 itations, pain intensity levels, motivation to perform, 4. Gibson L, Strong J (1997) A Review of Functional Capacity Evaluation Practice. Work 9:3Ð11 fear of movement or pain, and wellness on the day of 5. Gibson L, Strong J (1998) Assessment of Psychosocial Factors the assessment. Several approaches have been used in in Functional Capacity Evaluation of Clients with Chronic Back an attempt to judge sincerity of effort during FCE, or Pain. Br J Occ Ther 61:399Ð404 whether performance during testing is being limited 6. Gross DP, Battié MC, Cassidy JD (2004) The prognostic value of functional capacity evaluation in patients with chronic low by physical capacity or by some other factor (Lechner back pain: part 1: timely return to work. Spine 29:914-9 et al. 1998). These approaches include observations 7. Gross DP, Battié MC (2004) The prognostic value of functional of inconsistency between findings of musculoskeletal capacity evaluation in patients with chronic low back pain: part pathology and demonstrated functional performance, 2: sustained recovery. Spine 29:920-4 8. Gross DP (2004) Measurement properties of performance-based inconsistent performance on related functional tasks in assessment of functional capacity. J Occup Rehabil 14:165-74 an assessment, and other measures of inconsistencies, 9. Gross DP, Battié MC (2005) Factors influencing results of func- such as the coefficient of variation applied to maximal tional capacity evaluations in workert’s compensation claimants with low back pain. Phys Ther 85:315-22 strength tests. However, the validity of the various tests 10. Innes E, Straker L (1999) Reliability of Work-Related Assess- of sincerity of effort has not been thoroughly evaluated. ments. Work 13:107Ð124 More importantly, the reason why individual subjects 11. Innes E, Straker L (1999) Validity of Work-Related Assessments. do not perform to maximum physical ability levels is Work 13:125Ð152 12. Isernhagen SJ (1992) Functional Capacity Evaluation: Rationale, typically unknown. Poor or submaximal performance Procedure, Utility of the Kinesiophysical Approach. J Occup Re- on FCE appears to be related more to psychological hab 2:157Ð168 factors, such as depression or high perceived disability, 13. King PM, Tuckwell N, Barrett TE (1998) A Critical Review of than to true physical limitations (Gibson and Strong Functional Capacity Evaluations. Phys Ther 78:852Ð866 14. Lechner D, Roth D, Straaton K (1991) Functional Capacity Eval- 1998). In fact, given the important influence of psy- uation in Work Disability. Work 1:37Ð47 chological and environmental factors on performance 15. Lechner DE, Bradbury SF, Bradley LA (1998) Detecting Sin- during such testing, some authors have recommended cerity of Effort: A Summary of Methods and Approaches. Phys that FCEs be viewed not merely as maximum physical Ther 78:867Ð888 16. Matheson LN, Isernhagen SJ, Hart DL (2002) Relationships ability tests, but as behavioral assessments that must Among Lifting Ability, Grip Force, and Return to Work. Phys be interpreted within each subject’s unique personal and Ther 82:249Ð256 Disability in Fibromyalgia Patients 623

17. Rudy TE, Dieber SJ, Boston JR (1996) Functional Capacity As- prospects, social support systems, economic conse- sessment: Influence of Behavioural and Environmental Factors. quences and potential for being competitive in the J Back Musculoskel Rehabil 6:277Ð288 18. Takala EP, Viikari-Juntura E (2000) Do Functional Tests Predict workforce. The causes for functional impairment in Low Back Pain? Spine 25:2126Ð2132 FM include: 19. Waddell G, Somerville D, Henderson I, Newton M (1992) Ob- • jective Clinical Evaluation of Physical Impairment in Chronic Pain Low Back Pain. Spine 17:617Ð628 • Fatigue • Weakness D • Psychological distress • Mood disorders Disability in Fibromyalgia Patients • Personality disorders • Medications ROBERT BENNETT • Cognitive impairment Department of Medicine, Oregon Health and Science • Ongoing litigation University, Portland, OR, USA • Poor social support [email protected] • Job dissatisfaction • Lack of work autonomy Synonyms • Heavy physical work • Associated disorders Fibromyositis; fibromyalgia MostFMpatientsreportthatchronicpainandfatiguead- Definition versely affect the quality of their life, and negatively im- Fibromyalgia is a chronic pain syndrome defined in pact on their ability to be competitively employed. Pain terms of widespread pain and tenderness as per the and fatigability adversely affect motor performance in American College of Rheumatology 1990 Classifica- people with FM, asevery-day activitiestake longer. Two tion criteria (Wolfe et al. 1990). studies have reported that on self-assessment, FM patients have higher pain ratings and poorer functional sta- Characteristics tus than patients with rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus , and scleroderma. In Prevalence of Disability in Fibromyalgia general, they need more time to get going in the morn- Despitethesuperficialappearanceofnormality,manyfi- ing and usually require extra rest periods during the day bromyalgia(FM)patientshavedifficultywithremaining (Henriksson and Liedberg 2000). Although many peo- competitive in the work force (Liedberg and Henriksson ple with FM can tolerate work activity for short periods 2002). of time, the same tasks carried out for prolonged peri- Asurveyof1604patientswithFM,overacourseofeight ods result in increased pain and fatigue. Furthermore, yearsin six U.S. academic medicalcenters, reportedthat psychological stress, as is often found in time censored 64%wereableto work on allor mostdays, and over 70% work, aggravate FM symptomatology. In particular, FM were employed or homemakers. There was a consider- sufferers have difficulty with tasks involving repetitive ablevariationindisabilityratesfromcentertocenter,but activity or sustained muscle contraction. Cognitive dys- overall 16% of patients were receiving Social Security function, particularly short-term memory and recall, is disability benefits (lowest center-rate of 6.3% to highest increasingly recognized as being a common problem in center-rate of 35.7%), and 27% were receiving at least FMpatients(Parketal.2001)andhasdetrimentaleffects one form of disability payment (Wolfe et al. 1997). A on most jobs, especially those that are intellectually de- similar degree of disability has been reported in Canada manding. and Sweden (Henriksson and Liedberg 2000; White et ThefactthatpeoplediagnosedwithFMusuallylooknor- al. 1999). mal and can perform tasks effectively for short periods often generates pejorative attitudes in their immediate Causes of Disability supervisors and co-workers, who suspect that FM is just Disability is the result of an impairment. An impairment an “excuse for not pulling their full weight”. The result- is defined as an anatomical, physiological or a psycho- ing workplace disharmony causes further stress and ag- logical impediment. Impairment can relate to disorders gravation of fibromyalgia symptomatology. of function at organ level (e.g. a left-sided hemiple- gia Ð an anatomic problem, epilepsy Ð a physiologic problem, schizophrenia Ð a psychological problem). Assessment of Disability Disability is an integrated concept that views impair- The problems that physicians encounter in assessing the ment in a multidimensional context that embraces: chronic pain patient are largely related to 4 issues: (1) age, sex, educational level, psychological profile, past pain is a purely subjective perception which is usually attainments, job satisfaction, motivation, re-training interpretedinanemotionalcontext;(2)chronicpaincan- 624 Disability in Fibromyalgia Patients not be fully understood in terms of the classical model of Self-Efficacy disease that equates pathogenesis with tissue damage or The belief that one is capable of doing an activity is re- dysfunction;(3)many“non-sick”peoplehavepersistent lated to the development from an impairment to disabil- pain but are not disabled; and (4) apparent impairment ity. The coping strategies questionnaire has been used to due to pain results from a complex interplay between determine factors associated with disability (Martin et past experiences, education, income level, work related al. 1996). Coping attempts (reinterpreting pain, ignor- self-esteem, motivation, psychological distress, fatigue, ingpainsensations,divertingattention,copingselfstate- personal value systems, ethno-cultural background, and ments and increased activity level) were associated with the availability of financial compensation. lower levels of psychosocial disability but higher lev- In performing a disability evaluation, the physician els of physical and total disability. Catastrophizing was should take a detailed medical, developmental, behav- highly associated with disability. ioral, and psychosocial history to assess a patient’s current and premorbid level of functioning, in an at- Fibromyalgia Subgroups tempt to understand why the patient is now seeking disability. There are no validated instruments for as- FM patients are a very heterogeneous population, and it sessing disability in people with FM. A useful practical is likely that different subgroups will display different resource for the assessment of FM related disability is levels of disability. The Multidimensional Pain Inven- the American Medical Association Guides to the Eval- tory (Kerns et al. 1985) has been used to classify FM uation of Permanent Impairment (2001). The chapter (# subjects into three groups. It was found that nearly 90% 18) on chronic pain notes that: (1) pain evaluation does of patients could be classified as dysfunctional, inter- not lend itself to strict laboratory standards of accuracy; personally distressed or adaptive copers. The dysfunc- (2) the evaluation of chronic pain cannot be made on tional and interpersonally distressed groups had higher the basis of the degree of tissue damage Ð the classical levels of disability. Observed physical function (cervi- medical model; (3) pain evaluation requires a thor- calspinemobility)waspositivelycorrelatedwithpatient ough understanding of a multi-faceted biopsychosocial perceived disability in the adaptive copers group but not model of disease; and (4) the physicians judgment of in the other two groups (Turk et al. 1996). impairment represents a blend of the art and science of medicine, and judgment must be characterized not so Work Conditions much by scientific accuracy as by procedural regularity. Work that is physically demanding, especially in ad- It acknowledges that physicians are often uncomfort- verse environmental conditions, is strongly associated able in evaluating chronic pain states, but notes that with disability in people with FM. An inability or re- they regularly make decisions on the basis of proba- luctance to modify work conditions and a lack of work bilities backed up by experience and stated in terms of autonomy are associated with disability (Teasell and reasonable medical probability. Bombardier 2001). There are several studies that have correlated higher scores on the Fibromyalgia Impact Questionnaire (FIQ) Associated Conditions with disability (White et al. 1999). There is one study FM is often associated with other disorders (e.g. irrita- that evaluated the work performance of FM and rheuma- ble bowel syndrome, multiple chemical sensitivity, irri- toid arthritispatientscompared to healthycontrolsusing table bladder, restless leg syndrome, depression, ortho- a computerized workstation to physically stress shoul- static hypotension) that often tend to act synergistically ders, cervical/thoracic/lumbar spine, wrists and elbows in causing disability. in a simulated work environment. People with FM were equally as impaired as the rheumatoid patients and Chronic Fatigue Syndrome were only able to perform 62% of the healthy control workload. A follow-up of 630 patients concluded: “there is sub- The various factors that seemingly influence the devel- stantial illness/related disability among those evalu- opment of disability in people with FM should also be ated Ð those reporting the most pervasive disability met considered: criteria for fibromyalgia either alone or in conjunction with chronic fatigue syndrome” (Assefi et al. 2003). Coping Strategies The lack of belief in one’s own ability to manage pain, Rheumatic Disorders cope and function despite persistent pain, is a significant FM is commonly a complication of other rheumatic dis- predictor of the extent to which individuals with chronic eases, such as rheumatoid arthritis, systemic lupus ery- pain become disabled and/or depressed. Therefore, ther- thematosus and Sjogren’s syndrome. In such instances, apy should target multiple goals, including: pain reduc- the impact of the central sensitization component of tion, functional improvement and the enhancement of FM amplifies the associated rheumatic symptoms and self-efficacy beliefs (Arnstein et al. 1999). increases disability (Naranjo et al. 2002). Disability Management 625

Depression Chronic Fatigue Syndrome and Fibromyalgia Compared to other Fatiguing Conditions. J Rheumatol 30:804Ð808 Mood disorders, especially depression, are a common 3. Bennett RM (2002) The Rational Management of Fibromyalgia accompaniment of chronic pain states. Depression by Patients. Rheum Dis Clin North Am 28:181Ð199 itself is, of course, a common cause of disability. When 4. Cocchiarella L, Andersson GBJ, American Medical Association depression is accompanied by chronic pain, disability is (2001) Guides to the Evaluation of Permanent Impairment, 5th magnified (Greenberg et al. 2003). edn. AMA Press, Chicago, pp 565Ð591 5. Greenberg PE, Leong SA, Birnbaum HG et al. (2003) The Eco- nomic Burden of Depression with Painful Symptoms. J Clin Psy- D chiatry 64:17Ð23 Prevention of Disability 6. Henriksson C, Liedberg G (2000) Factors of Importance for Gainful employment is a powerful force in fulfilling Work Disability in Women with Fibromyalgia. J Rheumatol 27:1271Ð1276 one’s obligations to society, maintaining self-esteem 7. Kerns RD, Turk DC, Rudy TE (1985) The West Haven-YaleMul- andachievingfinancialsecurity.Chronicpaininvariably tidimensional Pain Inventory (WHYMPI). Pain 23:345Ð356 produces an existential crisis as it changes a person’s 8. LiedbergGM, Henriksson CM (2002) Factors of Importance for perception of “self”. This often results in varying de- Work Disability in Women with Fibromyalgia: An Interview Study. Arth Rheum 47:266Ð274 grees of anxiety, depression and anger with loss of 9. Martin MY, Bradley LA, Alexander RW (1996) Coping Strate- self-esteem, reduced self-efficacy and functional de- gies Predict Disability in Patients with Primary Fibromyalgia. cline. Enabling fibromyalgia patients to continue with Pain 68:45Ð53 productive employment must be based on two major 10. Naranjo A, Ojeda S, Francisco F et al. (2002) Fibromyalgia in Patients with Rheumatoid Arthritis is Associated with Higher strategies, namely (1) optimal management of FM Scores of Disability. Ann Rheum Dis 61:660Ð661 symptomatology, and (2) a willingness to intercede 11. Park DC, Glass JM, Minear M et al. (2001) Cognitive Function in issues relating to job and workplace modifications in Fibromyalgia Patients. Arthritis Rheum 44:2125Ð2133 12. Teasell RW, Bombardier C (2001) Employment-Related Factors (Liedberg and Henriksson 2002). in Chronic Pain and Chronic Pain Disability. Clin J Pain 17:39Ð45 Theoptimalmanagementof FMsymptomatologyneeds 13. Turk DC, Okifuji A, Sinclair JD et al. (1996) Pain, Disability, and to be based on a multimodal approach to management Physical Functioning in Subgroups of Patients with Fibromyal- (Bennett 2002). At a minimum this involves attention gia. J Rheumatol 23:1255Ð1262 14. White KP, Speechley M, Harth M et al. (1999) Comparing Self- to the following issues: patient education, pain, fatigue, Reported Function and Work Disability in 100 Community Cases sleep, psychological distress, deconditioning and at- of Fibromyalgia Syndrome versus Controls in London, Ontario. tention to commonly associated disorders (e.g. irritable The London Fibromyalgia Epidemiology Study. Arthritis Rheum bowel syndrome). 42:76Ð83 15. Wolfe F, Anderson J, Harkness D et al. (1997) Work and A readiness on the part of physicians to act in an admin- Disability Status of Persons with Fibromyalgia. J Rheumatol istrative role in making recommendations to employers 24:1171Ð1178 is an essential component of minimizing disability in 16. Wolfe F, Smythe HA, Yunus MB et al. (1990) The American FM patients. In most cases, a careful workplace eval- College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. uation by an occupational therapist is an invaluable tool Arthritis Rheum 33:160Ð172 for making appropriate recommendations. Health care provider’sunwillingnesstoactonapatient’sbehalfoften resultsinadownhillspiralofincreasingworkplacestres- sors, depressive symptoms, and sense of victimization by people with FM. Thus, the prevention of disability in Disability Insurance Benefits people with FM ultimately depends on both the expert management of their symptoms, and a willingness to act pro-activelyontheirbehalfinsecuringappropriatework Definition place modifications. Monthly benefits provided for under the provisions of ti- If work efficiency and productivity progressively de- tle II of the Social Security Act. Entitlement to disability cline over several years of observation, in a patient who insurancebenefits(DIB)requiresthatanindividualmeet hasbeen cooperative in managementrecommendations, both medical and legal requirements defined by law and then the physician should recommend the patient seek regulations. disability and be prepared to help administratively in Disability Evaluation in the Social Security Admin- this process. istration

References 1. Arnstein P, Caudill M, Mandle CL et al. (1999) Self Efﬁcacy as a Disability Management Mediator of the Relationship between Pain Intensity, Disability and Depression in Chronic Pain Patients. Pain 80:483Ð491 2. Asseﬁ NP, Coy TV, Uslan D et al. (2003) Financial, Occupa- tional, and Personal Consequences of Disability in Patients with Disability, Effect of Physician Communication 626 Disability Management in Managed Care System

Differences between Group Health and WC that are Relevant Disability Management in Managed Care to Managed Care System Returning patients to health and function in a cost effec- BILL MCCARBERG tive manner appears to be the goals of both group health Pain Services, Kaiser Permanente and Univesrity of and WC. However, there are fundamental differences California School of Medicine, San Diego, CA, USA that make use of group health managed care techniques [email protected] problematic and difficult to implement in WC plans. The state defines the level of coverage and medical ser- Synonyms vices under WC, which are employer arranged under Pre-paid care; capitated care; managed care group health. There is salary replacement in WC, not in group health. Duration of coverage for a medical Definitions condition is generally longer for group health plans than for WC, because group health plans have an open “ Managed care” does not have a precise definition. In ended commitment to a patient, whereas WC systems ageneralway,itreferstosettingswheregroupsofhealth- move toward claim closure when a person reaches max- care providers use a systematic approach to the delivery imal medical improvement. Employee productivity is ofhealthcare.Managedcaresystemmaybemandatedby all important. Since medical costs are just a part of governmentalagencies, orbe established spontaneously expenses in WC, salary replacement costs must also by groups of physicians or health insurance companies. be considered. Up to 60% of WC plan costs are non Sometimes, the providers accept financial risk for the medical (Ducatman AM 1987), arguing for more ag- costs associated with medical care. However, fee-for- gressive, earlier intervention to return employees to the service medical treatment can also be provided accord- workplace. More medical resources are used to treat ing to a managed care plan. The key feature of managed injuries under WC plans than under group health plans care is that a set of guidelines is established to determine (Johnson WG et al. 1996), expenditures that may be how certain medical conditions will be treated. Thus, a appropriate given the added cost of lost work time. managed care system can be contrasted with a medical The principles of managed care do not easily translate community in which several solo practitioners or small in WC. Managed care describes a broad concept of ac- medical groups provide medical care based on informal, tive managementand controlovertheuse ofmedicalser- decentralized understandings about when specialty re- vices. Active oversight and control of medical services ferrals will be made, when certain diagnostics will be reduces costs and eliminates unnecessary expenditures performed, and so on. under this model. Gate keeping is a fundamental tool of managed care, controlling access to providers and ser- Characteristics vices. Many of the fundamental precepts used to control Amajorgoalofmanagedcareistoprovidecost-effective costin managed care may notapply totheworkers’com- treatment with the use of evidence-based guidelines. pensation system. Rising medical costs in the 1980s and 1990s led to The primary care physician is the gatekeeper in the attempts by insurers to move from traditional fee-for- group health model. All access to care must come service to managed care plans. Workers’ Compensation through this provider. The primary care provider is less (WC) plans did not join this push to managed care well trained in specific areas than specialists, but more (MC) and continued fee-for-service financing. As a familiar with the patient and his or her family. Since result of this different strategy, from 1985 to 1992, the primary care provider can adequately treat 90% annual medical expenditures for WC rose 45% faster of medical conditions, this is the natural place for a than group health plans (Workers Comp Res Inst gatekeeper. However, lack of familiarity with WC rules 1997). WC cash indemnity and medical benefits pay- and procedures on the part of primary care providers ments increased (Worker’s compensation costs 1992), can have deleterious consequences on disability and despite nationally declining prevalence rates of work costs when these providers treat injured workers. Con- disability (Prevalence of work disability-United States versely, expedient and appropriate care by physicians 1990) between 1980 and1990. familiar with the WC system has, in several studies, In an attempt to control costs, many states made a con- demonstrated reductions in disability and litigation, certed effort to embrace the tenets of cost-containment and improvement in patient satisfaction. Workers with already proven effective in managed care group mod- chronic work-related conditions often require ongoing els (BNA’s Workers’ Compensation Report 1993). The specialty care by musculoskeletal specialists, rendering use of managed care in workers’ compensation has in- the primary care provider less effective. creased 150% since 1991. With 75% of employers who In group health, the parties involved are the patient and use manage WC plans finding them effective in control- the primary care provider. In WC, besides these parties, ling costs. the insurance carrier, the employer, and not infrequently Disability Management in Managed Care System 627 alawyerarealsoinvolved.Therefore,duetoamorecom- resulting in significantly reduced medical expenditures plicated treatment environment in WC, the primary oc- (Cheadle et al. 1999). cupationalprovider(POP)maybeabetterchoiceasgate- The disadvantage to restricting choice is decreased keeper, and is being employed in many WC managed patient satisfaction. Whether in group health models or care plans (Greenberg EL et al. 1998). WC, restricting the patient’s ability to choose a provider Cost sharing is frequently used in group health man- leads to unhappy patients. Evaluations of Florida, Ore- aged care. Co-paymentfor appointmentsor medications gon and Washington State WC managed care plans, D alerts the patient to the cost of services, and provides an which use restricted networks, found that injured work- incentive for patients to use fewer resources. WC laws ers were significantly less satisfied than similar workers explicitly prohibit patient cost sharing. States require in traditional WC plans. These results were independent employers to pay all medical expenses. of treatment outcomes (Dembe 1998). The incentive structure in WC favors continued disabil- Case management is another managed care strategy that ity.Withsalaryreplacement,fullcoverageofmedicalex- can be used in both group health and WC. It is frequently penses and exemption of WC salary from most income utilized for diseases that require a lot of patient com- taxes, return to work can be a problem. Generosity of pliance, are labor intensive and costly if not managed WC benefits and duration of illness have been linked in aggressively. Examples in group health settings include a number of studies (Loeser JD et al. 1995). Managed HIV,diabetes and congestive heart failure. Examples in care techniques do not alter this inherent incentive bias WC include work-related traumatic brain injuries and to remain disabled. spinalcord injuries. Case managersareoftennurseswho Provider risk sharing is another strategy frequently work with physicians and other providers to maximize used in group health managed care. The reward system the coherence of a treatment plan. Case management is provides an incentive to providers to decrease medical employed in WC due to the need for close follow-up, expenditures. Capitation is an example of risk sharing, and the negative incentive for patients to return to work. where providers receive a flat fee (often monthly) for Coordinating this care leads to better outcomes and re- each health plan enrollee. This payment is independent duced costs. of medical resource utilization, thereby favoring the Something akin to case management can be used as a provider who manages the patient more efficiently. Less preventative strategy to reduce work related injuries. resource utilization produces higher profits. Case rate A physician/nurse team assigned to an employer with arrangements are another risk sharing technique. Un- specific repeated work related injuries can risk manage, der case rate agreements, the provider receives a set modify return to work policies and be the first con- payment for a given diagnosis. The provider is incen- tact for the employer/employee in injury and illness tivized to use fewer resources. Restricting care due to (Feldstein et al. 1998). This is an example of health profit concerns may be effective in group health models maintenance through preventative services, long under- where benign neglect produces favorable results in stood and practiced in managed care. More use of these many medical conditions. In WC, where early return strategies, through preventative safety engineering and to work is the goal, waiting and watching the patient ergonomic controls to abate workplace hazards and recover may defeat this goal. Capitation is losing favor prevent injuries, are another managed care which needs in group health plans, and is rarely used in WC. Case to be used (Robinson 1998). Many of these techniques rate arrangements are also less common in WC, since are difficult when individual providers offer care to early and aggressive intervention may cost more yet the injured worker, but are ideal organizational fits for return the patient to work sooner. managed care and workers’ compensation.

Opportunities for Effective use of Managed Care in WC When is a Medical Condition Work-Related Many strategies have been effectively utilized in man- Separating work-related injuries from general medi- aged care WC despite the differences listed above. Re- cal health is often artificial. A patient with a chronic stricted provider networks allow for improved patient low back condition may worsen with repetitive work care, by steering patients to providers with expertise and stresses. What part of the condition is related to work, competence in the management of occupational injury what part is the underlying chronic condition? Attempts and illness. In so doing, managed care organizations can to integrate group health and WC into one managed leverage their control over membership in provider net- care delivery system are problematic. The advantage of works to negotiate lower fees. Fewer providers allows keeping all services in one seamless system of care is forfewerbillingsources,therebydecreasingadministra- obvious and enticing. Unfortunately, the culture, struc- tive and management costs. A defined network of physi- ture and financing of the WC system create barriers cians also promotes standardized care based on treat- to such integration. In addition, healthcare providers, ment protocols, such as the ones that Aetna US Health- unfamiliar with management of work related injuries care publishes in Coverage Policy Bulletins. With re- and the WC system, often have difficulty providing stricted provider networks, standardized care is possible effective care. Several pilot programs were started 628 Disability Prevention but never really developed fully due to these obsta- Disability Prevention, Table 1 Disability Prevention: Changing the cles. paradigm Primary prevention Prevent workplace injuries and illnesses References Secondary Precent disability among workers with 1. Workers Comp Res Inst (1997) managed Care and Medical Cost prevention work-related injuries and illnesses Containment in Workers’ Compensation: a National Inventory, 1997-1998. Rep WC-97-6, Workers Comp Res Inst, Cambridge, Tertiary prevention Manage disability to reduce residual deficit MA and dysfunction 2. Worker’s compensation costs (1992) In: Medical Benefits. September:1-2. Panel Publishers Inc, New York, NY 3. Prevalence of work disability-United States (1990) MMWR 42:39 injury, when such disability would not normally be ex- 4. Managed care for workers’ compensation up 150%, new survey pected to result from the natural history of that injury. finds (1993) BNA’s Workers’ Compensation Report. The Bureau The term includes the integrated actions (healthcare, of National Affairs Inc, Washington, DC, pp 181-182 5. Ducatman AM (1987) The inevitable growth of workers’ com- workplace, administrative) implemented to prevent pensation costs. In: Workers Compensation Best’s Review. AM long-term disability. Three types of prevention may Best Company, Oldwick, NJ, pp 50-52,79-80 be defined in the context of work-related injuries (see 6. Johnson WG, Baldwin ML, Burton JF Jr (1996) Why is the treatment of work-related injuries so costly? New evidence from Cal- Table 1: 1) Primary prevention Ð prevention of the ifornia. Inquiry 33:53-65 work-related injury (Frank et al. 1996a), 2) Secondary 7. Greenberg EL, Leopold R (1998) Performance measurement in prevention Ð prevention of long-term disability after workers’ compensation managed care organizations. Occup Med an injury has occurred (disability prevention) (Frank 13:755-72 8. Loeser JD, Henderlite SE, Conrad DA (1995) Incentive effects et al. 1996b); and 3) tertiary prevention Ð prevention of workers’ compensation benefits: a literature synthesis. Med. of additional clinical consequences once long-term Care Res Rev 52:34-59 disability has become established. 9. Cheadle A, Wickizer TM, Franklin G et al. (1999) Evaluation Long-term disability (LTD)can be defined as having oc- of the Washington state workers’ compensation managed care pilot project II. Med Care 37:982-93 curred, if the worker is still totally disabled from gainful 10. Dembe AE (1998) Evaluating the impact of managed health care employment (temporary total disability) for a continu- in workers’ compensation. Occup Med 13:787-98 ous, or nearly continuous, period of 3Ð6 months follow- 11. Feldstein A, Breen V (1998) Prevention of work-related disabil- inginjury.LTDcanbesaidtobeestablishediftheworker ity. Am J Prev Med 14(3S):33-30 12. Robinson JC (1998) The rising long term trend in occupational is still disabled at one year, because after that time, the injury rates. Am J Public Health 78:276-281 chances of ever returning to full-time productive work at reasonable wages is likely less than 15%. Disability management, a common term in the insurance industry, appears to be applied to a variety of case management Disability Prevention interventions aimed at both secondary and tertiary prevention. Thus, from the standpoint of the strategic use of Gary M. Franklin1, Judith A. Turner,2 resources, it is not an accurate term applied to the devel- Thomas M. Wickizer3, opment of prevention strategies prior to 3Ð6 months of Deborah Fulton-Kehoe4, Robert D. Mootz5 disability.Theuseofthisgenerictermshouldbestrongly 1Department of Environmental and Occupational discouraged in relation to disability prevention. Health Sciences Characteristics 2Department of Psychiatry and Behavioral Sciences 3Department of Rehabilitation Medicine Introduction – Disability Prevention as a Critical Public Health 4Department of Health Services Issue 5Department of Environmental and Occupational The development of disability after non-catastrophic Health Sciences work-related injuries is a critical public health prob- − 1 4University of Washington, Seattle, WA, USA lem. The indirect cost to workers and employers, in 1,5Washington State Department of Labor and Indus- terms of loss of productive work life, is enormous tries, Olympia, WA, USA (Fulton-Kehoe et al. 2000). In terms of direct costs, [email protected] approximately 5Ð10% of all injuries are LTD, but they account for approximately 80 %of all claim costs Synonyms (Hashemi et al. 1997). This translates to billions of dollars nationally per year. More hidden costs of long- Secondary Prevention term work disability are the devastating psychosocial consequences Ð depression, relationship difficulties, Definition and social isolation are common. For these reasons, Disability prevention is the prevention of long-term dis- disability prevention is of the utmost importance in ability (LTD)that may develop followinga work-related achieving the goals of fiscal stability of the workers’ Disability Prevention 629

The best available data can only provide clues. Turner et al (Turner et al. 2000) and others (Cats-Baril and Frymoyer 1991) have conducted systematic reviews of the extensive literature, and only a few factors are strong and consistent predictors of chronic disability: older age, greater baseline pain, and greater baseline disability. Many other factors have been found in some D studies to predict disability, but have not been replicated in multiple studies. Such factors include the presence of radiating leg pain in association with lumbar injuries, smaller company size, certain types of heavy work (e.g. construction), and not receiving an early offer of work Disability Prevention, Figure 1 Disability prevention in the key health accommodation (Turner et al. 2000). policy issue (adapted from Cheadle et al. (1994) Am J Publ Health 84:190– Much of the early literature on this topic identified the 196). principal culprit in LTD as the “accident process” itself (Behan and Hirschfeld 1963). Unfortunately, much of this literature placed blame on the worker seeking un- compensation system, and of preventing workers from deserved benefits. However, actual worker fraud in the falling into the disability chasm. workers’ compensation system has never been shown Is There a Natural History of Disabling Injury? to account for more than a few percent of LTD cases. Most workers who experience disabling injuries (at Mostworkerswould never chooseto livethelifeofadis- least 3Ð4 days of lost work time) return to work within abled, socially isolated person. However, injured work- 4Ð6 weeks (see Fig. 1) (Cheadle et al 1994). The slope ers may not recognize warning signs of disability be- of the disability curve changes abruptly, however, at coming chronic, or actions taken that might result in in- 3 months. A worker who has 3 months of disability has creased disability. a 50% chance of remaining disabled at one year. By one year of disability, the curve is nearly flat and the Which Predictors of Disability are Most Likely Modifiable? likelihood of returning to work at reasonable wages is To achieve the goal of preventing chronic disability, it probably less than 15%. Five percent of all work-loss is logical to identify factors that are both predictive of injuries result in LTD, but only 10% of these could be chronic disability and modifiable. Table 2 outlines gen- considered medically severe (e.g. requiring hospital- eral categories of risk factors. In our view, organization ization in the first 28 days) (Cheadle et al. 1994). Thus, and type of medical treatment, the opportunity to return the majority of LTD cases begin as routine injuries to work early, and timeliness and accuracy of adminis- (e.g. back sprains), and most physicians who see these trative decision making are modifiable areas. In the do- workers soon after their injuries are unaware of the main of medical care, for example, the availability of potential for serious disability. occupational health resources and timely communica- The reason for this partially lays in the fact that physi- tion with the employer and insurer are likely to be crit- cian’ expectations of the natural history of most injuries ical for early return to work (Loisel et al 1997). In the are that they heal. How a common back sprain may actu- employment category, an early offer of accommodation ally worsen over time, so that a worker with a seemingly (job modification) was found to predict less disability mild injury is completely unable to function three years (Hogg-JohnsonandCole2003).Finally,delaysinclaims later, defies current medical understanding. administration decision-making can cause substantially Afallacyinthisfieldrelatestotheconceptof“healingpe- worse outcomes for workers (Herbert et al 1999). riods,” which indicate the expected time for an injury to resolve. Data underlying healing periods are based upon injury-specific actuarial analyses, similar to the disability curve in Figure 1. These guidelines incorporate little Disability Prevention, Table 2 General categories of risk factors. clinical evidence but merely present average statistical What are the key ∗Medical profiles,whichtakenoaccountofthemanycase-specific modifiable factors leading ∗Work barriers to recovery or return to work that lead to sub- to disability? ∗ stantial variation around the means. Failure to address Administrative thesebarriersinthetreatmentofinjuredworkersislikely Demographic to promote Ð not prevent Ð long-term disability. Economic Prediction of long-term Disability Psychosocial At this time, no method exists for accurately predicting Legal whichinjuredworkerswilldeveloplong-termdisability. ∗most modifiable 630 Disability Prevention

Attentiontothemoremodifiablecategoriesofpredictors Labor and Industries 1997). While all parties were more does not mean that other categories are less important, satisfied with claims management response times and only that their potential for disability preventionmay not service, significant disability prevention did not occur. beasrobust.Psychosocialriskfactorssuchasdepression Claims administration changes alone, in the absence and other psychiatric disorders, fear of re-injury, unhap- of significant healthcare delivery and employer-based pinesswithone’sjob,andfamilyissuesthatworkagainst interventions, are not likely to substantially prevent return to work may be associated with increased likeli- LTD. hood of chronic disability, butthese individualissuesare less easy to address in broadscale programmatic efforts. Conclusions Althoughdemographicfactors,suchasolderage,arenot Systematic strategies aimed at work-related injury cases modifiable,itisimportanttoidentifytheminriskmodel- prior to three months of disability are needed to achieve ing, and may be an important consideration in selecting disability prevention. This will require: 1) substantially workers for early intervention programs designed to fa- better data from population-based prospective stud- cilitate return to work. ies that identify the most significant and modifiable Litigation or retention of attorneys to assist with claims, risk-factors for development of LTD, 2) reorganiza- while much heralded as an important contributor to dis- tion of healthcare delivery with enhanced capacity to ability,islikelytobesignificantlyoverrated.Mostwork- deliver timely, occupationally-focused care in the first ers retain attorneys either because they have received in- six weeks after injury, 3) reassessment of the current sufficient information regarding their right to benefits, incentives and resources available to employers and or because there hasbeen an administrative decision that workers that are most likely to enhance early return to the worker may see as adverse to his/her interests. How- work, and 4) reorganization of claims management to ever, most workers do not retain attorneys until late in focus on disability prevention as a strategy distinct from the first year or in the second year following injury, well disability management, and with greater integration in beyond a secondary prevention timeframe (Wickizer et assisting the delivery of appropriate healthcare services. al. 2004). Until more complete models of disability prediction are developed, and broad systems changes are imple- Timing and Type of Interventions Likely to Prevent Disability mented, clinicians should closely monitor elapsed time To have a substantial impact on disability prevention, an since injury. If a worker has gotten to four weeks of lost intervention would need to occur prior to three months work time from a non-catastrophic injury, and return of disability, and ideally, prior to six weeks of disabil- to work is not imminent, occupational health expertise ity. However, targeting every worker for special man- should be sought to assist recovery and return to work. agement at an early stage would be unnecessary and not cost-effective (Battie et al. 2002). A more cost-effective References targeted approach is needed. 1. Battie MC, Fulton-Kehoe D, Franklin G (2002) The Effects of Reorganization of healthcare delivery, with an occu- a Medical Care Utilization Review Program on Back and Neck pational medicine focus, holds considerable promise Injury Claims. J Occup Environ Med 44:365Ð371 2. Behan RC, Hirschfeld AH (1963) The Accident Process. II. as a cost-effective means to prevent chronic disability Toward More Rational Treatment of Industrial Injuries. JAMA (Wickizer et al. 2001). As workers’ compensation laws 186:300Ð306 in most states rely on the attending doctors’ assess- 3. Cats-Baril WL, Frymoyer JW (1991) Identifying Patients at Risk ments of an injured workers’ ability to return to work, of Becoming Disabled Because of Low-Back Pain. The Ver- mont Rehabilitation Engineering Center predictive model. Spine the actions of these providers are critical to disability 16:60Ð607 prevention. A related area, with substantial potential 4. Cheadle A, Franklin G, Wolfhagen C et al. (1994) Factors Influ- for secondary prevention, is the availability of exper- encing the Duration of Work-Related Disability: A Population- Based Study of Washington State Workers’ Compensation. Am tise and resources to assist the return to work effort. J Public Health 84:190Ð196 Opportunity for workers to return to modified work is 5. Frank JW, Brooker AS, DeMaio SE et al. (1996) Disability key. In one randomized trial, for example, an employer- Resulting from Occupational Low Back Pain. Part II: What based labor-management team that assisted healthcare do we Know About Secondary Prevention? A Review of the Scientific Evidence on Prevention before Disability Begins. providers, and/or promoted worksite interventions such Spine 21:2918Ð2929 as ergonomic changes, faciliated, disability prevention 6. Frank JW,Kerr MS, Brooker AS et al. (1996) Disability Resulting compared to routine medical care (Loisel et al. 1997). from Occupational Low Back Pain. Part I: What do we Know Finally, it seems plausible that improved timeliness About Primary Prevention? A Review of the Scientific Evidence on Prevention before Disability Begins. Spine 21:2908Ð2917 and accuracy of claims administration decision-making 7. Fulton-Kehoe D, Franklin G, Weaver M et al. (2000) Years of would be critical, but not sufficient, to achieve disability Productivity Lost Among Injured Workers in Washington State: prevention. For example, we conducted a field-based Modeling Disability Burden in Workers’ Compensation. Am J LTD prevention trial randomizing workers by employer Ind Med 37:656Ð662 8. Hashemi L, Webster BS, Clancy EA et al. (1997) Length of to either an elite, resource-rich claims unit or to usual Disability and Cost of Workers’ Compensation Low Back Pain claims administration (Washington State Department of Claims. J Occup Environ Med 39:937Ð945 Disability, Upper Extremity 631

9. Herbert R, Janeway K, Schechter C (1999) Carpal Tunnel may be temporary or permanent and is defined by the Syndrome and Workers’ Compensation Among an Occupa- American Medical Association Guides to the Evalua- tional Clinic Population in New York State. Am J Ind Med 35: 335Ð342 tion of Permanent Impairment (AMA Guides) (AMA 10. Hogg-Johnson S, Cole DC (2003) Early Prognostic Factors for 2000) as an alteration in an individual’s capacity to meet Duration on Temporary Total Benefits in the First Year Among personal, social or occupational demands or statutory Workers with Compensation Occupational Soft Tissue Injuries. or regulatory requirements, because of an impairment. Occup Environ Med 60:244Ð253 11. Loisel P, Abenhaim L, Durand P et al. (1997) A Population- Impairment is the loss of a physiological function or of D Based, Randomized Clinical Trial on Back Pain Management. an anatomical structure. Evaluation of impairment is Spine 22:2911Ð2918 addressed in the AMA Guides (AMA 2000) and is de- 12. Turner JA, Franklin G, Turk DC (2000) Predictors of Chronic fined as a deviation from normal in a body part or organ Disability in Injured Workers: A Systematic Literature Synthesis. Am J Ind Med 38:707Ð722 system and its functioning. Impairment assessment is 13. Washington State Department of Labor and Industries (1997) deemed a medical evaluation, while disability is deter- Long-term Disability Prevention Pilots, Annual Report to the mined in an operational setting, such as the workplace Legislature or in a structured, functional capacity evaluation where 14. Wickizer TM, Franklin G, Plaeger-Brockway R et al. (2001) Improving the Quality of Workers’ Compensation Health Care observations are made of the individual’s capacity to Delivery: The Washington State Occupational Health Services carry out particular tasks or perform specified func- Project. Milbank Q 79: 5Ð33 tions. Therefore, an impaired person is not necessarily 15. Wickizer TM, Franklin GM, Turner JA et al. (2004) Use of At- disabled. torneys in Appeal Filing in the Washington State Workers’ Com- pensation Program: Does Patient Satisfaction Matter? J Occup Pain is an unpleasant perception associated with Environ Med 46:331Ð339 actual or potential cellular damage (Turk and Okifuji 2001). Pain is a concept, not a thing. People do not have pain; they experience the unpleasant effects of Disability Rating nociceptive stimulation or they suffer in ways that they associate with pain. Recognition of this point is basic Rating Impairment Due to Pain in a Workers’ Com- to understanding pain and suffering. If pain consisted pensation System solely of a hard-wired stimulus response capability, there would be no role for learning or other cognitive processes.Conversely,ifahard-wiredstimulusresponse capability were the defining characteristic of pain, neu- Disability, Upper Extremity roanatomical and pathophysiological parameters would suffice in dealing with pain, which, obviously, they do J. MARK MELHORN Section of Orthopaedics, Department of Surgery, not (Melhorn 2002b). Persistent pain in the absence of University of Kansas School of Medicine, Wichita, continuedtissuetraumaispathologicalandisinfluenced KS, USA by learned behaviors. [email protected] Nociception is the response to an unpleasant (noxious) stimulusthatproducespaininhumansubjectsundernor- Synonyms mal circumstances (Turk and Okifuji 2001). Acute pain is elicited by the injury of body tissues and activation of Disability; work related upper-extremity disorders; nociceptive transducers at the site of local tissue dam- WRUEDs; Impairment, Functions Loss; musculoskele- age. The local injury alters the response characteristics tal pains; MSPs; musculoskeletal disorders; MSDs/ of the nociceptors and perhaps their central connections MSPs; cumulative trauma disorders; CTDs; repetitive and the autonomic nervous system in the region. In gen- strain injuries; RSIs eral, the state of acute pain lasts for a relatively limited time and generally remits when the underlying pathol- Definition ogy resolves. This type of pain is often a reason to seek Disability arises out of an individual’s inability to care and occurs after trauma, surgery and some disease perform a task successfully because of an insufficiency processes (Melhorn 2002b). in one or more areas of functional capability: physical Chronicpainiselicitedbyaninjurybutmaybeper- function, mental function, agility, dexterity, coordina- petuated by factors that are both pathogenetically and tion, strength, endurance, knowledge, skill, intellectual physically remote from the originating cause. Chronic ability or experience. Disability is not necessarily re- pain extends for a long period of time and represents lated to any health impairment or medical condition, low levels of underlying pathology not explained by the although a medical condition or impairment may cause presence and / or extent of the pain. This type of pain or contribute to disability. Disability requires a con- frequently prompts patients to seek health care and is ceptual definition and is context specific. Disability is rarely treated effectively. Because the pain persists, it is the gap between what a person can do and what the likely that environmental and affective factors eventu- person needs or wants to do in a specific environment, ally interact with the tissue damage, contributing to the 632 Disability, Upper Extremity persistence of pain and illness behaviors. Additionally, The definition of disability and the determination of just as the brain is modified by experiencesespecially in who is disabled continue to challenge governments and early life, it may also alter the way noxious information adjudicating bodies and therefore expand and contract isprocessed to augmentor reduce itseffecton subjective more along political and ideological lines than accord- awareness (Melhorn 2002b). ing to any clear physical determinations. If the cost Musculoskeletalpain(MSP)isanypainthatmayinvolve of exclusion from the workplace, medical care, legal the muscles, nerves, tendons, ligaments, bones or joints. services and earning replacements are summed, the This pain can be real or anticipated. Musculoskeletal 1980 estimate was $177 billion or approximately 6.5% disorders (MSDs) is a term used to describe mus- of the gross domestic product (Demeter et al. 2001). culoskeletal pain that may include indeterminate At any given time, up to 45% of currently employed or specific ICD-9 diagnoses. Other terms, such as workers could file work related injury or disability cumulative trauma disorders (CTDs), repetitive stress claims, but most do not, choosing instead to carry out injury (RSI) and repetitive motion injury (RMI) mean their job responsibilities, accepting some discomfort as roughly the same thing as MSDs. However, RSI and part of living (Biddle et al. 1998). This ability to tolerate RMI are arguably inaccurate, because these terms imply discomfort is determined by the level of the biological that repetition is the primary risk factor, which may or stimulus (pain), existing psychosocial or biosocial is- may not be the case. Again, MSDs are not a medical sues and previous learned behaviors (Melhorn 2002b). diagnosis but a descriptive term for musculoskeletal Whenever one of these elements exceeds a personal pain (Melhorn 2002a). toleration level, health care is sought. Work related or work compensable are terms used to Individual risk factors for the development of disability describe or assign responsibility. Musculoskeletal dis- from the biological stimulus include age, gender and in- orders that are determined to be associated with the herited health characteristics, from psychosocialand/or workplace may be considered work related or work biosocial issues depression, current substance abuse, compensable based on each state’s legislative require- somatoform pain disorders, longer duration of symp- ments (United States Bureau of Labor Statistics 1996). toms, higher association of anxiety disorders, higher Work related musculoskeletal disorders (WRMSDs) levels of stress in life events and lower levels of lifestyle require two elements, an individual and a job. Each organization (goal directedness, performance focus and element has unique risk factors. WRMSDs often be- efficiency, timeliness of task completion and organiza- come work compensable and fall under the workers’ tion of physical space). Risk factors from previously compensation system. learned behavior include less time on the job, more surg- Workers’ compensation is designed to be a no-fault and eries, a higher frequency of acute antecedent trauma, exclusive remedy system. Although described as a sys- indeterminate musculoskeletal diagnoses, self-reported tem, it isn’t; each state, territory and federal employees higher pain levels, more anger with their employer, a have different and separate workers’ compensation laws greater psychological response or reactivity to pain, and regulations. The workers and their dependents are having an attorney and being involved in litigation with not required to prove fault for personal injuries, diseases their employer (Himmelstein et al. 1995; Sikorski et al. or deaths arising out of and in thecourse of employment. 1989). The employer agrees to provide rapid payment to the in- Workplace risk factors for the development of mus- jured worker for lost wages and medical care costs in culoskeletal pain include any part of the production exchange for limiting or eliminating the employer’s po- process (the manufacturing of a product). The produc- tential liability for said occupational illness, injuries and tion process usually includes input (raw materials), death and, thereby, the possibility of large tort verdicts. the production (methods, materials, machines, environment, physical stressors Ð such as repetition, force, Characteristics posture, vibration, cold temperatures, contact stress and Work related upper-extremity disorders are an in- static muscle loads, unaccustomed activities and com- creasingly common cause of work related muscu- binations thereof) and the output (the finished product) loskeletal pain and disability. Although most upper (Melhorn 1998). Asdiscussedbefore, theindividualrisk extremity disorders are acute and self-limited, a small factors become contributors, moderators and buffers as percentage of workers develop chronic nonmalignant to how the workplace may affect the individual for the musculoskeletal pain which can progress to permanent development of MSDs. disability and this group accounts for the majority of Preventing disability and musculoskeletal pain is chal- costs associated with WRUEDs. The progression from lenging. Physicians cannot prove or disprove the exis- symptoms to disability and how the disability might tence of pain clinically. With traumatic injuries occur- be prevented requires an understanding of the multiple ring at a rate of 7.1 per 100 equivalentfull-time employ- factors involved. ees in the private business sector at an estimated cost of Depending upon one’s definition of disability, between over $1.25 trillion, there is a need for better disability 35 and 46 million Americans can be labeled as disabled. management. Discharge Frequency 633

Since the risk for developing musculoskeletal pain and 7. Himmelstein JS, Feuerstein M, Stanek EJ et al. (1995) Work the associated disability is65 percentindividual risk fac- related upper extremity disorders and work disability: clinical and psychosocial presentation. J Occup Environ Med 37:1278Ð1286 tors and 35 percent workplace, the solution will require 8. Melhorn JM (1998) Management of Work Related Upper Ex- intervention for both (Melhorn et al. 2001). Rest is often tremity Musculoskeletal Disorders. Kansas Case Managers An- over-prescribed (Deyo et al. 1986). Healing is usually nual Meeting. Wesley Rehabilitation Hospital, Wichita, pp 16Ð25 rapid and is often promoted by motion (Nachemson 9. Melhorn JM (2002a) Cumulative Trauma Disorders (CTDs): The Science, Myths and Folklore. 16th Annual Scientific Ses- 1992). Rest, excessively or carelessly prescribed, may sion. American Academy of Disability Evaluating Physicians, D inhibit or interfere with healing while also encouraging Chicago deactivation. The problem is compounded if the task of 10. MelhornJM(2002b)Understanding and Managing Chronic Non- determining whether healing has occurred and activity malignant Pain for the Occupational Orthopaedists. In: Melhorn JM, Strain RE Jr (eds) Occupational Orthopaedics and Work- is now appropriate is assigned to the untrained patient, ers’ Compensation: A Multidisciplinary Perspective. American as by saying to the patient, “Let pain be your guide” to Academy of Orthopaedic Surgeons, Rosemont determine when to terminate rest and resume activity 11. Melhorn JM, Wilkinson LK, O’Malley MD (2001) Successful (Fordyce et al. 1986). Often, the result of this arrange- management of musculoskeletal disorders. J Hum Ecolog Risk Assessment 7:1801Ð1810 ment is that the patient, on moving, experiences some 12. Nachemson AL (1992) Newest knowledge of low back pain. A discomfort and interprets it to mean that healing has critical look. Clin Orthop 8Ð20 not occurred and that continued movement may impair 13. Sikorski JM, Molan RR, Askin GN (1989) Orthopaedic basis healing. The patient then moves less, thereby increasing for occupationally related arm and neck pain. Aust N Z J Surg 59:471Ð478 the adverse effects of disuse and making it more proba- 14. Turk DC, Okifuji A (2001) Pain terms and taxonomies of pain. ble that future movement of the involved body part will Bonica’s Management of Pain. Lippincott Williams & Wilkins, be painful. Thus begins a vicious circle. Each painful Philadelphia, pp 17Ð25 15. United States Bureau of Labor Statistics (1996) Survey of Occu- movement is interpreted to reaffirm that healing has not pational Injuries and Illnesses in 1994. United States Government occurred and encourages greater disuse and more pain. Printing Office, Washington It also pairs movement with events in the environment that, through conditioning, become cues capable of eliciting more discomfort. In sum, the pain problem may persist and worsen despite adequate healing, be- Disability-Litigation System cause the consequences of use and movement were misinterpreted secondary to ambiguous clinician guid- Definition ance. Behavior that avoids or postpones an anticipated A method of compensation that rewards injured workers aversive consequence, known as avoidance learning, for non-function or the inability to recover. has been studied in clinical pain (Fordyce et al. 1982). Pain in the Workplace, Risk Factors for Chronicity, Therefore, physicians should discourage patients from Job Demands prolonging disability beyond medical necessity. This will require a more aggressive approach to pain control; prevention of unnecessary surgery, directed efforts to improve patients’ abilities to manage residual pain and Disc Displacement distress and attention to employer-employee conflicts may be important in preventing the development of Definition prolonged work disability in this population. Thecartilaginousdisc,interposedbetweenthemandibu- larcondyleandthefossaofthetemporomandibularjoint, may get displaced. Most often an anterior disc displace- References ment occurs, which may give rise to clicking noises dur- 1. AMA (2000) Philosophy, Purpose, and Appropriate Use of the ing mandibular movement. If the disc is displaced per- Guides. In: Cocchiarella L, Andersson GBJ (eds) Guides to the Evaluation of Permanent Impairment. American Medical Press, manently, a locking of the joint occurs that is habitually Chicago, pp 1Ð16 accompanied by a limitation of mandibular movement. 2. Biddle J, Roberts K, Rosenman KD et al. (1998) What percentage Orofacial Pain, Taxonomy/Classification of workers with work-related illnesses receive workers’ compensation benefits? J Occup Environ Med 40:325Ð331 3. Demeter SL, Andersson GBJ, Smith GM (2001) Disability Eval- uation. Mosby, St. Louis, MO 4. Deyo RA, Diehl AK, Rosenthal M (1986) How many days of Discharge Frequency bed rest for acute low back pain? A randomized clinical trial. N Engl J Med 315:1064Ð1070 5. Fordyce WE, Shelton JL, Dundore DE (1982) The modification Definition of avoidance learning pain behaviors. J Behav Med 5:405Ð414 The number of times a neuron produces an action po- 6. Fordyce WE, Brockway JA, Bergman JA et al. (1986) Acute back pain: a control-group comparison of behavioral vs traditional tential in a given unit of time. management methods. J Behav Med 9:127Ð140 Encoding of Noxious Information in the Spinal Cord 634 Discharge Pattern

with recumbency. Schwarzer et al. (1995) found no clin- Discharge Pattern ical features that could reliably distinguish patients with discogenic pain from those with other sources of low Definition back pain. The leg pain that arises from a symptomatic Particular form in which action potentials are fired in a annular tear may be mistaken for a true radiculopathy, given period of time. but typically extends into the dorsal thigh and rarely ex- Mechanonociceptors tends below the knee. Physical examination reveals no neurological deficits. On close observation, there may be a tendency for frequent changes in position and a relative intolerance to sitting, especially forward flexion. Discogenic Back Pain

1 VIVEKANANDA GONUGUNTA , Diagnosis 1, 2 EDWARD C. BENZEL 1 Plain spine radiographs are warranted to rule out verte- The Cleveland Clinic Foundation, Department of bral instability, but otherwise are not helpful. Neurosurgery, Cleveland, OH, USA 2 MRI (Fig. 1) is the single most sensitive and most The Cleveland Clinic Foundation, Cleveland Clinic specific investigation to exclude neoplasms, infections, Spine Institute, Cleveland, OH, USA soft tissue or neurologic lesions and disc herniations. [email protected] HIZ, or a high intensity zone, on T2 weighted images is a unique finding of a discrete bright zone within Synonyms the dorsal annulus fibrosus. It is felt to represent ei- Black Disc Disease; Dark Disc Disease; Symptomatic ther disc material visualized within an annular tear, Annular Tear or edema fluid located within the dorsal annulus. This may represent the site of pain; however, it may also Definition be asymptomatic. Endplate changes in the adjacent Discogenic low back pain is defined as axial lum- vertebral bodies (Modic changes, described by Modic bar/lumbosacral pain originating from the intervertebral disc and disc space due to degenerative changes. In 39% of low back pain (LBP) patients, the pain is discogenic in nature (Schwarzer et al. 1995) and should be differentiated from LBP of other causes like spinal instability, facet arthropathy, tumor, infection, etc. Pathophysioloy The intervertebral disc is supplied with pain fibers from sympathetic chain via the sinuvertebral nerve that inner- vates the periphery (outer six layers) of the annulus fibrosus. Pain occurs when these nerve fibers are stimulated directly by annular tears or by noxious breakdown products of the nucleus pulposus extending into the tear. Following injury to the annulus, sprouting of fibers into the site of injury has also been observed and may be a factor in the formation of a symptomatic annular tear. A varietyofinflammatoryagentslikeTNFα,IL-8,IL-6,nitric oxide, phospholipase A2 and others are expressed by the nucleus pulposus. They may stimulate and sensi- tizethenerveendings,causinglowbackpain(Hurrietal. 2004). They may even sensitize the dorsal root ganglion and spinal nerve root, causing radiculopathy. However, not all patients with degenerated discs have symptoms and, vise versa. Characteristics Pain is usually of gradual onset. It is characterized as a low back pain that may extend to the buttock, hip, groin Discogenic Back Pain, Figure 1 T2 weighted MRI of lumbar spine in a or even a lower limb. A hallmark ofa symptomatic annu- patient with chronic back pain showing a black disc at L5-S1, a sign of lar tear is characterized by sitting intolerance and relief disc dehydration. Discogenic Back Pain 635

and avoidance of smoking are the best ways of preventing painful disc disease. Treatment Treatment begins with conservative therapy. This in- cludesphysicaltherapy, weightloss, NSAIDsand rarely opioids in patients who have failed conservative therapy D or who are not candidates for invasive therapy. Invasive therapies can be subclassified into surgical and non-surgical.Non-surgicalmeasures include chemonucleolysis, IDET (intradiscal electrothermal therapy), nucleoplasty, PIRFT, laser discectomy etc. Various injectiontherapieslikeepiduralinjections,nerveblocks, facet injections etc. are other forms of treatment that are described elsewhere. Chemonucleolysis Lyman W. Smith first performed this procedure in 1963 to decompress a contained disc herniation. This involved percutaneous injection of chymopapain into Discogenic Back Pain, Figure 2 Post discography axial lumbar CT image demonstrating ’annular tear’ in the form of contrast leak into the annulus. the nucleus pulposus causing chemical dissolution, i.e. breaking down the proteoglycans in the nucleus. It is rarely used today in the United States due to the et al. 1987), especially Modic Type 1 may be associated reports of tranverse myelitis, paraplegia and death from with discogenic pain. anaphylactic reactions. Provocative discography involves injection of water- Annuloplasty (IDET – Intradiscal Electrothermal soluble contrast media into the involved disc, and a Therapy) control disc under fluoroscopy to determine if patient’s symptoms are reproduced, i.e. determining the level of First described by Saal and Saal in 1997, this technique concordance based on the development of the patient’s involves heating the posterior annulus with a thermal typical referred pain. With the increased sensitivity of resistive coil (similar to capsuloraphy-radiofrequency MRI, it is often difficult to identify the symptomatic treatment in arthroscopy that is designed to alter colla- disc and, hence, discography is advocated by many sur- gen fibers and to in turn stabilize the joint capsule) in an geons to resolve the issue. However, the reliability of the attempt to repair, denervate and stabilize an annual tear. patient response is fundamental to discography, which The theory of annuloplasty is based on thermal energy impacts sensitivity and specificity of the test. False pos- causing collagen fiber reorganization and denervation itive discography is likely to occur predominantly in of the annulus. However, the heat generated might be patients with abnormal psychometric testing, multiple sufficient enough to cause neurolysis of nociceptive somatic complaints and previous back surgery. Post- fibers to produce pain relief. Inclusion and exclusion discography CT scan (Fig. 2) can provide additional criteria for IDET are well summarized by Davis et al. information regarding anatomic abnormalities. as follows (Davis et al. 2003): Diagnostic anesthetic injections such as facet injections Inclusion Criteria (intra-articular injections or medial branch blocks) and • Unremitting, persistent low back pain of at least 6 sacroiliac joint injections are also used to identify the months’ continuous duration source of pain. These strategies are based on the premise • Lack of satisfactory improvement with a comprehen- that the pain generator is a single discrete identity, that sively applied non-operative care program including: the anesthetic blockade affects only the intended pain back education, activity modification, a trial of man- generator, and that it has no overlap with other nerves ual physical therapy, etc. or tissues. • Normal neurological exam Finally, CT scan and/or CT myelography are useful in • MRI that does not demonstrate a neural compressive patients who are unable to undergo MRI because of im- lesion planted metal or claustrophobia. • Positive concordant discography Prevention The degenerative process begins from the disc at the be- Exclusion Criteria ginning of the second decade of life. It is felt that ade- • Inflammatory arthritis quate physical exercise, minimization of harmful loads • Non spinal conditions that could mimic lumbar pain 636 Discogenic Back Pain

• Medical or metabolic disorder that would preclude plication rates and difficulty accessing the L5-S1 disc, appropriate follow-up and participation especially in obese patients. • Previous surgery at the proposed level • Overlying psychologic issues APLD (Automated Percutaneous Lumbar Discectomy) • > 50% disc height loss, instability First described by Onik et al. (1985), this procedure • Extruded or sequestered disc involves insertion of an 8-inch long probe through a Saal and Saal (2002) reported success rates of approx- 2.5 mm cannula positioned against the annulus fibrosus, imately 70% in their first studies, whereas other stud- and the probe is used both as a cutting instrument and iesfound successratesvarying from 23Ð60%depending for aspiration of disc material. Success rates ranged heavily on patient selection. The best results were ob- from 29Ð80% (Chatterjee et al. 1995, and Revel et al. served in patients with lesions confined to one quadrant 1993). of the posterior half of the disc, with 80% of disc height Laser Discectomy preserved and with a nearly intact annulus (Karasek et al. 2000). A large, randomized, double blinded, placebo Laser energy, using a variety of lasers like potassium- controlled trial measuring outcomes post IDET demon- titanyl-phosphate (KTP), neodymium:yttrium-alumin- strated an apparent benefit at short term follow up of 6 ium-garnet(Nd:YAG), holmium:YAG(Ho:YAG) is uti- months;however,longerfollow-uphasyettobereported lized to vaporize a part of the nucleus volume to debulk on these patients (Pauza et al. 2002). The procedure is the space and decrease discal pressure causing regres- safewithoccasionalcomplicationsofcatheterbreakage, sion of disc protrusion. The choice of laser depends on superficial skin burns and very rarely cauda equina syn- its ability to deliver energy through a fiberoptic system, drome or bladder dysfunction, hence, reversal of con- tissue absorption/ablationproperties, and the amount of scious sedation during the heating process is required thermal generation and spread (Chen et al. 2004). to evaluate neurological function. Surgical Treatment Nucleoplasty Open surgical treatment is reserved for carefully se- Approved by FDA in 2001 for treatment of contained lected patients who failed the optimal medical and less herniated discs, this is a non-heat-driven process utiliz- invasive treatments listed above. Lumbar spinal fusion ing Coblation technology Ð abipolar radiofrequency de- is the gold standard surgical procedure, which involves vice to create a localized energy field that dissolves tis- a discectomy (to eliminate the ‘pain generator’), and sue without excessive heating. The advantages claimed then performing fusion between the two vertebrae us- with the technique are minimal collateral tissue damage ing bone graft (to stabilize the spine). Fusion is often and thermal penetration while allowing tissue removal. supplemented with instrumentation to achieve a solid A slightly curved wand with a bipolarcoil at the distal tip bony union. The spinal canal and nerve roots can also is placed into the center of nucleus and the coil creates a be decompressed during the procedure as necessary. plasma field, which transforms the water content of the Various types of spinal fusion, indications and compli- discinto hydrogen and oxygen. Usually,thediscvolume cations of spinal fusion are discussed in another chapter canbereducedby1ccor10%,whichcausesdecompres- of spinal fusion. sion of the disc. Pain reduction is due to a decrease in New technologies are also evolving as alternative to intradiscal pressure and hence used only for smaller disc spinal fusion, which include nucleus pulposus replace- protrusionsand low-pressuresensitivediscs. Singh etal. ment and total disc replacement by prosthetic devices (2002) reported that 80% of patients (n = 67) obtained similar to artificial joint replacements in orthopedic statistically significant improvement in pain scales pre- field. served over 1 year. Nucleoplasty can be combined with heating treatments like IDET. References PIRFT (Percutaneous Intradiscal Radiofrequency 1. Chatterjee S, Foy PM, Findlay GF (1995) Report of a Controlled Thermocoagulation) Clinical Trial Comparing Automated Percutaneous Lumbar Dis- cectomy and Microdiscectomy in the Treatment of Contained A radiofrequency lesion is made in the nucleus pulpo- Lumbar Disc Herniation. Spine 20:734Ð738 sus, using the disc material as a vehicle for heat, causing 2. Chen Y, Derby R, Lee S (2004) Percutaneous Disc Decompres- thermal fibrosis which reduces nociceptive input from a sion in the Management of Chronic Low Back Pain. Orthop Clin N Am 35:17Ð23 painful intervertebral disc. 3. Davis TT, Sra P, Fuller N et al. (2003) Lumbar Intervertebral Thermal Therapies. Orthop Clin N Am 34:255Ð262 Percutaneous Manual Nucleotomy 4. Hurri H, Karppinen J (2004) Discogenic Pain. Pain 112:225Ð228 This technique involves annular puncture and allowing 5. Karasek M, Bogduk N (2000) Twelve Month Follow-Up of a the disc to extrude into the retroperitoneum and not into Controlled Trial of Intradiscal Thermal Annuloplasty for Back Pain Due to Internal Disc Disruption. Spine 25:2601Ð2007 the spinal canal, using specialized forceps and curettes. 6. Modic MT, Steinberg PM, Ross JS et al. (1987) Imaging of De- Thisisnotwidely practiced oraccepteddue tohighcom- generative Disk Disease. Radiology 163:227Ð231 Disruption 637

7. Onik G, Helms CA, Ginsburg L et al. (1985) Percutaneous Lum- Postsynaptic Dorsal Column Projection, Functional bar Disketomy using a New Aspiration Probe. Am J Roentgenol Characteristics 144:1137Ð1140 8. Pauza K, Howell S, Dreyfuss P et al. (2002) A Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy of Intradiscal Electrothermal Annuloplasty (IDET) for the Treat- Disease Modifying Antirheumatic Drugs ment of Chronic Discogenic Low Back Pain: 6 Month Outcomes. International Spinal Injection society. 10th Annual Meeting, Sept 7, 2002. Austin, Texas Synonyms D 9. Revel M, Payan C, Vallee C et al. (1993) Automated Percutaneous Lumbar Discectomy versus Chemonucleolysis in the Treatment DMARDs of Sciatica. A Randomized Multicenter Trial. Spine 18:1Ð7 10. Saal JA, Saal JS (2002) Intradiscal Electrothermal Treatment for Definition Chronic Discogenic Low Back Pain: A Prospective Outcome Disease modifying antirheumatic drugs (DMARDs) Study with Minimum 2 Year Follow-Up. Spine 27:966Ð973 11. Schwarzer AC, Aprill CN, Derby R et al. (1995) The Prevalence are used to treat chronic inflammatory diseases such as and Clinical Features of Internal Disc Disruption in Patients with rheumatoid arthritis: they target immune cells in order Chronic Low Back Pain. Spine 20:1878Ð1883 to inhibit the cellular inflammatory response. Examples 12. Singh V, Piryani C, Liao K et al. (2002) Percutaneous Disc De- are methotrexate, lefunomide, and cyclosporine. compression using Coblation (Nucleoplasty) in the Treatment of Chronic Discogenic Pain. Pain Phys 5:250Ð259 Neutrophils in Inflammatory Pain NSAIDs and their Indications

Discogenic Pain Disinhibition

Definition Definition Pain due to an abnormality of the vertebral disc. Excitation due to an inhibition of inhibitory processes. Chronic Back Pain and Spinal Instability Stimulation-Produced Analgesia Chronic Low Back Pain, Definitions and Diagnosis

Disinhibition of Nociceptive Neurons Discordant Illness Behaviour Definition Hypochondriasis, Somatoform Disorders and Abnor- A loss of inhibitory control of nociceptive neurons, mal Illness Behaviour which is normally exerted by GABAergic and glyciner- gicneuronsinthespinalcorddorsalhorn,isincreasingly recognized as a major source of chronic pain. It can Discriminability result from inhibition of glycine or GABA receptors, or reduced GABA or glycine release, apoptotic death Definition of GABA and glycinergic neurons and from changes in the chloride gradient, which renders GABAergic and Discriminabilityreflectsthecapacityfordetectionofthe glycinergic input less inhibitory. presence of a stimulus or differences between stimuli, GABA and Glycine in Spinal Nociceptive Processing usually those of intensity. Pain in Humans, Psychophysical Law Pain Measurement by Questionnaires, Psychophysi- cal Procedures and Multivariate Analysis Displacement Social Dislocation and the Chronic Pain Patient Discriminative Information Disposition Definition Input distinguishable in time, place and intensity to Personality and Pain which specific receptors in the skin are receptive. Refers to the processes that underlie localization and identification of the stimulus and its intensity, which Disruption can be differentiated by sensory afferent nerve fiber endings. Social Dislocation and the Chronic Pain Patient 638 Dissection

Dissection Distractibility

Deﬁnition Deﬁnition Separation of (usually arterial) vessel wall layers by an Tendency to give attention to any stimulus regardless of intramural hemorrhage. its relevance. Headache due to Dissection Hypervigilance and Attention to Pain

Dissociation Distracting Responses

Definition Definition Separation or detachment from one’s immediate en- Distracting responses refer to cues from significant oth- vironment; or the compartmentalization of various ers intended to encourage alternative, presumably more components of conscious experience. Hypnotic anal- adaptive, well behaviors (e.g. increased activity, use of gesia may be achieved, for example, by encouraging distraction to cope with pain) on the part of the person the subject to detach him or herself from the procedure experiencing pain. room, or detach from the painful body part. Spouse, Role in Chronic Pain Therapy of Pain, Hypnosis

Distraction Dissociative Imagery Deﬁnition Deﬁnition The use of materials to provide alternative sensory stim- Dissociative imagery is that form of imagery that is dis- ulationfortheinfantduringapainfulprocedure(e.g.mu- sic, mobiles). connected from the felt sense of the body. Hypnotic Analgesia Acute Pain Management in Infants Psychological Treatment in Acute Pain

Dissociative Sedation Distraction Signs

Definition Lower Back Pain, Physical Examination A trance-like cataleptic state induced by the dissociative agentketamine and characterized by profound analgesia and amnesia, usually with the retention of protective air- way reflexes, spontaneous respirations, and cardiopul- Distribution monary stability. Pain and Sedation of Children in the Emergency Set- Definition ting The distribution characterizes the reversible transfer of a drug or a substance into regions within the body. NSAIDs, Pharmacokinetics Distal Axonopathy

Deﬁnition Disuse Syndrome Peripheral nerve disorders beginning from degeneration Deﬁnition of the most terminal parts of both central and peripheral processes of neurons, the major pathology of toxic neu- Decreased level of physical activities in daily life, in the ropathies; also central-peripheral distal axonopathy and long-term leading to physical deconditioning. dying-back neuropathy. Disability, Fear of Movement Toxic Neuropathies Muscle Pain, Fear-Avoidance Model Diurnal Variations of Pain in Humans 639

psychogenic and organic aetiology: highest concen- Diurnal Variations of Pain in Humans trations were found in January and February, whereas GASTON LABRECQUE lowest concentrations occurred in July and August (see Faculty of Pharmacy, Université Laval, Quebec City, Labrecque and Vanier 1997; Labrecque and Vanier Montreal, QC, Canada 2003 for references). Thus, time-dependent variations [email protected] in pain level and/or in the requirements for analgesia should be expected in patients with pain. D Synonyms Circadian Rhythms in Human Pain 24-hour variation; biological rhythms; Circadian Vari- ations in Pain Level Patients often complain that pain intensity increases in the evening or at night. This phenomenon is usually ex- Definition plained by fatigue related to daily activity, or to the anxiety induced by the incoming sleeping period, or by the Diurnal changes in pain intensity usually mean that the departure of the family visitors. Clinicians rarely con- bouts of pain occur during the daytime. However, pain sider that the pain level changes specifically during the intensityfluctuatesthroughoutthedayandnight,andpa- dayornight,buttheyforgetthattime-dependentchanges tients often report that peak pain occurs at specific hours have been documented in hospitalised and outpatients. of the day. In this case, we will talk about biological In fact, these studies showed that the hour of highest and rhythms or circadian variations (about 24 h) in pain lowest pain level is specific for each painful stimulus. level. Table 1 shows that pain related to the onset of cardiovas- Characteristics cular events is found very early in the morning, while the peak in the frequency of migraine and toothache is Pain is one of the most common symptoms for which largest in the morning. On the other hand, the peak of patients seek advice and help from health profes- biliary colic, intractable and low back pain was found in sionals. This is a complex, subjective and unpleasant the evening. In cancer patients, most studies were car- phenomenon influenced by factors such as anxiety, ried out in patients receiving opioid analgesics, and they fatigue, suggestions or emotions and prior experience. were mainly concerned with the pain relief produced by Pain is rarely constant, and patients usually report bouts these drugs. For instance, Sittl et al. (1990) reported that of pain throughout the 24 h period. Using the Visual cancer pain was largest by 6 pm. Other studies are ob- Analog Scale (VAS), many studies have indicated that viously needed in cancer patients and it would be inter- the intensity of pain varied specifically during the day esting to find whether the hour of pain varies with the or the night spans. Clinicians must rely on the patient’s causes and/or the severity of this disease. evaluation of pain intensity to decide which and how The hour of arthritic pain deserves a special note, be- much drug must be prescribed, and when it must be cause the time of peak pain varies according to the cause taken by the patient. Information on biological rhythms of arthritis. In patients with rheumatoid arthritis (RA), of pain can be used to maximise the effect of analgesic theintensityofpainishighestatthebeginningoftheday, drugs and/or to minimise their side effects. A recent whereasitoccurred late in the afternoon, atthe end of the literature review summarises the information regarding day in patients with osteoarthritis (OA) of the knee (Bel- rhythms, pain and pain management (Labrecque and lamy et al. 2002; Kowanko et al. 1981; Lévi et al. 1985). Vanier 2003). It must be pointed out that inter-individualdifferences in Rhythms in Endogenous Opioid Peptide Levels the hour of highest pain intensity were reported in OA patients. Studies by Lévi et al. (1985) and Bellamy et In the last 25 years, data obtained from laboratory ani- al. (2002) indicated that most OA patients reported peak mals indicate the existence of 24 h variations in plasma pain between 4 pm and 11 pm, but they also reported that and brain concentrations of β-endorphin or enkephalin: morningpainwashighestinthemorningin5%oftheOA peak values were obtained late during the resting pe- patients, while about 10% of these patients did not find riod or at the beginning of the activity period. Similar any rhythmic changes in the intensity of their arthritic data were obtained in healthy volunteers and pregnant pain. These disease-related and the inter-individual dif- women: the highest β-endorphin plasma levels occurred ferences in the hour of arthritic pain should be taken into between 6 and 8 am, while the lowest levels were found account when prescribing anti-arthritic medications. between 8 pm and midnight. It is also interesting to point out that a 2 fold rise in the plasma endogenous opioid peptide was found in the last semester of the pregnancy. Biological Rhythm and the Effect of Medications This time-dependent variation was not found on the The circadian variation in arthritic pain can be used to 4th day after delivery (2). Finally, a circannual vari- maximise the effect of non-steroidal anti-inflammatory ation of endorphin levels was reported 20 years ago agents (NSAIDs). For instance, it was shown that RA in the CSF of patients with chronic pain syndrome of patients must take an evening dose of flurbiprofen to 640 Diurnal Variations of Pain in Humans

Diurnal Variations of Pain in Humans, Table 1 Biological rhythms of pain in patients (see Labrecque and Vanier 1997, 2003 for references) Causes of pain No. Patients Hours of peak Hours of trough

Anginal pain 7788 6 am –noon Midnight–6 am

Unstable angina 2586 8–10 am 2–4 am

Myocardial infraction 1229 5–9 am 703 5–10 am

Biliary colic 50 11 pm–3 am 9 am–1 pm

Cancer pain 130 6 pm 4–10 am

Heavy burns 9 8 am–4 pm Midnight–8 am

Intractable pain 41 10 pm 8 am

Migraine 15 10 am Midnight 117 8 am–noon Midnight 114 4–8 am noon

Osteoarthritis of the knee 20 10 pm 2–6 am 57 2pm–10pm 7am 4 7–11 pm

Rheumatoid arthritis 19 6–8 am 6 pm

Toothache 543 8 am 3 pm

control morning stiffness and pain (Kowanko et al. or abdominal surgery was 18% larger at 9 am than at 1981). In OA patients, a multicenter study was carried 9 pm. Similar data was obtained in post-surgical cancer out to answer the question often asked by patients: patients (Auvril-Novak et al. 1990), but morning and When should I take this once-daily NSAID? The opti- evening peaks in opioid demands were reported by mal time of administration for each patient was related others (Labrecque and Vanier 1997; Labrecque and to the time of peak pain. The evening administration Vanier 2003). of indomethacin was most effective in patients with Only 2 groups of investigators looked at the temporal a predominantly nocturnal pain, while drug ingestion changes in the effect of opioids in patients with chronic around noon was best for patients with peak pain oc- pain. In patients with chronic cancer pain and in patients curring late in the afternoon or early in the evening. The with metastasis, the dosesof Mo or Hmwassignificantly analgesic effect of the NSAID was increased by 60% larger late in the afternoon or early evening (Vanier et when the medication was taken at the time preferred al. 1992; Wilder-Smith and Wilder-Smith 1992).On the by the patients (Lévi et al. 1985). Furthermore, double- otherhand,theModosesrequiredtoreducethepainlevel blind crossover trials indicated that the frequency of ofpatientswithheavyburnsweresignificantlylargerbe- side effects of sustained-release indomethacin (Lévi tween 8 am and 4 pm, because this is the time of the day et al. 1985) and ketoprofen (Boissier et al. 1990) was for daily personal health by nurses and/or physiother- significantly larger when these drugs were taken at 8 am apy treatment (see Labrecque and Vanier 2003 for refer- than at 8 pm. Thus, appropriate selection of the time of ence). Finally, Bruera et al. (1992)reviewedthedistribu- ingestion of the well-established NSAIDs can increase tion of the extra doses of opioids received by 61 patients their effectiveness, and it may reduce the side effects admitted to a palliative care unit at 4 h intervals over 24 h of the well-established agents. Unfortunately, there is period. The data indicated that 76% of the patients re- no data for the newer NSAIDs, such as celecoxib and ceived their extra doses between 10 am and 10 pm than rofecoxib, but it is expected that biological rhythms can during the sleeping period; the number of extra doses also be used to maximise their effectiveness. duringthisperiodofdaywas60%largerduringthenight. Very few investigators have studied the temporal vari- As pain can easily be altered by many factors such as ation in the effects of morphine and other opioids in anxiety, suggestions and emotion, it is interesting to patients with acute pain. In acute surgical pain, the determine whether biological rhythms can be found demands for morphine (Mo) or hydromorphone (Hm) in the effect of placebo. To our knowledge, Pöllmann administered with a patient-controlled analgesia (PCA) (1987) is the only investigator who evaluated this effect device were largest in the morning than in the evening. of placebo on pain relief. When healthy individuals For instance, Graves et al. (Graves et al. 1983) reported ingested a sugar-coated placebo tablet in the morning, that the demands for Mo by patients with gastric bypass the pain threshold was increased by 25Ð30% between Dizziness 641

9 am and 9 pm. When administered at night, the placebo via Patient-Controlled Analgesia in Post-Operative Gynecologic did not produce any analgesic effect. Cancer Patients. Annu Rev Chronopharmacol 7:253Ð256 2. Bellamy N, Sothern RB, Campbell J et al. (2002) Rhythmic Vari- Guidelines for using Rhythmic Changes in Clinical Situations ations in Pain, Stiffness, and Manual Dexterity in Hand of Os- Pertinent to Pain teoarthritis. Ann Rheum Des 61:1075Ð1080 3. Boissier C, Decousus H, Perpoint B et al. (1990) Timing Op- The time-dependent changes in pain level and in the timizes Sustained Release Ketoprofen Treatment Osteoarthritis. analgesic action of medications are relevant for the Annu Rev Chronopharmacol 7:289Ð292 D daily practice of health professionals. By selecting the 4. Bruera E, Macmilland K, Huehn N et al. (1992) Circadian Dis- tribution of Extra Doses of Narcotic Analgesics in Patients with most appropriate time for ingestion of analgesic agents, Cancer Pain: A Preliminary Report. Pain 49:311Ð314 the clinicians can optimise and individualise drug treat- 5. Graves BA, Batenhorst RL, Bennett JG et al. (1983) Morphine ment and also reduce the frequency of side effects of Requirements using Patient-Controlled Analgesia: Influence of Diurnal Variation and Morbid Obesity. Clin Pharm 2:49Ð53 medications. To optimise and individualise the effect 6. Kowanko IC, Pownall R, Knapp MS et al. (1981) Circadian Vari- of analgesics, the clinicians should: ations in the Signs and Symptoms of Rheumatoid Arthritis and in • the Therapeutic Effectiveness of Flurbiprofen at Different Times Accept that pain intensity fluctuates during the 24 h of the Day. Br J Clin Pharmacol 11:477Ð484 period. Circadian variations are now well described 7. Labrecque G, Vanier MC (1997) Biological Rhythms in Pain in pain intensity. and in Analgesics. In: Redfern PH and Lemmer B (eds) Physiol- • Determine when the pain level is highest and lowest ogy and Pharmacology of Biological Rhythms. Springer, Berlin, pp 619Ð649 during the 24 h period. Using a VAS, the practitioner 8. Labrecque G, Vanier MC (2003) Rhythms, Pain and Pain Man- can quickly determine when pain levels are highest agement. In: Redfern PH (ed) Biological Clocks: Pharmaceutical and lowest. This approach also gives information on and Therapeutics Applications. Pharmaceutical Press, London 9. Lévi F, LeLouarn C, Reinberg A (1985) Timing Optimized Sus- the inter-individual variations in the intensity of pain. tained Indomethacin Treatment of Osteoarthritis. Clin Pharmacol • Be aware that the action and pharmacokinetics of Ther 37:77Ð84 analgesics and most medications are not constant 10. Pöllmann L (1987) Circadian Variation of Potency of Placebo throughout the day or night. The time-dependent as Analgesic. Funct Neurol 22:99Ð103 11. Räisänen I (1988) Plasma Levels and Diurnal Variation of β- variations were found with most drugs, even when Endorphin,β-LipotropinandCorticotropin during Pregnancyand the slow release formulation was used. Early Puerperium. Eur J Obstet Gynecol Reprod Biol 27:13Ð20 • Administer analgesics to produce highest blood lev- 12. Sittl R, Kamp HD, Knoll R (1990) Zirkadiane Rhythmik des elswhenpainishighest.Inpractice, drugs are admin- Schmerzempfindens bei Tumorpatienten. Nervenheilkunde 9:22Ð24 istered at regular intervals such as 4 h after the last 13. Vanier MC, Labrecque G, Lepage-Savary D (1992) Temporal dose. This traditional approach does not take into ac- Changes in the Hydromorphone Analgesia in Cancer Patients. count the time-dependent variations in pain intensity 5th Int Conf Biological Rhythms and Medications, Amelia Island and the effect of analgesics; determinations of tem- (Fl), Abstract # XIII-8 14. Wilder-Smith CH, Wilder-Smith OH (1992) Diurnal Patterns of poral changes in pain and in the effect of analgesics Pain in Cancer Patients during Treatment with Long-Acting Opi- are the basis for the chronotherapeutic approach to oid Analgesics. Proc. 5th Conf Biological Rhythms and Medi- pain management. cations, Amelia Island (Fl), Abstract #XIII-7 • Refrain from administering medications at time of highest toxicity or when the frequency of side effects is highest. Special attention must be given to the tem- Divalproex Sodium poral changes in the pharmacokinetics of NSAIDs. The data indicate clearly that early morning doses should be avoided, because this is the time of day Definition where the frequency of side effects is largest. Anticonvulsant medication. Migraine, Preventive Therapy Conclusions Pain is a very complex phenomenon influenced by anxiety, fatigue, suggestions or emotion and prior ex- Diver’s Headache perience. Human data now indicates that time of day is another factor that must be taken into account when Primary Exertional Headache prescribing pain medications. The data on biological rhythms suggest that inadequate pain management, which occurs frequently in clinical practice, may be reduced when time-dependent variations in pain and Dizziness analgesic action are taken into account in daily practice. References Definition 1. Auvril-Novak SE, Novak RD, Smolensky MH et al. (1990) Tem- A non-specific term that describes an altered orienta- poral Variation in the Self-Administration of Morphine Sulfate tion in space, reflecting a discrepancy between internal 642 DMARDs sensation and external reality, creating sensory conflicts. The conflicts can be due to peripheral problems Doctor-Patient Communication and occur between any of the vestibular, visual or somatosensory systems, or it may be caused by central Chronic Gynaecological Pain, Doctor-Patient Inter- problems involving not one particular modality, but action rather the integration and weighting of the different modalities and their relation to memory. Words like light-headedness, faintness, giddiness, unsteadiness, imbalance, falling, waving and floating may be used to DOMS describe dizziness. Coordination Exercises in the Treatment of Cervical Delayed-Onset Muscle Soreness Dizziness

DMARDs DOP

Disease Modifying Antirheumatic Drugs Delta Opioid Receptor(s)

DMSO DOP Receptor

Dimethylsulfoxide Definition The term δ-opioid peptide receptor represents the G-protein coupled receptor protein that responds selectively to a group of largely experimental opioid drugs DNA Recombination and endogenous opioid peptides. It is homologous with the MOP receptor and is expressed in areas of the ner- Definition vous system that moderately mediate analgesia with a side-effect profile distinct from μ-opioids. The DOP Biologically active deoxyribonucleic acid (DNA), receptor protein is produced by a single gene. When which has been formed by the in vitro joining of seg- activated, the DOP receptor predominantly transduces ments of DNA from different sources. cellular actions via inhibitory G-proteins. The electro- Cell Therapy in the Treatment of Central Pain physiological consequences of DOP receptor activation are usually inhibitory. Delta Opioid Receptor (s) Opioid Electrophysiology in PAG DNIC

Diffuse Noxious Inhibitory Controls Dopamine

Dobutamine Deﬁnition Dopamine , abiogenicamine or catecholomine,is syn- thesized in the body (mainly by nervous tissue and Deﬁnition adrenalglands) from theaminoacidtyrosine.Dopamine Dobutamine is an intravenously administered inotropic is also a precursor to epinephrine (adrenaline) and nore- sympathomimeticmedication,whichactsonbetarecep- pinephrine(noradrenaline) in thebiosyntheticpathways tors of cardiac muscle to increase contractility, and is for these neurotransmitters. It plays an important role used to stress the heart in ãstress tests“ to detect myocar- in the central nervous system and gastrointestinal reg- dial ischemia. ulation. Thalamus and Visceral Pain Processing (Human Cancer Pain Management, Gastrointestinal Dysfunc- Imaging) tion as Opioid Side Effects Thalamus, Clinical Visceral Pain, Human Imaging Descending Circuitry, Transmitters and Receptors Dorsal Horn 643

DOR-1 Dorsal Column Stimulators

Definition Synonyms DORÐ1 refers to a clone that encodes a delta opioid re- DCS ceptor. D Opioid Receptors Definition Are electrical stimulation from implanted electrodes placed over the dorsal columns of the spinal cord. It is thought to block or reduce nociceptive spinal transmis- Dorsal Column sion. Pain Treatment, Spinal Cord Stimulation Definition Postherpetic Neuralgia, Pharmacological and Non- Pharmacological Treatment Options The dorsal column is an afferent pathway with primarily myelinated axonal fibers, predominantly from low threshold cutaneous or deep mechanoreceptors, and less commonly from visceral, thermal or nociceptive receptors, with the cellular soma in the dorsal root ganglion Dorsal Horn thatprojectsthrough anuncrossed white mattertract, the posterior column spinal pathway, to the dorsal column nuclei. These nuclei give rise to the medial lemniscus Definition thatcrossesand projectsto the principlesomatic sensory nucleus of the thalamus. Accordingly, the posterior col- This structure is that part of the spinal cord gray matter umn spinal pathway carries sensation of vibration, pro- in which the cell bodies of neurons primarily involved prioception and some fine touch. Recent evidence also in the sensory part of the nervous system are housed. suggests a role in visceral pain sensation. Thedorsalhornisorganizedintolaminaeorlayers,num- AnginaPectoris,NeurophysiologyandPsychophysics bered I to VI in a dorsal to ventral direction. Although Pain Treatment, Spinal Cord Stimulation its architecture is extremely complex, with cells from Postsynaptic Dorsal Column Projection, Functional deeper laminae sending dorsal dendrites to more super- Characteristics ficial laminae, nociceptive interneuronal cell bodies in- Visceral Nociception and Pain volved in the processing of noxious inputs are princi- Visceral Pain and Nociception pally located in Lamina II (otherwise termed the ’substantia gelatinosa’). Among other cell types located in the dorsal horn are those whose axons constitute the as- cendingtractsofwhitematter,projectingtothethalamus and other structures within the brain, and also involved Dorsal Column Nuclei in the transmission of noxious inputs. The deeper laminae contain cells that encode non-noxious stimuli. Of interest in studies involving infants is that these lami- Definition nae undergo considerable reorganization during devel- The dorsal column nuclei represent a collection of sev- opment in terms of afferent input. Studies in newborn eral somatosensory relay nuclei in the dorsal midline of rats have shown that low threshold Aβ afferentfibers ter- the caudal medulla, which includes the nucleus cunea- minate more superficially in the newborn dorsal horn, tus and nucleus gracilis. The nucleus cuneatus contains which may allow them to activate cells that only have a representationofthemidthoracictouppercervicallevels high-threshold input in the adult. (upper trunk/forelimb), whilst the nucleus gracilis con- Amygdala, Pain Processing and Behavior in Ani- tains representation of levels caudal to the midthoracic mals region (lower trunk/hindlimb). Forebrain Modulation of the Periaqueductal Gray OpioidsintheSpinalCordandModulationofAscend- Infant Pain Mechanisms ing Pathways (N. gracilis) Opiates During Development Postsynaptic Dorsal Column Projection, Anatomical Postsynaptic Dorsal Column Projection, Functional Organization Characteristics Postsynaptic Dorsal Column Projection, Functional Prostaglandins, Spinal Effects Characteristics Somatic Pain Spinothalamic Projections in Rat Spinothalamocortical Projections from SM 644 Dorsal Horn Neurons

3) the dorsal-most layers of the dorsal horn, where Dorsal Horn Neurons the afferent fibers establish synaptic contacts with spino-reticulo-thalamic tract cells. Definition BrachialPlexusAvulsionandDorsalRootEntryZone Neurons whose cell bodies lie in the dorsal horn of the spinal cord. These neurons receive input from peripheral tissues through primary afferent fibers, from higher Dorsal Root Entry Zone Lesioning centers in the central nervous system, and/or from interneurons located within the dorsal horn. Synonyms Cancer Pain Model, Bone Cancer Pain Model Postsynaptic Dorsal Column Neurons, Responses to DREZ lesioning Visceral Input Definition The dorsal root entry zone includes the central portion of the dorsal rootlets, the medial portion of Lissauer’s Dorsal Horn Opiate Systems Tract and Rexed Lamina One through Five in the dorsal horn. These are all areas where afferent nociceptive Definition fibers enter and synapse in the spinal cord. Destroying Neurons in the dorsal horn that express opiate receptors, this anatomical area interrupts the nociceptive pathway activation of which may produce analgesia. and can result in decreased pain. DREZ lesioning can be Pain Treatment, Implantable Pumps for Drug Deliv- useful for well localized pain syndromes caused by can- ery cer pain, brachial plexus avulsion injuries, spinalcord or thalamic injuries, peripheral nerve lesion, and post herpetic pain. Dorsal Rhizotomy Cancer Pain Management, Overall Strategy

Definition Dorsal Root Ganglion Dorsal rhizotomy is the transection of the dorsal roots of spinal nerves as they enter the spinal cord. The dor- Synonyms sal roots contain the central process of primary afferent fibers, including those of nociceptors, and thus prevent DRG; Dorsal Root Ganglia transmission of sensory information from the peripheral terminalsofprimaryafferentfiberstothecentralnervous Definition system. The collection (ganglion) of pseudo-unipolar sensory Cancer Pain Management, Neurosurgical Interven- neuron cell bodies in the vicinity of the spinal cord, with tions a peripheral process to the target organs and a central Dorsal Root Ganglionectomy and Dorsal Rhizotomy process to the spinal cord to terminate in the dorsal horn Muscle Pain Model, Inflammatory Agents-Induced or the dorsal column nuclei. These cell bodies comprise of the nucleus as well as the cellular machinery for protein synthesis. Following their synthesis, the proteins Dorsal Root Entry Zone have to be axonally transported to both the central and peripheral nerve terminals. The axons within the dorsal Synonyms root mainly convey somatosensory information. Dorsal root ganglia also contain local glia cells. DREZ Central Pain, Diagnosis Cytokines, Effects on Nociceptors Definition Dorsal Root Ganglion Dorsal Root Entry Zone (DREZ) Ð according to the def- Dorsal Root Ganglionectomy and Dorsal Rhizotomy inition given by Sindou in 1972 Ð includes: Inflammation, Role of Peripheral Glutamate Recep- 1) the ventro-lateral part of the central portion of the dor- tors sal rootlets, where there is a lateral regrouping of fine Neuropathic Pain Model, Tail Nerve Transection fibers; Model 2) the medial part of the Lissauer’s tract, where the small Opioids and Inflammatory Pain afferent enter and where they trifurcate to reach the dor- Opioid Modulation of Nociceptive Afferents In Vivo sal horn, either directly or via pathways which ascend Opioid Receptor Localization or descend several segments; Prostaglandins, Spinal Effects Dorsal Root Ganglion Radiofrequency 645

Spinal Cord Nociception, Neurotrophins electrode should be placed has not been defined. Other Substance P Regulation in Inflammation investigators have advocated placing the electrode Toxic Neuropathies tip within the DRG (Stolker et al. 1994b), but the one Visceral Pain Model, Esophageal Pain anatomical study that has been conducted demonstrated that electrode placement is variable in relation to the target ganglion, and sometimes too far away for any lesion to have an effect on the nerve. Placement of the D Dorsal Root Ganglion Radiofrequency electrode tip within the DRG occurred in only 61% of WAY YIN,NIKOLAI BOGDUK levels studied (Stolker et al. 1994a). Department of Anesthesiology, University of Notwithstanding these limitations to the rationale and Washington, Seattle, WA, USA mechanismofthetreatment,RF-DRGhasassumedpop- [email protected]; [email protected] ularity in various regions across the world, to various extents. That popularity, however, is dissonant with the Synonyms quality of the available literature on the procedure and its results. Partial dorsal root ganglion lesioning; partial dorsal rhizotomy; partial radiofrequency dorsal root ganglion lesion; RF-DRG Efficacy The popularity of RF-DRG has been sustained largely Definition on the grounds of observational studies and word-of- Partial radiofrequency (RF) dorsal root ganglion (DRG) mouth. Those studies claim some degree of effective- lesion (RF-DRG) is a procedure in which a radiofre- ness, and the procedure has gained a reputation of being quency electrode is placed in the vicinity of the dorsal something that works. root ganglion of a spinal nerve, and a radiofrequency The first of the cervical studies (van Kleef et al. 1993) current is passed through the electrode, for the purpose reported that 2/20 patients (10%) were pain-free at 3 of creating a lesion in the nerve of sufficient magnitude months; 4/20 were so at 6 months, and 2/17 (11%) at sufficient to relieve pain, but without actually dam- 12 months. Eight patients had good relief at 3 months, aging the nerve (see Radiofrequency Neurotomy, but their numbers dropped to two at 6 months and Electrophysiological Principles). two at 12 months. The authors did not conclude that their treatment was successful. They portrayed it as a Characteristics “reversible procedure” that can be useful to provide a In principle, RF-DRGwasborn outof a need for a proce- relatively pain-free period, which can be used to ob- dure that could treat spinal pain arising from a particular tain the maximum benefit from conservative forms of spinal segment that could not be treated by other meth- treatment. ods, or which had not responded to other, more target- Despite the less than modest outcomes of this study, specific therapy. In practice, RF-DRG arose as a means investigators from the same institution undertook a of treating patients whose pain had not been relieved by placebo-controlledtrial (van Kleef et al. 1996). Success medial branch neurotomy. was defined as a reduction by 2 points or more on a 10-point visual analogue scale. A significantly greater Rationale proportion, (8/9) patients, had a successful outcome RF-DRG is not a procedure intended to destroy the dor- following active treatment than those (2/11) who under- sal root ganglion. Indeed, a critical objective of the pro- went sham treatment. Follow-up, however, was limited cedure is to preserve function in the target nerve and its to only eight weeks. At this time the actively treated dermatome. One stated rationale of the procedure is “to patients had reduced their mean pain-scores from 6.4 to expose the dorsal root ganglion to temperatures that pre- 3.3, whereas the sham-treated patients maintained the vail in the peripheral part of an RF lesion to preserve the same scores (5.9, 6.0). large myelinated fibers and to deactivate the small un- Although this study provided data to the effect that myelinated fibers” (van Kleef). the initial effects of cervical RF-DRG were not due to Notwithstanding numerous theories, the mechanism placebo, they did not attest to a successful, lasting effect. by which RF-DRG is supposed to operate has not been Unlike its preceding study, the controlled study did not demonstrated. A differential effect of heat lesions on report on the number of patients completely relieved. myelinated and unmyelinated sensory fibers has been Success was defined only as a 2-point decrease in pain refuted (Zervas and Kuwayama 1972). In effect, the scores. The duration of effect beyond 8 weeks was procedure advocated by some amounts to no more than not measured. These data attest only to a modest and placing an electrode sufficiently close to the target nerve short-lived therapeutic effect. The data of the preceding in order to do something, but not so close as to actually observational study would predict that outcomes would damage the nerve. How close, or how far away, the attenuate substantially beyond 8 weeks. 646 Dorsal Root Ganglionectomy and Dorsal Rhizotomy

The first of the lumbar studies (van Wijk et al. 2001) was by authorsof theforegoing observationalstudy,thattrial a retrospective review of 361 patients, but results were surely refutes lumbar RF-DRG as a valid treatment; and availablefor only 279.Attwo months,61 (17%)patients by extrapolation casts doubt on the validity of RF-DRG were pain-free. This number became 23 (6%) at a mean in general. follow-up of 22.9 months, but the range of that period ThoracicRF-DRGhasnotbeensubjectedtoacontrolled was 2Ð70 months. A further 103 (29%) patients reported trial, but it might be effective for certain typesof thoracic incomplete but greater than 50% relief at two months. pain, for which there is not an analogue at cervical and Thisnumber droppedto 73(20%) atlonger-termfollow- lumbar levels. The available data hint at the possibility up. that thoracic RF-DRG could be useful for post-surgical Lumbar RF-DRGwaseventually subjected to a rigorous pain, although not for neuralgias, and placement of the placebo-controlled trial (Geurts et al. 2003). In all pa- electrode within the DRG itself may be an intensive as tients, the DRG wasanaesthetized, and a radiofrequency well as procedural prerequisite. electrode was placed into position. The active treatment wasRF-DRGat67ûC.Thecontroltreatmentwasnogen- References eration of current. At three months, 16% of the 44 pa- tientstreated with RF-DRG had greater than 50%reduc- 1. Geurts JWM, can Wijk MAW, Wunne H et al. (2003) Radiofre- quency Lesioning of Dorsal Root Ganglia for Chronic Lum- tion in pain. Meanwhile, 25% of the 36 patients who had bosacral Radicular Pain: A Randomized, Double-Blind, Con- sham treatment experienced the same outcome. These trolled Trial. Lancet 361:21Ð26 proportions are not significantly different statistically. 2. Kleef M van, Barendse G, Sluijter M Response to Invited Com- mentary. Assessing a New Procedure: Thoracic Radiofrequency This study, therefore, denied any attributable effect of Dorsal Root Ganglion Lesions. Clin J Pain 12:76Ð78 the procedure. Patients whose DRG was anaesthetized, 3. Kleef M van, Barendse GAM, Dingemans WAAM et al. (1995) without a lesion being produced, had the same outcomes Effects of Producing a Radiofrequency Lesion Adjacent to the as actively treated patients. Dorsal Root Ganglion in Patients with Thoracic Segmental Pain. Clin J Pain 11:325Ð332 The first of the thoracic studies (Stolker et al. 1994b) an- 4. Kleef M van, Liem L, Lousberg R et al. (1996) Radiofrequency nounced astounding results. At two months, 30/45 pa- Lesion Adjacent to the Dorsal Root Ganglion for Cervico- tients (67%) were pain-free, and a further 11 (24%) had brachial Pain. A Prospective Double-Blind Study. Neurosurgery greater than 50%reductionin pain.Atlong-termfollow- 38:1127Ð1132 5. Kleef M van, Spaans F, Dingemans W et al. (1993) Effects and up, ranging from 13 to 46 months, 20 patients were pain- Side Effects of a Percutaneous Thermal Lesion of the Dorsal free, and 15 had greater than 50% relief of pain. Root Ganglion in Patients with Cervical Pain Syndrome. Pain The second thoracic study (van Kleef et al. 1995) did 52:49Ð53 not reproduce these outcomes. At eight weeks, only 8 6. Stolker RJ, Vervest AC, Groen GJ (1994b) The Treatment of Chronic Thoracic Segmental Pain by Radiofrequency Percuta- of 43 patients (18%) had complete relief of pain, and 9 neous Partial Rhizotomy. J Neurosurg 80:986Ð992 (21%) had greater than 50% relief. At follow-up beyond 7. Stolker RJ, Vervest ACM, Ramos LMP et al. (1994a) Electrode 36 weeks, only 5 patients (12%) were pain-free and 8 Positioning in Thoracic Percutaneous Partial Rhizotomy: An Anatomical Study. Pain 57:241Ð251 (18%) had greater than 50% relief. 8. Wijk RMAW van, Geurts J, Wynne HJ (2001) Long-Lasting There is no obvious explanation for the discrepancy Analgesic Effect of Radiofrequency Treatment of the Lum- between these two studies. Patient selection may have bosacral Dorsal Root Ganglion. J Neurosurg (Spine 2) been the source of difference. The first study had a large 94:227Ð231 9. Zervas NT, Kuwayama A (1972) Pathological Characteristics proportion (38%) of patients with post-surgical pain of Experimental Thermal Lesions. Comparison of Induction (thoracotomy, mastectomy, abdominal scar), in whom Heating and Radiofrequency Electrocoagulation. J Neurosurg good outcomes were achieved. Such patients were ab- 37:418Ð422 sentformthesecondstudy. Conversely,thesecondstudy had a large proportion (47%) of patients with neuralgia. In the first study, patients with neuralgias had less than average outcomes. (The second study did not stratify its results according to diagnosis.) Another factor which Dorsal Root Ganglionectomy and Dorsal may account for the discrepancies between the studies Rhizotomy may have been technical. In the first study, the goal was to place the electrode within the DRG whereas in the MICHAEL J. DORSI,ALLAN J. BELZBERG second study, the goal of electrode placement was next Department of Neurosurgery, Johns Hopkins School to the DRG. of Medicine, Baltimore, MD, USA The outcomes of RF-DRG are not consistent across cer- [email protected] vical, lumbar, and thoracic levels. The outcomes of cervical RF-DRG are less than modest, even in a controlled Synonyms trial.ForlumbarRF-DRG,arigorouscontrolledtrialhas shownthatshamtherapyachievesatleastequivalentout- Sensory Ganglionectomy; Sensory Rhizotomy; dorsal comes to those of active therapy. Since it was conducted rhizotomy and dorsal root ganglionectomy Dorsal Root Ganglionectomy and Dorsal Rhizotomy 647

Definition Indications Dorsal root ganlionectomy and dorsal rhizotomy are Neuroablation has been implemented in a diverse array neuroablative procedures, which interrupt peripheral of painful conditions including: radiculopathy, failed sensory pathways. Dorsal root ganglionectomy is the back surgery syndrome, post-herpetic neuralgia, ma- surgical removal of the dorsal root ganglion of a lignancy, and multiple sclerosis. Dorsal rhizotmomy at spinal nerve. Dorsal rhizotomy is the transection of the level of C-2 has been performed for treatment of the dorsal root of a spinal nerve. occipital neuralgia and cervicogenic headache. In gen- D eral, neuroablative procedures are carried out in patients who have failed physical therapy, medical treatment, Characteristics and other non-surgical therapies. Neuroablative techniques are a plausible approach Anatomy to pain treatment in cases in which there is a clearly The primary sensory afferents project proximally (via identifiable pain generator. Determination of the spinal the dorsal root) to form synapses in the dorsal horn of segmental level in which the pain occurs is complicated the spinal cord or the dorsal column nuclei, with pseu- by preganglionic inter-segmental anastomoses, ventral dobipolar cell bodies of these axons being located in the root afferents, and denervation hypersensitivity. Diag- dorsal root ganglion. The traditional belief, established nostic testing including electromyographic, imaging by the ”Law of Bell and Magendie”, is that for a given studies, and nerve blocks is implemented to identify the spinalnerve,sensoryandmotorfunctionsaresegregated painful segment. in the dorsal and ventral roots respectively. However, it Nerveblockshavenotproventobeareliablepredictorof is now clear that afferent sensory fibers are also found in outcome, and the validity of peripheralnerve blocks has the ventral roots, with up to 29% of fibers in human ven- beenbroughtintoquestion(Northetal.1996).Apositive tral roots being small unmyelinated (presumably affer- block occurs when there is good pain relief with a small ent) fibers (Coggeshell et al. 1975). Some of these fibers volume of local anesthetic injected in the neural fora- course from the periphery into the ventral root and loop men, and no pain relief achieved with placebo injection back into the dorsal root before entering the dorsal horn or injection at the nerve root above or below, performed (Coggeshell1979).Othersbypassthedorsalrootanden- in a blinded fashion. ter the spinal cord directly through the ventral root (Ya- Evenwhenasingle dermatomeisidentifiedasthepain mamoto et al. 1977). In addition, cell bodies of sensory generator, it is not clear how many roots may supply that afferents are sometimes located outside the DRG in the distribution or how many segments should to be dener- dorsal root, ventral root, or along thenerve in the periph- vated for pain relief. In primates, it is likely that at least ery. three adjacent roots innervate each dermatome. It may be that one segment above and one below the target level should be included to achieve a clinical effect. Rationale Neuroablative procedures, such as dorsal root gan- Outcome glionectomy and dorsal rhizotomy, block the trans- Response rates for dorsal rhizotomy and ganglionec- mission afferent activity arising from nociceptors, tomy vary between 19 and 69% for rhizotomy and and so diminish pain evoked by experimental stim- between 0Ð100% for ganglionectomy. The lack of uli. Dorsal rhizotomy interrupts input to dorsal horn consistent results can be attributed to multiple uncon- neurons from DRG cells that project centrally via the trollable variables. dorsal root. Removal of the dorsal root ganglion leads The results of dorsal rhizotomy performed in 51 patients to Wallerian degeneration of afferent fibers in the with chronic lumbar radiculopathy were published by periphery, dorsal root, and ventral root. Therefore, both Wetzel et al. (Wetzel et al. 1997). At 6 months after procedures lead to deafferentation of the central nervous surgery, 55% were believed to have a good or excellent system. outcome, while at 2 to 4 years such outcomes were It has been suggested that ganglionectomy is superior to obtained in only 19% of patients. Similar deterioration dorsal rhizotomy, because it results in interruption of all of outcomes has been observed in several series, and afferentinputatthatspinalsegment. One theoreticaldis- has lead many to favor ganglionectomyover rhizotomy. advantage of ganglionectomy is that the resulting Wal- The most impressive results following ganglionectomy lerian degeneration of peripheral afferents contributes have been reported for treatment of thoracic and occip- to neuropathic pain in animal models (Li et al. 2000). ital pain, with some series reporting long-term success Wallerian Degeneration in the periphery or target tissue rates as high as 68% for thoracic pain (Young 1996) denervation may alter the function of intact afferents ad- and 80% for occipital pain (Lozano et al. 1998). Results jacent to degenerating axons (Li et al. 2000). This effect of ganglionectomy for failed back surgery syndrome mayleadtosensitizationofafferentsorneuronsathigher (FBSS) are much less favorable. In one recent series, levels in the pain-signaling pathway. success was obtained in only 2 of 13 patients with FBSS 648 Dorsal Root Reflexes at two years after surgery and none at 5.5 years (North et al. 1991), although another series reported treatment Dorsolateral Fasciculus success in four of six patients with FBSS at greater than 2 years (Wilkinson and Chan 2001). Definition Insummary,bothdorsalrootganglionectomyanddorsal Small longitudinal bundle of nerve fibers traveling in rhizotomy are neuroablative procedures implemented the peripheral portion of the dorsolateral quadrant of the for treatment of chronic pain. These procedures should spinal cord. A major portion of descending axons from be considered carefully in the light of available aug- rostral ventromedial medulla have been localized to the mentative procedures, and should be limited to cases dorsolateral fasciculus. Targeted transection of the dor- where the spinal segmental level of pain generation has solateral fasciculus has been routinely used to investi- been clearly defined. gate the contribution of descending pathways in spinal pain transmission. References Descending Circuitry, Molecular Mechanisms of 1. Coggeshall RE, Applebaum ML, Fazen M, Stubbs TB 3rd,Sykes Activity-Dependent Plasticity MT (1975) Unmyelinated Axons in Human Ventral Roots, A Stimulation-Produced Analgesia Possible Explanation for the Failure of Dorsal Rrhizotomy to Vagal Input and Descending Modulation Relieve Pain. Brain 98:157Ð166 2. Coggeshell RE (1979) Afferent Fibers in the Ventral Root. Neu- rosurgery 4:443Ð448 3. Li Y, Dorsi MJ, Meyer RA, Belzberg AJ (2000) Mechan- ical Hyperalgesia after an L5 Spinal Nerve Lesion in the Rat is not Dependent on Input from Injured Afferents. Pain Dorsolateral Pons 85(3):493Ð502 4. Lozano AM, Vanderlinden G, Bachoo R, Rothbart P (1998) Mi- crosurgical C-2 Ganglionectomy for Chronic Intractable Occip- Definition ital Pain. J Neurosurg 89:359Ð365 The dorsolateral pons is a region that contains several 5. North RB, Kidd DH, Campbell JN, Long DM (1991) Dorsal Root Ganglionectomy for Failed Back Surgery Syndrome: A 5-Year nuclei that project noradrenergic axons to the spinal Follow-Up Study. J Neurosurg 74:236Ð242 cord. The particular nuclei that contain noradreneric 6. North RB, Kidd DH, Zahurak M, Piantadosi S (1996) Speci- neurons include the locus coeruleus, subcoeruleus, ficity of Diagnostic Nerve Blocks: A Prospective, Randomized Kölliker-Fuse and parabrachial nuclei. Study of Sciatica due to Lumbosacral Spine Disease. Pain 65:77Ð85 SpinothalamicTractNeurons,DescendingControlby 7. Wetzel FT, Phillips M, Aprill CN, Bernard TN, LaRocca HS Brainstem Neurons (1997) Extradural Sensory Rhizotomy in the Management of Chronic Lumbar Radiculopathy A Minimum 2-Year Follow-Up Study. Spine 22:2283Ð2292 8. Wilkinson HA, Chan AS (2001) Sensory Ganglionectomy: The- ory, Technical Aspects, and Clinical Experience. J Neurosurg Dorsomedial Nucleus (DM) 95:61Ð66 9. Young RF (1996) Dorsal Rhizotomy and Dorsal Root Gan- glionectomy. In: Youmans JR (ed) Neurological Surgery, 4th Definition edn. WB Saunders, Philadelphia, pp 3442Ð3451 10. Yamamoto T, Takahashi K, Staomi H, Ise H (1977) Origins of The largestof the medialnucleiofthethalamus.Itmakes Primary Afferent Fibers in the Ventral Spinal Roots in the Cat extensive connections with most of the other thalamic as Demonstrated by the Horseradish Peroxidase Method. Brain nuclei. Res 126:350Ð354 Human Thalamic Response to Experimental Pain (Neuroimaging)

Dorsal Root Reﬂexes Dose Titration

Definition Definition If primary afferentdepolarizationbecomessuprathresh- Dosetitrationreferstoanapproachforachievingathera- old, it can elicit action potentials in the central terminals peuticresponsethatinvolvestheadministrationofadrug of primary afferent nociceptors, which can then travel followed by an assessment of the response. This infor- retrogradely to the periphery, release proinflammatory mation is used to estimate the next dose. This dose, fol- neuropeptides, and support neurogenic inflammation. lowed by a response approach, is continued until a sat- ArthritisModel,Kaolin-CarrageenanInducedArthri- isfactory therapeutic response is achieved and the ther- tis (Knee) apeutic dose is determined. GABA and Glycine in Spinal Nociceptive Processing Opioid Rotation DREZ Procedures 649

Dosing Interval DREZ Procedures

KENNETH M. LITTLE,ALLAN H. FRIEDMAN Definition Division of Neurosurgery, Duke University Medical The dosing interval is the time interval between the ad- Center, Durham, NC, USA ministered doses of a drug. [email protected] Opioid Rotation D Synonyms Microsurgical DREZotomy; DREZ lesion; Junctional Dosing Regimen DREZ Coagulation Nucleus Caudalis DREZ Definition Definition The dosing regimen is the dose and frequency of admin- The dorsal root entry zone (DREZ) includes the central istration of a drug when that drug is used repeatedly. Opioid Rotation portion of the dorsal spinal rootlets, Lissauer’s tract, and layers I through V of the dorsal horn. At the cervicomedullary junction, the dorsal horn is contiguous with the nucleus caudalis, an analogous structure within DOT the spinal trigeminal nucleus. Surgical DREZ lesions may be accomplished with radiofrequency-induced Dictionary of Occupational Titles heating, mechanical incision, bipolar coagulation, laser coagulation, or ultrasonic destruction to treat a variety of central pain syndromes. Double Depression Characteristics Rationale Definition At the DREZ, fibers conveying nociceptive sensory in- Double Depression refers to a dual diagnosis of “Major formation enter the spinal cord in the ventrolateral as- Depression” and “Dysthymia”. pectofthedorsalroot.Theserelativelysmallaxons,with Psychiatric Aspects of the Epidemiology of Pain sparse or absent myelination, enter Lissauer’s tract, ascend and descend up to four segments, and terminate in laminae I through VI (principally I, II, and V) of the Double-Blind ipsilateral dorsal horn. Within the dorsal horn, sensory information, including pain, is modulated through neu- Definition rochemical signaling and inhibitory anatomical connections.Centralpainsyndromes(painmediatedbythecen- The patient and treating physician are both unaware tral nervous system), caused by spinal cord injury or pe- which treatment the patient is receiving. ripheral deafferentation, may result from aberrations of Antidepressants in Neuropathic Pain this system. In animal models, epileptiform activity has Central Pain, Pharmacological Treatments been observed within the dorsal horn after root avulsion, possibly because of regenerative sprouting with abnormal neuronal reorganization. The rationale for DREZ Down-Regulated procedures is to ablate or interrupt the central structures, and thus the abnormal physiological processes implicated in some pain syndromes. Definition A state whereby a physiologic feedback loop causes a Indications substance to reduce the production or action of another Spinaland nucleuscaudalisDREZ lesioningprocedures substance. can be an effective means of treating deafferentation Cancer Pain Management, Orthopedic Surgery pain syndromes, which are refractory to medical management or other operative interventions. The key to a successful outcome lies in careful patient selection. DREZ Brachial Plexus Avulsion Traumatic brachial plexus traction causing nerve root Dorsal Root Entry Zone avulsions frequently result in a characteristic pain syn- 650 DREZ Procedures drome. The patient notes a constant burning or aching Methods pain punctuated by paroxysms of crushing pain. Prior to Several DREZ lesioning methods have been described proceeding with DREZ lesioning in these patients, root (Nashold and El-Naggar 1992; Iskandar and Nashold avulsion must be confirmed, as peripheral nerve injury 1998; Sindou 2002). Laminectomies or, more elegantly, pain does not respond to DREZ lesions. Care must be hemilaminectomies are performed over the spinal levels taken to identify and treatallof thepainfulsegments, not to be lesioned. In the case of brachial plexus avulsion just those identified as abnormal by radiographic studies injuries and spinal cord trauma, the pathologic segments or gross inspection. are identified by a combination of gross inspection and impedance measurements. In cases in which there is no Spinal Cord Injury spinal cord pathology, the DREZ to be lesioned is iden- There are different types of pain associated with trauma tified by following nerve rootlets from their entry into to the cervical, thoracic, and lumbosacral spinal cord. the spine to their entry into the spinal cord, or by record- ThepainthatrespondsbesttoDREZproceduresisradic- ing evoked potentials from the DREZ while stimulating ular or segmental, occurring in the partially deafferented the affected dermatomes. Lesions are made along the in- levels adjacent to the level of injury. Diffuse pain occur- termediolateral sulcus, extending approximately 2 mm ring below the level of injury, especially constant burn- into the DREZ. They may be made with radiofrequency- ing pain in the sacral dermatomes, only occasionally re- generated heat to 80 degrees Celsius at 1 mm intervals, sponds to DREZ procedures. mechanical incision, laser coagulation, bipolar coagulation, or ultrasonic destruction. It is important that the Conus Medullaris and Cauda Equina Injury lesion extends into the DREZ above and below the affected dermatomes. For the caudalis DREZ procedure, a This type of pain often occurs following trauma to the smallsuboccipitalhemicraniectomyandbilateralC1-C2 T12 to L1 levels, injuring elements at both the conus laminectomy is performed (Iskandar and Nashold 1998; medullaris and cauda equina. Patients that respond best Nashold and El-Naggar 1992). Classically,a specialized to DREZ procedures in this region are those with incom- 3 mm electrode(with theproximal1 mmbeing insulated plete neurologic deficits, those with pain that is “elec- to protect the overlying spinocerebellar tract) is used to trical” in character, and those with injury due to blunt make two rows of RF lesions at the cervicomedullary trauma. junction. The first row begins at the dorsal rootlets of C2 extending rostrally to about 5 mm above the obex. Phantom Limb Pain The second row parallels the first, 1 mm dorsal to the Patients suffering pain after limb amputation may expe- DREZ. Recently, trigeminal evoked potentials, EMG, rience stump pain, phantom limb pain, or both. Typ- and SSEPs have been used during the caudalis DREZ ically, phantom limb pain responds significantly better procedure to target the symptomatic nucleus caudalis to DREZ procedures than does stump pain. region specifically, and to identify and protect the adjacent corticospinal tract and dorsal column (Husain et Cancer Pain al. 2002). The type of cancer related pain that responds best to DREZ procedures is topographically limited to a few Outcomes spinal segments (as with Pancoast syndrome). Patients In the larger series reported in the literature, adequate, with pain from thoracic or abdominal wall invasion long term pain relief has been reported in about 60 to or lumbosacral root involvement may also respond 90% (Dreval et al. 1993; Thomas et al. 1994; Rath et well. Lumbosacral pain must be limited, however, to al. 1997; Sindou et al. 2001). Variations in results can avoid the increased risk of lower extremity hypotonia be attributed to differences between criteria for patient or sphincter dystonia associated with bilateral or more selection, outcome measures, times of follow-up, and extensive DREZ lesions. techniques (Friedman et al. 1988; Nashold and El- Naggar 1992; Dreval et al. 1993; Thomas and Kitchen Craniofacial Pain 1994; Sampson et al. 1995; Iskandar and Nashold 1998; The caudalis DREZ procedure may be indicated in pa- Sindou 2002; Spiac et al. 2002). tients with central craniofacial pain including anesthesia dolorosa, post-tic dysesthesias, atypical facial pain, Complications postherpetic pain, pain related to neoplasms in the re- Following DREZ lesions for brachial plexus avulsion gion of the gasserian ganglion, and facial pain caused by pain, 41% experienced objective sensory deficits and brainstem lesions such as infarction, tumors, and multi- 41% objective motor deficits (Friedman et al. 1988). ple sclerosis. The caudalis DREZ procedure, however, However, the majority of these deficits were mild, with is controversial due to the relatively high risk of postop- only a single patient suffering a deficit sufficient to limit erative deficits and the transience of pain relief. ambulation. In spinal cord and conus medullaris DREZ Drugs Targeting Voltage-Gated Sodium and Calcium Channels 651 procedures, permanent sensory and motor deficits occur in about 13% and 12%, respectively. Non-neurologic DREZ Lesions complications such as infection, CSF leak, and epidural hematoma occur in about 7%. The nucleus caudalis Synonyms DREZ procedure is associated with more complications. Rates of postoperative ataxia have ranged from DREZotomy 39 to 54%, and diplopia or corneal anesthesia in about Definition D 20%. For this reason, the caudalis DREZ procedure is performed at a limited number of centers. In a recently DREZlesionsaredestructivetherapeuticlesionsapplied reported series of nucleus caudalis DREZ procedures, onto the dorsal root entry zone (DREZ). Therapeutic aided by trigeminal evoked potentials, EMG, and DREZ lesions include, according to the lesion-maker: SSEPs, fewer lesions were made resulting in no per- 1) the microsurgical DREZotomy (Sindou 1972), 2) the manent neurological deficits and pain relief in 71% of Radio-Frequency-Thermocoagulation (Nashold 1974), patients at 12 months (Husain et al. 2002). 3) the Laser DREZ lesion (Levy, 1983), and 4) the Ultrasonic DREZ lesion (Kandel and Dreval 1987). Anesthesia Dolorosa Model, Autotomy References BrachialPlexusAvulsionandDorsalRootEntryZone 1. Bullard DE, Nashold BS (1997) The Caudalis DREZ for Facial Dorsal Root Entry Zone Pain. Stereotactic & Functional Neurosurgery 68:168Ð174 Dorsal Root Entry Zone Lesioning 2. Dreval ON (1993) Ultrasonic DREZ-Operations for Treatment DREZ Procedures of Pain due to Brachial Pluxus Avulsion. Acta Neurochir 122:76Ð81 3. Friedman AH, Nashold NS Jr (1986) DREZ Lesions for the Relief of Pain Related to Spinal Cord Injury. J Neurosurg 65:465Ð469 DRG 4. Friedman AH, Nashold BS, Bronec PR (1988) Dorsal Root En- try Zone Lesions for the Treatment of Bracial Plexus Avulsion Injuries: A Follow-Up Study. J Neurosurg 22:369Ð373 Dorsal Root Ganglion 5. Gorecki JP, Nashold BS (1995) The Duke Experience with the Nucleus Caudalis DREZ Operation. Acta Neurochir S64:128Ð131 6. Gorecki JP, Nashold NS, Rubin L, Ovelmen-Levitt J (1995) The Duke Experience with Nucleus Caudalis DREZ Coagulation. Drug Guidelines Stereotactic & Functional Neurosurgery 65:111Ð116 7. Husain AM, Elliott SL, Gorecki JP (2002) Neurophysiological Monitoring for the Nucleus Caudalis Dorsal Root Entry Zone Operation. Neurosurgery 50:822Ð827 Analgesic Guidelines for Infants and Children 8. Iskandar BJ, Nashold BS (1998) Spinal and Trigeminal DREZ Lesions. In Gildenberg PL, Tasker RR (eds) Textbook of Sterio- tactic and Functional Neurosurgery, McGraw-Hill, Health Pro- fessional Division, New York, pp 1573Ð1583 9. Nashold BS Jr, El-Naggar AO (1992) Dorsal Root Entry Zone Drugs Targeting Voltage-Gated Sodium (DREZ) Lesioning. In: Rengachary SS, Wilkins RH (eds) Neuro- and Calcium Channels surgical Operative Atlas, vol 2. Williams & Wilkins, Baltimore, 1 2 pp 9Ð24 ANNE K. BERTELSEN ,MISHA-M. BACKONJA 10. Rath SA, Seitz K, Soliman N, Hahamba JF, Antoniadis G, Richter 1 HP (1997) DREZ Coagulations for Deafferentation Pain Related Department of Neurology, Haukeland University to Spinal and Peripheral Nerve Lesions: Indication and Results Hospital, Bergen, Norway of 79 Consecutive Procedures. Stereotactic and Functional Neu- 2Department of Neurology, University of Wisconsin- rosurgery 68:161Ð167 Madison, Madison, WI, USA 11. Sampson JH, Cashman RE, Nashold BS, Friedman AH (1995) Dorsal Root Entry Zone Lesions for Intractable Pain after [email protected], Trauma to the Conus Medullaris and Cauda Equina. J Neuro- [email protected] surg 82:28Ð34 12. Sindou MP (2002) Dorsal Root Entry Zone Lesions. In: Burchiel (ed) Surgical Management of Pain. Thieme Medical Publishers Synonyms Inc, New York, pp 701Ð713 13. Sindou M, Mertens P,Wael M (2001) Microsurgical DREZotomy Ion Channel Blockers; Membrane-Stabilizing Drugs; for Pain due to Spinal Cord and/or Cauda Equina Injuries: Long- voltage-gated channels; anticonvulsants; Antiarryth- Term Results in a Series of 44 Patients. Pain 92: 159Ð171 mics 14. Spaic M, Markovic N, Tadic R (2002) Microsurgical DREZo- tomy for Pain of Spinal Cord and Cauda Equina Injury Origin: Clinical Characteristics of Pain and Implications for Surgery in Definition a Series of 26 Patients. Acta Neurochir 144:453Ð462 Drugs that attenuate inward sodium or calcium ion cur- 15. Thomas DG, Kitchen ND (1994) Long-Term Follow-Up of Dor- sal Root Entry Zone Lesions in Brachial Plexus Avulsion. J Neu- rents in nociceptive afferent neurons, thus exhorting a rol Neurosurg & Psychiatry 57:737Ð738 membrane-stabilizing action on these neurones. 652 Drugs and Procedures to Treat Neuropathic Pain

1996; Kennedy et al. 1999) for quantitative analysis of Drugs and Procedures to Treat epidermal nerve fiber loss. Most recently, the identifi- Neuropathic Pain cation of a polymorphism in a voltage-gated sodium channel gene peculiar to peripheral nociceptors ac- GEORGE L. WILCOX companying a neuropathic pain disorder called ery- Department of Neuroscience, Pharmacology and thromelalgia is a most welcome reinforcement of the Dermatology, University of Minnesota Medical above inference from the efficacy of anticonvulsant School, Minneapolis, MN, USA therapy. Collectively, this body of knowledge applied [email protected] to individual neuropathic entities and cases has contributed to more objective diagnoses of some disor- Treatment of neuropathic pain continues to be a great ders, but has yet to provide a panacea of adequate ther- challenge. Neuropathic pain is defined by the Inter- apy applicable to a majority of neuropathic pain dis- national Association for the Study of Pain (IASP) as orders. It is hoped that this collection of syndrome- pain initiated or caused by a primary lesion or dysfunc- and mechanism-directed essays on the treatment of tion of the nervous system. It is therefore important to neuropathic pain will provide a roadmap for the next bear in mind that neuropathic pain is not a disease it- decade of development of new neuropathic pain ther- self, but a symptom of an underlying disease that has apies. causeddamagetothenervoussystem,eitherperipheral Although the aforementionedanimal models have im- or central. The treatment of neuropathic pain is thus proved our understanding of the taxonomy of and re- symptomatic rather than curative and the initial step vealed some of the complex mechanisms probably for every patient with neuropathic pain must therefore underlying peripheral and central neuropathic pain, always be to achieve an accurate diagnosis and an ad- translation of these findings into improved therapies equate treatment of the underlying disease. for neuropathic pain has been more difficult. It can Our improved knowledge of different neuropathic be argued that many of the improvements in therapy pain conditions can be attributed to a number of re- introduced in the 1990s have instead resulted from cent developments and this knowledge has in turn al- clinical experience with new agents exploiting previ- lowed improved management of many kinds of neuro- ously known mechanisms, for example extension of pathicpain.Clinicalresearchhascontributedimproved carbamazepine’s use in trigeminal neuralgia to include recognition of neuropathic pain as an entity, standard- newer anticonvulsantsin numerous neuropathicdisor- ization of likely syndrome etiologies and diagnostic ders. In addition, systematic clinical investigations of procedures and dissemination of this knowledge and patients with neuropathic pain, notably using QST and methodology; all of these advances contribute to make quantitation of epidermal nerve fibers in skin biop- outcomes of treatment more predictable and compa- sies, have also contributed to our assessment and un- rable among sites. The efficacy of a number of new derstanding of neuropathic pain. Exceptions include therapeutic agents belonging to the Anticonvulsant the alpha adrenergic agonist clonidine and the calcium (Agent) classthatactatvoltage-gatedsodiumchannels channel blocker ziconotide: intrathecal clonidine anal- to discourage repetitive firing of axons (see drugs gesia was characterized preclinically in the 1980s be- targeting voltage-gated sodium and calcium channels) fore translation to human use in the 1990s; ziconotide, and their broadening use over the past decade have im- developed from a naturally occurring peptide toxin tar- plicated action potential initiation or propagation as geting N-type calcium channels, was studied preclini- keytargetsforcontinuedtherapeuticdevelopment.The cally in the early 1990s before its introduction to clin- contemporary development over the past 15 years by ical use in 2004. basic science researchers of several different animal The pathophysiological phenotypes accompanying models (see Animal Models and Experimental Tests painful nervous system damage can include one or to Study Nociception and Pain) involving peripheral more of the following: 1) Wallerian degeneration nerve injury and emulating various peripheral, trau- and aberrations in peripheral nerves or dorsal root gan- matic, metabolic and toxic insults to the nervous sys- glia ( CRPS, evidence based treatment; trigeminal tem has allowed the testing of hypotheses concerning neuralgia, diagnosis and treatment) (Hsieh 2000), the etiology and therapy of neuropathic pain (Linden- 2) aberrant immune signaling, both peripherally and laub and Sommer 2002). Translational research has centrally ( proinflammatory cytokines; cytokines endeavored to bridge these two areas of development as targets in the treatment of neuropathic pain), 3) and contributed more objective methods of assessment aberrant neurotransmitter and neuropeptide signaling and diagnosis, for example quantitative sensory test- ( peptides in neuropathic pain states; purine re- ing (QST) and skin nerve biopsy (Karanth et al. 1991; ceptor targets in the treatment of neuropathic pain), 4) Kennedy et al. 1993; Hillges et al. 1995; Hsieh et al. aberrant metabolism in somatic or neural tissues as in Drugs and Procedures to Treat Neuropathic Pain 653 diabetesorlysosomalstoragediseases( diabeticneu- treatment and the degree of under-utilization is made ropathy, treatment; postherpetic neuralgia, pharma- difficult by the prevalence of “off label” use of drugs cologicaland non-pharmacologicaltreatmentoptions) such as antidepressants and anticonvulsants. More po- and 5) pathologicalcentral connectivity broughtabout tentially pain-indicated medications are at or near in- by CNS injury or peripheral pathology ( phantom troduction, including new antidepressants like dulox- limb pain, treatment; descending facilitation and in- etine, anticonvulsants like pregabalin and lamotrig- hibition in neuropathic pain; Cancer Pain Manage- ine,calciumchannelantagonistslikeziconotide,gluta- D ment, Treatment of Neuropathic Components); eleven mateantagonistslikememantineandcannabinoidago- of the essays in this section address various levels of nistslikethetetrabinex/nabidiolexcombinationagent. this taxonomy. A variety of etiologies and mediators, The safety and efficacy of neuropathic pain therapy both peripheral and central, account for these pheno- will probably be significantly different, hopefully im- types and an equally large variety of medical thera- proved, in 5 years. pies and surgical manipulations have been prescribed. There are three main approaches to attacking neuro- Disease Entities pathic pain in the clinic, medical management (five es- Of the disease entities covered explicitly by essays, says: drugs targeting voltage-gated sodium and cal- postherpetic neuralgia (PHN) (see drugs targeting cium channels; Alpha(α) 2-Adrenergic Agonists in voltage-gated sodium and calcium channels) and di- PainTreatment; antidepressantsinneuropathicpain; abetic neuropathy (DN) (see diabetic neuropathy, drugs with mixed action and combinations, empha- treatment) are the two with the highest incidence, persis on tramadol), interventionaltherapies such as CNS hapsaccountingforhalfoftheoverallincidenceofneu- stimulation, nerve blocks and surgical management ropathic pain. These high incidence disorders also ac- (one essay: central nervous system stimulation for count for the vast majority of well designed and con- pain) and non-medical alternative or non-invasive ap- clusive trials; therefore, the evidence basis for the ma- proaches (four essays: alternative medicine in neu- jority of several other disease entities is an extension ropathic pain; dietary variables in neuropathic pain; of what has been learned from these two entities. The fibromyalgia mechanisms and treatment; evoked multifactorial causesof cancer pain, including bothso- and movement-related neuropathic pain), with pro- matic and neuropathic components, makes estimation gressively diminishing efficacy. This essay seeks to of the incidence or contribution of neuropathic cancer align the etiologies, pathophysiology and mediators of pain difficult (see cancer pain management, treat- neuropathic pain with the therapeutic approaches used ment of neuropathic components). The combined inci- to manage it. denceof complex regionalpain syndrome(CRPS) (see Sales of pain products, which generated an estimated CRPS, evidence based treatment)andfibromyal- $40 billion USD in 2004, may double by the end gia (FMS) (see fibromyalgia, mechanisms and treat- of the decade. Pain accompanies many diseases and ment) is probably comparable to that of PHN or DN, its significance is underappreciated by many medi- alone. The other classifications trigeminal neuralgia cal specialties, which often focus attention on the dis- (TN) (see trigeminal neuralgia, diagnosis and treat- ease itself to the exclusion of the intensity or treatment), phantom pain (see phantom limb pain, treatment of the associated pain symptoms. Neuropathic ment), and movement-related neuropathic pain (see pain is estimated to affect 26 million patients world- evoked and movement-related neuropathic pain) wide, including 10 million in the US, 3 million in collectively represent a relatively small fraction of Europe and 1.5 million in Japan; spending on these neuropathic pain conditions. Comparison of the com- patients last year totaled $2.5 billion globally and mon treatment modalities effective across these var- will probably double by the end of the decade ("CNS ious types of neuropathic pain yields a homogene- Drug Discoveries: Analgesia,” June 2005, available at ity that both derives from the evidence basis men- www.researchandmarkets.com). This anticipated in- tioned above and suggests a commonality in under- crease is based on the likelihood that novel therapeutic lying mechanisms. This commonality of mechanisms agents will be developed that target subsets of neuro- is highlighted by the medical therapies, anticonvul- pathic pain, accompanying, for example, post-herpetic sants, antidepressants and calcium channel blockers, neuralgia (PHN, shingles), diabetes (DN), HIV im- described below. mune disorders and cancer chemotherapy. Neuro- pathic pain presents a substantial unmet clinical need due largely to inadequate pain management programs Medical vs. Non-Medical Therapies and global under-utilization of appropriate medica- Five essays address medical therapies used most fre- tions, such as antidepressants and opioids, particularly quently in management of neuropathic pain disorders in Europe. Understandingthecostsof neuropathicpain or a target of some of these therapies, descending 654 Drugs and Procedures to Treat Neuropathic Pain

modulatory systems. None of the therapies is cura- of development for controlling phantom pain, com- tive, rather treating the symptoms of painful periph- bining, for example, memantine and peripheral re- eral neuropathies. Antidepressants may be the most gional anesthesia. Four essays explore non-invasive, used medications, although their mechanisms of ac- non-medical therapies including complementary and tion are among the least well understood and the per- alternative medicine ( alternative medicine in neuro- hapsthe leasttarget-selective (see antidepressantsin pathic pain), dietary variables ( dietary variables in neuropathicpain). Anticonvulsants( drugs targeting neuropathic pain), the utility of exercise particularly voltage-gated sodium and calcium channels,andsee with respect to FMS ( fibromyalgia, mechanismsand voltage gated channels below) are perhaps becoming treatment) and movement-related pain ( evoked and the most frequently used agents in neuropathic pain; movement-related neuropathic pain). Although sev- most seem to target voltage-gated Na+ channels but eral studies document that many patients with neu- some of the newer agents in this class seem to tar- ropathic pain (20Ð50% in various countries) use al- get a subunit of voltage-gated Ca++ channels. Med- ternative and complementary medicine, only elec- ical treatments targeting multiple receptors, a proto- troacupuncture has been validated by randomized con- type for which is tramadol (see drugs with mixed trolled trials. Some aspects of diet probably contribute action and combinations, emphasis on tramadol), are to a patient’s predisposition to developing neuropathic less widely used, but nonetheless represent a signifi- pain, but research into pro-analgesic nutrients is in cant fraction of medical treatments. By comparison, its infancy. The causes and mechanisms underlying drugs targeting adrenergic receptors have a very low fibromyalgia (FMS) remain obscure, though sugges- prevalence of use, largely because of the necessity of tive evidence implicates glutamate, neuropeptidesand spinal targeting by implanted catheter ( Alpha(α)2- nerve growth factor. Tricyclic antidepressants and tra- Adrenergic Agonist). The spinal receptors for adrener- madol have shown efficacy, but exercise remains the gicagonistsarealso thetargetof descending inhibitory most effective therapy overall. This field of disorders, systems covered in descending facilitation and inhi- FMS and movement-relatedpain and therapeutic regi- bition in neuropathic pain; the descending terminals of mens, TENS, acupuncture and non-medical therapies, these inhibitory systems may be targeted indirectly by seems to constitute a fruitful area for development of antidepressants and tramadol ( drugs with mixed ac- future therapies. tion and combinations, emphasis on tramadol). Thees- say descending facilitation and inhibition in neuropathic pain also addresses the potential for descending Voltage-Gated Channels facilitatory influences to contribute to the neuroplastic The dominance of diverse anticonvulsants as effective changes thought to mediate formation of chronic neu- therapeutic agents in a broad range of neuropathic pain ropathic pain. These descending systems may be fruit- states (see drugs targeting voltage-gated sodium and ful future targets for therapies. calcium channels) together with the commonality of Five essays address non-medical therapies. The es- their molecular targets strongly links voltage-gated say central nervous system stimulation for pain dis- sodium and calcium channels to mediation of pain ac- cusses the indications and possible mechanisms for companying neuropathy. The involvement of calcium spinal cord (SCS), deep brain stimulation (DBS) and channels derives largely from presumptive targeting motor cortex stimulation; the first is useful in a broad of the alpha-2 delta subunit of voltage gated cal- range of disorders, such as CRPS, DN, PHN and spinal cium channels by gabapentin and newer pregabalin. cord injury pain, but not back pain; DBS is indicated Gabapentin’s targets would presumably be the central in central pain, anesthesia dolorosa, post-cordotomy terminals of primary afferent fibers where reduction dysesthesias and possibly cluster headaches; the cor- in calcium-dependent release of excitatory transmit- tical stimulation site has shown utility in pain follow- ter could account for a pain-attenuating action. A very ing deep brain or spinal ischemia and some forms of different recently introduced agent, ziconotide targets deafferentation pain. However, the mechanisms and with extreme selectivity N-type voltage-gated calcium utility of CNS stimulation for neuropathic pain re- channels, which are thought to be directly linked to main obscure and controversial. The essay phantom transmitter release in axon terminals. Ziconotide is ap- limb pain, treatment explores the therapies useful (and proved for intrathecal application in neuropathic pain not useful) in phantom pain: many treatments use- patients, but several side effects may limit the preva- ful in other forms of neuropathic pain fail to exceed lence of its ultimate use (Wallace 2002). the efficacy of placebo in phantom pain; nonethe- The important sites of action of agents targeting less, opioids, NMDA antagonists, gabapentin, TENS voltage-gatedsodiumchannelshavebeenvariouslyas- and sensory discrimination training appear to be ef- signed to peripheral and central targets, but are gen- fective. Prevention may be a promising future area erally invoked as sources of ectopic discharges in Drugs and Procedures to Treat Neuropathic Pain 655 hypersensitive zones of peripheral regenerating axon three agents have been investigated clinically for use in tips or in neuromas (Michaelis 2002). Axonal sensi- neuropathic pain; the other agents like AMPA antag- tization has been associated most often with injury- onists are not likely to be of clinical use due to numer- related or neurotrophin-imposed plasticity in expres- ous side effects. AMPA receptor activation produces sion of voltage-gated sodium channels (Black et al. strong depolarization that is not dependent upon con- 2002) and most recently with a genetic neuropathic current activity, making this process “non-contingent” D pain-linked polymorphism in the Nav1.7 subtype that On the other hand, the NMDA receptor is blocked by lowers the threshold for spike initiation (Dib-Hajj et al. Mg++ at resting potential, preventing ligand gating of 2005). This finding may prove to be seminal in seeking the channel; depolarization of the plasma membrane axonal mediators of sensory neuron sensitization ac- removes this Mg++ block allowing subsequent ligand companying neuropathic pain. Erythromelalgia mani- gating. Removal of this Mg++ block by prior depolar- fests with paroxysmal episodes of burning pain in dis- ization makes NMDA-evoked depolarization “contin- tal extremities initiated by warming; as such this dis- gent” and may underlie the participation of this recep- order embodies many of the enigmatic characteristics tor in the “wind-up” phenomenon recruited by repet- of several neuropathic pain syndromes, including DN, itive activation of C-fibers. NMDA receptors are crit- Fabry disease and idiopathic burning hands and feet. ical participants in the induction of acute (e.g. forma- Only rarely, has axonal sensitization after nerve in- lin) and chronic (the chronic constriction injury neu- jurybeenlinkedtoinflammatorymediatorsreleasedby ropathic pain model, CCI) hyperalgesia. mast cells, generally (Zuo et al. 2003), in proximal re- The essay peptides in neuropathic pain states ex- generating nerve tips (Zochodne et al. 1997) or distally plores five of the peptide neurotransmitters, vasoac- in the dermis (Marchand et al. 2005). Release of exci- tive intestinal polypeptide (VIP and similar PACAP), tatory substances (cytokines, histamine, serotonin, no- dynorphin (DYN), cholecystokinin (CCK) and neu- radrenaline or ATP) has also been hypothesized proxi- ropeptide Y (NPY), most directly contributing to en- mally in DRG (Michaelis 2002) and distally in dermis hanced excitatory neurotransmission following pe- (Marchandetal.2005)asapromoterofectopicactivity. ripheral nerve injury. VIP and PACAP, contained in Site-specific study of cellular and molecular mediators small diameter fibers, dramatically increase in DRG of axonal or terminal sensitization would appear to be after peripheral nerve injury and participate strongly a fruitful area for future study. in induction and maintenance of hyperalgesic states induced by these injuries (Kashiba et al. 1992). DYN Neurotransmitters expression is also dramatically increased after nerve Glutamate, the most prominent fast excitatory neuro- injury and somehow facilitates excitatory transmis- transmitter between nociceptors and spinal neurons, sion, but this occurs in spinal cord neurons rather than activates ligand-gated channels that admit monova- in DRG. CCK is another central neuropeptide that is lent (mostly Na+ and K+ for all AMPA- and kainate- up-regulated in spinal cord and in pain-relevant brain operated channels) and divalent (Ca++ or Mg++,some structures after peripheral nerve injury; CCK proba- AMPA / kainate receptors and all NMDA receptors) bly plays an important role in maintaining neuropathic cations, depolarizing neural processes (Wilcox et al. pain at both the spinal and supraspinal levels. Moder- 2005). Ca++ entry mediated by these channels can acti- ate levels of NPY normally occur in large diameter private such signaling systems as calcium-calmodulin ki- mary afferent fibers, but these levels are markedly up- nase (CaM-kinase II), which can set in motion numer- regulated after peripheral nerve injury; this increased ous intracellular cascades contributing to long-lasting expression is an important component of hypersensi- changes in synaptic strength. Both types of receptors tivity accompanying these injuries. These five peptides arethoughttobeinvolvedininitiationandmaintenance and their receptorsrepresentlikely targetsfornew drug of neuropathic pain states. Normally, NMDA recep- development directed at neuropathic pain therapy. tors are more directly involved in responses of dor- Several other neuropeptides are altered after periph- sal horn neurons to intense noxious stimuli than are eral nerve injury and may participate in development AMPA / kainate receptors, but increased surface ex- or maintenance of hyperalgesic states. Galanin (GAL) pression of AMPAreceptorsby spinalneuronsmay ac- levels in primary sensory neurons increase in DRG company neuropathic pain. NMDA receptors in spinal soon after nerve injury (Villar et al. 1991) or treatment cord are subject to positive modulation by PKC, which with the chemotherapeutic agent vinblastine (Kashiba accompaniesstrongactivationbyamongothersSPact- et al. 1992), apparently as a compensatory reaction ing at NK1 receptors (see below) and can be blocked via Gal1 receptors countering hypersensitivity (Blake- by dissociative anesthetics, including phencyclidine man et al. 2003). However, GAL actions via its three (PCP), MK-801, ketamine, memantine and the inac- receptor subtypes are complex, manifesting both in- tiveopioidcongenerdextromethorphan.Onlythelatter hibitory and excitatory effects depending on dose (Liu 656 Drugs and Procedures to Treat Neuropathic Pain

et al. 2001). Calcitonin gene-related peptide (CGRP) ing excitatory cascade thought to establish the spinal is found normally in small diameter primary afferent and spinal-supraspinal substrates of chronic pain. fibers and its levels in DRG decrease after axotomy Studies of peripheral neuroimmune action contempo- (Dumoulin et al. 1992) or partial sciatic nerve ligation rary with the central microglial studies from Watkins’s (Ma et al. 2003). Conversely, spinal nerve ligation in- andSalter’sgroupshaveinvestigatedtheroleofinflam- creases capsaicin-evoked CGRP release in spinal cord matory cells at sites of experimental nerve injury. The dorsalhorn coincidentwithhyperalgesia (Gardelletal. chronic constriction injury developed by Bennett and 2003). Evidently, CGRP participates in maintenance Xie (1988) was found to rely on a local inflammatory of persistent hyperalgesia following peripheral nerve reaction at the point of injury along the sciatic nerve. injury. Substance P (SP), like CGRP, is also found in However, few recent studies have investigated inflam- small diameter primary afferent fibers and its levels matory reactions taking place at the distal end of the similarly decrease in DRG after axotomy (Nietsch et afferent arm, that is in or near tissue hosting terminals al. 1987); as is the case with CGRP, SP signaling via of sensory nerves (e.g. epidermis) undergoing Wal- spinal neurokinin-1 (NK1) receptors is increased after lerian degeneration. Do activated immunocytes near peripheral nerve injury and contributes to nerve injury- the terminal fields (e.g. subepidermal plexus) release induced hyperalgesia (Cahill and Coderre 2002). Sur- Algogen capable of activating or sensitizing afferent prisingly, clinical trials of NK1 antagonists in patients axons? with painful diabetic neuropathy were negative (Gold- steinetal.2001).Somatostatin(SOM),anotherpeptide References contained in small diameter primary afferent fibers de- 1. Bennett GJ, (2000) A neuroimmune interaction in painful pe- creases in dorsal horn and increases in ventral horn af- ripheral neuropathy. Clin J Pain 16:139Ð143 ter partial sciatic nerve injury (Swamydas et al. 2004); 2. Black JA, Cummins TR, Dib-Haaj SD et al. (2002) Sodium channels and the molecular basis for pain. In: Malmberg AB, the mechanical hyperalgesia following this injury is Chaplan SR (eds) Mechanisms and Mediators of Neuropathic also reversed by systemically administered SOM re- Pain. Birkhäuser Verlag, Basel-Boston-Berlin, pp 23Ð50 ceptor antagonists (Pinter et al. 2002). One or more of 3. Blakeman KH, Hao JX, Xu XJ et al. (2003) Hyperalgesia and in- these peptides may also be fruitful targets for therapeu- creased neuropathic pain-like response in mice lacking galanin receptor 1 receptors. Neuroscience 117:221Ð227 tic drug development. 4. Cahill CM, Coderre TJ (2002) Attenuation of hyperalgesia in a rat model of neuropathic pain after intrathecal pre- or post- treatment with a neurokinin-1 antagonist. Pain 95:277Ð85 Inflammatory Mediators 5. Dib-Hajj SD, Rush AM, Cummins TR et al. (2005) Gain-of- functionmutationin Nav1.7infamilial erythromelalgia induces Although immunocytes and cytokines are often in- bursting of sensory neurons. Brain 128:1847Ð1854 voked as factors contributing to neuropathic pain, the 6. Dumoulin FL, Raivich G, Haas CA et al. (1992) Calcitonin sites of their actions are rarely invoked. For example, a gene-related peptide and peripheral nerve regeneration. Annals recent study of thalidomide in a rodentmodelof neuro- New York Acad Sci 657:351Ð360 7. Gardell LR, Vanderah TW, Gardell SE et al. (2003) Enhanced pathic pain opens with this sentence: “In almost every evoked excitatory transmitter release in experimental neuropa- neuropathic pain state causedbyperipheralnervedam- thy requires descending facilitation. J Neurosci 23: 8370Ð8379 age, whether due to trauma or disease, both structural 8. Goldstein DJ, Wang O, Gitter BD et al. (2001) Dose-response damageand an inflammatory responseexist.”(Bennett study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy. Clin Neuropharmacol 24:16Ð22 2000). The verity of this statement is accepted by most 9. Hilliges M, Wang L, Johansson O (1995) Ultrastructural evi- researchers in the field without question, but the de- dence for nerve fibers within all vital layers of the human epi- sign of this particular study, or indeed most such stud- dermis. J Invest Dermatol 104:134Ð137 10. Hsieh ST, Choi S, Lin WM et al. (1996) Epidermal denerva- ies, rarely offer significant data or interpretation ex- tion and its effects on keratinocytes and Langerhans cells. J plicitly delineating the specific sites of the inflamma- Neurocytol 25:513Ð524 tory response. Only within the past 8 years have cy- 11. Hsieh ST, Chiang HY,Lin WM et al. (2000) Pathology of nerve tokines and subsequently microglia been identified as terminal degeneration in the skin. J Neuropathol Exp Neurol 59:297Ð307 necessary and sufficient spinal cord mediators of hy- 12. Karanth SS, Springall DR, Kuhn DM et al. (1991) An imunocy- peralgesia in rodent models of neuropathic pain (see tochemical study of cutaneous innervation and the distribution also proinflammatory cytokines). Presumably, in- of neuropeptides and protein gene product 9.5 in man and com- tense activity on primary nociceptive afferent fibers is monly employed laboratory animals. Am J Anat 191:369Ð383 13. Kashiba H, Senba E, Kawai Y et al. (1992) Axonal block- sufficient to activate spinal microglia, which in turn ade induces the expression of vasoactive intestinal polypep- adopt an activated phenotype,up-regulate synthesis of tide and galanin in rat dorsal root ganglion neurons. Brain Res proinflammatory cytokinesandreleaseexcitatory neu- 577:19Ð28 rotransmitters and neuromodulators. The substances 14. Kennedy WR, Said G (1999) Sensory nerves in skin: answers about painful feet? Neurology 53:1614Ð1615 released by spinalmicroglia are thoughtto include glu- 15. Kennedy WR, Wendelschafer-Crabb G (1993) The innervation tamate and nitric oxide, which contribute to the ongo- of human epidermis. J Neurol Sci 115:184Ð190 Drugs Targeting Voltage-Gated Sodium and Calcium Channels 657

16. Lindenlaub T, Sommer C (2002) Epidermal innervation den- 23. Swamydas M, Skoff AM, Adler JE (2004) Partial sciatic sity after partial sciatic nerve lesion and pain-related behavior nerve transection causes redistribution of pain-related pep- in the rat. Acta Neuropathol 104:137Ð143 tides and lowers withdrawal threshold. Experimental Neurol- 17. Liu HX, Brumovsky P, Schmidt R et al. (2001) Recep- ogy 188:444Ð451 tor subtype-specific pronociceptive and analgesic actions of 24. Villar MJ, Wiesenfeld-Hallin Z, Xu XJ et al. (1991) Further galanin in the spinal cord: selective actions via GalR1 and studies on galanin-, substance P-, and CGRP-like immunore- GalR2 receptors. Proc Nat Acad Sci USA 98:9960Ð9964 activities in primary sensory neurons and spinal cord: effects 18. Ma W, Chabot JG, Powell KJ et al. (2003) Localization and of dorsal rhizotomies and sciatic nerve lesions. Exp Neurol D modulation of calcitonin gene-related peptide-receptor com- 112:29Ð39 ponent protein-immunoreactive cells in the rat central and pe- 25. Wallace M (2002) In: Malmberg AB, Chaplan SR (eds) Mech- ripheral nervous systems. Neuroscience 120:677Ð694 anisms and Mediators of Neuropathic Pain. Birkhäuser Verlag, 19. Marchand F, Perretti M, McMahon SB (2005) Role of the im- Basel-Boston-Berlin mune system in chronic pain. Nature Reviews Neuroscience 26. Wilcox GL, Stone LS, Ossipov MH et al. (2005) Pharmacology 6:521Ð532 of pain tranmission and modulation. I. Central mechanisms. In: 20. Michaelis M (2002) Electrophysiological characteristics of in- Pappagallo M (ed) The Neurologic Basis of Pain. McGraw-Hill, jured peripheral nerves. In: Malmberg AB, Chaplan SR (eds) New York, pp 31Ð52 Mechanisms and Mediators of Neuropathic Pain. Birkhäuser 27. Zochodne DW, Cheng C (2000) Neurotrophins and other Verlag, Basel-Boston-Berlin, pp 23Ð50 growth factors in the regenerative milieu of proximal nerve 21. Nielsch U, Bisby MA, Keen P (1987) Effect of cutting or crush- stump tips. J Anat 196:279Ð283 ing the rat sciatic nerve on synthesis of substance P by isolated 28. Zochodone DW, Theriault M, Cheng C et al. (1997) Peptides L5 dorsal root ganglia. Neuropeptides 10:137Ð145 and Neuromas. Peptides and neuromas: calcitonin gene-related 22. Pinter E, Helyes Z, Nemeth J et al. (2002) Pharmacological peptide, substance P and mast cells in a mechanosensitive hu- characterisation of the somatostatin analogue TT-232: effects man sural neuroma. Muscle Nerve 7:875Ð880 on neurogenic and non-neurogenic inflammation and neuro- 29. Zuo Y, Perkins NM, Tracey DJ et al. (2003) Inflammation and pathic hyperalgesia. Naunyn-Schmiedebergs Archives Phar- hyperalgesia induced by nerve injury in the rat: a key role of macology 366:142Ð150 mast cells. Pain 105:467Ð479

Characteristics with this condition will typicallyexperience stimulus- Voltage-gated sodium channels (VGSCs) and voltage- independent pain and/or stimulus-dependent pain as gated calcium channels (VGCC) have a fundamental hyperalgesia and allodynia. role in the excitability of all neurons. Agents that block There are at least eight VGSCs present in the nervous these channels or encourage inactivation, often referred system of mammals that differ in their expression pat- to as membrane-stabilizing agents, reduce nerve ex- terns within the nervous system, their kinetics, and citability by blocking the initiation of action potentials. their recovery from inactivation. There are, for ex- TheroleofVGCCsin neuropathic pain is under ample, certain VGSCs that are only expressed in the intense investigation, but their role is far from clear. dorsal root ganglia, secondary to down-regulation of In contrast, VGSCs in sensory neurons are well stud- certain sodium channel subtypes and the up-regulation ied and thought to play a crucial role in neuropathic of others (Cummins et al. 2000). Further, the sodium pain caused by peripheral nerve injury. Alteration in channels can be divided into tetrodotoxin-sensitive and VGSC expression or function has been shown to have tetrodotoxin-resistant channels, both of which play a profound effects on the firing pattern of primary affer- physiological role in nociceptive impulse transmis- ent sensory neurons, as well as neurons in the central sion (Brock et al. 1998). However, there is evidence to nervous system. After nerve injury, sodium channels suggest that preferential expression and accumulation may accumulate not only on the neuroma or sprouts of of tetrodotoxin-resistant sodium channels, especially damaged peripheral nerve endings, but also along the Nav1.8 channels, may be relevant to the mechanisms of rest of the axons and on uninjured neighboring axons peripheral nerve injury-induced neuropathic pain (Lai (Cummins and Waxman 1997; England et al. 1996). et al. 2004). This accumulation of sodium channels dramatically A number of drugs modulate sodium channels in the pe- lowers the depolarization threshold of the nerves, and ripheral nervous system, and are thought to provide re- the nerves fire more readily in response to low-threshold lief from neuropathic pain by suppressing ectopic dis- stimulation (Matzner and Devor 1994). Increased firing charges originating in the injured nociceptors,orat of primary sensory neurons results in increased release the level of the associated dorsal root ganglia. The fact of glutamate and substance P from central terminals thattheavailableagentslackselectivityforsodiumchan- of the primary afferent fibers, leading to subsequent nel subtypes means that multiple channel subtypes are activation of the NMDA receptors, and a state called affected, resulting in frequent adverse side effects. The central sensitization develops. Pathologically unsta- therapeutic effects of these sodium channel-modulating ble membranes on primary afferent neurons are critical drugs result from their ability to prolong the refractory forinductionofcentralsensitizationanddevelopmentof period following action potentials, and to prevent the neuropathic pain after peripheral nerve injury. Patients generation of spontaneousectopic dischargesatconcen- 658 Drugs Targeting Voltage-Gated Sodium and Calcium Channels trations lower than those required to block or inhibit nor- tient has TN or not. However, carbamazepine may not mal impulse generation and propagation. be aseffective for atypicaltrigeminalneuralgia,and data with regard to other neuropathic pain disorders is neg- Individual Ion Channel Modulators in Treatment of Neuro- ative or limited, or both. Dosages are adjusted for each pathic Pain person individually, but usually vary between 200 and A number of drugs have been used for treatment of neu- 1200mg/d.However,intolerancetothesideeffectsanda ropathic pain, and this use was primarily empirically de- need for laboratory monitoring limits its use, especially rived (Dworkin et al. 2003a). The drugs used for treat- in the elderly. Phenytoin, next to carbamazepine, is an- ment of neuropathic pain belong to a few classes and, other example of a drug that has negative clinical trial because they modulate the activity of the nervous sys- results. Theoretically, both ofthesedrugscouldbeeffec- tem to achieve this effect, they are sometimes referred to tive because of their specific effectson sodium channels, as neuromodulators. It should be noted that all of them but their complex pharmacology limits their use. provide only symptomatic pain relief and none of them Lamotrigine is a new sodium channel and presynaptic reverses underlying pathology. glutamate blocking drug that may possess beneficial properties for pain relief by suppressing abnormal Anticonvulsant Agents ectopic discharge. It has recently been reported that Gabapentin has been used since 1994 for the man- lamotrigine, at doses of 400Ð600 mg/d, results in mod- agement of partial epilepsy, and is now one of the erate pain relief with tolerable side effects in trials most widely used drugs in the management of neuro- involving patients with diabetic and human immunod- pathic pain. Structurally, it is an analogue of gamma- eficiency virus (HIV)-associated neuropathy (Simpson aminobutyric acid, GABA, but pharmacologically et al. 2000). gabapentin appears to have no direct effect on GABA Topiramate, tiagabine and bupropion are other new gen- uptake or metabolism. Its mechanisms of action ap- eration anticonvulsants that display an ability to modu- pear to involve antagonism of non-NMDA receptors late sodium channels, but randomized trials for topira- and binding to the alpha2delta subunit of voltage- mate have been negative, and for the others are still lack- dependent calcium channels. The latter action could ing in indicating their utility in neuropathic pain man- mediate reduced release of excitatory neurotransmit- agement. ters. Although gabapentin is associated with few drug interactions and is well tolerated, the concentration Local Anesthetics/Antiarrhythmics range and value of therapeutic drug monitoring of this Local anesthetic drugs should be considered as alterna- drug is unclear; therefore, the dosage should be ad- tive therapies in the treatment of chronic neuropathic justed based on efficacy and tolerability. Gabapentin pain, because they reportedly provide effective re- seems to be most effective at or above doses of 1800 (up lief in different neuropathic pain conditions such as to 3600 mg/d) divided into three doses. Lower doses painful diabetic neuropathy, postherpetic neuralgia, (<900 mg/d) have shown to have limited effect in the lumbar radiculopathies, complex regional pain syn- treatment of neuropathic pain (Backonja and Glanz- drome (CRPS) type I and II and in traumatic peripheral man 2003). The dosage should be increased slowly, nerveinjuries.However,theusefulnessoftheseagentsis from the lowest recommended therapeutic daily dose limited because of frequent association with numerous and up to the maximum recommended daily dose, or adverse effects, particularly CNS-related side effects, until adequate pain relief is achieved and/or the patient e.g. nausea and emesis, dizziness, ataxia and tinnitus, complains about side effects. as well as cardiotoxicity, which severely limits its use, Pregabalin, a follow-up drug to gabapentin, also binds especially in the elderly. to alpha2delta subunit of voltage-dependent calcium Intravenouslidocaine(lignocaine)isthemostfrequently channels, but has a more linear bioavailability than used local anesthetic in the treatment of neuropathic gabapentin. Lower doses are therefore needed for pain, and has been shown to produce a moderate re- reducing pain and allodynia than gabapentin, and the duction in pain in patients with diabetic neuropathy efficacy is more predictable. The therapeutic dose range (Kastrup et al. 1987). It has been shown to be especially for pregabalin is between 150 and 600 mg/d divided in effective in pain states like trigeminal and post-herpetic two or three doses (Dworkin et al. 2003b). neuralgia and painful diabetic neuropathy. However, Carbamazepine binds preferentially to the inactivated intravenous administration poses a challenge for the state of voltage-gated sodium channels, thereby stabi- long-term treatment because oral dosing is unavailable. lizing axonal membranes. It is approved by the US Food Therefore, this treatment is administered periodically and Drug Administration as the drug of first choice to on a scheduled basis, or for excruciating episodes relieve shock-like pain, such as that experienced with of neuropathic pain. In addition to its acute effect, it trigeminal neuralgia (TN). The pain relief in TN is so also produces pain relief for several days, an effect fast and effective with carbamazepine that it is some- far outlasting drug elimination from the plasma. The times used as a marker for determining whether a pa- mechanisms related to this phenomenon remain un- Drugs with Mixed Action and Combinations, Emphasis on Tramadol 659 clear. Intravenous lidocaine/lignocaine is advocated as Rapidly Repriming Tetrodotoxine-Sensitive Sodium Current in a diagnostic aid for the presence of pain associated with Small Spinal Sensory Neurons after Nerve Injury. J Neurosci 17:3503Ð3514 nerve injury, and for its predictive value of potential 4. Cummins TR, Dib-Hajj SD, Black JA et al. (2000) Sodium Chan- analgesic efficacy of oral local anesthetic agents, such nels and the Molecular Pathophysiology of Pain. Prog Brain Res as mexiletine. 129:3Ð19 The orally administered “local anesthetics” include 5. Dworkin RH, Backonja M, Rowbotham MC et al. (2003a) Ad- vances in Neuropathic Pain: Diagnosis, Mechanisms, and Treat- both tocainide and the type 1b antiarrythmic agent ment Recommendations. Arch Neurol 60:1524Ð1534 D mexiletine; both have been used with success either 6. Dworkin RH, Corbin AE, Young JP Jr et al. (2003b) Pregabalin as monotherapies, or sequentially following an initial for the Treatment of Postherpetic Neuralgia: A Randomized, lignocaine infusion. However, there have been incon- Placebo-Controlled Trial. Neurology 60:1274Ð1283 7. England JD, Happel LT, Kline DG et al. (1996) Sodium Channel sistent results with the use of mexiletine. Patients with Accumulation in Humans with Painful Neuromas. Neurology diabetic neuropathy obtained a beneficial effect from 47:272Ð276 mexiletine (Oskarsson et al. 1997), and another demon- 8. Kastrup J, Petersen P, Dejgård A et al. (1987) Intravenous Lido- strated efficacy with regard to secondary outcomes, caine Infusion Ð A New Treatment of Chronic Painful Diabetic Neuropathy? Pain 28:69Ð75 but not with regard to global pain relief (Stracke et al. 9. Kemper CA, Kent G, Burton S et al. (1998) Mexiletine for HIV- 1992); a fourth trial in patients with HIV-associated Infected Patients with Painful Peripheral Neuropathy; A Double- neuropathy failed to demonstrate a benefit (Kemper et Blind, Placebo-Controlled, Crossover Treatment Trial. J Acquir al. 1998). Immune Defic Syndr Hum Retrovirol 19:367Ð372 10. Lai Josephine, Porreca Frank, Hunter John C et al. (2004) A critical aspect of the analgesic action of local anes- Voltage-Gated Sodium Channels and Hyperalgesia. Annu Rev thetics is their ability, at low subanesthetic doses, to Pharmacol Toxicol 44:371Ð397 block the spontaneous and/or evoked repetitive, ectopic 11. Matzner O, Devor M (1994) Hyperexcitability at Sites of Nerve + impulse activity in afferent fibers apparently mediated Injury Depends on Voltage-Sensitive Na Channels. J Neuro- physiol 72:349Ð359 by both TTX-S and slowly inactivating TTX-R sodium 12. Oskarsson P, Lunggren JG, Lins PE (1997) Efficacy and Safety channels. Lidocaine/lignocaine can suppress the gener- of Mexiletine in the Treatment of Painful Diabetic Neuropathy. ation of this abnormal impulse traffic and restore a more Diabetes Care 20:1594Ð1597 normal firing rhythm by acting either directly at the site 13. Pancrazio JJ, Kamatchi GL, Roscoe AK et al. (1998) Inhibition of Neuronal Na+ Channels by Antidepressant Drugs. J Pharmacol of origin or at distant sites. Injured nerves that fire repet- Exp Ther 284:208Ð214 itively at high frequency are specifically sensitive to 14. Simpson DM, Olney R, McArthur JC et al. (2000) A Placebo- concentrations of these drugs that have minimal impact Controlled Trial of Lamotrigine for Painful HIV-Associated Pe- on normal, somatosensory (i.e. nociceptive) neuronal ripheral Neuropathy. Neurology 54:2115Ð2119 15. Stracke H, Meyer UE, Schumacher HE et al. (1992) Mexiletine function, and this sensitivity of injured neurons is the in the Treatment of Diabetic Peripheral Neuropathy. Diabetes basis for the efficacy of these drugs. Care 15:1550Ð1555 Antidepressant Drugs Tricyclic antidepressants are the most well-studied and most used agents for relief of neuropathic pain. Drugs with Mixed Action and Interestingly, amitriptyline, doxepin and desipramine Combinations, Emphasis on Tramadol havebeenfoundtobestrongsodiumchannelmodulators ROBERT B. RAFFA (Pancrazio et al. 1998), in addition to their well-known Department of Pharmacology, Temple University effect on reuptake of serotonin and noradrenaline. This School of Pharmacy, Philadelphia, PA, USA sodium channel-blocking effect is presumed to be the [email protected] pain-relieving mechanism of these drugs in the case of neuropathic pain due to peripheral nerve injury, and Synonyms they have efficacy on both spontaneous pain as well as for hyperalgesia. The accumulative efficacy reported Mixed-Acting Analgesics; Multimodal Analgesics; from trials suggests that about one third of patients Tramadol will achieve a 50% reduction in neuropathic pain; however, the benefits are often outweighed by side effects, Definition especially among the elderly. Analgesics for which a significant portion of their effect References is attributed to the combined action of more than one mechanism. The differentmechanismscan be contained 1. Backonja M, Glanzman RL (2003) Gabapentin Dosing for Neu- within one drug or by combination of separate drugs. ropathic Pain: Evidence from Randomized, Placebo-Controlled Clinical Trials. Clin Ther 25:81Ð104 2. Brock JA, McLachlan EM, Belmonte C (1998) Tetrodotoxin- Characteristics Resistant Impulses in Single Nociceptor Nerve Terminals in As the nature of neuropathic pain is diverse in its eti- Guinea-Pig Cornea. J Physiol 512:211Ð217 3. Cummins TR, Waxman SG (1997) Downregulation of Tetro- ology, neuro(chemical/logical) pathology, and clinical dotoxin-Resistant Sodium Currents and Upregulation of a manifestations, it is highly likely that multiple diverse 660 Drugs with Mixed Action and Combinations, Emphasis on Tramadol pain-signal transmitting pathwaysare involved.It seems neurons (thereby reducing the release of neurotransmit- reasonable, then, that a strategy to treat this type of pain ters), and (2) enhancement of post-synaptic neuronal mightincorporatethesimultaneouscombinedactivation K+ efflux (thereby hyperpolarizing the neuron and ofdiverseanalgesicpathways.Thissectionconsidersthe inhibiting excess neuronal firing). treatment of neuropathic pain with analgesic drugs that havemultiplemechanismsofanalgesicaction.Thestrat- Tricyclics egy of combining analgesics that have a single mecha- The tricyclics produce an analgesic effect that is demon- nism of action is also included. strably independent of their well-known antidepressant Individual Agents (Classes) action. The efficacy of TCAs against neuropathic pain has been documented in controlled clinical tri- In the recent comprehensive review by Dworkin and als (for summary, see Dworkin et al. 2003). TCAs twenty other distinguished experts (Dworkin et al. have varying degrees of selectivity for inhibiting the 2003), five medications are listed as ‘first-line’ ther- neuronal reuptake of norepinephrine and/or 5-HT (5- apy: gabapentin, 5% lidocaine patch, opioids, tramadol hydroxytryptamine; serotonin). They are not always hydrochloride,and Tricyclics (TCAs) (e.g. nortripty- well tolerated, but a recent systematic review concluded line hydrochloride or desipramine hydrochloride). This that they are effective in relieving at least some types list was selected on the basis of analgesic efficacy of neuropathic pain (McQuay et al. 1996). “consistently demonstrated in multiple randomized controlled trials”. Of this list of first-line therapies, Tramadol gabapentin, lidocaine, and opioids, can be considered Tramadolhydrochloride(tramadol)istheonlyanalgesic to be single-mechanism analgesics, non-selective TCAs of these first-line medications that has been demon- and tramadol can be considered to be mixed-action anal- strated to have at least two distinct mechanisms that gesics. contribute to its analgesic action. Tramadol, (1RS,2RS)- 1- Gabapentin 2-[(dimethylamino)methyl]- (3-methoxyphenyl) cy- The role of gabapentin in the management of neuro- clohexanol hydrochloride (Fig. 1), is a centrally acting pathic pain has been reviewed recently by Rosner and synthetic analgesic. Based on animal and human stud- Diwan (2003). The mechanism of analgesic action of ies, tramadol appears to produce its analgesic effect gabapentin in treating neuropathic pain is not known. through two mechanisms (for summary, see Raffa and Friderichs 1996). One of the mechanisms appears to re- Gabapentin does not have affinity for opioid recep- μ tors (μ, δ,orκ) and, based on a surgically induced late to a weak affinity for -opioid receptors, estimated neuropathic pain model in the rat (Hwang and Yaksh to be about 6,000-fold less than the affinity of morphine 1997), gabapentin-induced antinociception does not and about the same affinity as dextromethorphan. Its mono-O-desmethyl metabolite (designated M1) binds involve GABAA or GABAB binding sites. It is the only μ antiepileptic drug that attenuates both cold and touch to -opioid receptors with greater affinity than does induced hyperesthesias (Hunter et al. 1997). The the parent compound, and is presumably responsible analgesic efficacy of gabapentin, and side effect profile, for the opioid component. However, in most animal are summarized in Dworkin et al. (2003) and Rosner tests and in human clinical tests, the analgesic effect and Diwan (2003). of tramadol is only partially blocked (<50%) by the Lidocaine Synthesizedin1943byLöfgren,lidocaineisan amide anesthetic that blocks voltage-gated Na+ channels. The uncharged form of lidocaine, a weakbase, penetratesthe membrane. After re-establishment of steady state, the charged (cationic) form binds to the receptor accessi- ble from the internal side of the membrane. Low plasma blood levels during lidocaine patch (5%) (Rowbotham et al. 1996) application suggests a purely local effect. Opioids All of the opioids producetheir analgesic effect through a well-known single mechanism: agonist action at 7- transmembrane G protein-coupled opioid receptors located in the spinal cord and higher CNS regions. Activation of opioid receptors on neurons has two well- established direct actions (Schumacher et al. 2004): (1) Drugs with Mixed Action and Combinations, Emphasis on Tramadol, 2+ block of voltage-gated Ca channels on presynaptic Figure 1 Tramadol hydrochloride (a racemic mixture of enantiomers). Drugs with Mixed Action and Combinations, Emphasis on Tramadol 661 opioid antagonist naloxone, suggesting a significant catalyzed by the CYP-2D6 isozyme of cytochrome P- contribution of a non-opioid mechanism (Raffa and 450.Tramadolanditsmetabolitesareexcretedprimarily Friderichs 1996). The apparent non-opioid component via the kidney. The mean terminal plasma elimination of tramadol’s analgesic mechanism appears to be re- half-life of tramadol is about 6.3 h, which increases lated to its ability to inhibit the neuronal reuptake of slightly (about 1 h) upon multiple dosing. norepinephrine and 5-HT. Tramadol does not have a The efficacy of tramadol for treating neuropathic significant peripheral or anti-inflammatory action and pain has been reported from double-blind, placebo- D a mixed agonist-antagonist action has been ruled out. controlled randomized clinical trials (for review see In addition to the individual contributions made by the Dworkin et al. 2003). Pain was significantly reduced opioid and non-opioid components of tramadol’s mech- compared to placebo, and beneficial effects on allo- anism of action, it appears that there is a synergistic dynia and quality of life were reported. interaction between these two mechanisms. The (+) enantiomer of tramadol binds to μ-opioid receptors Combinations and inhibits neuronal reuptake of 5-HT more potently Another approach to introducing a diversity of anal- than does the (Ð) enantiomer, whereas the (Ð) enan- gesic mechanisms into neuropathic pain therapy is the tiomer inhibits the neuronal reuptake of norepinephrine use of combinations of individual agents. Advantages more potently than does the (+) enantiomer (Table 1). and potential disadvantages of this strategy have been Each of the enantiomers individually produces centrally reviewed (e.g. Raffa 2001; Raffa et al. 2003). In rela- mediated (spinal) antinociception in mice; however, in tion to neuropathic pain, the major advantages could be several tests, the combination of the enantiomers was facilitation of prescribing and enhanced compliance, more potent than either enantiomer alone (i.e. the inter- broader coverage of diverse pain types, decreased side action was synergistic) (Raffa et al. 1993). Importantly, effects, and a possible synergistic analgesic interac- the enantiomersinteract lessthan synergistically or even tion. The major potential disadvantage is higher cost, less than additively in several tests predictive of side- but many combination products are priced at about effect potential. Thus, the clinical profile of tramadol the combined expense of the single-entities. The most apparently results from the fortuitous combinations and common combinations involve opioids or tramadol interactions of its component parts. It is the proposed with non-steroidal anti-inflammatory drugs (NSAIDs) duality of mechanism of analgesic action that has been or with acetaminophen (paracetamol). suggested to form the foundation for understanding The mechanism of action of the NSAIDs was delineated tramadol’s clinical attributes (e.g. Raffa and Friderichs in the early 1970’s and is now generally accepted to be 1996). via inhibition of cyclooxygenase (COX) isozymes. Tramadol is rapidly and almost completely absorbed The mechanism of action by which acetaminophen, after its oral administration, with an absolute bioavail- N-acetyl-p-aminophenol, produces its analgesic ac- ability (100 mg dose) of about 75% that is not signif- tion is not well understood. It has been shown that icantly affected by food. The plasma protein binding acetaminophen-inducedantinociception is related to its of tramadol is relatively low (about 20%). Tramadol’s plasma concentration. It is also known that the analgesia volume of distribution is about 2.7 L/kg. The analgesic induced by acetaminophen is not attributable solely, or effect of tramadol in humans begins within 1 h after its even to any significant extent, to an anti-inflammatory oral administration, and usually peaks in about 2Ð3 h. In action. There is a significant amount of evidence that humans, about 30% of tramadol is excreted unchanged points to the CNS as the major site of analgesic action in the urine, whereas animals metabolize tramadol of acetaminophen (see reviews by Walker 1995 and much more extensively Ð only about 1Ð2% is excreted Björkman 1995). unchanged. The major metabolic pathways involve N- In the case of the recently introduced combination of tra- and O-demethylation and glucuronidation or sulfation madol plus acetaminophen (Ultracetª), in addition to in the liver. The M1 (O-desmethyltramadol) pathway is the expected advantages of the simple additive effect of

Drugs with Mixed Action and Combinations, Emphasis on Tramadol, Table 1 In vitro activity of tramadol, its enantiomers, and M1 metabolite (mono-O-desmethyl tramadol) at opioid µ, δ,andκ receptors and at norepinephrine (NE) and serotonin (5-HT) neuronal reuptake sites. Values are K i in µM. Modiﬁed from Raffa and Friderichs (1996). μδ κ NE 5-HT

Tramadol 2.1 57.6 42.7 0.78 0.99

(+) enantiomer 1.3 62.4 54.0 2.51 0.53

(–) enantiomer 24.8 213 53.5 0.43 2.35

M1 metabolite 0.0121 0.911 0.242 1.52 5.18 662 Dry Needling thecombination,thecombinationproducesasynergistic Characteristics antinociceptive effect (Tallarida and Raffa 1996). Muscle pain can be caused by various conditions, in- References cluding neurological lesions, muscular lesions, soft tissue lesions, skeletallesionsand systemic diseases. In the 1. Björkman R (1995) Central Antinociceptive Effects of Non- Steroidal Anti-Inflammatory Drugs and Paracetamol. Acta cases of neurological lesions or systemic diseases, the Anaesthesiol Scand 39:2Ð44 muscle pain is usually diffuse and without tender spots. 2. Dworkin RH, Backonja M, Rowbotham MC et al. (2003) Ad- More frequently, however, one or more tender spots can vances in Neuropathic Pain. Neurol Rev 60:1524Ð1534 be identified in a muscle. These tender spots are usu- 3. Hunter JC, Gogas KR, Hedley LR et al. (1997) The Effect of Novel Anti-Epileptic Drugs in Rat Experimental Models of Acute ally myofascial trigger points. A myofascial trigger and Chronic Pain. Eur J Pharmacol 324:153Ð160 point(MTrP)isahyperirritablespotthatiswelllocalized 4. Hwang JH, Yaksh TL (1997) Effect of Subarachnoid Gabapentin within a taut band of skeletal muscle fibers. Compres- on Tactile-Evoked Allodynia ina Surgically Induced Neuropathic sionofanMTrPcancausepain(tenderness).An active Pain Model in the Rat. Reg Anesth 22:249Ð256 5. McQuay HJ, Tramèr M, Nye BA et al. (1996) A Systematic Re- myofascial trigger point is a spot with spontaneous pain view of Antidepressants in Neuropathic Pain. Pain 68:217Ð227 or pain in response to movement, while a latent my- 6. Raffa RB (2001) Pharmacology of Oral Combination Analgesics: ofascial trigger point is a spot with pain or discomfort in Rational Therapy for Pain. J Clin Pharmacol Ther 26:257Ð264 response to compression only. Referred pain can also be 7. Raffa RB, Friderichs E (1996) The Basic Science Aspect of Tra- madol Hydrochloride. Pain Revs 3:249Ð271 elicited when the compression pressure is high enough. 8. Raffa RB, Friderichs E, Reimann W et al. (1993) Complementary If the examiner compresses the MTrP with a fingertip, and Synergistic Antinociceptive Interaction between the Enan- then follows with a snapping motion over the MTrP, in tiomers of Tramadol. J Pharmacol Exp Ther 267:331Ð340 9. Raffa RB, Clark-Vetri R, Tallarida RJ et al. (2003) Combina- a direction perpendicular to the muscle fibers (this motion Strategies for Pain Management. Expert Opin Pharmacother tion is known as snapping palpation), a brief contraction 4:1697Ð1708 of the tense muscle fibers may occur. This is a polysy- 10. Rosner H, Diwan S (2003) The Role of Gabapentin in the naptic spinal reflex known as a local twitch response Management of Neuropathic Pain. In: Bountra C, Munglani R, Schmidt WK (eds) Pain: Current Understanding, Emerging (LTR). Therapies, and Novel Approaches to Drug Discovery. Marcel Recent research studies on both human and animal sub- Dekker, New York, pp781Ð794 jects have determined that MTrPs are commonly found 11. Rowbotham MC, Davies PS, Verkempinck C et al. (1996) Lido- in the neuromuscular junction region (endplate zone). caine Patch: A Double-Blind Controlled Study of a New Treat- ment Method for Post-Herpetic Neuralgia. Pain 65:39Ð44 Latent MTrPs may be developed as early as 6 months 12. Schumacher MA, Basbaum AI, Way WL (2004) Opioid Anal- after birth (Hong 2000; Hong 2002). A latent MTrP is gesics & Antagonists. In: Katzung BG (ed) Basic & Clinical probably caused by minor peripheral nerve injury due to Pharmacology. McGraw-Hill, New York, pp 497Ð516 repetitive minor trauma early in life (Gunn 1996; Hong 13. Tallarida RJ, Raffa RB (1996) Testing for Synergism Over a Range of Fixed Ratio Drug Combinations: Replacing the Isobolo- 2000). A latent MTrP may become active (painful) af- gram. Life Sci 58:23Ð28 ter the soft tissue or the lesions involving various struc- 14. Walker JS (1995) NSAID: An Update on their Analgesic Effects. tures sustain an acute injury or endure chronic repetitive Clin Exper Pharmacol Physiol 22:855Ð860 trauma or even after the patient suffers emotional stress (Hong 1996; Hong and Simons 1998). It is possible that the formation of active MTrPs is actually a defense mechanism in the body. If muscle mobil- Dry Needling ity is limited, further damage to the existing lesion Ð and further injury to the already injured soft tissue Ð may be CHANG-ZERN HONG prevented (Hong 1996). In some cases though, chronic Department of Physical Medicine and Rehabilitation, active MTrPs may persist even after the etiological le- University of California Irvine, Irvine, CA, USA sion is controlled. If the pain becomes so intolerable that [email protected] it interferes with daily life, the MTrP may need to be inactivated. Conservative therapy, such as manual therapy combined with thermotherapy and electrotherapy Synonyms can usually inactivate painful MTrPs. Other situations, Intramuscular Sensory Nerve Stimulation; twitch- however, might necessitate dry needling. Such cases in- obtained intramuscular stimulation clude the following: 1) poor response to conservative therapy, 2) intolerable pain, 3) deep location of an MTrP, rendering it inaccessible by conservative manual ther- Definition apy, 4) unavailable orinadequate timetoacceptthe time- Dry needling is a procedure in which a small tipped consuming conservative therapy, 5) persistent pain or needle is inserted multiple times into a myofascial trig- discomfort after complete elimination of the underlying ger point region or acupuncture point in order to stimu- pathological lesions that activate MTrPs or 6) personal late the sensory nerve endings and relieve muscle pain. preference. Dry Needling 663

Mechanisms of acupuncture points (Hong 2000). In both human and rabbit subjects, the EMG activity of an LTR can Although dry needling is one of the most effective be recorded specifically from the muscle fibers of the methods for rapid inactivation of an active MTrP, the taut band in response to stimulation of the MTrP (Hong mechanism of pain relief is still unclear. Recently, and Simons 1998; Hong and Torigoe 1994). The EMG clinical and basic science research studies of MTrPs activity of an LTR is diminished in a denervated human have been summarized (Hong 1996, 2000, 2002; Hong muscle or in a rabbit muscle following lidocaine block D and Simons 1998; Simons et al. 1999). The animal or transection of the innervating nerve. In the rabbit model developed by Hong and Torigoe in 1994 has study, this activity disappeared temporarily after spinal facilitated understanding of the nature of MTrPs (Hong cord transection during the spinal shock stage, but was and Simons 1998; Hong and Torigoe 1994). Based on almost completely recovered following the spinal shock evidence from animal studies as well as clinical ob- period, indicating that the LTR is mediated through the servations, a model of multiple small MTrP loci in an spinal cord. The MTrP circuit (Hong 2002) cannot MTrP region has been proposed (Fig. 1) (Hong 1994a). only transfer the nociceptive impulses to the brain, but According to this model, there are two components of may also control the referral pain patterns via connec- an MTrP locus, the sensory component, known as the tions to other MTrP circuits (Fig. 3). Furthermore, the sensitive locus or local twitch response locus (LTR occurrence of LTRs is mediated via the MTrP circuit. locus) and the motor component, known as the active In a histological study of sensitive loci in rabbit skeletal locus or endplate noise locus (EPN locus). muscle, a small nerve fiber was frequently found at the A sensitive locus (LTR locus) is the site from which sensitive locus (Hong and Simons 1998), indicating local and referred pain and LTR can be elicited by me- that the sensitive loci in an MTrP region are sensitized chanical stimulation (Fig. 2). A weak stimulation to the nerve fibers (nociceptors). sensitive locus can elicit pain and sometimes referred An active locus (EPN locus) is the site from which pain, but a strong stimulation (high pressure with a spontaneous electrical activity, known as endplate needle tip) is usually required to elicit an LTR. If the noise (EPN), can be recorded. The active locus is in the MTrP is extremely hyperirritable (painful), the patient immediate vicinity of a sensitive locus, with the MTrP may consistently experience referred pain in addition locus comprising both active and sensitive loci. Simons to the local pain and LTRs can be elicited easily with a has suggested that EPN is a consequence of excessive light snapping palpation. Based on the studies by Mense acetylcholine release, which may subsequently cause and Simons (1999), the referred muscle pain (from “taut band” formation (Fig. 4) (Simons et al. 1999). muscle to muscle) elicited following noxious stimula- The contraction knots in an MTrP region appear to be tion to the sensitive loci in an MTrP region seems to be a directly responsible for the palpable nodule and the consequence of central sensitization in the spinal cord. taut band of an MTrP (Simons et al. 1999). The result- The consistent pattern of referred pain from the MTrP ing increase in energy consumption, combined with a of a specific muscle indicates that the interneuronal con- reduction in the energy supply, may produce a local nections among different dorsal horn neurons follow energy crisis evidenced by severe localized hypoxia a fixed pattern, similar to the “meridian connections” (Fig. 4) (Hong and Simons 1998; Simons et al. 1999).

Dry Needling, Figure 1 Multiple MTrP loci in an MTrP region. 664 Dry Needling

Dry Needling, Figure 2 Characteristics of a sensitive (LTR) locus.

Dry Needling, Figure 3 MTrP circuits.

Effectiveness with local anestheticinjection or dry needling, but only The effectiveness of dry needling in relieving MTrP if LTRs are elicited during needling (Hong 1994a, b). pain has been described in detail (Baldry 2000; Chu Since an MTrP can be inactivated without injection of 1999; Gunn 1996; Hong 1994b; Hong 2000; Lewit any solution, the mechanical stimulation of the MTrP 1979; Melzack 1981; Simons et al. 1999) but no ran- seems to be the most important factor for pain relief. It domized controlled trials are available. By using a has been hypothesized that hyperstimulation analgesia special technique of “fast-in, fast-out” needle move- “closes the gate” by disrupting reverberatory neural ment (to generate high pressure) into multiple loci in circuits (MTrP circuits) in the central nervous system an MTrP region, immediate pain relief can be achieved and that this is the mechanism of pain relief for both dry Dry Needling 665

Dry Needling, Figure 4 Energy crisis in a taut band. needling and acupuncture (Hong 2002; Melzack 1981). causes discomfort or pain should be carefully identified Many authors have documented the similarity between (pain recognition). Most of the time, patients can simply acupuncture and dry needling in treating MTrP (Baldry pointto the painfulspotwith their finger. In severe cases, 2000; Gunn 1996; Hong 1994a; Hong 2000; Lewit however,thepainmaybediffuseandvague.Illustrations 1979; Melzack 1981). The “Teh-Chi” effect, described in certain textbooks may thus be needed to help locate by acupuncturists as an important sign for obtaining MTrPs (Simons et al. 1999; Travell and Simons 1992). an optimal effect in acupuncture therapy, is similar to During dry needling, it is important to identify the most the sensation reported by patients when the needle tip painful region (MTrP site) by finger palpation with the approaches a sensitive locus in an MTrP region dur- hand not holding the needle (usually the non-dominant ing MTrP injection. The patients being treated by dry hand) (Fig. 5). Multiple rapid insertions of the needle needling or MTrP injection may also experience this into the MTrP site, without pulling the needle tip out sensation at the moment when an LTR is elicited. In from under the skin (i.e. the needle remains in the sub- fact, all MTrPs are acupuncture points, although many cutaneous layer) are then performed. It is important to acupuncture points are not trigger points. Additionally, maintainanup-and-downmotionoftheneedle,asaside- nociceptors are diffusely distributed in the subcuta- to-sidemotioncancutvesselsornerves.Movingthenee- neous tissues and may also connect to the MTrP circuit, dlerapidlywillalsoelicitLTRsmoreeasily.LTRsshould although stimulation of subcutaneous nociceptors will be elicited as often as possible by multiple needle inser- not cause LTRs. This may explain the effectiveness of tions into the MTrP region. superficial dry needling (Baldry 2000). Immediately after dry needling, the MTrP region should be compressed firmly for a few minutes to avoid bleed- Equipment ing, as this is the major cause of post-needling soreness. A hypodermal needle, an acupuncture needle or an elec- Post-needling pain usually occurs in fibromyalgia pa- tromyographic (EMG) needle (Chu 1999) can be used tients. If no excessive bleeding occursafter needling,ap- for this procedure. The disadvantage of a hypodermal plication of thermotherapy after compression may help needle is the sharp cutting edge of the needle tip, which to reduce pain or soreness. A cold pack is usually un- may actually damage muscle fibers. An acupuncture necessary Ð and not recommended Ð unless the bleeding needle is too flexible and is difficult to manipulate dur- is massive. Cold temperatures can induce vasoconstric- ing the multiple muscle insertions. An EMG needle tion, which may then lead to the impairment of local cir- is therefore the best selection, since it can avoid the disadvantages of the other two. However, EMG needles (even disposable ones) are quite expensive. Technique A specific and very effective technique of dry needling hasbeen recommended (Hong1994b). Thistechniqueis similar to the procedure of MTrP injection. Gunn (1996) andChu(1999)recommendasimilartechnique,butthey fail to stress the importance of MTrP palpation during needling.Beforedryneedling,theexactspot(MTrP)that Dry Needling, Figure 5 Palpation of the MTrP during dry needling. 666 DSM, DSM-IV, DSM-IVR culation and interfere with the resolution of any tissue damage caused by the needle. DTI Gunn uses an acupuncture needle ( intramuscular stimulation) (Gunn 1996), while Chu uses an EMG Diffusion Tensor Imaging needle ( twitch-obtaining intramuscular stimulation) (Chu 1999) to perform dry needling. Both apply multiple insertions into the MTrP region. Baldry applies the Dual Matrix (Agro Contin System) needle into the subcutaneous, but not into muscle tissue ( superficial dry needling) (Baldry 2000). Sometimes, Definition the needle is inserted into a trigger point in a region other than the subcutaneous tissue or muscle (such as a Adualmatrix (Agro Contin System)thatuses2 different ligament, tendon, bursa, etc.). types of retarding polymers is utilized to achieve mea- Acupuncture sured/controlled release of the active drug. Postoperative Pain, Oxycodone References 1. Baldry PE (2000) Superficial dry needling. In: Chaitow CL (ed) Fibromyalgia syndrome: a practitioner’s guide to treatment. Churchill Livingston, Edinburgh Ductus Arteriosus 2. Chu J (1999) Twitch-obtaining intramuscular stimulation: observation in the management of radiculopathic chronic low back Definition pain. J Musculoske Pain 7:131Ð146 3. Gunn CC (1996) Treatment of chronic pain. Intramuscular stim- Ductusarteriosusisabloodvesselinafetusthatbypasses ulation for myofascial pain of radiculopathic origin. Churchill pulmonary circulation by connecting the pulmonary Livingston, London 4. Hong C-Z (1994a) Consideration and Recommendation of My- artery directly to the ascending aorta. It is open in the ofascial trigger point injection. J Musculoske Pain 2:29Ð59 fetus but normally closes after birth. 5. Hong CZ (1994b) Lidocaine injection versus dry needling to my- NSAIDs, Adverse Effects ofascial trigger point: the importance of the local twitch response. NSAIDs and their Indications Amer J Phys Med Rehabil 73:256Ð263 6. Hong C-Z (1996) Pathophysiology of Myofascial trigger point. J Formos Med Assoc 95:93Ð104 7. Hong C-Z (2000) Myofascial trigger points: pathophysiology and Dummy correlation with acupuncture points. Acupunct Med 18:41Ð47 8. Hong C-Z (2002) New Trends in Myofascial Pain Syndrome. Chinese Medical Journal 65:501Ð512 Placebo 9. Hong C-Z, Simons DG (1998) Pathophysiologic and electrophysiologic mechanism of myofascial trigger points. Arch Phys Med Rehabil 79:863Ð872 10. Hong C-Z, Torigoe Y (1994) Electrophysiologic characteristics Dura Mater of localized twitch responses in responsive bands of rabbit skeletal muscle fibers. J Musculoske Pain 2:17Ð43 11. Lewit K (1979) The needle effect in relief of myofascial pain. Definition Pain 6:83Ð90 12. Melzack R (1981) Myofascial trigger points: relation to acupunc- A tough, fibrous membrane that surrounds the brain and ture and mechanism of pain. Arch Phys Med Rehabil 62:114Ð117 provides protection for the central nervous system. 13. Mense S, Simons DG (1999) Muscle Pain: understanding its na- Diencephalic Mast Cells ture, diagnosis, and treatment. Williams & Wilkins, Baltimore 14. Simons DG, Travell JG, Simons LS (1999) Travell & Simons’s Myofascial Pain and Dysfunction: The Trigger Point Manual, vol I, 2nd edn. Williams & Wilkins, Baltimore 15. Travell JG, Simons G (1992) Myofascial Pain and Dysfunction: Dural Puncture The trigger point manual, vol II. Williams & Wilkins, Baltimore Definition A puncture of the dura mater is associated with a spinal DSM, DSM-IV, DSM-IVR nerveblockandisacomplicationofepiduralnerveblock in about 1 in 100 patients. The puncture hole with an Diagnostic and Statistical Manual of Mental Disor- epidural needle of 16gauge is much larger than after a ders deliberate puncture with a spinal needle of 25 or smaller gauge. Headaches after dural puncture with an epidural needleoftenhavetobetreatedbyanepiduralbloodpatch in order to block the hole made in the dura. The rent in DSPN the dura may, if not treated, take days or months to heal by normal processes. Diabetic Neuropathies Postpartum Pain Dynamic Mechanical Hyperalgesia 667

Dural Receptors Dying Child

Nociceptors in the Orofacial Region (Meningeal/ Cancer Pain, Palliative Care in Children Cerebrovascular) D Duration of Ultrasound Treatment Dynamic Allodynia Deﬁnition Deﬁnition The duration is 1 Ð 15 min. Usually, the duration should be at least 3 min. Light brush evokes a sensation of pain. UltrasoundTherapyofPainfromtheMusculoskeletal Allodynia (Clinical, Experimental) System Hyperpathia, Assessment

Duration Requirement Dynamic Ensemble Definition The physical or mental impairment must be expected to Definition result in death, or have lasted or can be expected to last A conceptualization of pain mechanisms that suggests for a continuous period of not less than 12 months. that the experience of pain is brought about by a variable Disability Evaluation in the Social Security Admin- network of interconnected regions, subject to dynamic istration influences of past history and reproductive status; compare with pain pathway. Gynecological Pain, Neural Mechanisms Durogesic®

Definition Durogesic¨ is a transdermal patch system that continu- Dynamic Mechanical Allodynia ously delivers fentanyl for 72 hours. Postoperative Pain, Fentanyl Definition Pain produced by moving a normally innocuous mechanical stimulus such as a soft artist’s paint brush or Dyesthesias cotton wisp across the skin. Allodynia (Clinical, Experimental) Definition Hyperpathia, Assessment An unpleasant abnormal sensation that may or may not Quantitative Thermal Sensory Testing of Inflamed be painful. Skin Spinal Cord Injury Pain Model, Hemisection Model

Dying-Back Neuropathy Dynamic Mechanical Hyperalgesia

Deﬁnition Deﬁnition Peripheral nerve disorders beginning from degeneration Dynamic mechanical hyperalgesia refers to abnormal of the most terminal parts of both central and peripheral sensitivity, caused by activation of tactile receptors to processes of neurons, the major pathology of toxic neu- a gentle stimulation such as light stroking with a cotton ropathies; also central-peripheral distal axonopathy and wisp or Q-tip. This is also referred to as allodynia. distal axonopathy. Allodynia (Clinical, Experimental) Toxic Neuropathies Restless Legs Syndrome 668 Dynamic Pain

Dynamic Pain Dyschezia

Definition Definition Pain provoked by movement, such as deep breathing or Difficult or painful evacuation of feces from the rec- coughing,gettingoutofbed,orwalking(duringthepost- tum generally associated with endometriosis of the operative period). rectovaginal septum. Postoperative Pain, Acute Pain Management, Princi- Dyspareunia and Vaginismus ples Postoperative Pain, Acute Pain Team Dysesthesia, Assessment

ELLEN J¯RUM Dynorphins The Laboratory of Clinical Neurophysiology, Rikshospitalet University, Oslo, Norway [email protected] Definition Peptides of several sizes, including dynorphin A and Synonyms dynorphin B, which preferentially bind to KOP recep- There are no real synonyms to dysesthesia, but it may tors. They are formed from prodynorphin and found sometimes be difficult to decide whether one is dealing through the central and peripheral nervous system, with dysesthesia or paresthesia. The important differ- modulating pain sensation. encebetweenthetwotermsimplies,however,thatdyses- Endogenous Opioid Peptides thesia is always unpleasant, whereas paresthesia is de- Nitrous Oxide Antinociception and Opioid Receptors fined as an abnormal sensation which is not unpleasant Opiates During Development (Classification of chronic pain 1994). Peptides in Neuropathic Pain States Definition An unpleasant abnormal sensation, whether sponta- Dysaesthesia (Dysesthesia) neous or evoked (Classification of chronic pain 1994). Characteristics Definition Assessment of Dysesthesia An unpleasant abnormal sensation, whether sponta- Assessment of Spontaneously Occurring Dysesthesia neous or evoked. Dysesthesia is frequently present in neuropathic Anesthesia Dolorosa Model: Autotomy pain (Lindblom and Verrillo 1979; Eide et al. 1996; Central Nervous System Stimulation for Pain Nasreddine and Saver 1997), but may also occur in Cervical Transforaminal Injection of Steroids non-neuropathic pain states (Aikins et al. 2003) and Dorsal Root Ganglionectomy and Dorsal Rhizotomy in epilepsy (Duchowny 1993). The mechanisms un- Hyperpathia derlying dysesthesia are largely unknown. Since this Hyperpathia, Assessment chapter is dealing only with the assessment of dysesthe- Metabolic and Nutritional Neuropathies sia, further discussion of possible neurophysiological Postherpetic Neuralgia, Etiology, Pathogenesis and mechanisms will not be undertaken. The only possible Management way of assessing dysesthesia to spontaneous pain,is Postherpetic Neuralgia, Pharmacological and Non- to obtain thorough verbal information from the patient, Pharmacological Treatment Options where they are asked to describe in detail the various Viral Neuropathies sensations they may experience. It may be difficult for some patients to decide whether a sensation is unpleasant or not, and thereby sometimes difficult to decide whether one is dealing with dysesthesia or paresthesia. Dysautonomic However, if patients are describing a purely painful sensation, dysesthesia will be the right term. The descriptors used by the patients may vary, probably even Definition for the same experience, but since we are dealing with Color changes, temperature changes or edema. purely subjective sensations, a more objective evalua- CRPS-1 in Children tion is impossible. One may ask patients to describe the Dysesthesia, Assessment 669 quality of the unpleasant sensation, or use one of a Dysesthesia is frequently reported in studies of neuro- large variety of scales, where patients may choose from pathic pain, but listed here are some examples of other a list of pain quality descriptors. One frequently em- conditions where the term may be encountered: ployed scale is the McGill pain Questionnaire (MPQ), 1. Vulvar dysesthesia is a not uncommon condition, which is a well-validated and psychometrically reliable frequently described in the literature and wherespon- instrument consisting of 20 lists of pain descriptors taneous dysesthesia may occur. (Aikens et al. 2003; (Melzack 1975). However, many other scales also ex- Reed et al. 2003) The dysesthesia is often character- D ist. It may be worthwhile to assess not only the type of ized as a constant or intermittent burning sensation, sensation, but also the intensity of a dysesthetic sen- but descriptors such as tender and sore have also been sation, by, for example, using a visual analogue scale employed (Aikens et al. 2003) (VAS) from 0Ð10 cm or 0Ð100 mm, where 0 represents 2. Dysesthesia may occur in relation to epileptic no pain and 10 or 100 the worst thinkable pain (or other seizures or as an adverse effect to vagal nerve stim- intensity scales). ulation (Akman et al. 2003) Assessment of Evoked Dysesthesia In this report, the authors describe a patient who was One may assess evoked dysesthesia to tactile stim- treatedforrefractorycomplexpartialepilepsywithvagal uli or thermal stimuli. Special cases of dysesthesia nerve stimulation, who reported complaints of intermit- include hyperalgesia and allodynia, making the dis- tent and unpredictable“funny” feelings and tightness in tinctions between the different phenomena difficult. his throat and stomach 4 months after the implantation There is normally no painful sensation to light touch. of the vagal nerve stimulator. However, as the authors However, light touch may evoke a painful sensation in make clear, somatosensory symptoms, including vari- a patient with neuropathic pain. In daily life, patients ous forms of dysesthesia, may occur in various forms of may experience evoked dysesthesia in many situa- epilepsy, such asbenign epilepsy of childhoodwith tem- tions, such as being touched by fellow passengers in poral spikes, where pharyngeal sensations of tingling, a crowded bus, bed linen in bed etc. In many reports, burning, constriction or unpleasant sensations (dyses- there are no distinctions made between allodynia to thesia) are described (Duchowny 1993). light touch or to brush and dysesthesia (J¿rum et al. 2003). However, a dysesthetic sensation will always be an abnormal sensation, described by the patient References as different from painful touch. There may be a large 1. Aikens J E, Reed B, Gorenflo D et al. (2003) Depressive Symp- number of descriptors, which again may be assessed toms among Women with Vulvar Dysesthesia. Am J of Obstetrics by asking the patient for a description or, by letting and Gynecology 189:462Ð466 2. Akman C, Riviello JJ, Madsen JR et al. (2003) Pharyngeal the patient choose from various descriptors in one of Dysesthesia in Refractory Complex Partial Epilepsy: New many possible pain-scales. The intensity of an evoked Seizure or Adverse Effect of Vagal Nerve Stimulation? Epilep- sensation may also be assessed by means of VAS (or sia 44:855Ð858 another intensity-scale). Dysesthesia to thermal stim- 3. Berglund B, Harju E-L, Kosek E et al. (2001) Quantitative and Qualitative Perceptual Analysis of Cold Dysesthesia and Hyper- uli, especially to cold stimuli, is a common finding algesia in Fibromyalgia. Pain 96:177Ð187 in neuropathic pain (J¿rum et al. 2003) and in more 4. Duchowny M (1993) Identification of the Surgical Candidates generalized pain like fibromyalgia (Berglund et al. and Timing of the Operation: Overview. In: Wyllie E (ed) The 2001). In most studies where cold dysesthesia has been Treatment of Epilepsy: Principles and Practice. Lea & Fabiger, Philadelphia, pp 999Ð1008 described, the sensation of cold is studied by quanti- 5. Eide PK, J¿rum E, Stenehjeme A (1996) Somatosensory Findings tative sensory testing (QST), where the thresholds for in Spinal Cord Injury Patients with Central Dysesthesia Pain. J cold pain are assessed (Berglund et al. 2001; J¿rum et Neurol Neurosurg Psychiatry 60:411Ð415 6. J¿rum E, Arendt-Nielsen L (2003) Sensory testing and clini- al. 2003). In the study by Berglund and co-workers, cal neurophysiology. In: Breivik H, Campell W, Eccleston C the perceived quality of each thermal stimulus was (eds) Textbook of Clinical Pain Management. Arnold, London, assessed by means of a list of preselected verbal de- pp 27Ð38 scriptors. Patients with fibromyalgia not only had lower 7. J¿rum E, Warncke T, Stubhaug A (2003) Cold Allodynia and Hyperalgesia in Neuropathic Pain: The Effect of N-methyl- D threshold of cold pain and cold tolerance (allodynia aspartate (NMDA) Receptor Antagonist Ketamine: A Double- and hyperalgesia), but they also used more pain-related Blind, Cross-Over Comparison with Alfentanil and Placebo. Pain descriptors than normal controls. A hyperfunction 101:229Ð235 for heat pain and heat-pain tolerance was also found. 8. Lindblom U, Verrillo RT (1979) Sensory Functions in Chronic Neuralgia. J Neurol Neurosurg Psychiatry 42:422Ð435 Aberrant perceptions to cold stimulation were also re- 9. Melzack R (1975) The McGill Pain Questionnaire: Major Prop- ported (paradoxical heat, dysesthesia). In neuropathic erties and Scoring Methods. Pain 23:345Ð356 pain, the sensation of cold is frequently reported as 10. Nasreddine ZS, Saver JL (1997) Pain after Thalamic Stroke: dysesthetic, as an unpleasant aberrant sensation, of- Right Diencephalic Predominance and Clinical Features in 180 Patients. Neurology 48:1196Ð1199 ten a sensation of warmth (J¿rum and Arendt-Nielsen 11. Reed BD, Haefner HK, Cantor L (2003) Vulvar Dysesthesia (vul- 2002). vodynia). A Follow-Up Study. J Reprod Med 48:409Ð416 670 Dysesthetic Vulvodynia

this group. However most pain management physicians Dysesthetic Vulvodynia wouldthinkofsuchpainconditionsnotasneuropathicin the sense secondary to structuralnervechange butasdis- Synonyms turbances in nervous system function. I have earlier sug- Essential vulvodynia gested that pain conditions due to disturbances of function in the nervous system should be denoted dysfunc- Definition tional pain (Sjölund 1994). These conditions do not re- Subset of vulvodynia characterized by generalized, ally show“signsof organic disease” atallandmaythere- spontaneous vulvar pain in the absence of physical forebemisinterpretedas“somatizing”butareanalogous findings. to e.g. epilepsy. Vulvodynia To be able to interpret such chronic pain conditions we should therefore include among the nociceptive, neuropathic and psychogenic pain categories a fourth main category, dysfunctional pain. The diagnosis of Dysfunctional Pain and the International dysfunctional pain should be made whenever there are Classification of Function signs of central sensitization or central disinhibition, independent of type of afferent input. Likely examples BENGT H. SÖLUND Rehabilitation and Research Centre for Torture of dysfunctional pain would be fibromyalgia (Graven- Victims, South Danish University, Copenhagen, Nielsen et al. 2000), myofascial pain (Bendtsen et al. Denmark 1996) referred pain (Kosek and Hansson 2002) and [email protected] centralization phenomena in neuropathic pain (Eide 2000; Flor et al. 2001). This proposal is in agreement Synonym with the new principle suggested for classification of pain syndromes, based on underlying pain mechanisms Sensory Impairment (Woolf et al. 1998). Can we then adequately assess and manage a person Definition in chronic pain after labeling the category of pain / the Pain conditions due to disturbances of function in the mechanism of pain? Most clinicians trying to manage nervous system. In a wider sense, all ongoing (chronic) chronic pain patients work very hard to temporarily pre- paincanbeconsideredasasensoryimpairment,i.e.adis- ventthenociceptivestimulifrom reaching theconscious turbance of normal sensory nociceptive function (WHO sensory level (sensorium; Fig 1). 2001). What about all those other factors important for that patient? How do we label the consequences of pain for Characteristics that individual in a particular pain condition and in a Often, there is not a traditional pathology in chronic particular setting? More specifically, is it possible with pain conditions. For example, it was recently reported existing taxonomies to categorize the interpretation that 35% of nearly 2500 responders to a questionnaire by the patient as well as the affective and behavioral in a southern rural / small town area in Sweden reported consequences of that interpretation for a specific per- chronic musculo-skeletal pain (Bergman et al. 2001) son in a certain context? As illustrated in Fig. 2, the whereas thorough clinical screening of smaller cohorts awareness of painful stimuli immediately gives rise showed that only 0.5% fulfilled the criteria for rheuma- to an interpretative process where previous experience toid arthritis (Simonsson et al. 1999) and 1.3% those and environmentalcues as well as affective aspects play for fibromyalgia (Lindell et al. 2000). How should we classify such “non-specific” pain conditions? Several research groups have found that localized chronic musculoskeletal pain may be associated with sensory alterations in or close to the painful region, demonstrating a change of function in the sensory nervous system (Bendtsen et al. 1996; Graven-Nielsen et al. 2000; Kosek and Hansson 2002; Persson et al. 2003). It is not established at present whether such changes contribute to the pain but this may well be the case. With the current official definition of neuropathic pain by the International Association for the Study of Pain Dysfunctional Pain and the International Classification of Function, Figure 1 Sites of action of traditional pain therapies. Abbreviations: (Merskey and Bogduk 1994), not only conditions due NSAID, nonsteroidal anti-inflammatory drugs; TENS, transcutaneous elec- to primary lesions of the nervous system but also condi- trical nervestimulation; SCS, spinal cord stimulation. (Modified from Sjölund tions due to dysfunction of the nervous system belong to 2003). Dysfunctional Pain and the International Classification of Function 671

Dysfunctional Pain and the International Classification of Function, Dysfunctional Pain and the International Classification of Function, Figure 3 Pain versus health. The ICF components (italics) integrated into Figure 2 A comprehensive model of chronic pain. (Modified from Sjölund, the comprehensive model of chronic pain. (Modified from Sjölund 2003). 2003).

important roles. This interpretation thereby becomes To facilitate use of the ICF for the taxonomy and man- heavily influenced by personal factors. These cog- agement of chronic pain I have proposed that longstand- nitive processes also form the basis for the resulting ing pain in general (>3Ð6 months duration) should be motor output, i.e. behaviors. In addition, the behaviors classifiedasasignificantdeviationfromnormalfunction immediately influence the sensorium anew, since the of the nociceptive transmission and thereby be seen as occurrence and severity of pain is usually influenced a severe sensory impairment (Sjölund 2003). This im- by body movement, giving rise to phenomena like plementation enables us to use the ICF classifications fear-avoidance. The present lack of a more generalized to describe pain-related activity limitations and partic- taxonomy for a person in chronic pain hampers the ipation restrictions, both of which are cardinal features choice of treatment strategies, since the analysis may of the much used but officially denounced “chronic pain be limited to factors less relevant for the individual case. syndrome” (Sanders 1999) and of themuch debated (so- A more general and suitable system to describe pain matoform) pain disorder (APA 1994). As can be seen and related influences on health is now available in in Fig. 3, impairments, activity limitations and partic- the form of the international classification of function ipation restrictions act in an integrated fashion to ex- ( ICF) (WHO 2001) that is basically a component plain the complex resulting picture in the sensory / in- of a health system and describes functioning on the terpretative / behavioral clinical presentation of long- personal level. The new classification has two parts; standing pain. It may be much more meaningful (and one is denoted functioning and disability, where func- true!) to describe a person in chronic pain with a combi- tioning is an umbrella term encompassing all body nation of one or several of the four main pain categories functions, activities and participation and disability mentioned previously and the ICF, rather than speculat- serves as an umbrella term for impairments, activity ing if a particular organ system is affected by an uncer- limitations and participation restriction. The other tain pathology in a painful region and adding “pain be- part, contextual factors, forms the complete back- haviors” (Sanders 1999), “somatization / pain disorder” ground of an individual. By body functions is meant (APA1994) or an empirical psychological characteriza- the physiological functions of the body systems includ- tion (Rudy et al. 1995). ing psychological function. Impairments are problems For therapeutic strategiesit iseasier todefineindications in body function and structure such as significant de- for pain management by deriving them from the ICF ap- viation or loss. Activity is the execution of a task or proach, assessing the pain category and its characteris- action by an individual and activity limitations are tics (the sensory impairment) as well as the activity limi- difficulties an individual may have in executing activi- tations and participation restrictions in that individual in ties. Participation is involvement in a life situation and his / her context and to focus pain management on those participation restrictions are problems an individual persons who are distinctly limited or restricted by their may experience in involvement in such situations. In pain. The planning and goal setting of pain management addition, the ICF contextual factors are environmental can be facilitated by directly asking, how can we reduce factors, that make up the physical, social and attitudinal the sensory impairment? Can we remove the cause of environment in which people live and conduct their chronic pain? Can we achieve temporary or permanent lives and personal factors that are internal influences pain relief? How do we compensate for activity limita- and attributes, such as race, gender, lifestyle, education, tions and focus on specific participation restrictions in path and current experiences. These components have our rehabilitation efforts? How do we best consider en- multiple interactions. vironmental and personal factors? Such a structured and 672 Dysfunctional Segmental Motion individualized ICF-related assessment may allow pain Pain is often accompanied by other symptoms such as management to be tested in a more meaningful scientific sweating, tachycardia, headaches, nausea, vomiting, manner from now on. diarrhea, and tremulousness. Cyclic symptoms can result in significant physical and emotional distress, as References well as lifestyle disruption. Dysmenorrhea is a common 1. APA (1994) Diagnostic and Statistical Manual of Mental Dis- gynecologic condition, affecting up to 50% of men- orders. American Psychiatric Association, Washington DC struating women. It is the leading cause of short-term, 2. Bendtsen L, Jensen R, Olesen J (1996) Qualitatively altered nociception in chronic myofascial pain. Pain 65:259Ð264 repeated absenteeism from school or work among teens 3. Bergman S, Herrstrom P, Hogstrom K et al. (2001) Chronic and young adults. Diagnosis is based upon review of musculoskeletal pain, prevalence rates, and sociodemographic a daily pain diary indicating cyclicity of pain. Primary associations in a Swedish population study. J Rheumatol dysmenorrhea refers to pain with menses when there is 28:1369Ð1377 4. Eide P (2000) Wind-up and the NMDA receptor complex from no pelvic pathology, whereas secondary dysmenorrhea a clinical perspective. Eur J Pain 4:5Ð17 is painful menses with underlying pelvic pathology. 5. Flor H, Denke C, Schäfer M et al. (2001) Sensory discrimina- Non-steroidal anti-inflammatory drugs (NSAIDS), tion training alters both cortical reorganization and phantom limb with or without combined hormonal contraceptives, are pain. Lancet 357:1763Ð1764 6. Graven-Nielsen T, Aspegren Kendall S et al. (2000) Ketamine the cornerstone of therapy and can be quite effective reduces muscle pain, temporal summation, and referred pain in when used appropriately. Combined hormonal methods fibromyalgia patients. Pain 85:483Ð491 of birth control, including pills, the contraceptive patch 7. Kosek E, Hansson P (2002) The influence of experimental pain and the vaginal ring, result in pain relief for more than intensity in the local and referred pain area on somatosensory perception in the area of referred pain. Eur J Pain 6:413Ð425 90% of women with primary dysmenorrhea. There is 8. Lindell L, Bergman S, Petersson IF et al. (2000) Prevalence of also some evidence for acupuncture or transcutaneous fibromyalgia and chronic widespread pain. Scand J Prim Health electrical nerve stimulation (TENS) in the manage- Care 18:149Ð153 9. Merskey H, Bogduk N (1994) Classification of chronic pain. ment of dysmenorrhea. The management of secondary Descriptions of chronic pain syndromes and definitions of pain dysmenorrhea involves treatment of the underlying terms. IASP Press, Seattle pathology. Surgical approaches for dysmenorrhea in- 10. Persson AL, Hansson GA, Kalliomaki A et al. (2003) Increases in clude laparoscopic uterine nerve ablation, presacral local pressure pain threshold after muscle exertion in women with chronic shoulder pain. Arch Phys Med Rehabil. 84:1515Ð1522 neurectomy, and hysterectomy 11. Rudy T, Turk D, Kubinski JA et al. (1995) Differential treat- Dyspareunia and Vaginismus ment responses of TMD patients as a function of psychological Gynecological Pain and Sexual Functioning characteristics. Pain 61:103Ð112 Gynecological Pain, Neural Mechanisms 12. Sanders S (1999) Clinical practise guidelines for chronic non-malignant pain syndromes. J Back Musculoskel Rehab Visceral Pain Models, Female Reproductive Organ 5:115Ð120 Pain 13. Simonsson M, Bergman S, Jacobsson LT et al (1999) The prevalence of rheumatoid arthritis in Sweden. Scand J Rheumatol 28:340Ð343 14. Sjölund BH (1994) Chronic pain in society Ða case for chronic pain as a dysfunctional state? Qual Life Res 3:5Ð9 15. Sjölund BH (2003) Current and future treatment strategies for Dysnosognosia chronic pain. In: Soroker N, Ring H (eds) Advances in Phys- ical and Rehabilitation Medicine. Monduzzi Editore, Bologna, pp 307Ð313 16. WHO (2001) International Classification of Functioning, Dis- Hypochondriasis, Somatoform Disorders and Abnor- ability and Health. World Health Organization, Geneva, pp 1Ð209 mal Illness Behaviour 17. Woolf CJ, Bennett GJ, Doherty M et al (1998) Towards a mechanism-based classification of pain? Pain 77:227Ð229

Dysfunctional Segmental Motion Dyspareunia

Chronic Back Pain and Spinal Instability Deﬁnition Recurrent or persistent genital pain associated with sex- Dysmenorrhea ual intercourse. Dyspareunia and Vaginismus Gynecological Pain and Sexual Functioning Deﬁnition Gynecological Pain, Neural Mechanisms Painful cramping in the lower abdomen occurring Myalgia before, and/or during menses, primarily as a result Visceral Pain Models, Female Reproductive Organ of endogenous (uterine) prostaglandin production. Pain Dyspareunia and Vaginismus 673

pilot study investigating postpartum dyspareunia, 58% Dyspareunia and Vaginismus reported genital pain 3 months after delivery with 26% still experiencing dyspareunia 8Ð9monthsafter delivery MARIE ANDREE LAHAIE,YITZCHAK M. BINIK McGill University, Montreal, QC, Canada (Barrett et al. 1999). In post-menopausal women, dys- [email protected] pareunia has been reported to affect between 6Ð30% of women (Versi et al. 2001). Despite the fact that dyspare- Synonyms unia appears to be highly prevalent across the lifespan, D many women never seek treatment, and of those who Coital Pain; Sexual Pain Disorder; Urogenital Pain; do, many are never formally diagnosed (Harlow et al. Vaginismus and Dyspareunia; vulvar vestibulitis syn- 2001). drome; vulvar dysesthesia; vulvodynia Assessment Definition The primary step in evaluating patients with dys- Dyspareunia is currently defined as “recurring genital pareunia, is conducting a thorough multidisciplinary pain associated with sexual activity” (APA 2000). Most assessment of the pain and its resulting interference classification systems and practitioners subcategorize with quality of life. Assessment of the pain component dyspareunia as either of organicor psychological origin. should include specific information on its location, This conceptualization is problematic for a variety of history, quality, intensity, exacerbating and ameliorat- reasons: ing factors, temporal pattern, meaning and potential • There are no validated criteria to differentiate organic underlying pathology. Evaluation of the impact of the from psychogenic dyspareunia pain on the sexual response cycle (desire, arousal, or- • It is likely that both psychological and biological fac- gasm, and sexual frequency), the couple relationship, tors coexist for many cases of dyspareunia and on personal well being may be crucial to treatment • The genital pain of dyspareunia can be experienced planning. A comprehensive gynecological examina- duringnon-sexualactivitiessuchastamponinsertion, tion is also crucial, but the timing of this examination gynecological examinations, urination and sports should be carefully considered, since it can be very • “Dyspareunic pain” may precede first sexual experi- painful and sometimes a traumatic experience for both ences and occur in adolescence during tampon inser- the woman and the physician. Depending on the his- tion tory and interview, the examination might include the following: The focus on the “association with sexual activity” has • resulted in limited attention to the main symptom of An inspection and cotton swab evaluation of the vul- dyspareunia, the pain. It is unusual that dyspareunia var area • is defined by the primary activity with which it inter- Laboratory tests to investigate bacterial or viral in- feres, sexual intercourse, rather than by the location, fection • characteristics, and mechanisms of the pain. Its current Assessment for atrophic vaginitis • usage is inconsistent and vague, and is used by differ- Palpation and examination of the uterus, adnexa, ure- ent health professionals to refer to a number of poorly thra, bladder and surrounding structures • defined urogenital pain syndromes (e.g. vulvar vestibu- Evaluation of the pelvic floor musculature • litis, vulvodynia) and to pain symptoms presumably Colposcopy • linked to physical pathology. It has been proposed that Laparoscopy dyspareunia be reconceptualized as a pain syndrome, In general, the clinician should attempt, during the rather than as a sexual dysfunction or a simple mani- manual examination, to replicate the quality of the pain festation of underlying physical pathology (Binik et al. reported by the patient. It is crucial to keep in mind 1999). that the presence of physical pathology may or may Characteristics not be closely related to the experienced dyspareunia. Although there are a variety of “known syndromes” Epidemiology and physical and psychosocial pathologies associated Theprevalenceof dyspareuniain women variesdepend- with the diagnosis of dyspareunia (e.g. VVS, vulvody- ing on the definition used and the population sampled. A nia, vaginismus, lichen sclerosis etc.), the ability of recent epidemiological study found that 21% of women clinicians to differentiate these reliably has not been under the age of 30 suffered from recurrent genital carefully investigated. pain during sexual activity (Laumann et al. 1999). The most common form of superficial dyspareunia in pre- Physical Factors Associated with Dyspareunia menopausal women is vulvar vestibulitis syndrome There is a wide range of underlying physical patholo- (VVS), with approximately 15% of pre-menopausal gies associated with dyspareunia. Deep dyspareunia, women suffering from VVS (Harlow et al. 2001). In a characterized by diffuse pain or localized tenderness, 674 Dyspareunia and Vaginismus is frequently associated with chronic pelvic pain and Treatment for Dyspareunia pelvicpathology.Somereportedcausesofdeepdyspare- Given that dyspareunia is often conceptualized as re- unia are pelvic inflammatory disease, endometriosis, sulting from either a medical or psychosexual condition, ovarian pathology, fixed uterine retroversion, and in- most treatments to date have been unidisciplinary. A flammatory bowel disease. Superficial dyspareunia wide variety of psychological, medical, and surgical refers to pain localized at the entry of the vagina, which procedures have been used to treat dyspareunia but can be caused by vaginal infections, scar tissue in an very few have been evaluated empirically. Even though episiotomy repair, vaginitis, vulvo-vaginal atrophy, the central complaint of women with dyspareunia is VVS, interstitial cystitis and urethral conditions. pain, the vast majority of present therapeutic strategies Women suffering from VVS have been found to have focus on presumed underlying physical pathologies lower tactile and pain thresholds in the vulvar vestibule, or psychosexual distress. For example, estrogen re- deltoid, labium minus and forearm, and amplifications placement therapy is a common medical treatment of brain activity in processing tactile and pain sensa- for post-menopausal women suffering from dyspare- tions in the genital region compared to healthy women, unia. For dyspareunia resulting from VVS, common illustrating that they may suffer from a generalized treatments include corticosteroids, anesthetic topical sensory abnormality (Pukall et al. 2005). It is important creams, antidepressant medications, vestibulectomy, to keep in mind that the degree of diagnosable physical Cognitive-Behavioral Therapy, and pelvic floor pathology is only sometimes highly correlated with the physical therapy including biofeedback. As far as intensity and experience of genital pain, as well as with we are aware, there are no completed randomized con- the amount of interference with vaginal penetration trolled trials that have demonstrated the efficacy of any activities (Binik et al. 1999). treatment for dyspareunia, except for a recent study which compared group cognitive-behavioral therapy, biofeedback and vestibulectomy in the treatment of Psychosocial Factors Associated with Dyspareunia dyspareunia due to VVS (Bergeron et al. 2001). Results The psychosocial factors associated with dyspareunia showed that 60% of vestibulectomy patients were con- vary depending on the age of onset, duration, course and sidered ‘’treatment successes’’, compared to 30% of the subtype of dyspareunia.Not surprisingly,the psychoso- biofeedback and 40% of the group cognitive-behavioral cial profile of a 25-year-old single women suffering therapy participants. Multidisciplinary interventions from dyspareunia due to VVS, will be different from including sex therapy, physical therapy, and surgical that of a 55-year-old married women who just started interventions have been proposed as the most useful experiencing genital pain. Recent studies examining approach to treating dyspareunia (Bergeron et al. 2001). the psychosocial factors associated with dyspareunia found that women with recurrent genital pain show more psychological distress (e. g. increased interper- Biopsychosocial Characteristics of Vaginismus sonal sensitivity, depression and phobic avoidance), Vaginismus is currently defined as ‘’recurrent or persis- sexual dysfunction, negative attitudes about sexuality, tent involuntary muscle spasms of the outer third of the and relationship problems (Binik et al. 1999). In terms vagina which interferes with sexual intercourse’’ (APA of sexual dysfunction, they have lower frequencies of 2000). Women who suffer from vaginismus can have intercourse, lower levels of sexual desire and arousal diverse clinical presentations, with some experiencing and greater difficulty achieving orgasms through oral problems specific to sexual intercourse, while others stimulation and intercourse. Women suffering from demonstrating disturbances in all activities involving VVS have been found to display hypervigilance for vaginal penetration. There are no epidemiological stud- pain relevant information and a tendency to catastro- ies investigating the prevalence of vaginismus in the phize about their VVS pain, which may result in an general population, however, in clinical settings, the increased attention to pain and a diversion away from rates range from 12 to 17% (Binik et al. 1999). Nu- sexual stimuli (Payne et al. 2005). Other factors that merous factors have been implicated in the etiology of have been found to be associated with VVS are: a his- vaginismus such as a history of sexual abuse, religious tory of depression and physical abuse (Harlow et al. orthodoxy, negative sexual attitudes and dyspareunia: 2003), early puberty and pain with first tampon use there is, however, little empirical evidence to support (Harlow et al. 2001), early and prolonged use of oral these factors. Reissing et al. (2003) found that more contraceptives (Bouchard et al. 2002), and increased women with vaginismus reported a history of childhood state and trait anxiety (Payne et al. in press). Sexual sexual interference and less positive attitudes regarding abuse has been hypothesized to result in dyspareunia, sexuality compared to women with dyspareunia and however, current findings suggest that women suffering controls, however, the differences were small and need from dyspareunia without associated chronic pelvic to be replicated. pain do not significantly differ from healthy controls in Although dyspareunia and vaginismus are considered this respect (Binik et al. 1999). mutually exclusive disorders, according to the DSM-IV- Dysthesia 675

TR(APA2000), women suffering fromdyspareuniaand 13. Reissing ED, Binik YM, Khalife S, Cohen D, Amsel R (2004) vaginismus have many common characteristics, such as Vaginal Spasm, Behaviour and Pain: An Empirical Investigation of the Reliability of the Diagnosis of Vaginismus. Arch Sex Behav difficulty with and pain during vaginal penetration ac- 33:5-17 tivities. Moreover, health practitioners (i.e., gynecolo- 14. Versi E, Harvey MA, Cardozo L, Brincat M, Studd JW (2001) gists, physical therapists, psychologists) cannot reliably Urogenital Prolapse and Atrophy at Menopause: A Prevalence differentiate vaginismus from dyspareunia (Reissing et Study. Int Urogynecol J Pelvic Floor Dysfunct 12:107Ð110 al. 2004). In fact, recent findings (Reissing et al. 2004) D demonstrated that vaginal spasms, the principal diag- nosticcriteriaforvaginismus,wereneitherexclusivenor specific to vaginismus. Dyspareunia Model

Treatment for Vaginismus Currently, the most popular treatment for vaginismus is Visceral Pain Models, Female Reproductive Organ cognitive behavioral therapy. This treatment strategy fo- Pain cuses on erroneous cognitive beliefs, conditioned vaginal spasms, educational pelvic examination, Kegel’sex- ercises,andvaginaldesensitizationthroughvaginaldila- tors.Althoughthistreatmentregimeniswidelyaccepted Dyspepsia as effective, there have been no randomized controlled treatment outcome studies to support its use and critical Definition reviews do not support this view(Reissing et al. 1999). It hasbeenproposedthatpelvicfloorphysicaltherapymay Recurrent or persistent pain or discomfort in the upper beusefullyintegratedwiththecurrenttreatmentregimen abdomen, also used to describe sensations of nausea, (Binik et al. 1999). bloating and early satiety in relation to meals. Recurrent Abdominal Pain in Children References 1. American Psychiatric Association (2000) Diagnostic and Statis- tical Manual of Mental Disorders, 4th edn. American Psychiatric Association, Washington, DC Dysphagia 2. Barrett G, Pendry E, Peacock J, Victor C, Thakar R, Manyonda I (1999) Women’s Sexuality After Childbirth: A Pilot Study. Arch Sex Behav 28:179Ð191 Definition 3. Bergeron S, Binik YM, Khalife S, Pagidas K, Glazer HI, Meana M, Amsel R (2001) A Randomized Comparison of Dysphagia is defined as difficulty in swallowing. Group Cognitive-Behavioral Therapy, Surface Electromyo- Opioid Therapy in Cancer Pain Management, Route graphic Biofeedback, and Vestibulectomy in the Treatment of of Administration Dyspareunia from Vulvar Vestibulitis. Pain 91:297Ð306 4. Binik YM, Meana M, Berkley K, Khalife S (1999) The sexual pain disorders: is the pain sexual or is the sex painful? Annu Rev Sex Res 11:210Ð235 5. Bouchard C, Brisson J, Fortier M, Morin C, Blanchette C (2002) Use of Oral Contraceptive Pills and Vulvar Vestibulitis: A Case- Dysraphism Control Study. Am J Epidemiol 156:254Ð261 6. Harlow BL, Wise LA, Stewart EG (2001) Prevalence and Pre- dictors of Chronic Lower Genital Tract Discomfort. Am J Obstet Definition Gynecol 185:545Ð550 7. Harlow BL, Stewart EG (2003) Childhood Victimization and the Any failure of closure of the primary neural tube. Risk of Vulvar Dysesthesia. Ann Epidemiol 13:565Ð566 This general category would include the disorder 8. Laumann EO, Paik A, Rosen RC (1999) Sexual Dysfunction in the United States. Prevalence, Predictors and Outcomes. JAMA myelomeningocele. 281:537Ð545 Lower Back Pain, Physical Examination 9. Payne KA, Binik YM, Amsel R, Khalife S (2005) When Sex Hurts, Anxiety and Fear Orient Attention Towards Pain. Eur J Pain 9:427-436 10. Pukall CF, Strigo IA, Binik YM, Amsel R, Khalife S, Bushnell MC (2005) Neural Correlates of Painful Genital Touch in Women Dysthesia with Vulvar Vestibulitis Syndrome. Pain 115:118-27 11. Reissing ED, Binik YM, Khalife S (1999) Does Vaginismus Exist? A Critical Review of the Literature. J Nerv Ment Dis 187:261Ð274 Definition 12. Reissing ED, Binik YM, Khalife S, Cohen D, Amsel R (2003) Eti- An inappropriate sensation associated with a stimulus ological Correlates of Vaginismus: Sexual and Physical Abuse, Sexual Knowledge Sexual Self-Schema and Relationship Ad- or occurring in the absence of a stimulus. justment. Sex Marital Ther 29:47Ð59 Satellite Cells and Inflammatory Pain 676 Dysthymia

Dysthymia Dystonia

Definition Definition Dysthymia is the term for chronic depression of a dura- Involuntary tonic contraction of a muscle or a muscle tion of two years or more. group due to a central nervous or inflammatory lesion. Psychiatric Aspects of the Epidemiology of Pain Most cases of dystonia are painful. The reasons for the pain are assumed to be low tissue pH and ischemia. Sensitization of Muscular and Articular Nociceptors