M1 MAC Magnetic Resonance Imaging

external magnetic field, resulting in a net magnetization M1 of the human body. This net magnetization is measured to make the MR images. Primary Motor Cortex However, the net magnetization cannot be measured while it is lined up with the magnetic field of the MR system. By tilting the net magnetization away from its MAC alignment with the magnetic field of the MR system, the protons of the body generate the signals that are Minimal Alveolar Concentration used to make the MR images. The net magnetization of the protons behaves like a spinning top on a table; it wobbles around before finally Magnetic Resonance Imaging falling over. This phenomenon is called PRECESSION. Precession is simply the wobbling motion of the net PETER LAU magnetization of a group of the body’s protons around Department of Clinical Research, Royal Newcastle the main magnetic field of the MR system. Hospital, University of Newcastle, Newcastle, NSW, Thespeedatwhichmagnetizationprecessesisdescribed Australia by the Larmor equation [email protected] f= K x B where Synonyms f= Precessional or Larmor frequency (in MHz) MRI; Nuclear Magnetic Resonance; NMR K=the gyromagneticratio= 42.6 MHz per Tesla (for hy- Definition drogen nuclei) B= Magnetic field (in Tesla) Magneticresonanceimaging(MRI)isameansofobtain- The net magnetization is tilted by an RF pulse called ing images of the internal structure of the body based on the excitation pulse. The RF energy tilts the net mag- the detection of radio-frequency waves emitted from the netization from the longitudinal plane to the transverse body under special conditions when it has been placed plane. After the RF pulse is turned off, the natural ten- in a magnetic field. dency of the net magnetization of the protons is to re- Characteristics alignwiththeexternalmagneticfieldfromthetransverse plane back to the longitudinal plane. During this pro- Principles cess, which is called RELAXATION, energy that was Approximately 63% of the atoms in the human body absorbed by the excitation pulse is released back into are hydrogen atoms, largely in the forms of fat or water. the surrounding molecular environment in the form of These hydrogen atoms consist of an electron cloud and radio waves, which are measured as RF signals. a nucleus containing a single proton. The proton be- The amount of energy released by the relaxation process haves as a tiny magnet with a north and south pole. The of a decaying proton is small. Therefore, its emission is proton has a property called spin, which acts as a small faint. However, if a radiofrequency excitation pulse is magnetic field. When placed in an external magnetic again transmitted into the body, it effectively bounces field, the magnetic fields of the protons are forced to the proton’s net magnetization back into the transverse align with the external field. However, the alignment plane, from which its precession once again decays. As is not perfect. There are protons lining up with and it does so, it again emits the same amount of energy at against the external magnetic field. The distribution is the same rate as before. By repeating this process, the uneven as it takes less energy for a proton to line up behavior of the proton can be studied repeatedly. Each with than against the external magnetic field. Slightly faintsignalisrepeatedandacumulativeconsistentsignal more protons therefore line up with than against the that is no longer faint can beharvested. This repetitive 1086 Magnetic Resonance Imaging process is the basis of Pulse Sequences such as spin echo based on the inferred source of the emissions. These im- and fast spin echo sequences. ages can be printed as views at any depth across any In different molecules and in different tissues, the plane, but sagittal, axial and coronal or oblique viewsare precessions of protons decay at different rates. Conse- typically used. By varying the sampling times and other quently, at different times after the commencement of variables such as the timing of radiofrequency pulses, decay, different tissues emit radio waves of different the images obtained can focus on different types of tis- intensities. By sampling emissions at various selected sues. The terms T1 and T2 refer to different time con- times, a picture can be generated of different tissues stantsthatapply to the netmagnetization decaybehavior according to the energy that they are emitting at that of protons. Images based on these constants are referred time. By exploiting the properties of frequency (how to as T1-weighted and T2-weighted, respectively. fast the net magnetization of the protons is precessing) In general, T1-weighted signals generate images of and phase (the direction in which the net magnetization solid structures, such as muscles and bones and are of the protons is pointing), the sampling of each RF ex- used to assess the anatomical details of body structures. citation pulse forms the basis of encoding anatomically T2-weighted signals generate images of more fluid tis- where within a slice of the body specific echo informa- sues and are used for tissue differentiation, particularly tion originated. Furthermore, by exploiting variations in pathological states. Fat and water have similar signal in the gradient strengths of the external magnetic field intensities under normal conditions, but a particular in the X, Y and Z axes, the net magnetization of the pre- pulse sequence, known as fat saturation, can be used cessional frequency of the protons can be varied. This to suppress signals from fat, so that fatty tissue signals variation will allow sampling in different slice locations can be differentiated from water signals. This becomes and thickness in all three planes (The MR CrossTrainer relevant when signals from inflammatory exudates need Study modules, Medical Imaging Consultants, Inc). to be differentiated from normal fatty tissue signals. In By recording the emissions across various diameters of clinical practice, external magnets of low, mid and high the body, a computer can be used to synthesize a virtual field strengths can be used, ranging in strength from anatomical image of the internal structure of the body, 0.3 to 1.5 Tesla. Super-high field strength magnets are

Magnetic Resonance Imaging, Figure 1 A sagittal MRI scan showing a metastasis in a thoracic vertebral body, crossing the intervertebral disc into the next vertebral body. (a) T1-weighted image. (b) T1-weighted image with gadolinium enhancement. The gadolinium shows the increased vascular activity of the tumour as a white signal. Magnetic Resonance Imaging 1087

Magnetic Resonance Imaging, Figure 2 Axial MRI scans of a septic arthritis of a right L1-2 zygapophysial joint. (a) The joint on the right exhibits a slightly bright signal in its cavity (arrow) compared with the opposite side. In addition, the architecture of the multifidus (m) is distorted comparedwith the other side. (b) Administered intravenously, gadolinium enhances the oedema in the multifidus behind the infected joint, rendering it bright white (arrow). M reserved for research purposes, but recently, 3 Tesla In neurology, headache is a common clinical prob- units have become commercially available. The drive lem. Some 10–15% of MR studies are undertaken for to higher field strength magnets is driven by higher headache but fewer than 1% of these investigations signal to noise ratios and greater speed of imaging. As reveal significant pathology. Apart from tumours and field strength increases however, safety issues increase. infections, subarachnoid haemorrhage due to a leaking These include not only the need for greater magnetic aneurysm in the circle of Willis can be demonstrated by shielding but also possible adverse biological effects, MRI and by MR-angiography. This has the advantage although to date, there have been no significant reported of being non-invasive and avoids the complications of clinical side-effects. Body heating and possible super- a more invasive procedure such as four-vessel cerebral ficial burns have been reported, but these have been angiography. MRI can be used to diagnose headaches attributed to faulty equipment such as surface coils and due to changes in pressure of cerebrospinal fluid (CSF), unsuspected internal metallic objects, rather than to the benign intracranial hypertension, idiopathic low CSF magnetic field itself (Shellock 2000). pressure and post-traumatic CSF leakage. In musculoskeletal medicine, MRI is the best way to de- Applications tect osteonecrosis (Fig. 3). For this condition, MRI is Of all medical imaging tests, MRI has the highest sensi- both sensitive and specific and is able to detect changes tivity and highest specificity. It can detect lesions, such earlier than plain radiography or CT or even bone scan. as tumours, infections and osteonecrosis, early in their MRI is also able to measure the size of the osteonecrotic evolution(Figs.1,2).Moreover,itallowstheselesionsto bone fragment. bespecificallyidentified.Nootherimagingtesthasthese Because of its better resolution of nerves and its abil- properties. MRI defines soft tissue lesions as clearly as, ity to provide coronal and sagittal images as well as ax- or better than, ultrasound. For these reasons MRI has as- ial images, MRI is the preferred means of investigat- sumedaparamountpositioninimagingforgeneralmed- ing radiculopathy (Fig. 4). The dorsal root ganglion, the ical conditions. Its relevance in pain medicine, however, spinal nerve roots and nerve-root sleeves can be clearly is more limited. differentiated from the adjacent dura and the CSF in the The cardinal application of MRI in pain medicine is as a spinal canal, making assessment of nerve root compres- screening test to detect occult or cryptic lesions that do sion more reliable than is possible by CT. not manifest distinctive clinical features. Such lesions, Its ability to demonstrate the internal structure of inter- however,areunusualandrare.Consequently,whenMRI vertebral disks accords MRI a unique role in the investi- is used as a screening test, the default expectation is that gation of chronic back pain. Some 30% of patients with it will not reveal lesions. Under those conditions, MRI lowback pain exhibitahigh intensity zonein oneof their is used to clear patients of serious disorders such as tu- disks (April and Bogduk 1992). This zone is a bright mours, infection or osteonecrosis. spot located in the posterior anulus fibrosus (Fig. 5). The 1088 Magnetic Resonance Imaging

Magnetic Resonance Imaging, Figure 3 A coronal MRI scan of the pelvis and hips, showing avascular necrosis of the head of the left femur. The necrosis appears as a darkened area (arrow). zone corresponds to a collection of fluid in a circumfer- entialfissurecrossingtheposterioranulusandcorrelates strongly with that disk being the source of pain. When present, this sign has positive likelihood ratio of about 6 for incriminating the affected disc as the source of pain (Bogduk and McGuirk 2002). For other lesions and abnormalities affecting the spine, the utility of MRI is far more questionable. Lesions such asdiscbulges,discherniationsanddegenerativediscdis- ease occur very commonly in patients with no pain and increasinglywithage(Jensenetal.1994).Consequently, they are not diagnostic signs of back pain. MR neurography can be used to enhance the appearance of nerves, such as the brachial plexus and lumbar plexus and large peripheral nerves such as the sciatic nerve, ra- dial and ulnar nerves. However, unless there is gross lesion, such as tumour infiltration or neuroma, MR neurography has no proven role in detecting causes of pain arising in nerves. The ability of MRI to resolve connective tissues makes it the premier means of assessing joints and periarticular structures. In some instances, MRI has an estab- Magnetic Resonance Imaging, Figure 4 MRI scans of a herniation of lished and valid role. In others, the validity of various an L5-S1 intervertebral disc. (a) Sagittal scan. The disc herniation (arrow) MR findings has not been established. In patients with protrudes beyond the posterior margin of the L5 vertebral body. (b) Axial chronic knee pain, MRI can detect meniscal tears, an- scan. The herniation (arrow) protrudes posteriorly to the right, towards the zygapophysial joint. terior cruciate or posterior cruciate ligament tears and is replacing direct arthroscopy as the preferred, primary diagnostictest.Fortheassessmentofacutekneeinjury,a short MRI examination following radiographyhas been der pain. Pains in the elbow, wrist, ankle or foot are com- shown to save costs and improve quality of life after in- mon problems encountered by sportspeople, either after jury, in terms of time absent from work, additional in- acute injury or as a result of chronic repeated stress. In vestigations and time required to recover (Nikken et al. such individuals, MRI is being used increasingly to de- 2003). Although MRI can demonstrate the structure of tect bone bruises and chronic enthesopathy or to rule out the shoulder in great detail, tears of the rotator cuff and these conditions so that the athlete may resume activi- other lesions occur in totally asymptomatic subjects and ties. increasingly with age. Therefore, demonstrating these Muscles pain and muscle imaging, however, remain an lesions by MRI is not diagnostic of the cause of shoul- enigma. Signal changes, due to tissue disruption and Magnetic Resonance Imaging 1089

Magnetic Resonance Imaging, Figure 6 Axial MRI scans of the calf showing the effects of strenuous exercise. (a) Before exercise. (b) After exercise. The gastrocnemius muscles exhibit a faint increase in signal intensity, making them appear slightly whiter than the soleus and anterior tibial muscles and whiter than they were before exercise.

ment patterns in the muscle ﬁbres in response to an external harmonic shear wave. Amplitude changes are detectable at the level of microns or less. Amygdala, Pain Processing and Behavior in Animals fMRI Headache Due to Arteritis Magnetic Resonance Imaging, Figure 5 MRI scans of a high-intensity zone (HIZ) in an L4-5 intervertebral disc. (a) Sagittal scan. In T2-weighted Motor Cortex (M1) images, the HIZ appears as a bright signal in the posterior anulus ﬁbrosus SecondarySomatosensoryCortex(S2)andInsula,Ef- (arrow). (b) Axial scan. The HIZ corresponds to a circumferential tear (arrow), fectonPainRelatedBehaviorinAnimalsandHumans which appears as a bright crescentic signal in the posterior anulus.

References oedema, can be seen in patients with muscle strains 1. April C, Bogduk N (1992) High intensity zone: a diagnostic sign or tears or with overuse and compartment syndromes of painful lumbar disc on magnetic resonance imaging. Br J Ra- diol 65:361–369 (Fig. 6). However, no role for MRI has been established 2. Bogduk N, McGuirk (2002) Medical Management of Acute and for more common entities such as myofascial pain and Chronic Low Back Pain. An Evidence Based Approach. Elsevier, fibromyalgia. No features have been identified that Amsterdam, p 136 3. Jensen MC, Brant-Zawadzki MN, Modic MT et al. (1994) Mag- allow these conditions to be diagnosed or studied by netic resonance imaging of the lumbar spine in people without MRI. back pain. N Eng J Med 331:69–73 There is work in progress on MR elastography (MRE), 4. Nikken J, Edwin O, Hunink M (2003) A short low-field MRI which may throw some imaging light on the elas- examination in all patients with recent peripheral joint injury: th tic biomechanical property of muscles in health and is it worth the costs? 89 Annual Meeting of the Radiological Society of North America. Chicago, Illinois, November 2003 disease. MRE is a non-invasive, phase-contrast MRI 5. Shellock FG (2000) Radiofrequency energy-induced heating dur- technique used to spatially map and measure displace- ing MR procedures: a review. J Magn Res Imag 12:30–36 1090 Magnetoencephalography

To record clear MEG, at least 20000 or 30000 neurons Magnetoencephalography mustbeactivatedsimultaneously,whichcausesthesame directed intra-cellular currents. A summation of the cur- Synonyms rents of many neurons with the same positive-negative MEG direction can be mimicked as one strong dipole. Since it is easy and simple to imagine it present in the cortex, Definition we hypothesized it by naming the equivalent current dipole (ECD). Synchronized extracellular currents in a few square cen- timeters of cortex generate magnetic fields measurable with sensors on the surface of the scalp. The biggest ad- Characteristics vantage of MEG, as compared with electroencephalog- Atfirst,theadvantagesofMEGcomparedwithEEGwill raphy(EEG),isitshighspatialresolutionduetolessofan be introduced. When electric currents generated in the effect of cerebrospinal fluid, skull and skin, since mag- cortex are recorded using scalp electrodes, there are ef- netic fields are not affected by electric current conduc- fects of cerebrospinal fluid, skull and skin, whose elec- tivity. tricconductivitiesvarymarkedly.Incontrast,sincemag- Insular Cortex, Neurophysiology and Functional netic fields are not affected by current conductivity, the Imaging of Nociceptive Processing recorded MEG is theoretically unchanged. Therefore, Magnetoencephalography in Assessment of Pain in the spatial resolution of MEG is higher than that of EEG. Humans The advantages and disadvantages of MEG compared Thalamotomy for Human Pain Relief with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are listed below. Magnetoencephalography in Assessment Advantages of MEG of Pain in Humans 1. Completely non-invasive. RYUSUKE KAKIGI,KOJI INUI, 2. Measures neuronal activity rather than blood flow MINORU HOSHIYAMA,SHOKO WATANABE, changes or metabolic changes. DAISUKE NAKA,KENSAKU MIKI, 3. Temporal resolution is much larger, in the order of HIROSHI YAMASAKI,DIEP TUAN TRAN, ms. YUNHAI QIU,XIAOHONG WANG 4. Stimulusevoked or eventrelated responsescan easily Department of Integrative Physiology, National be measured in detail. Institute for Physiological Sciences, Okazaki, Japan 5. Frequency response (brain rhythm) analysis can be [email protected] done, which means physiologicalchanges can be analyzed spatiotemporally. Synonyms 6. Results in an individual subject can be analyzed in detail,sothataveragingresultsinanumberofsubjects Topography; Source Analysis; magnetoencephalo- isnotnecessary.Inotherwords,onecananalyzeinter- gram; Superconducting Quantum Interference Device; individual differences. Gradiometer; Biomagnetometer; Magnetometer

Definition Disadvantages of MEG Cortical neurons are excited by the signals conducted 1. Spatial resolution is lower than for PET and fMRI, through thalamo-cortical fibers from the thalamus. Af- particularly when the signal-to-noise ratio is low. ter signals are received, electric currents are conducted 2. An inverse problem solution program is necessary. In through apical dendrites of pyramidal cells of the cere- other words, measuring results are indirectly or arti- bral cortex. The electric currents generate magnetic ficially induced. fields. The electric currents are recorded as electroen- 3. The quality of algorithms (solution programs) is cephalography (EEG) and magnetic fields are recorded not good enough at present when multiple areas are as magnetoencephalography (MEG). There are two activated simultaneously. Therefore, it is sometimes kinds of postsynaptic potentials (PSP), excitatory ones difficult to use MEG to analyze long-latency compo- (EPSP) and inhibitory ones (IPSP). EPSP are consid- nents mainly relating to emotional and / or cognitive ered to be the main generators for both EEG and MEG. functions. However, this is an endless game, since There are two kinds of cellular currents, intra-cellular users always want new and improved software. and extra-cellular. MEG mainly records intra-cellular 4. It is difficult to detect magnetic fields generated in currents. EEG records both, but mainly extra-cellular deep areas. Therefore, the smaller the distance be- currents. tween activated regions and detecting coils the better. Magnetoencephalography in Assessment of Pain in Humans 1091

5. It is impossible to record activities generated in white matter and pathways, since EPSPs are not generated there. 6. It isdifficult or impossible to record activitiesin some regions such as the thalamus showing a so-called physiological closed field. 7. Activated location measured by MEG must be overlaid on CT or MRI, but the location can change, though the change must be very small. Considering the advantages and disadvantages of MEG outlined above, the temporal characteristics of primary componentsjustafter the period whensignalsascending through Aδ fibers and CFiberreach the cortex are the best indication for MEG and later activities relating to cognition are mainly analyzed by PET and fMRI.

Methods Various methods are used to record pain-related SEP and SEF (see review by Kakigi et al. 2000a,b; 2003a; 2005). The first study was reported by Hari et al. based on dental pulp stimulation (Hari et al. 1983). Then, CO2 gas was applied to the nasal mucosa, a painful impact stimulation (Arendt-Nielsen et al. 1999), and epider- M mal electrical stimulation was applied (see review by Kakigi et al. 2000a,b; 2003a; 2005). Each method has its own advantages and disadvantages, but the ideal pain stimulation is pain-specific, controllable, safe and repeatable. At present, there are two main methods for recording pain-related SEP (SEF); (1) SEP (SEF) Magnetoencephalography in Assessment of Pain in Humans, following high-intensity painful electrical stimulation Figure 1 The procedure using our MEG device (VectorView 306- (see review by Kakigi et al. 2000a,b) and (2) SEP (SEF) channels, Elekta Neuromag Oy, Helsinki). The laser stimulator is set outside the shielded room because of its large magnetic artifacts and following painful CO2 laser beam stimulation (see the laser beam is applied to the subject’s hand through optical fibers. reviews by Bromm and Lorentz 1998; Kakigi et al. The laser beam can be applied any part of the body except the eyes, 2000a,b; 2003a; 2005). Since the latter method, which so both the experimenter and the subject must wear special glasses or is usually called pain-related SEP (SEF), or laser evoked swimming goggles. potential (LEP) or magnetic field (LEF), has several advantages as described below, it is more popular. in the epidermis where only free nerve endings are 1. Other methods causing pain or heat sensation such as present, named ES stimulation (Inui et al. 2003a,b). needle stimulation of the skin activate not only noci- The biggest advantages of this method are: (1) Only ceptive receptors but also mechanoreceptors. There- Aδ and C fibers are stimulated. (2) When the needle is fore, for example, the SEP waveform recorded fol- inserted, subjects feel no uncomfortable painful feeling lowing needle stimulation is very similar to that fol- and show no bleeding. (3) Since a small intensity with a lowing electricalstimulation. Incontrast, since aCO 2 short duration is enough for recording Aδ fiber-related laser beam is light, it does not activate mechanore- MEG, subjects feel only a tolerable jingling pain. (4) ceptors of the skin, i.e. it is a purely noxious stimu- No special device is necessary except for a hand-made lation. short needle, which is easily made. 2. For analyzing temporal information in the order of One of the biggest recent topics in this field is the MEG msec, the time difference (lag) between the stimulus response to the signals ascending through unmyelinated timingandthebeginningofthesweepofthecomputer C fibers (see review by Kakigi et al. 2003a; 2005). Sev- should be very stable and short, less than 1 ms. Figure eral methods have been reported to selectively stimu- 1 shows the procedure using our MEG device. Alaser late C fibers, but they were difficult to record and the beam is applied to the subject’s hand through optical responses obtained were not consistently recorded. Our fibers. method was based on that reported by Brussels’s group One interesting method reported recently is electrical (Bragard etal. 1996). Since the number of polymodalre- stimulation of a very short needle, whose tip is located ceptors of C fibers relating to second pain is larger than 1092 Magnetoencephalography in Assessment of Pain in Humans that of Aδ fibers, and since the temperature threshold of the former is slightly lower than that of the latter, C fiber receptors can be selectively activated by using a low-intensity CO2 laser beam on tiny areas of skin. We made a new device for recording C fiber-related MEG responses.

Results Results using ES stimulation are shown as a representative case, since it is the newest method in this field and the results were fundamentally similar to those obtained using a CO2 laser (Inui et al. 2003) (Figs. 2, 3). First,theprimarysomatosensorycortex(SI)inthehemi- sphere contralateral to the stimulation was activated, whose peak latency was approximately 100 ms. It is very small in amplitude and the generator is considered to be area 1 in SI. This long latency is, of course, due to the slow conduction velocity of Aδ fibers (10–20 m / s). Then, secondary somatosensory cortex (SII) and insula in the bilateral hemispheres were activated simultaneously as the primary major component, even after stimulation applied to othersites, i.e.bilateral function. Their peak latencies were approximately 150 ms, but ipsilateral responses were significantly longer than contralateral ones, probably through the corpus cal- losum. SI component in the contralateral hemisphere was also recorded by laser stimulation (Kanda et al. 2000; Ploner et al. 1999). Then, cingulate cortex and mid-temporal regions around the amygdala in the bilateral hemispheres were activated; peak latencies of the first negative and second positive components were approximately 200 and 300 ms, respectively. Webelieve that MEG is the most appropriate method for a detailed spatio-temporal analysis of these early activities within 300–400 ms after stimulation, which PET and fMRI cannot do.

Factors that Affect the Waveforms of Pain One frequently sustains an injury while playing sport, Magnetoencephalography in Assessment of Pain in Humans, Figure 2 MEG waveforms measured using the ES method (intra- but does not notice it until after the game. This clearly epidermal electrical needle stimulation) for primary pain perception indicates that psychological conditions affect pain per- in humans by activating Aδ fiber stimulation. C and I: Hemispheres ception. These interesting findings were also confirmed contralateral and ipsilateral to the stimulation, respectively. SI and by MEG (see reviews by Kakigi et al. 2000a,b; 2003b; SII: Primary and secondary somatosensory cortices, respectively. MT Mid-temporal region around amygdala. (Applied from Inui et al. 2003). Kakigi 2005; Kakigi and Watanabe 1996). When subjects paid close attention to a mental activity such as a calculation or memorization (distraction task), MEG responses, particularly the later components generated in ulation. Therefore, second pain may be more related to limbic systems, were much reduced in amplitude or dis- cognitive functions than the first pain. appeared and a mental pain rating ( visual analogue During sleep, we usually do not notice pain, unless scale, VAS)showed a positive correlation with the MEG it is very strong, so what happens in the brain while changes. In contrast, early responses in SI and SII were receiving painful sensations during sleep (see review reduced but still present. Therefore, early components by Kakigi et al. 2003b)? Most of the MEG responses, seem important for primary functions such as the local- particularly later components, were much reduced in ization of stimulus points, but later components are very amplitude or disappeared. This finding is very sim- related to cognitive functions of pain perception. This ilar to the changes in the distraction task, but more pattern was more remarkable after C fiber than Aδ stim- remarkable. Interestingly, MEG responses during sleep Magnetoencephalography in Assessment of Pain in Humans 1093

Magnetoencephalography in Assessment of Pain in Humans, Figure 3 Activated regions using the ES method (intra-epidermal electrical needle stimulation) for primary pain perception in humans by activating Aδ fiber stimulation. The calculated equivalent current dipole (ECD) of each region was overlaid on the MRI of this subject. See also legend of Fig. 2. (Applied from Inui et al. 2003). M to other modalities, such as touch, auditory or visual References stimuli were enhanced, probably due to an inhibition 1. Arendt-Nielsen L, Yamasaki H, Nielsen J et al. (1999) Mag- of the inhibitory system while awake. Therefore, pain netoencephalographic responses to painful impact stimulation. perception seems very different from other kinds of Brain Res 839:203–208 sensations. 2. Bragard D, Chen ACN, Plaghki L (1996) Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO2 laser stim- MEG and EEG changes and VAS were also significantly ulation of tiny cutaneous surface areas in man. Neurosci Lett reduced in amplitude by other kinds of sensations such 209:81–84 as touch, vibration, cooling and movements (see review 3. Bromm B, Lorentz J (1998) Neurophysiological evaluation of pain. Electroencephalogr Clin Neurophysiol 107:227–253 by Kakigi et al. 2000a; Kakigi et al. 2000b; Kakigi et al. 4. Flor H, Elbert T, Knecht S et al. (1995) Phantom-limb pain as 2003a; Kakigi et al. 2005; Kakigi and Watanabe 1996). a perceptual correlate of cortical reorganization following arm The effects of pain relief by tactile stimulation applied amputation. Nature 375:482–484 to painful areas simultaneously is utilized in transcuta- 5. Hari R, Kaukoranta E, Reinikainen K et al. (1983) Neuromag- netic localization of cortical activity evoked by painful dental neous electric nerve stimulation (TENS). I think “move- stimulation in man. Neurosci Lett 42:77–82 ment” is most effective for pain relief, since weautomat- 6. Inui K, Tran TD, Qiu Y et al. (2003a) A comparative magne- ically move painful regions to reduce pain. For example, toencephalographic study of cortical activations evoked by nox- if we touch a very hot object with our hand, we invol- ious and innocuous somatosensory stimulations. Neuroscience 120:235–248 untary shake that hand strongly. We are now trying to 7. Inui K, Wang X, Qiu Y et al. (2003b) Pain processing within clarify the underlying mechanisms by MEG. the primary somatosensory cortex in humans. Eur j Neurosci 18:2858–2866 Clinical Application 8. Kakigi R, Watanabe S (1996) Pain relief by various kinds of interference stimulation applied to the peripheral skin in humans: Unfortunately, the clinical application of MEG for pain-related brain potentials following CO2 laser stimulation. J pain relief is not very popular at present. Most inter- Peripher Nerv Syst 1:189–198 9. Kakigi R, Watanabe S, Yamasaki H (2000a) The pain-related so- esting studies were reported from Germany on MEG matosensory evoked potentials J Clin Neurophysiol 17:295–308 responses following tactile stimulation in patients with 10. Kakigi R, Hoshiyama M, Shimojo M et al. (2000b) The phantom limb pain after amputation (Flor et al. 1995). somatosensory evoked magnetic fields. Prog Neurobiol They confirmed a plasticity of the somatosensory cortex 61:495–523 11. Kakigi R, Tran TD, Qiu Y et al. (2003a) Cerebral responses fol- using MEG. These interesting and important issues are lowing stimulation of unmyelinated C-fibers in humans: Electro- described in detail in another chapter. and magneto-encephalographic study. Neurosci Res 45:255–275 The following 3 review articles are recommended on the 12. Kakigi R, Naka D, Okusa T et al. (2003b) Sensory perception during sleep in humans: A magnetoencephalographic study. Sleep basic physiological and clinical background of pain in- Med 4:493–507 cluding MEG (Bromm and Lorentz 1998; Treede et al. 13. Kakigi R, Inui K, Tamura V (2005) Electrophysiological studies 1999, 2000). on human pain perception. Clin Neurophysiol 116:743–763 1094 Magnetometer

14. Kanda M, Nagamine T, Ikeda A et al. (2000) Primary somatosen- sorycortexisactivelyinvolvedinpain processinginhuman. Brain Major Depressive Disorder Res 853:282–289 15. Ploner M, Schmitz F, Freund HJ et al. (1999) Parallel activation of primary and secondary somatosensory cortices in human pain Synonyms processing. J Neurophysiol 81:3100–104 16. Treede RD, Kenshalo DR, Gracely RG et al. (1999) The cortical MDD representation of pain. Pain 79:105–111 17. Treede RD, Apkarian AV, Bromm B et al. (2000) Cortical repre- Definition sentation of pain: functional characterization of nociceptive areas near the lateral sulcus. Pain 87:113–119 Major Depressive Disorder (MDD), as defined by the Diagnostic and Statistical Manual of Mental Disorders 4th ed. (DSM-IV)(American Psychiatric Association, 1994), is the presence of a collection of symptoms Magnetometer that must include depressed mood or loss of interest or pleasure in most activities lasting at least 2 weeks. Magnetoencephalography in Assessment of Pain in Additional symptoms include fatigue, feelings of ex- Humans cessive or inappropriate worthlessness or guilt nearly every day, significant weight loss or gain, insomnia or hypersomnia, diminished concentration or ability to make decisions, frequent thoughts of death, suicidal Magnification ideation or suicide attempt. In order to meet criteria for MDD, symptoms must cause distress or impairment in functioning. Definition Depression and Pain The tendency to exaggerate the threat value associated with a particular symptom, situation or outcome. Catastrophizing Maladaptive Coping

Catastrophizing Magnocellular Neurons

Deﬁnition Maladaptive Thoughts Magnocellular neurons are neurons with soma of a large size located in the paraventricular and supraoptic Deﬁnition hypothalamic nuclei. These neurons synthesize vaso- pressin and oxytocin and transport them via their axons Cognitions that interfere with successful coping and to the posterior neurohypophysis. adaptation to noxious stimuli or aversive events, or Hypothalamus and Nociceptive Pathways contribute to inappropriate behavior. Multiaxial Assessment of Pain

Maintenance Malalignment Syndromes

Deﬁnition Deﬁnition A readiness to change stage, in which a person has made Malalignment syndromes are abnormal body align- a behavior change and has maintained that change for ments (for example, an abnormally pronated rear foot) long enough that relapse is unlikely. thought to predispose overuse syndromes. Motivational Aspects of Pain Stretching Operant Perspective of Pain

Malignant Bone Pain Maitland Mobilisation Adjuvant Analgesics in Management of Cancer- Passive Spinal Mobilisation Rated Bone Pain Malingering, Primary and Secondary Gain 1095

Malignant Bowel Obstruction Malingering, Primary and Secondary Gain

DAV I D A. FISHBAIN Definition University of Miami School of Medicine and The Rosomoff Pain Center at South Shore Hospital, Miami A mechanical obstruction of the gastrointestinal tract Beach, FL, USA secondary to a malignant tumor that occurs in 5% to dfi[email protected] 43% of all terminally ill patients. The obstruction may be partial or complete and at one site or multiple sites, Synonyms however, the small bowel is more commonly involved than the large bowel. It is associated with colorectal, Sick role; reinforcers pancreatic, endometrial, gastric, mesothelial, breast, Definitions and prostatic cancers, but may develop with any cancer predisposed to metastases to the gastrointestinal Primarygain(Fishbain1994;Fishbainetal.1995):Ade- tract. Malignant bowel obstruction may occur sec- crease in anxiety (gain) from an unconscious defensive ondary to extrinsic compression of the bowel lumen, operation, which then causes a physical or conversion intraluminal occlusion, intramural occlusion, intestinal symptom, e.g. an arm is voluntarily paralyzed because motility disorders, and miscellaneous causes such as it was used to hurt somebody, thereby allaying guilt and fecal impaction. anxiety. Cancer Pain Management, Adjuvant Analgesics in Secondary gain (Fishbain 1994; Fishbain et al. 1995): Management of Pain Due To Bowel Obstruction Thegainachievedfromthephysicalorconversionsymp- tom, which enables the patient to avoid a particularly noxious activity or which enables the patient to get support from the environment (gain) not otherwise forth- M coming. Malignant Pain Malingering (Fishbain et al. 1999; Fishbain et al. 2002): It is the intentional production of false or grossly exag- Definition gerated physical or psychological symptoms motivated by external incentives (secondary gain), such as avoid- Pain associated with cancer. ing military duty or work or criminal prosecution and Cancer Pain obtaining financial compensation or drugs. Pain Treatment, Implantable Pumps for Drug Deliv- ery Characteristics Primary and Secondary Gain Sigmund Freud was the first to define primary and secondary gain and apply these concepts to illness behav- Malingerer ior, which was not medically explained. Since then, the concept of secondary gain has infiltrated the nomencla- ture of every medical specialty, usually being applied Definition in case of medically unexplained symptoms, and/or ill- A malingerer is an individual who consciously and de- ness affirming states. The following is a list of previ- liberately feigns incapacitation. Malingering is a form ously described secondary gains: gratification of depen- of fraud. dency or revengeful strivings; fulfillment of needs for Impairment, Pain-Related sympathy, concern, solicitousness, or attachment;maintenance of family status, love or domination; desire for financial rewards and to prove entitlement for disability; avoidance of hazardous work conditions; permis- sion to withdraw from an unsatisfactory life or socioe- Malingering motional role; need for the sick role; acquisition of drugs; manipulation of spouse; and contraception. It is not clear whether secondary gains are the same as re- Definition inforcers. Operationally, some are equivalent; the gain A conscious decision to deliberately fake or lie about may be the reinforcer. Secondary gains, however, are the having pain in order to fool someone. more unconscious motivation for the observed behav- Credibility, Assessment iors. PainintheWorkplace,RiskfactorsforChronicity,Job Secondary losses has been described as follows: eco- Demands nomic; inability to now relate to others through work; 1096 Malingering, Primary and Secondary Gain loss of family life, social support, and recreational ac- this alleged impairment or symptoms. This task is such tivities; loss of community approval and resultant social that the patient isforced tomakea choice(e.g.thepatient stigma of being disabled; guilt over disability; negative complaining of sensory loss will be asked to close his sanctionsfrom family and thosein thehelpingroles(e.g. or her eyes and guess which hand was being touched for doctors; and loss of a clearly defined role). In general, a large number of trials). This is called a forced choice the secondary losses far outweigh the secondary gains. technique. In this case the patient has a 50% chance of Yet, patients act in spite of this economy. This problem being correct if he has a sensory impairment. However, with the economy of secondary gains and losses is a di- hystericaland malingering patientsusually willperform rect challenge to the integrity of the secondary gain con- at significantly below chance levels, indicating that they cept and its importance to some of the Illness Affirming may be deliberately providing false answers. States. The second approach involves a volunteer group per- Scientifically,therearealsomajorproblemswiththesec- forming a task such as completing a psychological test ondary gain concept. It is poorly defined and rests on battery pretending to fake an illness (e.g. fake insanity). psychoanalytic concepts, which are difficult to prove or The resultant volunteer “faking scores” can be used in disprove. Fishbain et al. (1995) recently reviewed the two ways. First, the “the faking scores” can be compared scientific evidence for this concept. They found that re- with normal scores for differences and for the develop- sults of studies relating to this issue were in conflict, and ment of a “faking” profile. Second, the “faking scores” many had methodologicalflawsrelatingto howthe pres- can be compared with authentic patient scores for dif- ence of secondary gain was established. However, the ferences and perhaps for the selection of similar faking presence of a secondary gain agenda did change patient profiles. behaviors. The third approach involves actual patients. In this case, The secondary gain concept is also clinically abused. a patient or groups of patients are asked to complete a The presence of financial incentives, such as disability task (e.g. a psychological battery) in such a way as to payments if associated with treatment failure, results in simulate an illness. theaccusationofsecondarygain,whichinturnisutilized These faking patient scores may then be compared asarationalizationforthetreatmentfailure.Cliniciansin with scores from a new group of patients for identifi- this paradigm usually focus on the secondary gains and cation of similar or different profiles. Fishbain et al. ignore the secondary losses. In addition, clinicians ig- (1999) recently reviewed these different approaches in nore two facts. The alleged presence of a secondary gain reference to pain. Their findings/conclusions were as does not necessarily mean that the gain has had an etio- follows. Malingering and dissimulation do occur within logical or reinforcing effect on the illness, and there is a the chronic pain patient setting. Malingering may be significant amount of evidence that indicates that physi- present in 1.25% to 10.4% of chronic pain patients. cian practices are influenced by secondary gain agendas However, because of poor study quality, these preva- (Fishbain et al. 1995). lence percentages are not reliable. The study evidence also indicated that facial expression testing, question- Malingering naire, sensory testing, or clinical examination were Malingering can be divided into the following types not reliable ways of identifying malingering. There (Fishbain et al. 1999): Pure malingering is the feigning was no acceptable scientific information on symp- of disease or disability when it does not exist. Positive tom magnification syndrome. Hand-grip testing using malingering (simulation) is the feigning of symptoms the Jamar Dynamometer and other types of isometric that do not exist. Partial malingering is the conscious strength testing did not reliably discriminate between exaggeration of symptoms that do exist. False impu- a submaximal/malingering effort and a maximal/best tation is the ascribing of actual symptoms to a cause effort. However, isokinetic strength testing appeared to consciously recognized to have no relationship to the have potential for discriminating between maximal and symptoms. Dissimulation, also a form of malingering, submaximal effort, and between best and malingered ef- is the concealment or minimization of symptoms for forts. Repetitive testing with the coefficient of variation secondary gain reasons. Two other types of malingering was not a reliable method for discriminating a real/best may also occur: genuine symptoms formerly present effort from a malingered effort. It was concluded that as may cease to exist but may be fraudulently alleged to yet there is no reliable method for detecting malingering continue, or genuine symptoms may be fraudulently within chronic pain patients, although isokinetic testing attributed to a cause other than the actual one. shows promise. There are no reliability studies on malingering, as these A final issue relating to malingering is that of Waddell can only be generated if someone admits to being a ma- Signs. These are 8 physical signs frequently found in lingerer. This is rarely the case. As such, three unique chronic pain patients. Historically, there has been dis- approaches for the study of malingering/disease simu- agreement on what these signs indicate. However, in a lation have evolved. In the first approach, a patient sus- recent evidence-based structured review, Fishbain et al. pected of malingering is assigned a task that impacts on (2003) concluded the following about Waddell signs: Marital Status and Chronicity 1097

• They do not discriminate organic from nonorganic problems Management of Postoperative Pain • May represent an organic phenomenon • Are associated with poorer treatment outcome Postoperative Pain, Appropriate Management • Are associated with greater pain levels • Are not associated with secondary gain; and as a group • Studies demonstrate methodological problems Mandibular Dysfunction

In a further evidence-based review, speciﬁcally address- Orofacial Pain, Movement Disorders ing the issue of whether Waddell signs indicate malingering, Fishbain et al. (2004) concluded the following: there is little or no evidence that Waddell signs are associated with malingering. Manipulation Without Impulse

References Passive Spinal Mobilisation 1. Fishbain DA (1994) The Secondary Gain Concept: Definition Problems and Its Abuse in Medical Practice. Am Pain Soc J 3:264–273 2. Fishbain DA, Rosomoff HL, Cutler RB, Rosomoff RS (1995) Manipulation Without Thrust, Secondary Gain Concept: A Review of the Scientific Evidence. Clin J Pain 11:6–21 Oscillatory Mobilisation 3. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS (1999) Chronic Pain Disability Exaggeration/Malingering and Sub- maximal Effort Research. Clin J Pain 15:244–274 Passive Spinal Mobilisation 4. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS (2002) Does M the Conscious Exaggeration Scale Detect Deception within Pa- tients with Chronic Pain Alleged to have Secondary Gain? Pain Medicine 3:39–46 5. Fishbain DA, Cole B, Cutler RB, Lewis J, Rosomoff HL, Manual or Continuous Traction Rosomoff RS (2003) A Structured Evidence-Based Review on the Meaning of Nonorganic Physical Signs: Waddell signs. Pain Lumbar Traction Medicine 4:141–181 6. Fishbain DA, Goldberg M, Rosomoff RS, Rosomoff H (1991) Chronic Pain Patients and the Nonorganic Physical Sign of Non- Dermatomal Sensory Abnormalities (NDSA). Psychosomatics 32:294–303 Manual Therapy 7. Fishbain DA, Cutler RB, Lewis J, Cole B, Rosomoff RS, Ro- somoff HL (2003) Is the Location of Nondermatomal Sensory Abnormalities (NDSAs) Related to Pain Location? Pain Med Definition 4:238–243 8. Fishbain DA, Cutler RB, Lewis J, Cole B, Rosomoff RS, Ro- Manipulation of body tissues to restore movement. somoff HL (2004) Do Waddell Signs Indicate Malingering? An Chronic Pain in Children, Physical Medicine and Re- Evidence-Based Structured Review. Clin J Pain 20:399–408 habilitation

MAO Malnutrition Monamine Oxidase Inhibitors Metabolic and Nutritional Neuropathies

MAPK

Managed Care Mitogen-Activated Protein Kinase

Deﬁnition A board term used to describe various health care pay- Marital Status and Chronicity mentsystemsthatattempttocontaincostsbycontrolling the type and level of services provided. Pain in the Workplace, Risk Factors for Chronicity, Disability Management in Managed Care System Demographics 1098 Marstock Method

Friction Marstock Method Friction (or rubbing) should be done in a slow elliptical or circular movement with the fingertips or the thenar Definition eminence. It is a deep penetrating technique to relieve trigger points. There may be pain from the application The Marstock method is a threshold determination of deep friction massage so this technique is optional. It protocol for the thermal senses. This is a reaction time- should not be confused with deep transverse frictions. dependent protocol that was originally developed by Drs. Heinrich Fruhstorfer and W. Schmidt of Marburg, Tapotement and Dr. Ulf Lindblom of Stockholm, hence the name. Tapotement (or hacking) is a series of blows that may Threshold Determination Protocols alsobedescribedasslapping,tapping,clapping,hacking or cupping, depending on the positioning of the hands. Vibration Vibration (or shaking) consists of small tremulous Massage and Pain Relief Prospects movements with the hands and fingers and in some MICHAEAL QUITTAN cases with a electromechanical device. The vibration Department of Physical Medicine and Rehabilitation, is performed rhythmically in an attempt to enhance Kaiser-Franz-Joseph Hospital, Vienna, Austria relaxation or stimulation. [email protected] Before initiating massage, the patient’s individual pref- erencesandresponsivenesstotouchandmassageshould be assessed. Cultural and social feelings towards mas- Synonyms sage should be considered, as well as the patient’s abil- Effleurage; Petrissage; friction; Tapotement; vibration itytocommunicateconcernsorexpressunwillingnessto receive massage therapy. Deep transverse friction massage is a technique popularised by Dr. James Cyriax for Definition pain and inflammation relief in musculoskeletal condi- The English word ’massage’ is derived from the Arabic tions (Cyriax 1975). It is a technique that attempts to re- word “mass’h” which means to press gently. At its most duce abnormal fibrous adhesions and makes scar tissue basic, massage is a simple way of easing pain, while at moremobileinsub-acuteandchronicinflammatorycon- the same time aiding relaxation, promoting a feeling of ditions by realigning the normal soft tissue fibres. The well being and a sense of receiving good care. Scientifi- technique has been advocated to enhance normal heal- cally,massagemaybedefinedasgroupofsystematicand ing conditions by breaking cross bridges and preventing scientific manipulations of body tissues best performed abnormal scarring. Its mechanical action causes hyper- with the hands, for the purpose of affecting the nervous aemia, which results in increased blood flow to the area. and muscular system and the general circulation. Besidetheseclassictechniquestherearenumerousother Although massage techniques may vary considerably proceduresclaimingspecificeffects.Reflexologistspro- between therapists, classical massage consists of a num- posethattherearereflexpointsonthefeetcorresponding ber of basic techniques that have remained essentially to organs and structures of the body and that pain may be unchanged for centuries. Per Henrik Ling is consid- reduced by gentle manipulation or pressing certain parts ered the founder of modern massage and subsequently of the foot. Pressure applied to the feet has been shown these techniques are referred to as Swedish massage. to result in an anaesthetizing effect on other parts of the Five elemental techniques are used in classical mas- body (Ernst and Koeder 1997). sage named effleurage, petrissage, friction, tapotement Characteristics and vibration. Specific purposes are attributed to each technique. Analgesic Mechanisms Classical massage is thought to improve physiological Effleurage andclinicaloutcomesbyofferingthesymptomaticrelief Effleurage (or stroking) is a deep stroking performed in of pain through different mechanisms. Massaging a par- the direction of venous or lymph flows. It is used to ac- ticular area stimulates large diameter nerve fibres, thus custom the subjectto the following massage procedures. mechanisms described by the gate-control theory. Addi- tionally, a moderate elevation of serum beta-endorphin Petrissage levels lasting 1 h after cessation of massage has been Petrissage (or kneading) is a deeper technique than ef- demonstrated (Goats 1994). Motoneuron activity may fleurage and consists of repeated rolling, grasping and be attenuated during application of massage thus ben- lifting. The technique is directed towards muscles and eficially influencing the ”pain-spasm-pain” cycle. It is connective tissue. noteworthy that massage both affects the motoneuron Massage and Pain Relief Prospects 1099 pool of the massaged muscles and lasts solely during Another RCT compared massage therapy with progres- application of massage (Dishman and Bulbulian 2001). sive muscle relaxation (Hernandez-Reif et al. 2001). It has recently been shown that intramuscular temper- Twenty-four adults with low back pain of nociceptive ature in superficial layers of the m.vastus laterals is in- origin with a duration of at least 6 months were ran- creased after application of massage, mainly due to me- domly assigned to a massage therapy or a progressive chanical manipulation of the skin (Drust et al. 2003). muscle relaxation group. Sessions were 30 min long Blood flow is increased, predominantly by dilatation of twice a week for 5 weeks. By the end of the study, the superficial blood vessels. Vigorous massage techniques massage therapy group, as compared to the relaxation enhance these effects by additional histamine release, group, reported experiencing less pain, depression which may then last as long as 1 h (Goats 1994). Finally, and anxiety and improved sleep. They also showed massage promotes physical and mental relaxation con- improved trunk and pain flexion performance. Fur- tributing to pain relief. thermore, their serotonin and dopamine levels were higher. The authors conclude that massage therapy is Indications and Outcomes effective in reducing pain, stress hormones and symptoms associated with chronic low back pain. Finally, Despite definitions described above, there have been Cherkin et al. randomly assigned 262 patients with low many variations, with differences in masseur expertise back pain to receive therapeutic massage compared and time of application. This lack of standardisation to acupuncture or self-educational material. After the renders comparison of studies difficult. Nevertheless, 10 week treatment period massage was found to be su- massage has been increasingly investigated in the pain perior both to acupuncture (function) and self education management area, for its potential to be a functional, (function and symptoms). At 1 year follow-up massage nonpharmacological intervention for reducing chronic remained superior to acupuncture regarding function pain. and symptoms (Cherkin et al. 2001). M Back Pain Cancer-related Pain Massage therapy is among the most popular therapeu- At present, evidence exists from multiple time series tic strategies used by back pain patients. A survey of an with or without the intervention that massage is bene- urban rehabilitation medicine outpatient office in New ficial in pain relief in cancer patients (Pan et al. 2000). York, addressing the use of alternative therapy and its In their review, Pan and co-workers identified two stud- perceived effectiveness indicated that 29% of the sub- ies evaluating massage as single treatment for pain in jects had used one or more alternative medical therapies palliative care patients and 1 study in combination with inthepast12monthsandthemostcommontherapycited aromatherapy. In an unblinded randomised controlled was massage (Wainapel et al. 1998). This evidence is trial, 28 patients (mean age 61.5 years) with cancer were confirmed by European data indicating that up to 87% assigned to either Swedish massage therapy or a visitor of back pain patients received massage as one form of for 10 min. Men experienced immediate pain relief treatment (Wiesinger et al. 1997). (VAS from 4.2–2.9, P <0.01), but this effect subsided Until recently, massage was included in RCTs only as a by1hafterthemassage.Therewasnosignificantben- control treatment for various physical treatments. These efit in women (Weinrich and Weinrich 1990). In a case massage control treatments were poorly described and series, 9 male cancer patients (mean age 56.6 years) often involved superficial massage techniques, brief who received two consecutive 30 min evening massages treatment sessions of 10–15 min or few sessions (<5) reported significant reductions in pain as compared to (for reviews see Ernst 1999; Furlan et al. 2002). Recent baseline, lasting for 2 days. There was also a reduction published trials therefore address the effectiveness of in anxiety and enhanced feelings of relaxation (Ferrell- massage therapy for back pain. Preyde randomly as- Torry and Glick 1993). In a case series involving 103 signed 104 patients with low back pain (lasting 1 week patients with cancer, a combination of massage and to 8 months) to comprehensivemassage therapy includ- aromatherapy promoted pain relief in 33% of patients ing stretching exercises, soft tissue manipulation alone, who completed the study (47%) (Wilkinson 1995). remedialexercise with posture education and sham laser therapy. Over a 1 month period, all patients received 6 Massage and Critical Care therapies. At 1 month follow-up 63% of subjects in the Arecentreviewidentifiedasmanyas19researcharticles comprehensive massage therapy group reported no pain evaluating the effectof back massage on pain, relaxation as compared with 27% of the soft tissue manipulation and sleep in patients in various forms of critical care set- group, 14% of the remedial exercise group and 0% of tings (Richards et al. 2000). The authors conclude that the sham laser therapy group. Clinical significance was the most consistent effect of massage is a significantly evident for the comprehensive massage therapy group decreased anxiety or perception of tension. Massage is and the soft tissue manipulation group on the measure therefore advocated as an effective treatment for proof function (Preyde 2000). moting relaxation as indicated by significant changes in 1100 Massage, Basic Considerations the expected direction in one or more physiological in- 17. Weber MD, Servedio FJ, Woodall WR (1994) The effects of three dicators. Additionally, massage was found to be effec- modalities on delayed onset muscle soreness. J.Orthop.Sports Phys Ther 20:236–242 tive in reducing pain. Further investigationsof the bene- 18. Weinrich SP, Weinrich MC (1990) The effect of massage on pain ficial effects of massage therapy comprise the incidence in cancer patients. Appl Nurs Res 3:140–145 of chronic tension headache (Quinn et al. 2002) and post 19. Wiesinger GF, Quittan M, Ebenbichler G et al. (1997) Benefit and exercise muscle pain (Weber et al. 1994). costs of passive modalities in back pain outpatients: A descriptive study. Eur J Phys Med Rehabil 7 / 6:186 20. Wilkinson S (1995) Aromatherapy and massage in palliative care. Contraindications and Safety Considerations Int J Palliat Nurs 1:21–30 Massage is recognised as a safe therapeutic modality, with little risk or adverse effects. However there are contraindications such as applying massage over Massage, Basic Considerations an area with acute inflammation, skin infection, non- consolidated fracture, burn, deep vein thrombosis or SUSAN MERCER over sites of active cancer tumour (Vickers and Zollman School of Biomedical Sciences, University of 1999). Caution should be used in patients with advanced Queensland, Brisbane, QLD, Australia osteoporosis regarding applying only a little pressure [email protected] on the tissue and the underlying bones. Synonyms References Soft tissue manipulation; Classical Massage; Swedish 1. Cherkin DC, Eisenberg D, Sherman KJ et al. (2001) Randomized massage; friction massage trial comparing traditional Chinese medical acupuncture, therapeutic massage, and self-care education for chronic low back Definition pain. Arch Intern Med 161:1081–1088 2. Cyriax J (1975) Textbook of Orthopaedic Medicine, vol 2, 9th Massage is the application of force, typically by the edn. Williams and Wilkins, Baltimore hands, to the skin, fascia and muscles of the body. Var- 3. Dishman JD, Bulbulian R (2001) Comparison of effects of ious techniques, e.g. stroking and gliding (effleurage), spinal manipulation and massage on motoneuron excitability. Electromyogr Clin Neurophysiol 41:97–106 kneading (petrissage), tapping, clapping, percussion 4. Drust B, Atkinson G, Gregson W et al. (2003) The effects of (tapotement), and deep friction that uses different rates massage on intra muscular temperature in the vastus lateralis in and rhythm, direction, pressure and duration of move- humans. Int J Sports Med 24:395–399 5. Ernst E (1999) Massage therapy for low back pain: a systematic ments are utilized in an effort to enhance circulation review. J Pain Symptom Manage 17:65–69 and remove waste products from the soft tissues of the 6. Ernst E, Koeder K (1997) An overview of reflexology. Eur J Genl body. Pract 97:52–57 7. Ferrell-Torry AT, Glick OJ (1993) The use of therapeutic massage Characteristics as a nursing intervention to modify anxiety and the perception of cancer pain. Cancer Nurs 16:93–101 Mechanism 8. Furlan AD, Brosseau L, Imamura M et al. (2002) Massage for low-back pain: a systematic review within the framework Massage therapy is believed to relieve pain by increas- of the Cochrane Collaboration Back Review Group. Spine ing local circulation, stimulating large diameter nerve 27:1896–1910 fibers, stimulating the release of endorphins, decreasing 9. Goats, G. C. (1994) Massage-the scientific basis of an ancient muscle tone, normalizing the general mobility of mus- art: part 2. Physiological and therapeutic effects. Br J Sports Med 28:153–156 cles, tendons, ligaments, and fascia, reducing swelling 10. Hernandez-Reif M, Field T, Krasnegor J et al. (2001) Lower back and relaxing the mind (Ernst 2003; Furlan et al. 2002; pain is reduced and range of motion increased after massage Nicholson and Clendaniel 1989). therapy. Int J Neurosci 106:131–145 11. Pan CX, Morrison RS, Ness J et al. (2000) Complementary and Applications alternative medicine in the management of pain, dyspnea, and nausea and vomiting near the end of life. A systematic review. Massage is used for its psychological and physiological J Pain Symptom Manage 20:374–387 effects.Slowtoevenlyappliedstrokesoflighttomedium 12. Preyde M (2000) Effectiveness of massage therapy for sub- pressure are used in the direction of muscle fibers if gen- acute low-back pain: a randomized controlled trial. CMAJ 162:1815–1820 eral relaxation is desired. To stretch scarring in skin and 13. Quinn C, Chandler C, Moraska A (2002) Massage therapy and subcutaneous tissue, moderate to heavy pressure in all frequency of chronic tension headaches. Am J Public Health directions is applied at a moderate, even rhythm. If the 92:1657–1661 desired effect is to loosen or stretch connective tissue, 14. Richards KC, Gibson R, Overton-McCoy AL (2000) Effects of massage in acute and critical care. AACN Clin Issues 11:77–96 a slightly less heavy pressure is applied more slowly. 15. Vickers A, Zollman C (1999) ABC of complementary medicine. However, if adhesions in ligaments, tendons and muscle The manipulative therapies: osteopathy and chiropractic. BMJ are to be broken, a heavy pressure perpendicular to the 319:1176–1179 direction of fibers applied at a moderate, even speed is 16. Wainapel SF, Thomas AD, Kahan BS (1998) Use of alternative therapies by rehabilitation outpatients. Arch Phys Med Rehabil advocated. Here the therapist’s fingers and the patient’s 79:1003–1005 skin move as one. To reduce swelling moderate to deep Mastery Experience 1101 pressure is applied slowly and evenly in the direction of 14. Weber MD, Servedio FJ, Woodall WR (1994) The Effects of venousreturn.Tappingisusedindesensitizingoperative Three Modalities on Delayed Muscle Soreness. J Orthop Sports sites e.g. following amputation. Phys Ther 20:236–242 Efficacy Massage is widely used in the general community for the treatment of painful conditions. It can be provided Masseter Inhibitory Reflex by professional, remedial massage therapists. Physio- therapists and osteopaths may incorporate it into their Definition treatment regimens. Lay persons, such as spouses, may Reflex inhibition of the jaw-closing muscles (masseter, provide it. temporalis, or pterygoid) that appears as a double phase Despite the popularity of massage, the literature proof electric silence during voluntary contraction, and is vides little evidence of efficacy. Reviews have estab- elicited by electrical or mechanical stimuli in the intra- lished that massage has little or no effect in relieving or perioral region. pain (Ernst 2004), headaches (Jensen et al. 1990), post Jaw-Muscle Silent Periods (Exteroceptive Suppres- exercise muscle pain (Ernst 1998); Weber et al. 1994), sion) or acute, subacute or chronic low back pain (Ernst 1999; Furlan et al. 2002; Godfrey et al. 1984; Hoehler et al. 1981; Preyde 2000). Side Effects Masseter Muscle Incidences of adverse effects are unknown, but are probably low. Reports include fracture of osteoporotic bone, Definition haematoma, peripheral nerve damage, and hearing loss The jaw-closer muscle. This muscle elevates the M typicallyassociatedwiththeuseoftoomuchforce(Ernst mandible for mouth closing and during chewing. 2003a; Ernst 2003b). Nociceptors in the Orofacial Region (Temporo- mandibular Joint and Masseter Muscle) References 1. Cherkin DC, Eisenberg D, Sherman KJ et al. (2001) Random- ized Trial Comparing Traditional Chinese Medical Acupuncture, Therapeutic Massage, and Self-Care Education for Chronic Low Back Pain. Arch Int Med 161:1081–1088 Masseter Silent Periods 2. Ernst E (1998) Does Post-Exercise Massage Treatment Reduce Delayed Onset Muscle Soreness? A Systematic Review. Br J Sports Med 32:212–214 Jaw-Muscle Silent Periods (Exteroceptive Suppres- 3. Ernst E (1999) Massage Therapy for Low Back Pain. A System- sion) atic Review. J Pain Symptom Manage 17:65–69 4. Ernst E (2003a) Massage Treatment for Back Pain. Evidence for Symptomatic Relief is Encouraging but not Compelling. BMJ 326:562–563 5. Ernst E (2003b) The Safety of Massage Therapy. Rheumatology Mast Cells 42:DOI:10.1093 6. Ernst E (2004) Manual Therapies for Pain Control: chiropractic and massage. Clin J Pain 20:8–12 Definition 7. Furlan AD, Brosseau L, Imamura M et al. (2002) Massage for Mast cells are immune competent cells recruited to re- Low-Back Pain: A Systematic Review within the Framework of the Cochrane Collaboration Back Review group. Spine gions of injury including the skin. They are resident in 27:1896–1910 most tissues and release proinflammatory mediators in- 8. Jensen OK, Nielsen FF, Vosmar L (1990) An Open Study Com- cluding NGF when activated. paring Manual Therapy with the Use of Cold Packs in the Treat- ment of Post-Traumatic Headache. Cephalalgia 10:241–250 Nerve Growth Factor, Sensitizing ActiononNocicep- 9. Godfrey CM, Morgan PP, Schatzker J (1984) A Randomized tors Trial of Manipulation for Low-Back Pain in a Medical Setting. Spine 9:301–304 10. Hsieh CY, Adams AH, Tobis J et al. (2002) Effectiveness of Four Conservative Treatments for Subacute Low Back Pain: A Mastery Experience Randomized Clinical Trial. Spine 27:1142–1148 11. Hoehler FK, Tobis JS, Buerger AA (1981) Spinal Manipulation for Low Back Pain. JAMA 245:1835–1838 Definition 12. Nicholson GG, Clendaniel RA (1989) Manual Techniques. In: Scully RM, Barnes MR (eds) Physical Therapy. JB Lippincott, Experiencesthat result in the elevation of anindividual’s Philadelphia assessment of his or her abilities in a specific skill do- 13. Preyde M (2000) Effectiveness of Massage Therapy for Subacute Low-Back Pain: A Randomized Controlled Trial. Can Med Assoc main. J 162:1815–1820 Psychology of Pain, Self-Efficacy 1102 Mastitis

In addition to the list of pain descriptors, the question- Mastitis naire contains descriptors of the overall present pain intensity (PPI). The PPI is recorded as a number from 1 to Gynecological Pain, Neural Mechanisms 5, in which each number is associated with the following words: 1, mild; 2, discomforting; 3, distressing; 4, horrible; 5, excruciating. The mean scale values of these words, which were chosen from the evaluative category, Matrix Metalloproteinases are approximately equally far apart, so that they represent equal scale intervals and thereby provide “anchors” Synonyms for the specification of the overall pain intensity. MMP Characteristics Definition The descriptor lists of the MPQ are read by (or to) a pa- Matrix Metalloproteinases (MMP) are a zinc- and cal- tient, with the explicit instruction that he or she choose cium-dependent family of proteins that are collectively only those words that describe his or her feelings and responsible for the degradation of the extracellular sensations currently, or during a specific period (such as matrix tissues. MMP are involved in wound healing, “during the pastweek.” Four major indicesare obtained: angiogenesis, and tumor cell metastasis. An imbalance 1. The pain rating index (PRI) based on the rank val- between the active enzymes and their natural inhibitors ues of the words. In this scoring system, the word in leads to the accelerated destruction of connective tissue, each subclass implying the least pain is given a value which is associated with the pathology of diseases such of 1, the next word is given a value of 2, and so on. asarthritis,cancer,multiplesclerosisandcardiovascular The rank values of the words chosen by a patient are diseases. summed to obtain a score separately for the sensory Neutrophils in Inflammatory Pain (subclasses1–10),affective(subclasses11–15),evaluative (subclass 16), and miscellaneous (subclasses 17–20) words, in addition to providing a total score (subclasses 1–20) McGill Pain Questionnaire 2. The PRI-corrected scores, using empirically deter- RONALD MELZACK ,JOEL KATZ mined scale values to enhance discriminability Department of Psychology, McGill University, 3. The number of words chosen (NWC) in the word sets Montreal, QC, Canada 4. The PPI, the number-descriptor combination chosen [email protected] as the indicator of the current overall pain intensity. Since its introduction in 1975, the MPQ has been trans- Synonyms lated into more than 25 languages. As pain is a private, Subjective pain measurement; Pain evaluation; MPQ; personal experience, it is impossible for us to know pre- SF-MPQ cisely what someone else’s pain feels like.However, the MPQ provides us with an insight into the qualities that Definition are experienced. Recent studies indicate that each kind of pain is characterized by a distinctive constellation of The McGill Pain Questionnaire (MPQ) consists of words. There is a remarkable consistency in the choice 78 words, obtained from pain-patient interviews and of words used by patients suffering the same or similar the clinical literature, which describe distinctly differ- pain syndromes, and there is strong evidence that the ent aspects of the experience of pain. The words are MPQ is a valid, reliable tool for pain measurement. categorized into three major classes: The short-form McGill Pain Questionnaire (SF-MPQ) 1. Words that describe the sensory qualities of the expe- (Fig. 1) was developed for use in research settings when rienceintermsoftemporal,spatial,pressure,thermal, the time to obtain information from patients is limited, and other properties and when more information is desired than that pro- 2. Words that describe affective qualities in terms of vided by intensity measures such as the VAS or PPI. tension, fear, and autonomic properties that are part The SF-MPQ consists of 15 representative words from of the pain experience 3. Evaluative words that describe the subjective overall McGill Pain Questionnaire, Figure 1, The short-form McGill Pain Questionnaire. Descriptors 1–11 represent the sensory dimension of pain intensity of the total pain experience. experience and 12–15 represent the affective dimension. Each descriptor is ranked on an intensity scale of 0 = none, 1 = mild, 2 = moderate, 3 = se- Each class comprises several subclasses, which contain vere. The Present Pain Intensity (PPI) of the standard long-form McGill Pain a group of words that are considered by most subjects Questionnaire and the visual analogue scale are also included to provide to be qualitatively similar. overall pain intensity scores. McGill Pain Questionnaire 1103

M 1104 MCID the sensory (n = 11) and affective (n = 4) categories of the standard, long-form (LF) MPQ. The PPI and a MDdc VAS are included to provide indices of overall pain intensity. The 15 descriptors making up the SF-MPQ Densocellular Subnucleus of the Mediodorsal Nu- were selected based on their frequency of endorse- cleus ment by patients with a variety of acute, intermittent, and chronic pains. Each descriptor is ranked by the patient on an intensity scale of 0 = none, 1 = mild, 2 Measuring Tools = moderate, 3 = severe. The SF-MPQ correlates very highly with the major PRI indices (sensory, affective, Outcome Measures and total) of the LF-MPQ, and is sensitive to traditional clinical therapies-analgesic drugs, epidural blocks, and transcutaneous electrical nerve stimulation.The Mechanical Allodynia SF-MPQ is now available in over 30 languages. A pro- cedural model for testing the factorial validity of the Deﬁnition SF-MPQ, which can be applied to translated versions, Mechanical allodynia is the abnormal sensation of pain is provided by Wright et al. (2001). from usually non-painfulmechanical stimulation and is Amygdala, Pain Processing and Behavior in Animals elicited by, for example, lightly touching. fMRI Cancer Pain Headache Due to Arteritis GABA Mechanisms and Descending Inhibitory Motor Cortex (M1) Mechanisms SecondarySomatosensoryCortex(S2)andInsula,Ef- NeuropathicPain Model, ChronicConstrictionInjury fectonPainRelatedBehaviorinAnimalsandHumans Neuropathic Pain Model, Partial Sciatic Nerve Liga- References tion Model Neuropathic Pain Model, Tail Nerve Transection 1. MelzackR, TorgersonWS(1971)Onthe Language of Pain. Anes- thesiology 34:50–59 Model 2. Melzack R (1975) The McGill Pain Questionnaire: Major Prop- Spinal Cord Injury Pain Model, Contusion Injury erties and Scoring Methods. Pain 1:277–299 Model 3. Melzack R (1987) The Short-Form McGill Pain Questionnaire. Pain 30:191–197 4. Melzack R, Katz J (2001) The McGill Pain Questionnaire: Ap- praisal and Current Status In: Turk DC and Melzack R (eds) Mechanical Allodynia Test Handbook of Pain Assessment, 2nd edn. Guilford Press, New York 5. Wright KD, Asmundson GJ, McCreary DR (2001) Factorial va- Allodynia Test, Mechanical and Cold Allodynia lidity of the short-form McGill pain questionnaire (SF-MPQ). Eur J Pain 5:279–284 Mechanical Effects of Ultrasound

MCID Deﬁnition The mechanical effect on the target tissue results in an Minimal Clinical Important Difference increased local metabolism, circulation, extensibility of connective tissue, tissue regeneration and bone growth. UltrasoundTherapyofPainfromtheMusculoskeletal Mcl–1 System

Deﬁnition Human myeloid cell differentiation protein, which is in- Mechanical Hyperalgesia volved in programming of differentiation and concomi- tantmaintenanceofviabilitybutnotofproliferation.Iso- Deﬁnition form 1 inhibits apoptosis. An exaggerated response to a painful mechanical stimu- NSAIDs and Cancer lus(e.g.apin-prickproducingsevereorprolongedpain). A sign that pain pathways are functioning abnormally and may be damaged. MDD Diabetic Neuropathies Freezing Model of Cutaneous Hyperalgesia Major Depressive Disorder Restless Legs Syndrome Mechano-Insensitive C-Fibres, Biophysics 1105

Mechanical Low Back Pain Mechano-Insensitive C-Fibres, Biophysics

HRISTIAN EIDNER C W Chronic Back Pain and Spinal Instability Department of Physiology and Experimental Pathophysiology, University Erlangen, Erlangen, Germany Mechanical Nociceptors [email protected]

Mechanonociceptors Synonyms Action Potential Conduction of C-Fibres; Post-Excita- tory Effects of C-Fibres Mechanical Stimuli Deﬁnitions

Definition Biophysical properties of nerve fibres comprise passive properties of the membrane and nerve (resistance, Inputproducedbyphysicalforces,suchastouch,stretch, capacitance and derived measures like time con- pressure, and vibration. stant) and active properties of membrane channels. Postsynaptic Dorsal Column Projection, Functional For unmyelinated (C-) fibres i.e. nerve fibres with a Characteristics functionally accessible receptive field in vivo and in vitro, these properties can only be derived from indirect measures e.g. with the teased fibre technique in animals Mechanical Syndrome or microneurography in humans. M Characteristics Lower Back Pain, Physical Examination Directly after an action potential, several phases of after-effects can be distinguished (see Fig. 1). An action potential is immediately followed by the absolute Mechanically-Evoked Itch refractory period, which is determined by inactivity of most voltage gated Na+ channels and a repolaris- Definition ing current through open voltage gated K+ channels. Sensation of itch produced by innocuous mechanical stimulation of the skin. Spinothalamic Tract Neurons, Central Sensitization

Mechanism-Based Approaches to Pain and Nociception

Definition A therapeutic approach to the treatment of pain and pain syndromes that is based upon treatment of the underlying mechanisms, as opposed to an empirical approach based on symptoms. The prerequisite to this approach is: 1) knowledgeof the mechanisms underlying the pain Mechano-Insensitive C-Fibres, Biophysics, Figure 1 Summary of process or disorder in question; and 2) knowledge of the after-effects. Threshold (inversely correlated to conduction velocity) of this mechanisms of action of the therapeutic intervention exemplified nociceptive nerve fibre starts at an unconditioned level A, increases to an infinite level during the absolute refractory period B followed proposed. by a subnormal level during the relative refractory period C. Several sec- Quantitative Sensory Testing onds after the excitation there is still a remaining subnormality D which cumulates after a series of action potentials to a level E. Starting at level E an action potential of the accommodated nerve fibre again increases threshold during absolute (F) and relative refractory period (G). Thereafter Mechanoheat Nociceptor a supernormal period H intermittently renders the nerve more excitable than before the respective action potential (level E) but never more than initially (level A). This relative supernormality is typical for human C-fibres whereas Nociceptors in the Orofacial Region (Skin/Mucosa) other species can also develop absolute supernormality (exceeding level Polymodal Nociceptors, Heat Transduction A). Again a late subnormality I follows this activation. 1106 Mechano-Insensitive C-Fibres, Biophysics

Thereafter, during the relative refractory period ac- development of chronic and pathological forms of pain. tion potentials can be induced at higher than normal Besides these receptive differences the two fibre classes stimulus strength and at lower than normal conduction also differ with regard to their biophysical properties, velocity. The refractory periods together last at least in particular to the long-term effects described in the 10 ms in all human C-fibre afferents without a differ- next paragraph. ence between receptive classes. In other species they are shorter. After the refractory periods, a supernormal pe- Long-Term After-Effects riod might briefly turn a nerve fibre hyperexcitable and After-effects with time constants in the range of sec- make action potentials travelling faster than initially. onds are studied with repetitive pulse protocols. These This supernormal period is not constantly observed effects are well known from animal experiments and but varies between species, fibre classes and state of good evidence is available that the threshold increase accommodation of nerve fibres. While an abso- and conduction velocity decrease are equivalent mea- lute supernormal period could be observed in different sures (Raymond and Lettvin 1978). For experimental species, in human C-fibres the observed supernormality ease of assessment, all human studies use conduction has always been relative. “Relative” means, that cumu- velocity decrease as the measure. After the onset of lating long-term after-effects must have established an a repetitive stimulation at a certain frequency or the accommodation that slows down all action potentials of increase to a higher frequency, the conduction latency the ongoing stimulus train. If a conditioning stimulus increases until reaching a plateau. A frequency de- is interposed at an inter-stimulus interval adequate to crease leads to a velocity increase again. The time induce supernormality in the conditioned action poten- constants are in the range of 10–60 s. The amount tial, this supernormality can speed up the conditioned of activity dependent conduction velocity slowing, action potential as compared to the conduction velocity but not the time constant clearly separates mechano- it would have had without the conditioning stimulus insensitive “sleeping” from mechano-responsive affer- (relative supernormality). The initial conduction ve- ents (Serra et al. 1999; Weidner et al. 1999). Taking into locity prior to accommodation cannot be exceeded. account the difference in the unconditioned conduc- The supernormal period is directly followed by the tion velocities of mechano-insensitive (~0.8 m/s) and subnormal periods. On a cellular basis several sub- mechano-responsive (~1.0 m/s) afferents, the amount of types of afterhyperpolarisation with different time conduction velocity slowing separates the two classes constants have been suggested as a basis for the late without overlap. A dissociation of these closely linked subnormal period. For peripheral nerves, these types conductive and receptive properties in patients with are intermingled and a separation using a pharmaco- pathological pain has been interpreted as “sleeping” logical access has not been reported. However, the nociceptors that “woke up”, i.e. have been sensitised in cumulating long lasting subnormality can most proba- the course of the disease and gained receptive properties bly be equated with the slow AHP observed in central like mechano-responsiveness while their conduction neurons. velocity slowing remained typical for “sleeping” nociceptors (Orstavik et al. 2003). Differences Between Human C-Fibre Classes Different mechanisms that could influence or account Biophysical and receptive properties of human affer- for the accommodation of nerve fibres have been sug- ent C-fibres are strongly correlated and separate two gested. The Na/K ATPase activity should lead to hy- distinct fibre classes, the mechano-responsive (usually perpolarisation of a nerve fibre and should be activated also heat responsive) fibres known as CMH fibres or by Na ions that are brought into the cell by its activity. polymodal nociceptors and the mechano-insensitive Hyperpolarisation in turn will slow down action poten- fibres, with two subclasses, heat responsive (CMi) and tial propagation by increasing the difference of resting heat-insensitive (CMiHi). membrane potential and the activation threshold of Unlike other species, mechano-insensitive fibres of voltage gated sodium channels. Therefore electrotonic humans do not even respond to the strongest mechan- depolarisation of the membrane in front of a fully depo- ical stimuli but can gain mechanical responsiveness larised (Na channels open) part of the axon will exceed as a result of primary sensitization (“waking up” of a the Na channel threshold over a shorter distance. The Sleeping Nociceptor). Mechano-insensitive fibres effect of ouabain, a blocker of the Na/K pump, on activ- have larger receptive fields (Schmidt et al. 2002) and ity dependent threshold increase makes its contribution higher heat thresholds than CMH fibres (Weidner et al. likely but not necessarily the only factor (Raymond 1999), sensitise to tonic pressure (Schmelz et al. 1997), and Lettvin 1978). Changes of K conductance can also respond longer to capsaicin injection (Schmelz et modulate the resting membrane potential and have an al. 2000b) and are responsible for neurogenic in- influence on conduction velocity and activation thresh- flammation (Schmelz et al. 2000a). These properties old. An apamin insensitive Ca dependant K current is make mechano-insensitive human afferent C-fibres responsible for the slow after-hyperpolarisation (AHP) prominent candidates for an outstanding role in the incentralneurons(WilsonandGoldberg2006).Further- Mechano-Insensitive Nociceptor 1107 more the AHP itself can activate the inward rectifying tested by external electrical stimulation is increased, all Ih current carried by hyperpolarisation activated cyclic receptor potentials will meet the same increased excita- nucleotide gated channels (HCN) that have also been tion threshold. Paradoxically the maximum frequency found in peripheral nerves (Takigawa et al. 1998). The that can be reached by a high frequency burst of an Ih current counteracts the AHP and therefore limits accommodated nerve fibre exceeds that in an unused the activity dependent conduction velocity slowing. fibre. This is because an unused fibre will only have Finally, geometrical reasons could also partly account subnormal after-effects delaying an action potential for the observed differences in accommodation be- quickly following another. For an accommodated nerve tween mechano-responsive and mechano-insensitive fibre, the supernormalperiod can speed up a succeeding C-fibres. The large receptive field of “sleeping” no- action potential. For a train of four action potentials at ciceptors is an indication of an extensively branched 50 Hz in the receptive field, this can lead to an “intra- terminal arborisation with long and thin terminals. In burst” frequency of 160 Hz at the knee level. This is an thin fibres with an increased surface to volume quotient effective contrast enhancement mechanism. (it is indirectly proportional to the radius), all surface bound channels/pumps at a given density (parts per References surface-area) will have a higher effect on intracellular 1. Bostock H, Campero M, Serra J et al. (2003) Velocity re- concentration (parts per volume). covery cycles of C fibres innervating human skin. J Physiol (Lond) 553:649–663 Short-Term After-Effects 2. Orstavik K, Weidner C, Schmidt R et al. (2003) Patholog- ical C-fibres in patients with a chronic painful condition. Short-term after-effects with time constants in the Brain 126:567–578 range of milliseconds cannot be assessed with the 3. Raymond SA, Lettvin JY (1978) Aftereffects of activity in pe- above-mentioned method. The delay between condi- ripheral axons as a clue to nervous coding. In: Waxman SG (ed) tioning and conditioned action potential must be in the Physiology and pathobiology of axons. Raven Press, New York, pp 203–225 M same range. Therefore, a protocol with a stable ongoing 4. Schmelz M, Schmidt R, Bickel A et al. (1997) Differential sen- frequency and interposed conditioning action poten- sitivity of mechanosensitive and -insensitive C-fibers in human tials at varying inter-stimulus intervals can be used to skin to tonic pressure and capsaicin. Society of Neuroscience assess short term after-effects (Weidner et al. 2000; Abstract 23:1004 5. Schmelz M, Michael K, Weidner C et al. (2000a) Which nerve Weidner et al. 2002; Bostock et al. 2003). Extracellular fibers mediate the axon reflex flare in human skin? Neurore- accumulation of potassium was made responsible for port 11:645–648 the supernormal period and could explain relative and 6. Schmelz M, Schmidt R, Handwerker HO et al. (2000b) Encod- absolute supernormality. In human C-fibres, however, ing of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 123:560–571 another mechanism seems to account for the relative 7. Schmidt R, Schmelz M, Weidner C et al. (2002) Innervation ter- supernormality. After an action potential, voltage gated ritories of mechano-insensitive C nociceptors in human skin. J potassium channels repolarise the axon to the resting Neurophysiol 88:1859–1866 membrane potential. If accommodation has made the 8. Serra J, Campero M, Ochoa J et al. (1999) Activity-dependent slowing of conduction differentiates functional subtypes of C axon hyperpolarised, these potassium channels will fibres innervating human skin. J Physiol (Lond) 515:799–81 only repolarise the fibre to the normal resting mem- 9. Takigawa T, Alzheimer C, Quasthoff S et al. (1998) A brane potential but not to the hyperpolarised level special blocker reveals the presence and function of the hyperpolarization-activated cation current IH in peripheral prior to excitation. After closure of the repolarising mammalian nerve fibres. Neuroscience 82:631–634 potassium channels, the remaining repolarisation back 10. Weidner C, Schmelz M, Schmidt R et al. (1999) Func- to the accommodated hyperpolarised level is carried tional Attributes Discriminating Mechano-Insensitive and out by the “leakage” current, i.e. the current with all Mechano-Responsive C Nociceptors in Human Skin. J Neu- rosci 19:10184–10190 gated channels closed. It resembles the time constant 11. Weidner C, Schmidt R, Schmelz M et al. (2000) Time course of to charge or discharge the membrane capacitor. No post-excitatory effects separates afferent human C fibre classes. difference in the supernormal period and the under- J Physiol (Lond) 527:185–191 lying time constant of the axon could be observed 12. Weidner C, Schmelz M, Schmidt R et al. (2002) Neural signal processing: the underestimated contribution of peripheral human for mechano-responsive or mechano-insensitive fibres C-fibers. J Neurosci 22:6704–6712 with the provision that the same amount of accommo- 13. Wilson CJ, Goldberg JA (2006) Origin of the slow afterhyper- dation is present. As described above, a higher stimulus polarization and slow rhythmic bursting in striatal cholinergic frequency is needed for mechano-responsive fibres to interneurons. J Neurophysiol 95:196–204 yield the same accommodation as mechano-insensitive fibres.

Functional Implications Mechano-Insensitive Nociceptor The most obvious implication of the long-term after- effects is the use dependent desensitisation of nerve ﬁbres. If the threshold to induce an action potential as Silent Nociceptor 1108 Mechanonociceptors

by noxious mechanical forces in this type of nociceptor Mechanonociceptors is shown in Fig. 1. ELVIRA DE LA PEÑA GARCÍA The classification of a peripheral sensory afferent as Instituto de Neurociencias, Universidad Miguel a mechanonociceptor, polymodal nociceptor, cold no- Hernández-CSIC, Alicante, Spain ciceptors or ‘silent’ (mechano-insensitive) nociceptor [email protected] (see nociceptor, categorization), has been established experimentally by applying stimuli of different modal- Synonyms ity such as mechanical (pressure), thermal (heat or cold), and chemical (acid, inflammatory mediators) Mechanical nociceptors; high-threshold mechanore- stimuli to the receptive field of the fiber. Often, the δ ceptors; C-mechanoreceptor; A Delta( )-mechanore- initial classification of a sensory afferent as nociceptive ceptor was defined by its response only to mechanical force Definition of near injurious or injurious intensity. In most cases, strong heating was subsequently used to determine the Subpopulation of sensory afferents activated only by polymodality of the nociceptive fiber. Nevertheless, strong mechanical stimulation, most effectively by in the skin, C- and A-delta fibres responsive to high sharp objects. intensity mechanical stimuli but also to strong heating, named respectively CMHs, and AMHs, have often been Characteristics Mechanonociception has been observed in organisms of various evolutionary levels: paramecium, worm, insects and mammals. In mammals, mechanonociceptors are peripheral endings of primary sensory neurons that are activated only when harmful mechanical stimuli are applied to their receptive field, that is located in the skin, superficial mucosa and cornea (Belmonte et al. 1991; Burgess and Perl 1967), in deep tissues, such as joints and muscles (Mense 1977; Schaible and Schmidt 1983) and in the viscera (Cerveró 1994). The force necessary to evoke a nerve impulse discharge in mechanonociceptors is several orders of magnitude higher than the force required for the activation of low- threshold mechanoreceptors, which are the sensory receptors detecting innocuous mechanical stimuli. Mechanonociceptor neurons have peripheral axons of variable diameter and degree of myelination belonging either to the thin myelinated, Aδ (conduction velocity: 2–20 m/s) or to the unmyelinated, C (conduction velocity < 2m/s) fiber type thatend asnaked nerve endings. Their somas are located in the dorsal root and cephalic sensory ganglia, and are in general of small diameter. Mechanonociceptors were first described by Burgess and Perl in 1967 in recordings of single Primary Af- ferents/Neurons fibres innervating the hind limb of the cat. These authors reported the presence of fibres conducting between 6 and 37 m/s, which were classified as mechanonociceptors because they were activated only by damaging mechanical stimulation of the skin. Burgess and Perl observed that such fibres responded maximally to cutting or pinching the skin with serrated forceps, while noxious heat (50˚), noxious cold (20˚), Mechanonociceptors, Figure 1 Responses of a nociceptive fibre to me- acid applied to the receptive fields and bradykinin chanical stimuli. Fibre conduction velocity, 29 m/s. Upper traces in (a), (b), injected into skin did not excite this class of sensory (c) and (d) show the output of a pulse circuit triggered by unitary action afferents. Typically, their receptive fields were 2–5 cm potentials. (a) Pressure is used to stimulate the receptive field. (b) Pinching with a needle used as stimuli. (c) Fold of skin in the centre of the receptive long by 1–2,5 cm wide, and consisted of responsive field squeezed with serrated forceps used as stimuli. (d) Clip used to pinch spots (under 1 mm diameter) separated by unresponsive the centre of the receptive field used as stimuli. Calibrations on right in areas. An example of the discharge pattern evoked g. (Modified from Burgess and Perl 1967). Mechanonociceptors 1109 referred to as mechanonociceptors. This is incorrect, With the advent of microneurography in humans (Hallin and only those units with high mechanical thresholds, and Torebjörk 1970), mechanonociceptors have also absence of heat response and no initial sensitivity to been identified in the skin of the leg and foot of human chemical stimuli (although these have been seldomly subjects (Schmidt et al. 1997). Their receptive fields tested systematically), can be considered pure mechan- are not single sensitive spots as classical psychophysical nociceptors, sometimes also called “high threshold ical studies had suggested, but cover a relatively large mechanoreceptors”. The designation as polymodal innervation territory. nociceptor is preferred for CMHs, AMHs and other The cellular and molecular mechanisms by which sensory afferent types that, in addition to their sensitiv- mechanonociceptors are sensitive only to mechanical ity to high intensity mechanical forces, also respond to stimuli of noxious or near noxious intensity, in contrast other stimulus modalities (Lynn 1994). with the responsiveness to very light mechanical forces Pure mechanonociceptors have a wide range of sensitiv- that characterizes low threshold mechanoreceptors, are ities to mechanical stimuli varying from near noxious still unknown. to overtly noxious intensities. In this population, A fi- Mechanotransduction is finally accomplished by open- bres generally respond to equivalent stimuli at higher ing or closing ion channels present in the cellular rates of firing than C fibres (Garell et al. 1996). No back- membrane. Many different types of mechanosensitive ground discharges are usually present in mechanonoci- (MS) channels have been characterized in a wide va- ceptors, which develop partial inactivation after repeti- riety of cell types (García-Añoveros and Corey 1997; tivestimulationoftheirreceptivefield.The adaptation Kellenberger and Schild 2002). Also, a variety of extra- of mechanonociceptors to a sustained stimulus was in- cellular and intracellular proteins have been implicated termediate, when compared with that of typical phasic in the transmission/amplification/modulation of me- or tonic mechanoreceptors (Perl 1967). chanical force to the MS channels present in the cellular M

Mechanonociceptors, Figure 2 Electrofisiological 2+ properties and [Ca ]i responses to hypotonic solution. (a) Time course of the increase in [Ca2+] in response to a 5-min application of a 30% hypotonic solution of a possible mechano nociceptor neuron. (b) Membrane voltage responses of the same neuron to hyperpolarizing current steps of 15 pA. (c) Action potential evoked in the same neuron by depolarizing current pulse at threshold. (d) Time course of the increase in [Ca2+] in response to a 5-min application of a 30% hypotonic solution of a possible mechanosensitive neuron. (e) Membrane voltage responses of thesameneurontohyperpolarizing current steps of 10 pA. (f) Action potential evoked in the same neuron by depolarizing current pulse at threshold. (Modified from Viana et al. 2001) 1110 Mechanonociceptors membrane during the transduction process. CaV3.2, a produced smaller and slower elevations of intracellular T-type calcium channel, seems to be required for nor- calcium in response to hypoosmotic stimuli and were mal function of D-hair mechanosensory neurons, but it classified as mechano nociceptor neurons. has not yet been directly related with mechanonocicep- In spite of the progress made in the last years, the tion (Dubreuil et al. 2004; Shin et al. 2003). TREK-1, molecular and cellular basis of mechanotransduction TREK-2 and TRAAK of the 2P domain mechano- in mammalian mechano and polymodal nociceptors, gated K+ channels exhibit mechanosensitivity, but and the molecular basis of their differences with low- there is no experimental proof of their relationship threshold mechanoreceptors, require further research. with mechanonociception (Patel et al. 2001). The role Nociceptors in the Orofacial Region (Skin/Mucosa) played by ASICs, the mammalian homologues of MEC- Sensitization of Visceral Nociceptors 4 and MEC-10 that mediate mechanotransduction in References Caenorhabditis elegans, appears to be minor in mechanical sensibility in mammals (Drew et al 2004). 1. Alessandri-Haber N, Yeh JJ, Boyd AE (2003) Hypotonicity In- duces TRPV4-Mediated Nociception in Rat. Neuron 39:497–511 TRPV4, an osmosensitive channel in mammalian 2. Belmonte C, Gallar J, Pozo MA et al. (1991) Excitation by Irri- cells, has also been implicated in mechanotransduction tant Chemical Substances of Sensory Afferent Units in the Cat’s (Alessandri-Haber et al. 2003). P2X3 receptors are Cornea. J Physiol 437:709–725 3. Burgess PR, Perl R (1967) Myelinated Afferent Fibres Respond- present in small primary sensory neurons and respond ing Specifically to Noxious Stimulation of the Skin. J Physiol to strong mechanical stimuli when expressed in oocytes 190:541–562 of Xenopus. Thus, their implication in the mechanical 4. Cerveró F (1994) Sensory Innervation of the Viscera: Peripheral sensitivity of nociceptor neurons has also been sug- Basis of Visceral Pain. Physiol Rev 74:95–138 5. Cho H, Shin J, Shin CY et al. (2002) Mechanosensitive Ion Chan- gested (Cook et al. 1997; Nakamura and Strittmatter nels in Cultured Sensory Neurons of Neonatal Rats. J Neurosci 1996). 22:1238–1247 However, the nature of the MS channels and of the 6. Cook SP, Vulchanova L, Hargreaves KM et al. (1997) Distinct extra- and intracellular matrix proteins involved in the ATP Receptors on Pain-Sensing and Stretch-Sensing Neurons. Nature 387:505–508 different types of mechanotransduction in mammalian 7. Dubreuil AS, Boukhaddaoui H, Desmadryl G et al. (2004) Role of sensory neurons is still unsolved. Whether differences T-Type Calcium Current in Identified D-Hair Mechanoreceptor in mechanical threshold between low- and high thresh- Neurons Studied In Vitro. J Neurosci 24:8480–8484 old mechanosensory neurons are due to the expression 8. Drew LJ, Rohrer DK, Price MP et al. (2004) Acid-Sensing Ion Channels ASIC2 and ASIC3 Do Not Contribute to Mechanically of different MS channels, to differences in channel Activated Currents in Mammalian Sensory Neurones. J Physiol density, or to the presence of different associated pro- 556:691–710 teins has been ignored. Cho et al (2002) identified two 9. García-Añoveros J, Corey DP (1997) The Molecules of types of mechanosensitive (MS) channels in isolated Mechanosensation. Annu Rev Neurosci 20:567–594 10. Garell PC, Mcgillis SL, Greenspan JD (1996) Mechanical Re- membrane patches of cultured neurons of the dorsal sponse Properties of Nociceptors Innervating Feline Hairy Skin. root ganglion, with different pressure thresholds as J Neurophysiol 75:1177–1189 well as distinct biophysical properties, that they named 11. Hallin RG, Torebjork HE (1970) C-Fibre Components in Electri- cally Evoked Compound Potentials Recorded from Human Me- Low-threshold Mechanosensitive (LT-MS) and High- dian Nerve Fascicles In Situ. A Preliminary Report. Acta Soc threshold Mechanosensitive channels (HT-MS). The Med Ups 75:77–80 reversal potential of these MS channels was near zero, 12. Kellenberger S, Schild L (2002) Epithelial Sodium Chan- as occurs with non-selective cationic channels, and they nel/Degenerin Family of Ion Channels: A Variety of Functions 3+ for a Shared Structure Physiol Rev 82:735–767 were blocked by the MS channels blocking agent Gd . 13. Lynn B (1994) The Fibre Composition of Cutaneous Nerves and HT-MS channels were present only in small sensory the Classification and Response Properties of Cutaneous Affer- neurons (10–17,5 μm), and were activated only by high ents, with Particular Reference to Nociception. Pain Reviews pressures and sensitized by PGE2, suggesting their 1:172–183 14. Mense S (1977) Muscular Nociceptors. J Physiol 73:233–240 implication in nociceptive transduction. 15. Nakamura F, Strimatter SM (1996) P2Y1 Purinergic Receptors in Neurons with low and high sensitivity to mechanical Sensory Neurons: Contribution to Touch-Induced Impulse Gen- stimuli appear to have distinct electrophysiological eration. PNAS 93:10465–10470 properties. Viana et al. (2001), in cultured trigeminal 16. Patel AJ, Lazdunski M, Honoré E (2001) Lipid and Mechano- Gated 2P Domain K+ Channels. Curr Op Cell Biol 13:422–427 neurons of the mouse, mechanically stimulated with 17. Perl ER (1968) Myelinated Afferent Fibres Innervating the Pri- hypoosmotic solutions, described a small fraction of mate Skin and their Response to Noxious Stimuli. J Physiol neurons (12%) that exhibited narrow action potentials 197:593–615 and marked time dependent inward rectification, which 18. Schaible HG, Schmidt RF (1983) Activation of Groups III and IV Sensory Units in Medial Articular Nerve by Local Mechanical responded to hypoosmotic solution with fast and promi- Stimulation of Knee Joint. J Neurophysiol 49:35–44 nentelevationsofintracellularcalcium(Fig.2),andwere 19. Schmidt R, Schmelz M, Ringkamp M et al. (1997) Innervation classified as low threshold mechanosensitive neurons. Territories of Mechanically Activated C Nociceptor Units in Hu- In contrast, they identified another group of neurons man Skin. J Neurophysiol 78:2641–2648 20. Shin JB, Martinez-Salgado C, Heppenstall PA et al (2003) A (19%) showing large and wide action potentials, with an T-Type Calcium Channel Required for Normal Function of a inflexion in the falling phase and no rectification, which Mammalian Mechanoreceptor. Nat Neurosci 6:724–730 Medial Pain System 1111

21. Viana F, Pena E de la, Pecson B et al. (2001) Swelling-Activated Calcium Signalling in Cultured Mouse Primary Sensory Neu- Mechanosensitivity rons. Eur J Neurosci 13:722–734 Deﬁnition Mechanosensitivity is the ability to perceive a tactile in- Mechanoreceptive/Mechanosensitive put. Visceral Receptors Fibromyalgia, Mechanisms and Treatment

Definition Receptive endings in viscera that respond to mechanical MED stimuli. The receptors are not designated as nociceptors, because many mechanoreceptive/mechanosensitive Synonyms visceral receptors respond to low intensity mechan- Minimum Erythema Dose ical stimulation in the physiological range. Some mechanoreceptive/mechanosensitive visceral recep- Definition tors, however, have response thresholds above the MED is the abbreviation for Minimum Erythema physiologicalrange, and thuslikely functionasnocicep- Dose. Ascending doses of UV irradiation determine tors. In viscera (and in muscle), both low threshold and the individual MED, and enables the quantification high threshold mechanoreceptive/mechanosensitive of inter-individually UV-evoked skin reactions. The visceral receptors encode stimulus intensity into the lowest dose of UV radiation, just sufficient to induce a noxious range. visible erythema that can be distinguished from normal Sensitization of Visceral Nociceptors and untreated skin, is defined as one-fold MED. In- creasing doses of irradiation are expressed as multiples M of the MED. The MED is an accepted measure to assess Mechanoreceptor Afferents the skin sensitivity of humans; it does not define the irradiance power or the duration of the UV irradiation. Definition UV-Erythema, a Model for Inducing Hyperalgesias Peripheral afferent fibers that respond to mechanical stimulation. They may begin in “specialized” endings to the skin (sensory receptors e.g. Pacinian corpuscles) Medial Branch Block or as free nerve endings. Hyperaesthesia Facet Joint Procedures for Chronic Back Pain Hypoaesthesia Nick Model of Cutaneous Pain and Hyperalgesia Medial Lemniscus (ML)

Mechanosensitive Definition The medial lemniscuses is the fiber bundle that origi- Definition nates from the dorsal column nuclei and projects to the thalamus. Mechanosensitive is the characteristic of nociceptors Spinothalamic Projections in Rat that are responsive to stimuli such as touch, stretch, Thalamocortical Loops and Information Processing vibration and pressure. Postsynaptic Dorsal Column Projection, Functional Characteristics Medial Pain System

Mechanosensitive Sympathetic Definition Afferent Fibers The medial pain system is the neural circuit consisting of medially projecting spinothalamic pathways that terminate in medial thalamic nuclei, which in turn project Definition to limbic and cortical structures (anterior cingulate cor- Afferent fibers that transmit information about mechan- tex, insula, prefrontal cortex, amygdala) that underlie ical changes that occur in the heart. the processing of the affective-motivational dimension Visceral Pain Model, Angina Pain of pain. 1112 Medial Part of the Posterior Complex

Spinothalamocortical Projections to Ventromedial and Parafascicular Nuclei Mediate Thalamo-Amygdala Interactions and Pain Definition The mechanism or process through which one variable Medial Part of the Posterior Complex exerts its influence on a second variable. Psychology of Pain, Self-Efficacy Synonyms POm Definition Medical Decision-Making Model

The medial part of the posterior complex receives ter- Deﬁnition minations from the spinothalamic tract and probably projects to the insula. The exact functional role remains Medicaldecision-makingmodelreferstotheapplication unclear. of statistical decision theory to judgments concerning Thalamus, Nociceptive Cells in VPI, Cat and Rat diagnostic decisions and treatment outcomes. Statistical Decision Theory Application in Pain As- sessment Medial Thalamotomies

Definition Medical History Medial thalamotomies are stereotactic operations that WADE KING have been performed since the beginning of the nine- Department of Clinical Research, Royal Newcastle teen fifties against chronic pain. They have been used Hospital, University of Newcastle, Newcastle, NSW, against both chronic nociceptive and neurogenic pain Australia syndromes, and several different targets within the me- [email protected] dialtierofthethalamushavebeenexplored,forexample, the centre médian-parafascicular complex, central lat- Definition eralnucleus,posteriorcomplexandmedialpulvinar.The Medical history is the account given by a patient of their results of these operations have been characterized by symptoms, relevant matters, and their general health. pain relief without production of somatosensory deficits History-taking forms the basis of clinical assessment, and without risk for postoperative pain increase. and also helps establish the doctor-patient relationship Thalamotomy for Human Pain Relief that is essential for medical care.

Characteristics Medial Thalamus One imperative in eliciting a history is for the physician to be alert to so-called “red flags”, i.e. clinical features Definition known to correlate with serious pathology such as infec- The intralaminar and midline nuclei of the thalamus. tion or neoplasm. In the interest of securing the patient’s This region of the thalamus most likely contributes to safety, such possibilities must be explored at the initial the affective components as well as to attention and assessment and at every subsequent contact. arousal associated with pain. Taking a history needs to be thorough, lest important is- Spinothalamic Tract Neurons, Visceral Input sues pertaining to the patient’s problems be overlooked. Thalamo-Amygdala Interactions and Pain A comprehensive history would entail exploring each of the following domains: • Identification Median Branch Block • Presenting symptoms • History of the index condition Facet Joint Procedures for Chronic Back Pain • Concurrent conditions • Concurrent medical treatment • General medical history Median Nerve Compression at the Wrist • Systems review • Psychological history Carpal Tunnel Syndrome • Social history Medical History 1113

Identification et al. 1996), thoracic spine (Dreyfuss et al. 1994) and The physician should ask the patient’s name, address, lumbar spine (Mooney and Robertson 1976; Fukui et age, lateral dominance and occupation. Age is a risk fac- al. 1997), from sacroiliac joints (Fortin et al. 1994) and tor for some conditions. Lateral dominance and occupa- from peripheral joints such as the sternoclavicular joint tion relate to how the affected part has been used in the (Hassett and Barnsley 2001). In other instances, such past and activities the patient may undertake in the fu- as abdominal pain, the distribution of pain may be used ture. to explore sources amongst structures with the same segmental innervation as the area of distribution. Presenting Symptoms All current symptoms should be listed and ranked in or- Quality der of significance to the patient. The one for which the Dull, aching pain is typical of somatic pain, and if it patient is seeking treatment should be identified as the radiates from the spine to a limb it suggests somatic “index condition”. referred pain of spinal origin. Sharp pain shooting from the spine into a limb is likely to be radicular. Burning History of the Index Condition pain is often, if not typically, neuropathic. The physician should elicit the history of the index condition systematically, using simple questions to guide Duration the patient so they describe all relevant features. A suit- Establishing if the pain is acute, subacute, or chronic able approach to a pain history is to follow the checklist (see Acute Pain, Subacute Pain and Chronic Pain), is below: important for it predicates treatment. Interventions that • Site work for acute pain may not be appropriate for chronic • Distribution pain, and vice-versa. • Quality M • Duration Periodicity • Periodicity Constantpainmaybeassociatedwithcontinuingpathol- • Intensity ogy. Intermittent pain, especially pain on movement, • Aggravating Factors may be associated with injury of parts that become • Relieving Factors painful under load. Some forms of neurogenic pain, • Effects on Activities of Daily Living particularly the neuralgias, may be intrinsically peri- • Associated Symptoms odic, i.e. occurring in bursts. Some forms of headache • Onset have characteristic periodicities. • Previous Similar Symptoms • Previous Treatment Intensity • Current Treatment The intensity of pain should be measured on a visual analogue scale or other instrument. If pain is not mea- Site suredinitiallyitcannotlaterbesaidtohavebeenrelieved The site of pain is the anatomical region or area in which (Huskisson 1974). Severe pain, of sudden onset, may in- the patient perceives their pain. That may or may not be dicate a serious cause that requires rapid diagnosis and the site of origin of the pain. The patient may be describ- immediate management. inganareaintowhichpainis referred. In recording Aggravating Factors the site of pain, the physician should take care to ensure that any terms used by the patient are not incorrect, and Aggravating factors include stresses that load impaired arecorrectlyunderstoodbythephysicianandotherswho tissues.Identifyingaggravatingfactorsmayassistinfor- mightbecomeengagedinthepatient’smanagement.For mulating management, which includes not only specific example, what a patient calls ‘back pain’ may not ac- interventions but also guiding the patient as to what they curately be “lumbar spinal pain”, which should be dis- should not do, and what they might do in better ways de- tinguished from loin pain or buttock pain (Merskey and spite the pain. Pain that is not aggravated by moving or Bogduk 1994). “Leg pain”should bedistinguished from palpating the region in which pain is perceived suggests pain in the thigh or pain in the (entire) lower limb. the possibility of a remote origin, which should be pursued. Distribution The distribution of pain, and to where it spreads, can Relieving Factors provide clues to its origin. Patterns called “pain maps” Relieving factors usually reduce stresses on the affected have been determined experimentally for pain from part; e.g. avoiding certain movements. Pain that is not particular segments of the cervical spine (Dwyer et relieved by rest raises concern about a possible serious al. 1990; Aprill et al. 1990; Dreyfuss et al. 1994; Fukui cause that needs to be investigated. 1114 Medical History

Effects on Activities of Daily Living Past Medical History The effects of pain on activities of daily living (ADLs) Past history can provide clues to possible serious causes provide an index of ways in which the pain disables or of current pain. A past history of cancer warns of pos- handicaps the patient. These should be addressed in the sible recurrence or metastases. Recent skin penetration, plan of management, lest the patient become unneces- current infections, or immunological compromise warn sarily disabled for fear of aggravating their pain. of possible infection. Prolonged use of corticosteroids is a risk factor for peptic ulceration and osteoporosis re- Associated Symptoms sulting in stress factors. Renal disease, use of corticos- Associated symptoms are important clues to serious teroids, immunosuppression, and diabetes mellitus are causes of pain. Sooner or later, serious causes will pro- risk factors for osteonecrosis. duce features other than pain. These features serve to identify the cause. In the absence of associated symp- Systems Review toms, a serious cause of pain is highly unlikely. For Askingspecificallyaboutpastorpresentsymptomsfrom different conditions, different associated symptoms ap- each bodily system may yield clues to possible serious ply, and should be asked about, lest a serious condition causes that may not have been evident otherwise. be missed. Infection can be associated with fever and malaise; tumours with weight loss, malaise, or neu- Psychological History rological symptoms; vascular disorders with transient The physician should consider how the patient reacts ischaemic attacks. to the condition mentally, and should identify any psychosocial risk factors, i.e. psychological and social Onset issues correlated statistically with the likelihood of The onset means the first appearance of the pain and the chronic disability. Sensitive exploration of a patient’s circumstances in which it started. Those circumstances psyche can enhance the doctor–patient relationship, may provide clues to the cause of the pain. Sometimes enable development of empathy, and help the physician this may be an injury. Sometimes it might be an an- care for them in the manner advocated by Cochrane tecedent infection. These features can provide clues as (Cochrane 1977). to the possible cause of pain and its aetiology. Aspects to be addressed include affect, in particular if anxious or depressed; understanding of the condition; Previous Similar Symptoms anyassociatedfears;relevantcognitionsandbeliefs;and Previous related symptoms suggest a chronic or recur- copingstrategies.Thephysicianmustdecideifthesefac- rent condition. In that event, persistent risk factors for tors are likely to influence the course of the condition recurrence should be explored and managed. (Lethem et al. 1983), and whether special psychological management is needed. Previous Treatment All measures used to treat the condition, their outcomes Social History and any unwanted effects should be noted. Interventions Thesocialhistory helpsthephysicianunderstand thepa- to which there have been favourable responses may be tient in their social environment. It should include their harnessed for further management. Treatment failures family, other close relationships, home, employment, may provide clues to the nature of the cause of pain; fail- sources of income, education, occupational qualifica- ures also suggest treatments to avoid. tions and leisure interests. These factors may bear on what strategies may or may not be employed in the Current Treatment for the Index Condition management plan. Some may constitute risk factors All current treatment should be recorded, including for impeded recovery. In which case, they need to be self-applied measures like local heat and all substances addressed. whether prescribed or otherwise, with the patient’s appraisal of each. Knowing the current treatment serves References to warn about possible deleterious interactions with 1. Aprill C, Dwyer A, Bogduk N (1990) Cervical Zygapophyseal treatment about to be prescribed. Joint Pain Patterns: II – A Clinical Evaluation. Spine 15:458–461 2. Cochrane AL (1977) Effectiveness and Efficiency. Random Re- Intercurrent Conditions flections on Health Services. Cambridge University Press, Cam- Any intercurrentproblems should be noted, and consid- bridge, p 95 3. Dreyfuss P, Michaelsen M, Fletcher D (1994) Atlanto–Occipital eration given to any “red flags”. and Lateral Atlanto–Axial Joint Pain Patterns. Spine 19:1125– 1131 Other Current Medical Treatment 4. DreyfussP,TibilettiC, DreyerSJ(1994)Thoracic Zygapophyseal All forms of treatment in use for other conditions should Joint Pain Patterns. Spine 19:807–811 5. Dwyer A, Aprill C, Bogduk N (1990) Cervical Zygapophyseal be considered for any effect they may have on the index Joint Pain Patterns: I – A Study in Normal Volunteers. Spine condition or its treatment. 15:453–457 Meditation 1115

6. Fortin JD, Dwyer AP, West S, Pier J (1994) Sacroiliac statements (symptoms). Signs must be shown by med- Joint: Pain Referral Maps upon Applying a New Injec- ically acceptable clinical diagnostic techniques. Psy- tion/Arthrography Technique; Part 1: Asymptomatic Volunteers. Spine 19:1475–1482 chiatric signs are medically demonstrable phenomena 7. Fukui S, Ohseto K, Shiotani M, Ohno K, Karasawa H, Naganuma that indicate specific psychological abnormalities, e.g. Y, Yuda Y (1996) Referred Pain Distribution of the Cervical Zy- abnormalities of behavior, mood, thought, memory, gapophyseal Joints and Cervical Dorsal Rami. Pain 68:79–83 orientation, development, or perception. They must 8. Fukui S, Ohseto K, Shiotani M, Ohno K, Karasawa H, Naganuma Y (1997) Distribution of Referred Pain from the Lumbar Zy- also be shown by observable facts that can be medically gapophyseal Joints and Dorsal Rami. Clin J Pain 13:303–307 described and evaluated. 9. Hassett G, Barnsley L (2001) Pain Referral from the Stern- Disability Evaluation in the Social Security Admin- oclavicular Joint: A Study in Normal Volunteers. Rheumatology istration 40:859–862 10. Huskisson EC (1974) Measurement of Pain. Lancet 2:1127–1131 11. Lethem J, Slade PD, Troup JDG, Bentley G (1983) Outline of a Fear Avoidance Model of Exaggerated Pain Perception – I. Behav Res Ther 21:401–408 12. Merskey H, Bogduk N (1994) Classification of Chronic Pain. Medically Incongruent Symptoms and Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edn. Seattle, IASP Press, pp 3, 11–12 Signs 13. Mooney V,Robertson J (1976) The Facet Syndrome. Clin Orthop 115:149–156 Non-Organic Symptoms and Signs

Medical Hydrology Medication-Induced Headaches Spa Treatment M Headache Attributed to a Substance or its Withdrawal Medical Misadventures

Postoperative Pain, Adverse Events (Associated with Acute Pain Management) Mediodorsal Nucleus (MD)

Deﬁnition Medical Mishaps The main medial nucleus of the thalamus, limited by the intralaminar nuclei. Postoperative Pain, Adverse Events (Associated with Spinothalamic Terminations, Core and Matrix Acute Pain Management) Thalamus, Visceral Representation

Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) Mediolongitudinal Myelotomy

Deﬁnition Midline Myelotomy The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a 36 item general measure of perceived health status that is usually self-administered. Pain Inventories Meditation

Deﬁnition Medical Signs Meditation is a means of narrowing the focus of one’s attention to a simple activity (e.g. awareness of the breath) Deﬁnition or word (e.g. a mantra),therebyquietingandcalmingthe Anatomical, physiological, or psychological abnor- mind. malities that can be observed, apart from a person’s Relaxation in the Treatment of Pain 1116 Medullary Dorsal Horn

Medullary Dorsal Horn Melatonin

Definition Definition The medullary dorsal horn is a caudal portion of thesub- Melatonin is a substance secreted by the pineal gland as- nucleus caudalis of the spinal trigeminal nucleus, which sociated with circadian rhythms such as the sleep-wake has laminated cytoarchitecture analogous to the dorsal cycle. horn of the spinal cord. The medullary dorsal horn plays Hypnic Headache a major role in the processing of nociceptive information from the head, face and mouth regions. DREZ Procedures Membrane Capacitance Trigeminothalamic Tract Projections Definition The ability of a cell membrane to store ionic charge. Medullary Lateral Reticular Formation Demyelination

Definition Membrane Potential Lying dorso-medially to the spinal trigeminal nucleus, it contains the interneurons that mediate the long-latency trigeminal reflexes. Definition Jaw-Muscle Silent Periods (Exteroceptive Suppres- The electric potential difference across the membrane sion) of living cells at rest, due to a differential distribution of ions (particularly Na+,K+ and Cr) consecutive to the variable permeability of the membrane and the active transport of ions. MEG Nociceptor Generator Potential

Magnetoencephalography Pain in Humans, EEG Documentation Membrane Resistance

Definition A measurement of how easily ions cross the cell mem- Meissner Receptor brane. Demyelination Definition Encapsulated cutaneous mechanosensory receptors specialized for the detection of fine touch and pressure. Membrane Stabilising Agents Meissner receptors transmit information about the velocity of the stimulus. They belong to the moderately Postoperative Pain, Membrane Stabilising Agents rapid adapting detectors. Perireceptor Elements Membrane Stabilizers

Melanotic Deﬁnition Pharmacological agents that reduce the electrical excitability of neurons. Typical membrane stabilizing Deﬁnition drugs are local anesthetics and other Na+ channel Melanotic refersto a high level of blackish pigmentation blockers. that produces a very dark or black color. Pain Paroxysms Lower Back Pain, Physical Examination Tic and Cranial Neuralgias Mental Disorders, Diagnostics and Statistics 1117

Membrane-Stabilizing Drugs Meningoencephalitis

Drugs Targeting Voltage-Gated Sodium and Calcium Deﬁnition Channels Of the brain stem and cerebellum: neurologic manifestation of Behçet‘s disease. Headache Due to Arteritis Memory Decision Theory

Deﬁnition Meniscus Memory decision theory refers to the application of signal detection theory to judgments concerning whether a Deﬁnition descriptor is “old“, that is, previously used to describe a symptom, or „new“, that is, not previously used. Flattened cartilaginous plate found in certain joints, in- Statistical Decision Theory Application in Pain As- cluding the knee. The meniscus serves to maintain the sessment apposition of the opposed surfaces in their various mo- tions, to ease the gliding movement of the joint, and to decrease the effects of pressure and sudden impact on the joint. Meningeal Afferents Arthritis Model, Osteoarthritis

Nociceptors in the Orofacial Region (Meningeal/Ce- rebrovascular) M Mensendieck System

Meningeal Carcinomatous Definition A pedagogically designed system of functional exer- Definition cises based on an analysis of human anatomy, physiology, and biomechanics, developed by MD Bess M. This is wide spread infiltration of the meninges with Mensendieck, in the early 1900s. The aims are to better cancer. Symptoms and signs may reflect involvement the individual’s functional capacity in daily life by of multiple sites in the central nervous system and may increasing understanding of anatomically and physio- include altered mental status, headache and pain. Car- logically correct movements, and improving the ability cinomatous meningitis occurs in two to three percent to interpret body signals. of patients with adenocarcinoma of the lung and small Body Awareness Therapies cell lung cancer. The median survival of patients with carcinomatous meningitis is two to four months. Cancer Pain Management, Overall Strategy Menstrual Suppression

Meningeal Layer Definition The use of hormonal or anti-hormonal medication Definition such as combined hormonal contraception, high dose progestins, androgens or GnRH agonists for prolonged The protective membranes that encase the central ner- periodsoftimeinordertoobviateorminimizemenstrual vous system. flow and pain. Motor Cortex (M1) Dyspareunia and Vaginismus SecondarySomatosensoryCortex(S2)andInsula,Ef- fectonPainRelatedBehaviorinAnimalsandHumans Mental Disorders, Diagnostics Meningeal Nociceptors and Statistics

Nociceptors in the Orofacial Region (Meningeal/Ce- Diagnostic and Statistical Manual of Mental Disor- rebrovascular) ders 1118 Mental Pain

Mental Pain Mesencephalic Tractotomy

Pain, Psychiatry and Ethics Pain Treatment, Intracranial Ablative Procedures

Menthol Mesencephalon Deﬁnition Deﬁnition Menthol is a natural substance (2-isopropyl-5-methyl- cyclohexanol) obtained from plant leaves of the genus The narrow short part of the brain stem above the pons Mentha, widely used in products such as common cold andbelowthethalamus.Anoperationtointerruptapath- medications, toothpastes, confectionery and cosmetics. way at the level of the mesencephalon is called a mes- l-menthol evokes a sensation of coolness by stimulation encephalotomy. of oral, nasal and skin cold thermoreceptors. Menthol Pain Treatment, Intracranial Ablative Procedures can also act as an irritant involving capsaicin-sensitive pathways. Acold and mentholreceptor,namedTRPM8, was cloned from peripheral sensory neurons. Nociceptors, Cold Thermotransduction Mesencephalotomy

Pain Treatment, Intracranial Ablative Procedures Meralgia Paresthetica

Deﬁnition Mesmerism Meralgia Paresthetica is a painful mononeuropathy of the lateral femoral cutaneous nerve due to focal entrapment in the inguinal ligament. It results in pain in the Therapy of Pain, Hypnosis lateral thigh. Neuralgia, Assessment Sciatica Meta-Analysis

Merkel Receptor Definition Meta-analysisisastatisticaltechniqueforcombiningthe Definition findings from independent studies. It is a systematic re- Encapsulated cutaneous mechanosensory receptors view that uses quantitative methods to summarize the specialized for the detection of fine touch and pressure. results. It is most often used to assess the clinical ef- Merkel receptors transmit information about the inten- fectivenessof healthcare interventions. Meta-analysisis sity of the stimulus. They belong to the slowly adapting an effective means of correcting both for bias and lack detectors. of power in individual randomized controlled studies. It Perireceptor Elements provides a precise estimate of treatment effect, providing due weight to the size of the studies included. The validity of meta-analysis depends on the quality of the systematic review. A meta-analysis may also allow the Mesencephalic Nucleus investigator to explore whether features associated with studies influence the magnitude of the effects observed, e.g. do studies using skilled therapists obtain better ef- Definition fect than those using relatively unskilled ones? Mesencephalic nucleus, containing the cell bodies of Operant Treatment of Chronic Pain primary afferents innervating the jaw muscle spindles Postoperative Pain, Preoperative Education or periodontal ligaments. Psychology of Pain, Efficacy Trigeminal Brainstem Nuclear Complex, Anatomy Transition from Acute to Chronic Pain Metabolic and Nutritional Neuropathies 1119

Metabolic and Nutritional Neuropathies

ALEX BARLING,JOHN B. WINER Department of Neurology, Birmingham Muscle and Nerve Centre, Queen Elizabeth Hospital, Birmingham, UK [email protected], [email protected]

Synonyms Vitamin Neuropathy; Beri Beri Disease; Malnutrition; Alcoholism; Cuban Neuropathy Fabry’s Disease; Para- proteinemic Neuropathies; Nutritional Neuropathies; Metabolic Neuropathies Metabolic and Nutritional Neuropathies, Figure 1 Teased fibre preparation of a peripheral nerve showing axonal degeneration as seen in alcoholic neuropathy. Definition Neuropathy encompasses conditions occurring with systemic organ failure as well as inherited or acquired potentials. Histology demonstrates axonal loss in fibres metabolic defects. Nutritional neuropathies are those of all sizes in the absence of inflammation (Fig. 1). related to malnutrition and resulting vitamin deficiency. Treatment of alcoholic neuropathy requires abstinence Neuropathy related to alcoholism is also discussed in and multivitamins including thiamine. Sensory symp- this section as a toxic metabolic cause that has been toms may initially worsen on treatment. suggested for the axonal injury, it is also frequently Nutritional Neuropathies M related to malnutrition. Axonal neuropathies usually result in damage to the nerve cell body and lead to a Nutritional neuropathies occur predominantly in devel- dying back of the longest axons. oping countries where crop failure and malnutrition are common. The last major outbreak was in Cuba in 1992 Characteristics (Roman 1994). In developed countries nutritional neuropathies are rare but still occur in the context of alco- Alcohol holism, malignancy, chronic infection and pregnancy. Alcoholremainsthesecond mostcommon causeof neu- They are important to recognise, as prompt treatment ropathyafterdiabetesmellitusandaffectsathirdofalco- canhalttheprogressionandsometimesimprovetheneu- holics (Neundorfer 2001). It is unclear whether alcohol ropathy. is toxic itself or simply associated with malnutrition that resultsin neuropathy. ArecentstudybyKoike suggested Thiamine Deficiency, B1 a direct causal role (Koike 2003). Thiamine deficiency causes the syndrome of Beri Beri, The neuropathy typically manifests as burning feet which encompasses peripheral neuropathy (dry Beri with distal, symmetrical loss of pain sensation and Beri) and congestive cardiac failure (wet Beri Beri). allodynia in the lower limbs. As the neuropathy pro- Initially recognised early in the 19th century, it was asso- gresses distal weakness occurs, initially in the legs and ciatedwithadietofprocessedriceorduringseavoyages. then the arms. These features can be accompanied by Thiamine deficiency should be suspected in any mal- ataxia from joint position loss or cereballar degenera- nourishedpatient.Thesymptomsandsignsaresimilarto tion, Wernick-Korsakoff encephalopathy and stigmata alcoholic neuropathy with burning dysaesthesia in the of chronic liver disease. Impotence and postural hy- legs. The condition progresses over weeks and months, potension from autonomic nerve involvement are often with the sensory symptoms spreading proximally fol- under diagnosed (Monforte 1995). lowed by weakness. Less commonly, the cranial nerves There are no diagnostic investigations, but the clin- can be affected e.g. laryngealweakness, facialweakness ical signs in conjunction with a history of alcohol and tongue deviation. consumption, typically greater than 3 litres of beer Laboratory studiesof thiamine levelsare unreliable.Nu- or 300 ml of spirits per day for three years, are sugges- merous studies have looked at pyruvate which accumu- tive (Behse 1977). A red cell macrocytosis, elevated lates in thiamine deficiency, however the sensitivity is transaminase and gamma glutamyltransferase are also poor. Assay of erythrocyte transketolase levels, a vita- pointers. Analysis of cerebral spinal fluid should be min B1 dependant enzyme, is more helpful if measured normal, although the protein may be minimally ele- priortoanysupplementationasitreflectsB1 stores.NCS vated. The nerve conduction studies, (NCS), mirror the are similar to that of alcoholic neuropathy with predom- clinical findings and show distal, predominantly lower inantly distal, symmetrical axonal loss. The pathology limb, symmetrically, reduced sensory nerves action shows distal axonal degeneration. 1120 Metabolic and Nutritional Neuropathies

Metabolic and Nutritional Neuropathies, Table 1 Features of Metabolic and Nutritional Neuropathy Cause Symptoms Pain Examination Speciﬁc Investigations Pathology

Alcohol burning feet +++ distal, symmetrical, loss of raised red cell mean cell sensory axonal pain and hyperasthesia to volume light touch raised transaminase raised gamma glutamyltransferase

thiamine deﬁciency burning Feet +++ distal, symmetrical, loss of raised erythrocyte axonal pain and hyperasthesia to transketolase light touch

pyridoxine deﬁciency Distal numbness and distal, symmetrical sensory sensory axonal tingling loss

cobalamine deﬁciency Distal tingling and distal loss of vibration low B12.,raised homocysteine axonal numbness followed by joint position and methionine +/- ataxia &weakness sense variable increase in Absent ankle reﬂexes haemoglobin &mean cell volume

vitamin E deﬁciency ataxia and weakness distal areﬂexia and loss of vitamin E level (in presence axonal vibration +/- ataxia of normal lipid levels)

uraemia Distal paraesthesia + distal sensory loss raised urea axonal

hepatic dysfunction variable variable deranged liver function tests demyelinating +/- vitamin E deﬁciency or axonal

thyroid disease Distal paraesthesia ++ distal sensory loss TSH and T4 sensory axonal

Porphyria Distal pareasthesia + distal paraesthesia &proximal urinary porphobilinogens axonal &proximal weakness weakness +/- Respiratory muscle weakness

Amyloid Distal paraesthesia distal, symmetrical loss of Congo red staining of nerve Axonal pain and temperature biopsy +/- autonomic dysfunction

Refsums Disease Distal paraesthesia + distal, symmetrical loss of raised plasma phytanic acid demyelinating vibration and proprioception and pipecolic acid Mild distal weakness

Fabrys Disease burning hands &feet +++ progressive or episodic α-galactosidase levels in axonal sensory loss ﬁbroblasts

The treatment of polyneuropathy is with oral thi- day are toxic to nerves, leading to a pyridoximeinduced amine, 300 g per day. In the presence of heart failure neuropathy. or Wernicke’s encephalopathy, thiamine should be administered parenterally (see Wernicke-Korsakoff Cobalamine Deficiency, B12 Syndrome). Supplementation with multivitamins is ThemostcommoncauseofB12 deficiencyismalabsorp- recommended as the neuropathy is often not the result tion secondary to pernicious anaemia. In this condition, of a single vitamin deficiency state. antibodies to intrinsic factor prevent absorption of B12 specifically. A deficiency state is also well documented Pyridoxine Deficiency, B6 in patients post gastrectomy or resection of the terminal Pyridoxine deficiency is rare and usually secondary to ileum. Less frequent causes of deficiency include tropi- treatment with isoniazid or hydralazine. These drugs cal sprue, severe steatorrhoea, drugs such as colchicine inhibit the phosphorylation of pyridoxine to the active which reduce absorption and rarely a strict vegan diet. coenzyme pyridoxal phosphate. Distal, symmetrical Occasionally general anaesthesia with nitrous oxide can numbness with tingling is the common presentation. precipitate a deficit; this is because nitrous oxide can in- Discontinuing the offending drug usually reverses the terfere with the B12 dependant conversion of homocys- symptoms. A daily oral dose of 50–100 mgs of pyri- teine to methionine. B12 is stored in the liver and many doxime is generally advised. Doses above 180 g per years of deficiency are needed to deplete the stores. Metabolic and Nutritional Neuropathies 1121

B12 deficiency usually begins insidiously and pro- and weakness. Examination reveals distal areflexia, gresses over weeks and months. Practically it is very prominent loss of vibration and joint position sense difficult to separate the symptoms or neuropathy from with minimal weakness. Other sensory modalities such the myelopathy of sub-acute combined degeneration as light touch are seldom affected. Ataxia can be a of the spinal cord as they usually coexist. In the early feature of both joint position loss and cerebellar in- stages paraesthesia and numbness are the most com- volvement. The clinical picture can be confounded by mon symptoms. Lower limb weakness and ataxia then proximal muscle weakness and a positive Babinski ensues. Other symptoms include impotence, memory sign. loss and mental slowing. Vitamin E assays are accurate in the presence of normal Examination typically reveals loss of vibration sensa- lipid levels as vitamin E is primarily located in lipopro- tion in the early stages followed by loss of joint posi- tein, however, hyperlipidaemic patients with normal vi- tion sense and then light touch. The ankle reflexes are tamin E assays, may still have a deficiency. In general, reduced or absent. The myelopathy leads to pyramidal levels need to be undetectable to be able to attribute neu- motor dysfunction, hyperreflexia at the knee and a pos- rological disease to vitamin E deficiency. NCS demon- itive Babinski sign. strate a reduction in sensory nerve action potentials with Serum B12 levels can be measured but the methods preservation of conduction velocity. Motor nerves are of assay varies, and all are prone to inaccuracy, as usually unaffected. Somatosensory evoked potentials B12 is predominantly protein bound. This means that and visually evoked potentials ( visual evoked poten- a normal B12 concentration does not exclude a defi- tials) are often delayed due to spinal or central nerve in- ciency state. Also, falsely elevated levels are seen in volvement. Electromyography can show mild denerva- myeloproliferative and hepatic disorders and falsely tion. CSF examination is normal. low levels are seen in pregnancy. B12 deficiency is The role of vitamin E as an antioxidant and free radical also associated with a macrocytic anaemia. There is scavenger are well documented, but the mechanism by debate about whether significant neurological dysfunc- which vitamin E deficiency affects the nervous system M tion from B12 deficiency can occur in the presence of is not established. a normal haemoglobin level. Significant reduction of Treatment of vitamin E deficiency involves large doses the B12 concentration will cause an elevation in B12 of oral vitamin E, 1–4 g/day (Sokol 1990). Every case dependant metabolites, homocysteine and methionine. should be carefully monitored and the dose individu- Measuring the levels of these metabolites can be useful ally tailored. In cases of severe damage to the nervous in cases of borderline deficiency, to help establish those system, regression is unlikely and treatment would aim with neurology resulting from their deficiency. Ninety to halt the progress of the disease. If conditions such percent of patients with significant neurologicaldisease as abetaliproteinaemia are diagnosed early enough, have elevated levels (Yuen 2001). NCS show reduced the condition may be prevented by supplementing sural nerve action potentials resulting from presumed vitamin E. axonopathy. The pathological studies in this area are limited and inconclusive (Windebank 1993). Metabolic Vitamin B12 deficiency is treated with intramuscular Chronicuraemiacausesaprogressivesensorymotor,ax- injections. Partial neurological improvement is usually onalneuropathy which canbepainful(Wolfe 2002).The seen predominantly in the first six months, but recovery frequencyhasdecreasedoverthelasttenyearsduetoim- can continue for up to a year or more. proved management with dialysis and renal transplant (Said 1987; Lagueny 2002), although the exact mecha- Vitamin E Deficiency nism underlying this neuropathy is unknown. Vitamin E is a fat soluble vitamin and absorption is Toxins can effect both the peripheral nerve and liver, but dependent on bile salts and pancreatic esterases in the some neuropathies do occur as a consequence of hepatic small bowel. Causes of the deficiency include cystic dysfunction alone: Chronic hepatic failure can lead to an fibrosis, bile salt deficiency from congenital cholesta- asymptomatic demyelinating neuropathy, and neuropa- sis and small bowel resection, a rare inherited defect thy is detectable in 93% of patients pre liver transplant of chylomicrons and lipoprotein synthesis known as (McDougall 2003); An acute demyelinating polyneu- abetalipproteinaemia, and defects in alpha-tocopherol ropathy similar to Guillian Barré can accompany viral transfer protein genes which are inherited in an autoso- hepatitis. A sensory neuropathy is associated with Pri- mal recessive manner. maryBiliaryCirrhosis,whilechildhoodcholystaticliver There are significantreservesof vitamin E in the adipose disease can cause a sensory neuropathysecondary to vi- tissue; this means that deficiency states in adults take tamin E deficiency. many years or decades to become clinically significant. A mild chronic sensory motor neuropathy can be seen Deficiency of vitamin E leads to spinocerebellar dys- in both hyperthyroidism and hypothyroidism. function with variable peripheral nerve involvement; Acute intermittent porphyria can cause an axonal neu- affected patients usually complain of an unsteady gait ropathy which is preceded by the first attack of abdom- 1122 Metabolic and Nutritional Neuropathies

Metabolic and Nutritional Neuropathies, Table 2 Paraproteinemic Neuropathies Condition Systemic Symptoms Neuropathy Pain Examination Speciﬁc Pathology Investigations

MGUS Nil Distal numbness, +++ Predominantly IgG or IgM-K Predominantly paraesthesia and pain sensory loss paraprotein <3g/dl demyelinating with ataxia. Weakness occurs Bone marrow biopsy Can resemble late < 5% plasma cells chronic inﬂammatory demyelinating polyneuropathy, CIDP

Multiple Fatigue, bone pain Distal weakness and Distal, IgM or IgG-K Predominantly Myeloma dysaesthesia symmetrical, paraprotein >3g/dl. axonal weakness and Low haemoglobin numbness Raised calcium Renal impairment Skeletal survey

Waldenstrom’s Fatigue, weight Numbness in the feet + Distal, symmetrical IgM-K paraprotein Demyelinating macroglobulin- loss, bleeding and followed by foot drop paraesthesia Full blood count aemia hyper-viscosity and numbness followed by distal weakness initially in the lower limbs

Amyloidosis Autonomic symptoms, Numb feet initially +++ Symmetrical, IgG or IgA- λ Axonal (usually e.g. postural progressing to distal, paraprotein systemic) hypotension, diarrhoea lancinating pain and predominantly Biopsy of sural nerve, and impotence loss of temperature sensory rectum or bone Weight loss sensation. disturbance. marrow with congo cardiac and renal red staining dysfunction can occur

POEMS Polyneuropathy Progressive distal +/- Symmetrical, IgG or IgA-λ Demyelinating Syndrome Organomegaly sensory disturbance distal, allodynia, paraprotein (osteoscle- Endocrinopathy and weakness numbness, loss Skeletal survey rotic Mprotein of joint position myeloma) Skin changes sensation and +/- plasmacytoma weakness.

Castleman’s Lymphadenopathy Variable: can resemble +/- Variable IgM or IgG paraprotein Axonal Disease +/- POEMS syndrome motor neurone disease Lymph node or CIDP biopsy looking for angiofollicular hyperplasia

Cryoglobulin- Raynaud’s phenomenon Pain in the early stages +++ Symmetric or IgM or IgG Axonal aemia Evidence of Generalized or asymmetric paraprotein, but can lymphoproliferative multi-focal weakness sensorimotor be polyclonal disorders, collagen Paraesthesia can be disturbance Precipitation of vascular or chronic precipitated by the cold cryoglobulins from inflammatory disease serum. inal pain. Motor involvement is typically proximal and curs and frequently presents as carpal tunnel syn- can affect the respiratory muscles; sensory involvement drome. is mild, distal and symmetrical. The neuropathy can also Refsums disease is an autosomal recessive condition affect the autonomic system leading to tachycardia, la- caused by a defect in phytanoyl-CoA-hydroxylase bile blood pressure, urinary retention and diarrhoea. that causes ataxia, retinal damage and deafness. The Amyloid neuropathy occurs in twenty percent of pa- associated demyelinating neuropathy causes a slow, tients with light chain disease. This axonal neuropathy progressive, distal, symmetrical loss of vibration and is predominantly sensory, distal and symmetrical. Pain proprioception. Weakness also occurs and progresses and temperature loss occurs initially, but distal weak- proximally. Painful paraesthesia can be a feature. ness can develop in the later stages. Involvement of Fabry’s disease, caused by α Galactosidase deficiency, the autonomic nerves leads to orthostatic hypoten- is a X linked condition that affects the peripheral ner- sion, impotence, bladder dysfunction, hypohydrosis vous system, the central nervous system, the heart and and meiotic pupils. A multifocal neuropathy also oc- the kidneys. The associated neuropathy is particularly Metabolism 1123 painful. Patients describe burning in the hands and feet References which can be episodic or chronic and progressive. Neu- 1. Behse F, Buchthal F (1977) Alcoholic Neuropathy: Clinical, rophysiology demonstratesan axonalneuropathywhich Electrophysiological and Biopsy Findings. Ann Neurol 2:95 affects the small fibres initially. 2. Kelly JJ, Kyle RA, O’Brien PC et al. (1981) Prevalence of Mon- oclonal Protein in Peripheral Neuropathy. Neurology 31:1480- 1483 3. Koike H, Iijima M, Sugiura M et al. (2003) Alcoholic Neuropa- Paraproteinemic Neuropathies thy is Clinicopathologically Distinct from Thiamine-Deficiency Paraproteins are associated with ten percent of periph- Neuropathy. Ann Neurol 54:19-29 4. Kyle RA, Therneau TM, Rajkumar SV et al. (2003) Long-Term eral neuropathies, and they can be detected by immu- Follow-up of IgM Monoclonal Gammopathy of Undetermined noelectrophoresis or immunofixation of blood or urine. Significance. Semin Oncology 30:169-171 The identified proteins are usually the product of a sin- 5. Lagueny A (2000) Metabolic and Nutritional Neuropathies. Rev gle clone of plasma cells and are therefore termed mon- Prat 50:731-5 6. McDougall AJ, Davies L, McCaughan GW (2003) Autonomic oclonal, M proteins. and Peripheral Neuropathy in End Stage Liver Disease and fol- Paraproteinaemic neuropathies can precede or be asso- lowing Liver Transplant. Muscle Nerve 28:595-600 ciated with a number of systemic disorders. 7. Monforte R, Estruch R, Valls-Sole J et al. (1995) Autonomic and Monoclonal gammopathy of undetermined signifi- Peripheral Neuropathies in Patients with Chronic Alcoholism. Arch Neurol 52:45-51 cance, MGUS, is the most common (Kelly 1981). In 8. Neundorfer B (2001) Alcohol Polyneuropathy. Fortschr Neurol this condition the paraprotein level is less that 3 g/dl in Psychiatr 69:341-5 the serum, the paraprotein usually possesses a kappa 9. Pestronk A, Florence J, Miller T et al. (2003) Treatment of IgM Associated Polyneuropathies using Rituximab. J Neurol Neuro- light chain component. IgG is the most common para- surg Psychyatry 74:485-489 proteinfoundinpatientswithMGUSandnoneuropathy, 10. Renaud S, Gregor M, Fuhr P et al. (2003) Rituximab in the Treat- but when MGUS accompanies a neuropathy the IgM ment of Anti-MAG Associated Polyneuropathy. Muscle Nerve isotype is more frequent. MGUS is distinguished from 27:611-615 11. Roman GC (1994) An Epidemic in Cuba of Optic Neuropa- M Myeloma by the lower level of paraprotein and the thy, Sensorineural Deafness, Peripheral Sensory Neuropathy and absence of systemic features. The condition typically Dorsolateral Myeloneuropathy. J Neurol Sci 127:11-28 affects men over the age of fifty and presents with distal 12. Ropper AH, Gorson KC (1998) Neuropathies Associated with numbness and paraesthesia. Fifty percent of patients Paraproteinemia. N Engl J Med 338:1601-1607 13. Said G (1987) Acquired Metabolic Neuropathies (2): Kidney develop lancinating pains, dysaesthesia or aching dis- Failure, Hypothyroid and Hypoglycaemia. Rev Neurol 143:785- comfort in the limbs; light touch, joint position sense 90 and vibration sensation are also affected (Ropper 1998). 14. Sokol RJ (1990) Vitamin E and Neurologic Deficits. Adv Pediatr In advanced cases distal weakness can occur. Investi- 37:119-148 15. Veneri D, Aquel H, Franchini M et al. (2004) Malignant Evolu- gations usually reveal a demyelinating but occasional tion of Monoclonal Gammopathy of Undetermined Significance: axonal neuropathy. Cerebral spinal fluid protein is Analysis of 633 Consecutive Cases with Long-Term Follow-Up. typically elevated. Haematologica 89:876-878 The treatment of MGUS is not established but intra- 16. Windebank A (1993) Polyneuropathy due to Nutritional Defi- ciency and Alcoholism. In: Peripheral Neuropathy 3rd edn. W venous immunoglogulin, plasma exchange, steroids B Saunders Company, Philadelphia, pp 1310-1321 and immunosuppresion have all been used with vari- 17. Wolfe GI, Barohn RJ (2002) Painful Peripheralneuropathy. Curr able success. A number of recent small studies have Treat Options Neurol 4:177-188 reported beneficial effects treating MGUS with ritux- 18. Yuen T (2001) Nutritional and Alcoholic Neuropathies. In: Pe- ripheral Neuropathy: A Practical Approach to Diagnosis and imab, this is a humanized monoclonal antibody directed Management. Lippincott Williams and Walkins, Philadelphia, against CD20 antigens. (Pestronk 2003; Renaud 2003) pp 223-232 These studies have not been as promising as originally anticipated, large randomised control trials are awaited to further assess the efficacy of rituximab. In addition to managing the neuropathy, it is important to monitor Metabolic Neuropathies the paraprotein level in patients with MGUS, as 30% will develop a malignant plasma-cell disorder within Metabolic and Nutritional Neuropathies 25 years (Veneri 2004). The risk of progression of MGUS to malignancy is, on average, 1.5% per year (Kyle 2003). Other paraproteinaemic disorders associated with a Metabolism neuropathy are listed in Table 2. These conditions are important to recognise, as treatment can lead to remis- sionoftheconditionandimprovementintheneuropathy. Definition Therefore, immunoelectrophoresis and immunofixa- The metabolism of a drug describes its biotransformation should be an essential part of the investigations of tion into other substances due to chemical conversion. any unexplained neuropathy. NSAIDs, Pharmacokinetics 1124 Metabotropic Glutamate Receptors

N-terminal extracellular domain, which contains im- Metabotropic Glutamate Receptors portant residues for ligand binding and forms two lobes that close like a Venus’ flytrap upon ligand binding Synonyms (Bockaert and Pin 1999). The second intracellular loop mGlu Receptors; mGluRs determines G-protein specificity and the intracellular C-terminal interacts directly with intracellular proteins Definition such asHomer proteins(Bhave etal. 2003;Bockaertand Family of G-protein-coupled glutamate receptors Pin 1999; De Blasi et al. 2001). Eight mGluR subtypes (mGluRs) that are coupled to intracellular second have been cloned to date and are classified into groups I messenger (G-Protein) systems. There are eight known (mGluRs 1 and 5), II (mGluRs 2 and 3) and III (mGluRs mGlu receptor subtypes (mGlu1 - mGlu8), and some of 4, 6, 7 and 8) based on their sequence homology, signal these are known to form homo-dimers. The eight recep- transduction mechanisms and pharmacological profile tors can be placed into three groups (Groups I, II, III) (De Blasi et al. 2001; Gasparini et al. 2002; Neugebauer on the basis of sequence homology and pharmacology. 2001; Schoepp et al. 1999; Varney and Gereau 2002) They trigger long-lasting intracellular processes and (see Table 1). Several splice variants have been identi- mediate slow synaptic components, s. also Glutamate fied which may differ with regard to their pharmacology Receptor. and G-protein coupling. Inflammation, Role of Peripheral Glutamate Recep- Signal Transduction tors Metabotropic Glutamate Receptors in the Thalamus Group I mGluRs couple through Gq/11 proteins to the Molecular Contributionsto the MechanismofCentral activation of phospholipase C (PLC), resulting in phos- Pain phoinositide (PI) hydrolysis, release of calcium from Nociceptive Neurotransmission in the Thalamus intracellular stores and protein kinase C (PKC) activa- NociceptiveProcessingintheAmygdala,Neurophys- tion (Anwyl 1999; Gasparini et al. 2002; Neugebauer iology and Neuropharmacology 2001; Schoepp et al. 1999). Tyrosine kinase activation is another signaling pathway of group I mGluRs. The PKC- and tyrosine kinase-dependent pathways are two major signal transduction mechanisms that can acti- Metabotropic Glutamate Receptors vate the mitogen-activated protein kinases (MAPKs) in Spinal Nociceptive Processing such as the extracellular signal-regulated kinase 1/2 (ERK1/2) (Karim et al. 2001). Group II and group III VOLKER NEUGEBAUER mGluRs are negatively coupled to adenylyl cyclase Department of Neuroscience & Cell Biology, University of Texas Medical Branch, Galveston, TX, (AC) through Gi/Go proteins, thereby inhibiting cyclic AMP (cAMP) formation and cAMP-dependent protein USA [email protected] kinase (PKA) activation (Anwyl 1999; Gasparini et al. 2002; Neugebauer 2001; Schoepp et al. 1999).

Synonyms Modulation of Voltage- and Ligand-Gated Ion Channels Spinal Cord Nociception, Glutamate Receptor (Meta- In general, the predominant effect of group I mGluR botropic) activation is enhanced neuronal excitability and synaptic transmission, whereas activation of groups II and III Deﬁnition typically produces inhibitory effects. Exceptions exist G-protein-coupledreceptors that are activated by gluta- however, and different subtypes within one group (e.g. mate and are linked to a variety of signal transduction mGluR1 and mGluR5) may exert opposing effects. pathways to regulate neuronal excitability and synaptic mGluRs can regulate neuronal excitability through di- transmission in normal nervoussystemfunctionsaswell rect or indirect effects on a variety of voltage sensitive as in neurological and psychiatric disorders. They also ion channels, including high voltage-activated Ca2+ modulatenociceptiveprocessingatdifferentlevelsofthe channels, K+ channels and nonselective cationic chan- pain neuraxis, including the spinal dorsal horn. nels (Anwyl 1999; Neugebauer 2001; Schoepp et al. 1999). The modulation of ligand-gated ion channels by Characteristics mGluRsincludesthegroupImGluR-mediatedenhance- Metabotropic glutamate receptors (mGluRs) (see ment of ionotropic glutamate receptor (see ionotropic metabotropic receptor) belong to family 3 of G- receptor) function, which probably involves receptor protein-coupled receptors, which can trigger long- phosphorylation (Anwyl 1999; Neugebauer 2001). lasting intracellular processes and ”metabolic” changes Group I mGluRs also potentiate the function of the cap- and mediate synaptic plasticity. They are characterized saicin/vanilloid receptor (VR1) (Neugebauer 2001). by a seven transmembrane domain topology and a large Convincing evidence suggests that mGluRs interact Metabotropic Glutamate Receptors in Spinal Nociceptive Processing 1125

Metabotropic Glutamate Receptors in Spinal Nociceptive Processing, Table 1 Classiﬁcation and pharmacology of mGluRs Group Group I Group II Group III

Subtype mGluR1,5 mGluR2,3 mGluR4,6,7,8

Agonist S-DHPG (1,5) LY354740 LAP4 CHPG (5) LY379268 LSOP 2R,4R-APDC

Antagonist CPCCOEt (1) EGLU UBP1112 LY367385 (1) LY341495 MSOP BAY36-7620 (1) MAP4 MPEP (5) SIB-1757 (5) SIB-1893 (5)

Effector Gq-protein (Gs-protein) Gi/o-protein Gi/o-protein PLC ↑ AC ↓ AC ↓ ERK ↑ (PLD ↑) (AC ↑) tyrosine kinase ↑ with the opioid system and play a role in the develop- (Fundytus 2001; Neugebauer 2001; Neugebauer 2002; ment of opioid tolerance and dependence (Fundytus Varney and Gereau 2002). The current focus of research 2001). mGluRs can also modulate the release of trans- is on the role of individual mGluR subtypes and signal mitters by acting as autoreceptors (glutamate) or het- transduction pathways. M eroreceptors (GABA, substance P, serotonin, dopamine Group I mGluRs and acetylcholine)(Cartmell and Schoepp 2000). Both mGluR1 and mGluR5 are functionally expressed Pharmacology and Modulation of mGluRs in the spinal dorsal horn. Anatomical and recent elec- Several potent and mGluR subgroup/subtype selective trophysiological data further suggest that mGluR1 and compounds have been developed in recent years (see mGluR5 are localized pre- as well as post-synaptically Table 1). Presently available agonists are subgroup- (Neugebauer 2002; Neugebauer 2001; Park et al. 2004; selective; the only subtype-selective agonist is CHPG Varney and Gereau 2002). (for mGluR5). LY367385 is a competitive mGluR1 Agonists subtype-selective antagonist. Other subtype-selective group I antagonists that distinguish between mGluR1 Activation of spinal group I mGluRs generally pro- (CPCCOEt, BAY36-7620) and mGluR5 (MPEP, SIB- duces pro-nociceptive effects in behavioral and elec- 1757, SIB-1893) are non-competitive antagonist s trophysiological assays, although mixed excitatory or inverse agonist s. Competitive antagonists that and inhibitory effects have been reported (Fundytus are selective for group II and group III mGluRs are 2001; Neugebauer 2001; Varney and Gereau 2002). available (Gasparini et al. 2002; Schoepp et al. 1999; Intrathecal administration of group I agonists such as Varney and Gereau 2002). S-DHPG evokes spontaneous nociceptive behavior, The intracellular C-terminal of group I mGluRs is also thermal hyperalgesia (cold and heat), mechanical the target of interacting proteins, such as the Homer pro- hyperalgesia, mechanical allodynia and enhanced teins, which can regulate subcellular receptor localiza- formalin-induced nociception in the second phase tion, G-protein coupling and constitutive (basal) activity (Fundytus 2001; Neugebauer 2001; Varney and Gereau of mGluR1 and mGluR5 (Gasparini et al. 2002). Recep- 2002). These effects are mediated through mGluR1 as tor phosphorylation is another important mechanism for well as mGluR5 since they were blocked with antag- modulating mGluR function, including PKC-mediated onists or antibodies for mGluR1 or mGluR5, where desensitization of group I mGluRs and uncoupling of tested (Fundytus 2001; Neugebauer 2001; Varney and groups II and III mGluRs from G proteins by PKC and Gereau 2002). PKA (Karim et al. 2001; Neugebauer 2001; Varney and In electrophysiological studies in anesthetized animals Gereau 2002). in vivo, intraspinally administered group I mGluR agonists, including S-DHPG, had excitatory effects on Spinal Nociception spinal dorsal horn neurons and increased their responses The important role of group I mGluRs in spinal nocicep- to Innocuous Input/Stimulus and, less consistently, to tive processing, central sensitization and spinally me- noxious mechanical stimulation of cutaneous or deep diated pain behavior is now well established. The func- tissue (Neugebauer et al. 1999; Neugebauer 2001). In tions of groups II and III mGluRs are less well known addition, dual excitatory-inhibitory effects of group I 1126 Metabotropic Glutamate Receptors in Spinal Nociceptive Processing mGluR activation have been observed in vivo as well as are localized predominantly on presynaptic terminals in in spinal cord slices in vitro (Chen et al. 2000, Gerber the dorsal and ventral horns whereas group II mGluRs et al. 2000; Neugebauer 2001). The facilitatory effects have been detected on presynaptic terminals in the of group I agonists can be blocked with antagonists superficial dorsal horn as well as on postsynaptic el- selective for mGluR1 (CPCCOEt) or mGluR5 (MPEP) ements in deeper laminae (Neugebauer 2001; Varney whereas the inhibitory effects are mimicked by an and Gereau 2002). mGluR5 agonist (CHPG), suggesting that mGluR1 Behavioral studies showed antinociceptive effects of and mGluR5 are involved in excitation whereas inhibi- group II or group III mGluR activation (Neugebauer tion is mediated through mGluR5 (Neugebauer 2001; 2002; Neugebauer 2001; Varney and Gereau 2002). Neugebauer 2002; Park et al. 2004). Intrathecal administration of a nonselective group II The functional differences between mGluR1 and mGluR agonists increased withdrawal thresholds to mGluR5 may be due to differences in their pre- and noxious mechanical cutaneous stimuli in the absence postsynaptic distribution, localization on excitatory of tissue damage or inflammation, and this effect was and inhibitory synapses, regulation of excitatory and blocked by a group II antagonist (EGLU). Intrathecal inhibitory transmission and different cellular effects, administration of a group III agonist (LAP4) produced including signal transduction mechanisms and effec- antinociceptive effects both early and late in the second tors. phase of the formalin test. Effects of group II activation are less well documented, but preliminary data suggest Inhibition that selective group II agonists (LY354740, LY379268) The endogenous activation of spinal group I mGluRs, can inhibit nociceptive behavior in the formalin test and particularly mGluR1, in prolonged nociception and carrageenan-induced thermal hyperalgesia. persistent pain states is well documented in behavioral Electrophysiological studies in anesthetized animals in and electrophysiological studies using antagonists, an- vivo measured inhibitory effects of group II and group tibodies and antisense oligonucleotides in models of in- III agonists on spinal nociceptive processing (Neuge- flammatory (second phase of formalin test; intradermal bauer 2001; Varney and Gereau 2002). Activation of capsaicin; intraplantar carrageenan; kaolin/carrageenan spinal group II mGluRs inhibited electrically evoked kneejointarthritis;completeFreund’sadjuvant-induced C-fiber responses of nociceptive dorsal horn neurons in inflammation) and neuropathic pain (Fundytus 2001; carrageenan-induced hind paw inflammation, whereas Karim et al. 2001; Neugebauer et al. 1999; Neugebauer mixed effects(inhibition andfacilitation)were observed 2001; Neugebauer 2002; Varney and Gereau 2002; in control rats. Similarly, intraspinal administration of a Zhang et al. 2002). The role of group I mGluRs in brief selective group II agonist (LY379268) inhibited central nociception and acute phases of pain remains unclear. sensitization of primate spinothalamic tract cells in Some studies suggested that the block of spinal group the capsaicin pain model, but had no effect on normal I mGluRs reduced noxious heat responses and the first transmission in non-sensitized neurons (Neugebauer phase of the formalin test whereas several other studies et al. 2000). A group III agonist (LAP4) inhibited the were unable to detect such effects (Fundytus 2001; responses of spinothalamic tract cells to brief noxious Neugebauer 2001; Varney and Gereau 2002). and innocuous mechanical cutaneous stimuli as well Electrophysiological studies of spinal dorsal horn neu- as capsaicin-induced central sensitization (Neugebauer rons, including spinothalamic tractcells, in anesthetized et al. 2000). These data suggest a dramatic change animals in vivo further emphasize the important role in the functional role of group II, rather than group of spinal group I, particularly mGluR1, in nociceptive III, mGluRs in central sensitization associated with transmission and pain-related central sensitization in prolonged pain. the capsaicin model of central sensitization and mustard oil-induced spinal hyperexcitability and in the References kaolin/carrageenan-induced knee joint arthritic pain model (Fundytus 2001; Neugebauer 2001; Neugebauer 1. Anwyl R (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res et al. 1999; Varney and Gereau 2002). The involvement Rev 29:83–120 and intrinsic activation of mGluR5 during brief and 2. Bhave G, Nadin BM, Brasier et al. (2003) Membrane topol- prolonged nociceptive processing in spinal neurons ogy of a metabotropic glutamate receptor. J Biol Chem remains to be investigated. 278:30294–30301 3. Bockaert J, Pin JP (1999) Molecular tinkering of G protein- coupled receptors: an evolutionary success. EMBO J 18:1723– Groups II and III mGluRs 1729 The roles of group II and group III mGluRs in spinal 4. Cartmell J, Schoepp DD (2000) Regulation of neurotransmit- nociceptive processing are less clear. Both group II ter release by metabotropic glutamate receptors. J Neurochem 75:889–907 mGluR2/3 and group IIImGluR4 and7,but not mGluR6 5. Chen J, Heinke B, Sandkuhler J (2000) Activation of group I and 8, are present in the spinal cord. Group III mGluRs metabotropic glutamate receptors induces long-term depression Metabotropic Glutamate Receptors in the Thalamus 1127

at sensory synapses in superficial spinal dorsal horn. Neurophar- Characteristics macology 39:2231–2243 6. De Blasi A, Conn PJ, Pin, J et al. (2001) Molecular determinants Eight metabotropic glutamate receptor subtypes of metabotropic glutamate receptor signaling. Trends Pharmacol (mGlu1–mGlu8) have been characterised to date. They Sci 22:114–120 can be placed into three Groups (I, II, III) on the basis of 7. Fundytus ME (2001) Glutamate receptors and nociception. Im- plications for the drug treatment of pain. CNS Drugs 15:29–58 their sequence homology, their pharmacological char- 8. Gasparini F, Kuhn R, Pin JP (2002) Allosteric modulators acteristics and the types of intracellular transduction of group I metabotropic glutamate receptors: novel subtype- cascade to which they may couple in in vitro expres- selective ligands and therapeutic perspectives. Curr Opin sion systems (Conn and Pin 1997). In such expression Pharmacol 2:43–49 9. Gerber G, Youn DH, Hsu CH et al. (2000) Spinal dorsal horn systems, Group I (mGlu1, mGlu5) receptors typically synaptic plasticity: involvement of group I metabotropic gluta- couple to postsynaptic inositol phosphate metabolism, mate receptors. Prog Brain Res 129:115–134 while Group II (mGlu2, mGlu3) and Group III (mGlu4, 10. Karim F, Wang CC, Gereau RW (2001) Metabotropic glutamate mGlu6–8) receptors may couple to an inhibitory cyclic- receptor subtypes 1 and 5 are activators of extracellular signal- regulated kinase signaling required for inflammatory pain in AMP cascade. All of these receptors can be activated mice. J Neurosci 21:3771–3779 by L-glutamate with a variety of affinities. This amino 11. Neugebauer V (2001) Metabotropic glutamate receptors: novel acid is assumed to be the endogenous ligand, but the targets for pain relief. Expert Rev Neurotherapeutics 1:207–224 receptors may also be activated by other endogenous 12. Neugebauer V (2002) Metabotropic glutamate receptors - important modulators of nociception and pain behavior. Pain 98:1–8 ligands (e.g. sulphur-containing amino acids such as 13. Neugebauer V,Chen PS, Willis WD (1999) Role of metabotropic L-homocysteic acid or dipeptides such as N-acetyl- glutamate receptor subtype mGluR1 in brief nociception and aspartyl-glutamate or NAAG). A variety of synthetic central sensitization of primate STT cells. J Neurophysiol agonists and antagonists have been developed, some 82:272–282 14. Neugebauer V, Chen P-S, Willis WD (2000) Groups II and III of which show selectivity for mGlu receptor groups or metabotropic glutamate receptors differentially modulate brief even subtypes (Table 1). and prolonged nociception in primate STT cells. J Neurophysiol The Group I receptors have been thought to predomi- 84:2998–3009 M 15. Park YK, Galik J, Ryu PD et al. (2004) Activation of presy- nantly mediate postsynaptic actions, whereas the Group naptic group I metabotropic glutamate receptors enhances gluta- II receptors and Group III receptors have been found to mate release in the rat spinal cord substantia gelatinosa. Neurosci have presynaptic actions, regulating transmitter release. Lett 361:220–224 It is however becoming evident that the situation is more 16. Schoepp DD, Jane DE, Monn JA (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neu- complex than this and that receptors of all three groups ropharmacology 38:1431–1476 can have pre-, post- or extra-synaptic actions (Conn and 17. Varney MA, Gereau RW (2002) Metabotropic glutamate receptor Pin 1997). The complexity introduced by the variety of involvement in models of acute and persistent pain: prospects glutamate receptor types is compounded by their non- for the development of novel analgesics. Current Drug Targets 1:215–225 uniform distribution within the brain and within the neu- 18. Zhang L, Lu Y, Chen Y et al. (2002) Group I Metabotropic glu- ropil, synapses and extra-synaptic areas. Within the tha- tamate receptor antagonists block secondary thermal hyperalge- lamus, the distribution of a considerable number of the sia in rats with knee joint inflammation. J Pharmacol Exp Ther various mGlu receptors has been described in some de- 300:149–156 tail (Martin et al. 1992; Petralia et al. 1996; Godwin et al. 1996; Liu et al. 1998; Mineff and Valtschanoff 1999; Neto et al. 2000; Tamaru et al. 2001). Metabotropic Glutamate Receptors in the Thalamus Group I Receptors

THOMAS E. SALT There is expression of the mRNA for the group I mGlu Institute of Ophthalmology, University College receptors(mGlu1 and mGlu5)in thethalamus(Martinet London, London, UK al. 1992; Abe et al. 1992), with both mGlu1 and mGlu5 [email protected] receptor-likeimmunoreactivitiesbeingfoundonthedis- tal dendrites of thalamocortical neurons opposed to Synonyms the corticothalamic axon terminals (Martin et al. 1992; Godwin et al. 1996; Liu et al. 1998) and also on the den- Metabotropic glutamate receptor; mGlu receptor; drites of local circuit interneurons pre-synaptic to tha- mGluR; G-Protein-coupled glutamate receptor; Thala- lamocortical neurons (Godwin et al. 1996). A particular mus, Metabotropic Glutamate Receptors focus has been the function of mGlu1 receptors, as these have been localised postsynaptically predominantlybe- Deﬁnition neath terminals of cortico-thalamic ﬁbres (Martin et al. Metabotropic glutamate (mGlu) receptors are gluta- 1992;Godwin etal. 1996). ActivationofmGlureceptors mate receptors that are coupled to intracellular second inthalamicrelayneuronescausesaslowdepolarisingre- messenger (G-protein) systems. sponse associated with an increase in membrane resis- 1128 Metabotropic Glutamate Receptors in the Thalamus

Metabotropic Glutamate Receptors in the Thalamus, Table 1 Metabotropic Glutamate Receptor Subtypes Group Receptor Transduction Agonists Antagonists Mechanism

subtype-selective group-selective subtype-selective group-selective

ImGlu1IP3 /Ca++cascade DHPG LY367385, 4CPG CPCOOEt

mGlu5 CHPG MPEP

II mGlu2 Inhibitory cAMP LY354740, CCG-1, LY341495

mGlu3 cascade NAAG APDC

III mGlu4 Inhibitory cAMP L-AP4, MAP4,

mGlu6 cascade L-SOP CPPG

mGlu7

mGlu8 DCPG

Abbreviations APDC, 2R,4R-4- aminopyrrolidine-2,4-decarboxylate; CCG-1, (2S,1’S,2’S)-2-(2-carboxycyclopropyl)glycine; CHPG, 2-chloro-5-hydroxyphenylglycine; CP- COOEt, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate; 4CPG, (S)-4-carboxyphenylglycine; CPPG, alpha-cyclopropyl-4-phosphonophenylglycine; DCPG, (S)-3,4-dicarboxyphenylglycine; DHPG, 3,5-dihydroxyphenylglycine; L-AP4, L-2-amino-4-phosphonobutyric acid; L-SOP, L-serine-O- phosphate; LY341495, 2S-2-amino-2 (1S,2S-2-carboxcyclopropyl-1−yl)-3-(xanth-9-yl)propanoic acid; LY354740, (+)-2-aminobicyclo [3.1.0]hexane- 2,6dicarboxylate; LY367385, (+)-2-methyl-4-carboxyphenylglycine; MAP4, (S)-2-amino-2-methyl-4-phosphonobutanoic acid; MPEP, 2-methyl-6- (phenylethynyl)-pyridine; NAAG, N-Acetyl-aspartyl-glutamate tance, as seen in many other parts of the brain, probably Group III Receptors due a reduction in a potassium conductance. This has Of the Group III receptors, only mGlu7-like immunore- been shown to be mediated specifically via mGlu1 reactivity has been demonstrated in the thalamus (Ki- ceptors, which can be synaptically activated by stimula- noshita et al. 1998). However, the mRNAs for mGlu4, tion of cortico-thalamic afferents (Turner and Salt 2000; mGlu7 and mGlu8 receptors are expressed throughout Hughes et al. 2002). A specific synaptic role for mGlu5 the thalamus-TRN-cortex network (Ohishi et al. 1995; receptors in the thalamus remains to be demonstrated, Saugstad et al. 1997; Neto et al. 2000). This suggests although these receptors do appear to be activated under that these receptors may be involved in the control of physiological conditions (Salt and Binns 2000). transmission at cortico-thalamic and TRN-thalamic Group II Receptors synapses. Consistent with this are electrophysiological data, which suggest that Group III (probably mGlu7) High levels of mRNA and protein for Group II recep- receptors mediate a presynaptic reduction of the cor- tors have been found in the thalamic reticular nucleus ticothalamic excitatory postsynaptic potential (Turner (TRN), and much of this may be attributable to mGlu3 and Salt 1999) and a presynaptic reduction of the TRN- receptors, some of which may be localised in glial cells mediated inhibition of VB neurone responses to sensory as well as neuronal bodies and dendrites (Petralia et al. stimuli in vivo and in vitro (Turner and Salt 2003). 1996; Neto et al. 2000; Tamaru et al. 2001). Intriguingly, it has been shown that activation of these receptors can Functional Considerations lead to an inhibition of TRN neurone activity (Cox There is little evidence to suggest that mGlu receptors and Sherman 1999). Ultrastructural information from are directly involved in ascending sensory transmission rodent ventrobasal thalamus (VB) suggests that Group to the thalamic relay nuclei; rather it seems that such fast II receptors are localised in glial processes, some of transmission is mediated via ionotropic glutamate re- which appear to be surrounding GABAergic terminals ceptors of the NMDA and AMPA variety (Salt and (Liu et al. 1998; Mineff and Valtschanoff 1999). More Eaton 1996). The characteristics of mGlu receptors are recently mGlu3 receptors have been found to be con- more suited to slow synaptic transmission or modulation centrated on GABAergic axons in VB arising from (Conn and Pin 1997) and the roles in thalamic function TRN (Tamaru et al. 2001). Thus Group II receptors that have been determined fit into this category. may modulate GABAergic transmission within VB, The cortico-thalamic projection has been the subject of a notion supported by the finding that activation of many studies. It has been speculated that the influence Group II receptors within VB results in a reduction of of the cortical input may operate via NMDA recep- TRN-originating inhibition onto relay cells (Turner and tors or mGlu receptors (Sherman and Guillery 2000), Salt 2003). largely because transmission via these receptor types Metabotropic Glutamate Receptors in the Thalamus 1129 would allow non-linear amplification of excitatory in- References puts mediated via, for example, AMPA receptors. 1. Abe T, Sugihara H, Nawa H et al. (1992) Molecular characteri- This is a particularly attractive hypothesis in the case of zation of a novel metabotropic glutamate receptor mGluR5 cou- mGlu1 receptors, as these are restricted to corticotha- pled to inositol phosphate/Ca2+ signal transduction. J Biol Chem lamic synapses and because NMDA-receptor mediated 267:13361–13368 2. Conn PJ, Pin JP (1997) Pharmacology and functions of responses have been shown to be modulated by acti- metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol vation of Group I (i.e. mGlu1 / mGlu5) receptors in 37:207–237 several brain areas. In the VB, activation of mGlu1 3. Cox CL, Sherman SM (1999) Glutamate Inhibits Thalamic Retic- receptors potentiates responses mediated either ular Neurons. J Neurosci 19:6694–6699 via 4. Godwin DW, Van Horn SC, Erisir A et al. (1996) Ultrastructural AMPA or NMDA receptors in vivo (Salt and Binns localization suggests that retinal and cortical inputs access dif- 2000). It is probable that this is due to the direct effects ferent metabotropic glutamate receptors in the lateral geniculate of mGlu1 activation on neuronal membrane potential nucleus. J Neurosci 16:8181–8192 5. Henderson Z and Salt TE (1988) The effects of N-acetyl- and resistance rather than a specific interaction at the aspartylglutamateanddistributionofN-acetyl-aspartylglutamate- receptor level, or that the potentiation that is seen is like immunoreactivity in the rat somatosensory thalamus. a combination of these factors (Salt and Binns 2000). Neurosci 25:899–906 Thus, although the isolated cortico-thalamic synaptic 6. Hughes SW, Cope DW, Blethyn KL, Crunelli V (2002) Cellular Mechanisms of the Slow (< 1 Hz) Oscillation in Thalamocortical potential which can be attributed to mGlu1 receptors Neurons in Vitro. Neuron 33:947–958 in vitro appears to be rather small, it would be able to 7. Kinoshita A, Shigemoto R, Ohishi H et al. (1998) Immunohis- exert a large influence on ionotropic receptor mediated tochemical localization of metabotropic glutamate receptors, responses, if the sensory stimulus was appropriate to mGluR7a and mGluR7b, in the central nervous system of the adult rat and mouse: a light and electron microscopic study. J recruit activity in the cortico-thalamic output. Condi- Comp Neurol 393:332–352 tions where this might come into play are, for example, 8. Kullmann DM (2000) Spillover and Synaptic Cross Talk Medi- during the processing of nociceptive information in the ated by Glutamate and GABA in the Mammalian Brain. Prog thalamus (Salt and Binns 2000). Brain Res 125:339–351 M 9. Liu XB, Munoz A, Jones EG (1998) Changes in subcellular The GABAergic inhibitory output from the TRN onto localization of metabotropic glutamate receptor subtypes dur- relay cells is a major contributor to the overall response ing postnatal development of mouse thalamus. J Comp Neurol profile of the relay cells, and thus the control of this 395:450–465 10. Martin LJ, Blackstone CD, Huganir RL et al. (1992) Cellular inhibition by mGlu receptors is potentially of great localization of a metabotropic glutamate receptor in rat brain. functional significance. The location of Group II re- Neuron 9:259–270 ceptors and the effects of their activation in this circuit 11. Mineff E, and Valtschanoff J (1999) Metabotropic Glutamate suggest they play a pivotal role in these mechanisms. Receptors 2 and 3 Expressed by Astrocytes in Rat Ventrobasal Thalamus. Neurosci Lett 270:95–98 All of these receptors are in locations removed from 12. Neto FL, Schadrack J, Berthele A et al. (2000) Differential dis- sites of synaptically released glutamate. Thus this raises tribution of metabotropic glutamate receptor subtype mRNAs in the possibility that these receptors are activated by glu- the thalamus of the rat. Brain Res 854:93–105 tamate which spills out of the conventional synaptic 13. Ohishi H, Akazawa C, Shigemoto R et al. (1995) Distributions of the mRNAs for L-2-amino-4-phosphonobutyrate-sensitive area, possibly under conditions of intense synaptic metabotropic glutamate receptors, mGluR4 and mGluR7, in the activity. This concept of “synaptic spillover” has been rat brain. J Comp Neurol 360:555–570 postulated on the basis of in vitro experiments from a 14. Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The number of non-thalamic brain areas (Kullmann 2000). metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neu- This raises the possibility that the Group II (and possi- rosci 71:949-976 bly Group III) receptors may be activated by glutamate 15. Salt TE, Binns KE (2000) Contributions of mGlu1 and mGlu5 via a synaptic spillover mechanism. This glutamate receptors to interactions with N-methyl-D-aspartate receptor- could be released from terminals of sensory or cor- mediated responses and nociceptive sensory responses of rat thalamic neurones. Neurosci 100:375–380 tical afferents or from astrocytes. This might occur 16. Salt TE, Eaton SA (1996) Functions of ionotropic and under conditions of intense synaptic activation, perhaps metabotropic glutamate receptors in sensory transmission during nociceptive processing or seizure activity. An in the mammalian thalamus. Prog Neurobiol 48:55–72 17. Saugstad JA, Kinzie JM, Shinohara MM et al. (1997) Cloning and intriguing further possibility is that mGlu3 receptors Expression of Rat Metabotropic Glutamate Receptor 8 Reveals could be activated by the endogenous mGlu3 agonist a Distinct Pharmacological Profile. Mol Pharmacol 51:119–125 NAAG, which is co-localised with GABA in TRN neu- 18. Sherman SM, Guillery RW (2000) Exploring the Thalamus. Aca- rones and within the neuropil within VB (Henderson demic Press, New York 19. Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribu- and Salt 1988). This raises the possibility that NAAG tion of Metabotropic Glutamate Receptor mGluR3 in the Mouse may be released from GABAergic TRN terminals so CNS: Differential Location Relative to Pre- and Postsynaptic as to down-regulate GABA release, thus reducing IPSP Sites. Neurosci 106:481-503 amplitude. Thus it may be that NAAG has a function as 20. Turner JP, Salt TE (1999) Group III metabotropic glutamate receptors control corticothalamic synaptic transmission in the rat a co-transmitter to regulate GABAergic transmission thalamus in vitro. J Physiol 519:481–491 from TRN to VB, possibly coming into play at higher 21. Turner JP, Salt TE (2000) Synaptic activation of the Group I stimulus frequencies. metabotropic glutamate receptor mGlu1 on the thalamocortical 1130 Metabotropic Receptor

neurones of the rat dorsal lateral geniculate nucleus in vitro. Neurosci 100:493–505 Methadone 22. Turner JP,Salt TE (2003) Group II and III metabotropic glutamate receptors and the control of the TRN input to rat thalamocortical Postoperative Pain, Methadone neurones in vitro. Neurosci 122:459–469

Method of Adjustments Metabotropic Receptor Definition Definition Apsychophysicalprocedureusedin adiscrimination(or A Metabotropic Receptor is a G-protein-coupledrecep- detection) experiment and in which the subjects adjust tor. The term reflects the fact that transmitter binding the value of the stimulus (e.g. by turning a dial) and sets results in the production of intracellular metabolites. it to apparent equality with a standard or reference stim- Metabotropic receptors that couple to G-proteins are ulus. Repeated applications of the procedure yields an a complex of three proteins. Transmitter binding to empirical distribution of stimulus intensities that is used the receptor results in a conformation change in the to estimate the just-noticeable-difference (or threshold). receptor, thereby activating the G-protein. One subunit Pain Evaluation, Psychophysical Methods of the G-protein may modulate ion channels, other sub- units may increase or decrease the activity of enzymes that produce intracellular messengers that modulate Method of Constant Stimuli the activity of kinases. Small molecule neurotransmitters such as glutamate, acetylcholine, and serotonin Apsychophysicalprocedureusedin adiscrimination(or activate metabotropic receptors as well as ionotropic detection) experiment, which consistsof repeatedly pre- receptors; mammalian peptides generally activate only senting the same set of stimuli (between 5 and 9 differ- metabotropic receptors. ent intensities each presented a large number of times) Amygdala, Pain Processing and Behavior in Animals in a random order throughout the experiment. The pro- GABA Mechanisms and Descending Inhibitory portion (p) of “yes” responses is recorded and graphed Mechanisms as a psychometric function of stimulus intensity. Criti- Metabotropic Glutamate Receptors in Spinal Noci- cal values (e.g. p=0.5) of the psychometric function are ceptive Processing then estimated from the data. Spinothalamic Tract Neurons, Peptidergic Input Pain Evaluation, Psychophysical Methods

Method of Limits Metalloproteases Definition Definition Apsychophysicalprocedureusedin adiscrimination(or Metalloproteases are peptide hydrolases using a metal detection)experiment,whichconsistsinvaryingoneach in the catalytic mechanism, and are implicated in many successive trial the intensity of the stimulus, in small as- inflammatory processes. cending or descending steps. At each step the subject Vascular Neuropathies reports whether the stimulus appears smaller or larger than the reference stimulus (or is perceived or not). The values of the stimulus at which the subject’s response shifts from one category to another is recorded and the Metastasis threshold is estimated by averaging these values. Pain Evaluation, Psychophysical Methods Definition Metastasis means the spread of cancer cells from the tis- Methotrexate sue of origin to distantorgans. Cancer cellscanbreak out oftheprimarytumor,penetrateintolymphaticandblood vessels, circulate through the bloodstream, and form a Definition newfocus(metastasize)withinnormaltissueselsewhere Methotrexate is a steroid sparing agent in cranial arteri- in the organism. tis. NSAIDs and Cancer Headache Due to Arteritis Microglia Activation 1131

Methyl-2-(2,6-Xylyloxy)-Ethylamine- Micro-Arousal Hydrochloride Deﬁnition Postoperative Pain, Mexiletine An increase in EEG and heart rate frequency with a possible rise in muscle tone. It should last more than 3 sec. but less than 10 seconds. The subject is unaware of such Methylprednisolone physiological activity. Orofacial Pain, Sleep Disturbance Deﬁnition Steroid drug. Whiplash Microdialysis

Definition Methysergide Microdialysis is a technique that allows the administration of drugs or sampling of substances in the extracellu- Serotonin antagonist. larfluidbymeansofasmalldialysisfiberofthetypeused Migraine, Preventive Therapy for renal dialysis. The semi-permeable dialysis membrane has pores of a certain size, and molecules smaller than these pores diffuse across the dialysis membrane Metopropol due to concentration gradients, either into the extracellular space or into the dialysate. The dialysis fluid is con- M Definition tinually pumped through the fiber. Microdialysis allows minimal invasive insights into tissue metabolism. Drugs Beta-blocker. can be dissolved in the dialysate for tissue administra- Migraine, Preventive Therapy tion, or samples of the dialysate can be taken for analysis of extracellular fluid concentrations of substances. Amygdala, Pain Processing and Behavior in Animals Mexiletine/Mexitil GABA Mechanisms and Descending Inhibitory Mechanisms Postoperative Pain, Mexiletine Spinal Dorsal Horn Pathways, Dorsal Column (Vis- ceral) Spinothalamic Tract Neurons, Role of Nitric Oxide Sympathetically maintained Pain and Inflammation, mGLu Receptors/mGluRs Human Experimentation Metabotropic Glutamate Receptors Metabotropic Glutamate Receptors in the Thalamus Microglia

MH,HTM,PMN Deﬁnition Microglia are considered to be theresidentimmune cells Deﬁnition of the CNS. These cells release classical immune pro- Nociceptorsareoftendesignatedasmechanoheat(MH), teins, respond to immunogenic stimuli, and express cell high threshold mechanoreceptive (HTM), or polymodal surface receptorscharacteristic ofperipheralphagocytic (PM). These designations refer to their capacity to re- cells. Blocking microglial activation inhibits the onset spond to mechanical, thermal or chemical stimuli. The of exaggerated pain. designation HTM implies that the nociceptor responds Cord Glial Activation only to mechanical stimuli. The designation MH, im- pliesthatthenociceptorrespondstobothmechanicaland heat stimuli. The designation PMN, implies that the nociceptor responds to mechanical thermal and at least one Microglia Activation kind of chemical stimulus (e.g. bradykinin). Nociceptors in the Orofacial Region (Skin/Mucosa) Cord Glial Activation 1132 Microinjection

terminal endbulbs, and there is usually aborted sprout- Microinjection ing. If these regenerative sprouts are not able to elon- gate they often form a tangled mass at the nerve end. If Deﬁnition only a part of the cross-section of the nerve is cut, the Microinjection is a common technique in behavioral cutaxonsformaneuroma-in-continuityadjacenttotheir neuroscience in which micro- or nanoliter amounts of intact neighbors. Transection of small groups of axons a liquid is directly infused into a speciﬁc brain region. scattered throughout a nerve trunk, or of tiny nerve fas- Cingulate Cortex, Nociceptive Processing, Behav- cicles or tributary yields microneuromas. ioral Studies in Animals Neuroma Pain Peripheral Neuropathic Pain

Microiontophoresis Microstimulation Definition Definition Microiontophoresis is a technique for releasing active agents near a neuron from which recordings are made. Low current stimulation (μA) through a small diameter A multibarreled array of micropipettes is generally electrode, either intraoperatively or during experiments. used. The central barrel records the activity of a neuron, Central Pain, Human Studies of Physiology whereas the other barrels are filled with solutions that contain agonist or antagonist drugs or other substances. The dissolved agents are usually charged, and so they Microsurgical DREZotomy can be released from the micropipette by passing a current of the appropriate sign through the micropipette. A BrachialPlexusAvulsionandDorsalRootEntryZone current of the opposite sign is generally used to restrain DREZ Procedures the agent when its release is not desired. GABA Mechanisms and Descending Inhibitory Mechanisms Microswitch

Definition Microneurography A microswitch is a very small switch that acts by the and Intraneural Microstimulation movement of a small lever and is sensitive to minute mo- tions. Definition Assessment of Pain Behaviors Microneurography is a sophisticated neurophysiologi- caltechnique for recording electricalactivityfrom anin- tact peripheral nerve using a sharp tungsten microelec- Microvascular Decompression trode inserted into the nerve percutaneously. It allows in vivo action potential recording (single or multifiber- Synonyms recordings) from sympathetic efferent and nociceptive MVD afferent neurons in awake human subjects. Mechano-Insensitive C-Fibres, Biophysics Definition Nociceptors, Action Potentials and Post-Firing Ex- citability Changes Neurosurgical procedures to relieve cranial nerve com- Painless Neuropathies pressionbyintracranialarteriesorveinsasdescribedun- Polymodal Nociceptors, Heat Transduction der ’vascular compression syndromes’. The main indication is for pain relief in cranial nerve neuralgias. Sympathetically maintained Pain and Inflammation, Human Experimentation Pain Paroxysms Tic and Cranial Neuralgias Trigeminal, Glossopharyngeal, and Geniculate Neu- ralgias Microneuroma

Deﬁnition Microwaves A neuroma is the proximal cut end of a peripheral nerve branch or nerve fascicle. Severed axons form swollen Therapeutic Heat, Microwaves and Cold Midline Myelotomy 1133

Characteristics Midazolam Background The spinal cord is commonly characterized by both its Definition segmental organization, and the long tracts that link Midazolam is a benzodiazepine drug with an imidazole the segments to each other and to the brain. Surgical structure, commonly used as an anxiolytic, amnesic, interventions on the spinal cord similarly can be char- and sedative/hypnotic. Spinal administration has re- acterized by their effects on segmental components, cently been advocated in the management of complex long tracts, or both. The distinction is important. If the pain syndromes. goal is to interrupt a long ascending tract, then a single Postoperative Pain, Appropriate Management lesion should suffice. If the goal is an intervention at the segmental level, then typically several spinal levels must be accessed, and an incision made in the spinal cord over several segments. Myelotomy – Origin from Procedures Directed Midline Commissural Myelotomy at Segmental Structures, not Long Tracts The original myelotomy procedures were directed at Definition the segments of the spinal cord for treatment of pain or spasticity. The long spinal cord incision distin- Dividing the spinal cord longitudinally in the midline guished myelotomy from “cordotomy”, where a single to ablate nerve fibers at the point where they cross the rostrocaudal level lesion is made, which interrupts spinal cord. longitudinal pathways. The distinction between myelo- Cancer Pain Management, Neurosurgical Interven- tomy and cordotomy has blurred over time. It is now M tions fairly safe to say that while the anterolateral cordotomy procedure continues to be understood as interrupting ascending tracts related to the conduction of pain, only the Bischoff myelotomy (Bischof 1951; Bischof 1967), still occasionally used to treat painful spasticity, con- Midline Epidural Steroid Injection tinues to be understood as a procedure directed at the segmental level, and therefore requiring a long incision Epidural Steroid Injections for Chronic Back Pain into thespinalcord. Theoriginalmyelotomy procedures used to treat pain have mutated into much more concise procedures, and are now understood to be effective through their interruption of ascending pain tracts near the midline of the dorsal columns (Nauta et al. 2002). Midline Myelotomy Due to their history, however, these procedures continue to be described as myelotomies, although they no H. J. W. NAUTA longer require a long incision into the spinal cord. University of Texas Medical Branch, Galveston, TX, USA Impetus to Develop Myelotomy and Original Concepts [email protected] of Benefit Anterolateral cordotomy for interruption of the long tractsystemrelatedtopainhasevolvedintoanele- Synonyms gant fluoroscopic-guided percutaneous procedure at Longitudinal Myelotomy; mediolongitudinal myelo- the C1-C2 level, which is effective for all levels below tomy; dorsal longitudinal myelotomy. Related terms the lesion. The principal disadvantage of the antero- include commissural myelotomy; Punctate Midline lateral cordotomy was the unavoidable concomitant Myelotomy; extralemniscal myelotomy; Bischof interruption of descending pathways in the anterolat- Myelotomy; Pourpre Myelotomy; myelotomy eral quadrant related to respiration and bladder control. The potential for the loss of automatic respiration (On- dine’s curse) and developmentof incontinence required Definition special strategies, if bilateral anterolateral cordotomy Midlinemyelotomyreferstosurgicalproceduresthatin- was contemplated for the all too common bilateral, volve an incision in the dorsal midline of the spinal cord. midline or visceral pain. These problems with bilateral More recently, the term has come to include derived pro- cordotomy led to the proposal in 1926, by the neu- cedures that continue to include an intervention through ropathologist Greenfield, that a longitudinal midline the dorsal midline of the spinal cord. incision of the spinal cord could interrupt the crossing 1134 Midline Myelotomy

fibers of the spinothalamic pathway bilaterally, near cord suggested the presence of a synapse in the path- their segmental level of origin and before these fibers way (Al Chaer et al. 1996a; Al Chaer et al. 1996b). assemble into a long ascending tract. The longitudinal Retrograde tracer studies, depositing a marker in the midline myelotomy required definition of segmental nucleus gracilis (Christensen et al. 1996), revealed the levels of pain origin, and a large enough exposure to likely cell bodies of origin of the pathway to reside incise the cord deeply over enough levels to bracket the at the medial base of the dorsal horn just above the levels of pain origin. central canal, an area known from earlier experiments to receive primary visceral fiber input. Injection of Clinical Observation at Odds with the Original Concept anterograde tracers into the same cell territory (Wang The long midline myelotomy for pain was first per- et al. 1999) resulted in fiber labeling ascending near the formed by Armour in 1926 (Armour 1927), and while dorsal column midline, to end in the medial part of the there were several early advocates, the procedure as nucleus gracilis. Further studies by this group defined originally conceived required a big operation which a somatotopic organization within the postsynaptic limited its wider acceptance. However, it became clear dorsal column pathway, wherein the fibers originating that the procedure was effective, even when a short in the lumbosacral cord ascend near the midline of the myelotomy was performed at a level well above the dorsal columns, while fibers originating in the thoracic segmental origin of the treated pain, and that pain relief cord terminate in the lateral part of nucleus gracilis and extended to levels caudal to the zone of decreased pin adjacent medial parts of nucleus cuneatus (Wang et al. sensation. Hirshberg et al. (1996) and Hitchcock (1974) 1999; Willis et al. 1999). originally attempting to treat neck and upper extremity pain, made lesions of only limited rostro-caudal extent Subsequent Clinical Observations near the midline at C1, and observed relief of pain with Once the basis for the benefit from midline myelotomy analgesia extending into the legs. Such observations was better understood, Nauta et al. (1997, 2000) made suggested that the midline myelotomy procedure was very small transverse (rather than sagittal longitudinal) interrupting an ascending pain conducting system, midline incisions in the dorsal columns, well above perhaps a multisynaptic pathway separate from the the segmental level of pain origin, to treat medically spinothalamic tract, as proposed by Hitchcock (Hitch- intractable pelvic pain. The incisions, later crush, across cock 1969; Hitchcock 1974) and others (Davis et al. the midline of the dorsal columns extended only 1mm 1929; Noordenbos 1959). Surprisingly, the midline to either side of the exact midline, and only to a depth myelotomy procedure remained effective even if a of 5 mm. The effective lesion was so small that it was short midline incision was made above and not deep dubbed “punctatemyelotomy”sincetheoriginallesions enough to reach either the commissural fiber systems were made with what amounted to a puncture across or the central grey matter (Hirshberg et al. 1996). the spinal cord midline with a 16 gauge hypodermic needle. Pain relief from these tiny lesions confirmed Laboratory Evidence of a Dorsal Column Pain Pathway that an ascending pathway in the dorsal column was The literature concerning myelotomy for pain shows being interrupted. The lesions were effective without an interesting progression, with late recognition that reaching the commissures or the central grey, demon- there is a pain pathway ascending near the midline strating that these latter structures were not essential of the dorsal columns (Hirshberg et al. 1996; Nauta to the benefit. Surprisingly, postoperative neurological et al. 2002). The old concept is that there are two examination in these patients by an independent neu- pathways carrying somatic sensation to the brain: the rologist failed to reveal any new deficit, emphasizing spinothalamic system described as conducting crude or an important distinction between the consequences “protopathic” sensations such as pain and temperature, of small midline lesions of the dorsal columns and the dorsal column pathway conducting the “epicritic” tabes dorsalis, in which a pathologic process effects sensations, such as vibration and proprioception. Re- the dorsal root ganglia in a widespread manner and recent evidence demonstrates that the dorsal columns do sults not only in visible changes in the dorsal columns, contain a post-synaptic pain pathway (Rustioni et al. but less visible changes in other sensory pathways 1979; Uddenberg 1968; Willis and Coggeshall 1991), as well. While Nauta et al. (1997, 2000) treated only but its role in somatic pain conduction was considered pelvic origin visceral pain, more recent reports (Kim minor. Berkley and Hubscher (1995) gave evidence and Kwon 2000) suggest that more rostral visceral that neurons in the dorsal column nuclei can respond origin pain related to gastric cancer can also be treated to innocuous and noxious stimulation of both pelvic effectively by punctate midline myelotomy at an up- viscera and skin. Finally, Al Chaer and others (1996b) per thoracic level. Since it is now understood that the demonstrated that the post synaptic dorsal column pain benefit depends on the interruption of an ascending pathway predominated in the conduction of visceral pathway, there are good theoretical reasons to believe pain. Microdialysis fiber infusion of neurotransmitters that it would be worthwhile to revive the percutaneous or antagonists (morphine or CNQX) into the spinal procedure described by Hitchcock (1970, 1974) and Midline Myelotomy 1135

Schvarcz (1984), only modified to emphasize the me- the lateral funiculus containing whatever corticospinal dial dorsal columns rather than the subjacent central fibers may still be functional. grey. Clearly the term “extralemniscal myelotomy” Postsynaptic Dorsal Column Neurons, Responses to used by Schvarcz (Kanpolat 2002) would no longer Visceral Input apply to such an operation, because the dorsal columns Spinal Dorsal Horn Pathways, Dorsal Column (Vis- are well known to contribute to signaling within the ceral) medial lemniscus. References The Bischof myelotomy and its variants can be used to treat severe, medically intractable, often painful, lower 1. Al Chaer ED, Lawand NB, Westlund KN et al. (1996a) Pelvic Visceral Input into the Nucleus Gracilis is Largely Mediated limbspasticity,usuallyinquadri-orparaplegicorparetic by the Postsynaptic Dorsal Column Pathway. J Neurophysiol patients (Livshits et al. 2002; Putty and Shapiro 1991). 76:2675–2690 The goal of the procedure is to interrupt the segmental 2. Al Chaer ED, Lawand NB, Westlund KN et al. (1996b) Visceral reflex arcs underlying spasticity that pass between the Nociceptive Input into the Ventral Posterolateral Nucleus of the Thalamus: A New Function for the Dorsal Column Pathway. J dorsal horn and the motor neurons in the ventral horn. Neurophysiol 76:2661–2674 The goal is also to preserve as much residual function as 3. Armour D (1927) Surgery of the Spinal Cord. Lancet 2:691 possible and, above all, the anterior horn cells and their 4. Berkley KJ, Hubscher CH (1995) Are There Separate Cen- continuitywiththemusclessothatatrophyisminimized, tral Nervous System Pathways for Touch and Pain? Nat Med 1:766–773 and padding over boneyprominencesmaintainedto pro- 5. Bischof W (1951) Die Longitudinale Myelotomie. Zentralbl tectagainstthe developmentof pressure sores. Thelatter Neurochir 11:79–88 can be a significant problem following ventral root sec- 6. Bischof W (1967) Zur Dorsalen Longitudinalen Myelotomie. tion or neurectomy. The myelotomy method also offers Zentralbl Neurochir 28:123–126 7. Christensen MD, Willis WD, Westlund KN (1996) Anatomical an advantage over simple dorsal rhizotomy where re- Evidence for Cells of Origin of a Postsynaptic Dorsal Column currence of spasticity is more common. Since the avail- Visceral Pathway: Sacral Spinal Cord Cells Innervating the Me- abilityofintrathecalBaclofeninfusionpumps(Pennand dial Nucleus Gracilis. Society for Neuroscience Abstract 22:109 M 8. Davis L, Hart JT, Crain RC (1929) The Pathway for Visceral Kroin 1987), the procedure is performed less frequently, Afferent Impulses within the Spinal Cord. II. Experimental Di- but still remains a reasonable option for cases where se- latation of the Biliary Ducts. Surg Gynecol Obstet 48:647–651 vere problems with the pump are experienced or antic- 9. Hirshberg RM, Al Chaer ED, Lawand NB et al. (1996) Is There ipated. a Pathway in the Posterior Funiculus that Signals Visceral Pain? Pain 67:291–305 Since the Bischof myelotomy is directed at the segmen- 10. Hitchcock E (1969) Stereotaxic Spinal Surgery. A Preliminary tal level, there is no alternative to an exposure of the Report. J Neurosurg 31:386–392 spinal cord by laminectomy (typically, vertebral levels 11. Hitchcock E (1970) Stereotactic Cervical Myelotomy. J Neurol T10-L1) to gain access to those levels determined pre- Neurosurg Psychiatry 33:224230 12. Hitchcock E (1974) Stereotactic Myelotomy. Proc R Soc Med operatively to give rise to the worst spasticity (typically 67:771–772 T12-S1). The required spinal cord incision is made in 13. Kanpolat Y (2002) Percutaneous Stereotactic Pain Procedures: the longitudinal plane, perpendicular to the midsagittal Percutaneous Cordotomy, Extralemniscal Myelotomy, Trigemi- plane. This plane passes through the central canal and nal Tractotomy-Nucleotomy. In: Burchiel KJ (ed) Surgical Man- agement of Pain. Thieme, New York, pp 745–762 dentate ligament of either side, thus filleting the spinal 14. Kim YS, Kwon SJ (2000) High Thoracic Midline Dorsal Column cord into a dorsal and ventral half. The incision along Myelotomy for Severe Visceral Pain due to Advanced Stomach this plane was originally described from the lateral Cancer. Neurosurg 46:85–90 aspect of the cord (Bischof 1951) on either side, and 15. Livshits A, Rappaport ZH, Livshits V et al. (2002) Surgical Treat- ment of Painful Spasticity after Spinal Cord Injury. Spinal Cord was typically performed with an angled triangular oph- 40:161–166 thalmology knife inserted just posterior to the dentate 16. Nauta HJ, Hewitt E, Westlund KN et al. (1997) Surgical Inter- ligament and directed towards the central canal. Great ruption of a Midline Dorsal Column Visceral Pain Pathway. Case Report and Review of the Literature. J Neurosurg 86:538–542 care is required to minimize injury to the spinal cord 17. Nauta HJ, Soukup VM, Fabian RH et al. (2000) Punctate Midline vasculature. Pourpre (Pourpre 1960), who proposed a Myelotomy for the Relief of Visceral Cancer Pain. J Neurosurg Myelotomy en croix, in which the cord is entirely bi- 92:125–130 sected into a rightand lefthalf. (Bischof 1967), modified 18. Nauta HJW, Westlund KN, Willis WD (2002) Midline Myelo- tomy. In: Burchiel KJ (ed) Surgical Management of Pain. Thieme, his original lateral approach making an upside down New York, pp 714–731 “T” incision instead, beginning with a long myelotomy 19. Noordenbos W (1959) Pain: Problems Pertaining to the Trans- in the midsagittal plane to a depth reaching the center of mission of Nerve Impulses Which Give Rise to Pain. Elsevier, the cord but sparing the anterior white commissure. An Amsterdam 20. Penn RD, Kroin JS (1987) Long-Term Intrathecal Baclofen In- angled triangular ophthalmology knife is then passed fusion for Treatment of Spasticity. J Neurosurg 66:181–185 laterally along the depth of the midline incision aimed 21. Pourpre MH (1960) Traitement Neuro-Chirurgical des Contrac- at the pia just above the dentate ligament of either side, tures chez les Paraplegiques Posttraumatiques. Neurochirurgie thereby separating the dorsal horn from the ventral horn 6:229–236 22. Putty TK, Shapiro SA (1991) Efficacy of Dorsal Longitudinal of each side. The lateral limbs of this myelotomy are Myelotomy in Treating Spinal Spasticity: A Review of 20 Cases. intended to pass through the grey matter, but not far into J Neurosurg 75:397–401 1136 Migraine

23. Rustioni A, Hayes NL, O’Neill S (1979) Dorsal Column Nuclei Definitions and Ascending Spinal Afferents in Macaques. Brain 102:95–125 24. Schvarcz JR (1984) Stereotactic High Cervical Extralemniscal There are many paroxysmal disorders of childhood Myelotomy for Pelvic Cancer Pain. Acta Neurochir 33:431–435 that have been associated with migraine. The link to 25. Uddenberg N (1968) Functional Organization of Long, Second- migraine is very strong for some of these childhood syn- Order Afferents in the Dorsal Funiculus. Exp Brain Res 4:377–382 dromes, and more tenuous for others. The International 26. Wang CC, Willis WD, Westlund KN (1999) Ascending Projec- Headache Society (The International Classification of tions from the Area around the Spinal Cord Central Canal: A Headache Disorders 2004) considers the following to Phaseolus Vulgaris Leucoagglutinin Study in Rats. J Comp Neu- be linked to migraine: rol 415:341–367 27. Willis WD, Coggeshall RE (1991) Sensory Mechanisms of the • Abdominal migraine Spinal Cord. Plenum Press, New York • Cyclic vomiting syndrome 28. Willis WD, Al Chaer ED, Quast MJ et al. (1999) A Visceral Pain Pathway in the Dorsal Column of the Spinal Cord. Proc • Benign paroxysmal vertigo Natl Acad Sci USA 96:7675–7679 • Alternating hemiplegia of childhood • Familial hemiplegic migraine Benign paroxysmal torticollis is probably associated Migraine with migraine, based on genetic links. Ophthalmo- plegic migraine, originally considered to be linked to Definition migraine, is probably not actually a migraine variant. Other disorders probably represent unusual auras of Migraine is an common, episodic neurovascular migraine rather than separate entities. These include headache disorder characterized by unilateral pul- acute confusional migraine, basilar-type migraine sating moderate to severe headache, typically lasting 4 and Alice in Wonderland syndrome. to 72 hours, of throbbing quality and with associated symptoms of light and sound sensitivity, nausea and Characteristics vomiting, phono-and/or photophobia. The headache Migraine with or without aura may differ slightly be- may be preceded by visual disturbances (aura). tween children and adults. The diagnostic criteria pro- CalcitoninGene-RelatedPeptideandMigraineHead- posed by the International Classification of Headache aches (IHS)DisordersIIforchildrenlessthan15yearsrequires Human Thalamic Response to Experimental Pain headaches of 1 to 48 hours in duration instead of the 4 (Neuroimaging) to 72 hours in individuals greater than 15 years of age. Migraine, Preventive Therapy The remainder of the criteria are similar to the adult di- New Daily Persistent Headache agnostic criteria, including at least five attacks with either photophobia and phonophobia, nausea or vomiting and two symptoms out of unilateral pain, throbbing or Migraine Accompagnee pulsatile pain, moderate or severe pain intensity or exacerbation by routine activity (Tab. 1). Clinical Migraine with Aura There are features of headache in children that are not specifically recognized by the IHS classification, but are commonly noted in adolescents and children (Table 2). The quality of the pain may be described as constant or Migraine Aphasic squeezing instead of throbbing. Children also are more likely to report bilateral, bifrontal or a nondescript lo- Clinical Migraine with Aura cation rather than unilateral pain. Adults who have migraine with aura have onset and resolution of their aura before the onset of head pain. When aura occurs in children, it may also overlap with the actual headache in on- Migraine, Childhood Syndromes set. Aurashouldresolvebeforetheheadachephaseends. ERIC M. PEARLMAN The onset of the head pain may be quite dramatic in chil- Pediatric Education, Mercer University School of dren, with maximal pain achieved within 15 minutes. Medicine, Savannah, GA, USA Pain also may resolve fairly quickly, i.e. in 2–4 hours, [email protected] and may require just a short period of sleep to achieve resolution. Synonyms Abdominal Migraine Childhood Migraine; Pediatric Migraine; Periodic Dis- Abdominal migraine is an idiopathic disorder char- ordersof Childhood thatare Precursorsto Migraine;Mi- acterized by discreet episodes of abdominal pain, is graine Variants of Childhood poorly localized, is moderate to severe in intensity Migraine, Childhood Syndromes 1137

Migraine, Childhood Syndromes, Table 1 Classiﬁcation of adolescent and pediatric migraine with and without aura (The International Classiﬁcation of Headache Disorders 2004) Pediatric Migraine without Aura Pediatric Migraine with Aura

A. At least 5 distinct attacks E. Fulﬁlls criteria for migraine without aura

B. Headache attack lasting 1–48 hours F. At least 3 of the following: 1. One or more fully reversible aura symptoms indicating focal cortical and/or C. Headache has at least 2 of the following: brainstem dysfunction 1. Bilateral location (frontal/temporal) or unilateral location 2. At least one aura developing gradually over more than 4 minutes or two 2. Pulsating quality or more symptoms occurring in succession 3. Moderate to severe intensity 3. No aura lasting more than 60 minutes 4. Aggravation by routine physical activity 4. Headache follows in less than 60 minutes D. During headache, at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and/or phonophobia

Migraine, Childhood Syndromes, Table 2 Differentiating features in childhood vs. adult migraine

Duration 1 hour to 48 hours 4 hours to 72 hours

Quality May or not be described as throbbing Throbbing/pulsatile

Location Unilateral, bilateral, whole head Unilateral; bilateral less likely

Aura May overlap with head pain Resolves prior to head pain

Resolution Resolves with rest or brief sleep Resolves with longer sleep

Associated Features Nausea/vomiting, photophobia or phonophobia – may be Nausea/vomiting, photophobia, phonophobia – necessary M less prominent for diagnosis and lasts from 1 to 72 hours. These episodes are often 5.2 years (Li and Balint 2000). The duration of attacks associated with anorexia, nausea, vomiting and pallor. is usually 2–3 years and is associated with significant Sometimes headache, photophobia and phonophobia morbidity. Children with cyclic vomiting syndrome accompany migraine episodes. Eight percent of school miss on average 20 days of school each year, and more children between 5–15 years reported recurrent ab- than 50% will require hospitalization for rehydration. dominal pain and 4.1% reported episodes that fulfilled Almost half of the children with a diagnosis of cycli- the criteria for the diagnosis of abdominal migraine. cal vomiting will go on to develop migraine later in Abdominal migraine affects both boys and girls equally life. with a peak age of onset at 10 years. Affected chil- Bothcyclicvomitingsyndromeandabdominalmigraine dren are otherwise normal between attacks. Often, have a periodicity to attacks, so that many families can children undergo extensive gastrointestinal evalua- predict when the next attack might occur. Attacks can be tions before the diagnosis of abdominal migraine is triggered by many of the same triggers as migraine, for considered. Individual attacks will ultimately resolve example, infection, certain foods, menstruation, sleep spontaneously and the syndrome can last from months changes, physical exertion and psychological stress. to years before abating. In these children, there is a strong family history of migraine and individuals who Benign Paroxysmal Vertigo suffer from abdominal migraine are more likely to Benign paroxysmal vertigo is another paroxysmal dis- develop migraine as adults than the general popula- order linked to migraine. It is characterized by attacks tion. of vertigo, dizziness or unsteadiness lasting minutes to hours. These attacks occur in toddlers or preschoolers Cyclic Vomiting Syndrome and are associated with nystagmus, irritability, pallor, Cyclic vomiting syndrome consists of stereotypical at- nausea and vomiting. Children will describe an unreal tacks of intense nausea and vomiting lasting from 1 hour sense of movement. Younger children will often refuse to 5 days. Vomiting can be quite dramatic, occurring at to walk, sit down or cling to a parent until the episode least 4 times in 1 hour. It can lead to significant dehydra- subsides. Attacks are usually brief and do not require tion and children often require intravenous rehydration. any treatment. The key in distinguishing these attacks Associated features include lethargy, pallor, headache, from seizures or metabolic disturbances is the sparing photophobia, phonophobia, vertigo, diarrhea, excess of consciousness. Attacks often resolve with sleep and salivation and fever. It is equally distributed between can occur in clusters. As with the other paroxysmal dis- males and females and has a mean age of onset of orders, individuals often go on to develop migraine. 1138 Migraine Epidemiology

Alternating Hemiplegia of Childhood Benign Paroxysmal Torticollis Alternating hemiplegia of childhood is another rare, Benign paroxysmal torticollis is an uncommon disorder perplexing paroxysmal disorder of childhood with a re- occurringininfants.Thissyndromeconsistsofrecurrent centlyidentifiedgeneticlinktomigraine.Thissyndrome attacks of head tilt, truncal ataxia and occasionally vom- consists of repeated, frequent attacks of hemiparesis, iting.Theattackslastfromseveralhourstodays.Attacks monoparesis or diparesis usually beginning before may be associated with some irritability but no alter- 18 months of age. Episodes can last from hours to days ationinconsciousness.Thedifferentialdiagnosisforthis and may include dystonia or athetosis along with the conditionincludescongenitaltorticollis,disordersofthe weakness, which can be on either side of the body or craniocervical junction, intracranial abnormalities, es- shift from side to side during an attack. There also can be peciallyintheposteriorfossaandmetabolicdisorders.A bulbar dysfunction leading to swallowing and respira- completely normal interictal examination and repeated tory difficulties, which may result in respiratory failure. pattern of attacks is reassuring, but further diagnostic All these features disappear during sleep. Attacks may evaluations are certainly appropriate. A strong family increase in frequency, plateau and eventually decrease history of migraine and tendency to develop migraine in frequency, often resolving after 5–7 years. The syn- later in life suggested a link between benign paroxysmal drome may occur in the setting of mild developmental torticollisandmigraine.Recently,ageneticlinkhasbeen delays and can rarely be associated with developmental suggested. Giffin and colleagues have found mutations regression. The exact etiology is unknown but inborn in the CACNA1A gene in 4 cases of benign paroxysmal errors of metabolism, mitochondrial dysfunction and torticollis. Mutations in this P/Q-type calcium channel channelopathy have all been suggested. Recently, a gene have been linked to familial hemiplegic migraine, genetic link with familial hemiplegic migraine has been a rare migraine phenotype (Giffin et al. 2002). identified. In a family with alternating hemiplegia of childhood; affected individuals had a mutation in the References ATP1A2 gene, which is an ATP-dependent Na/K 1. Abu-Arafeh I, Russell G (1995) Prevalence and clinical fea- pump (Bassi et al. 2004). Interestingly, mutations in tures of abdominal migraine compared with those of migraine this gene are also associated with familial hemiplegic headache. Archives of Disease in Childhood 72:413–417 2. Bassi MT, Bresolin N, Tonelli A et al. (2004) A novel mutation migraine. in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet 41:621–628 3. Ducros A, Denier C, Joutel A et al. (2001) The clinical spectrum Familial Hemiplegic Migraine of familial hemiplegic migraine associated with mutations in a Familial hemiplegic migraine is a rare autosomal dom- neuronal calcium channel. N Engl J Med 345:17–24 4. Giffin NJ, Benton S, Goadsby PJ (2002) Benign paroxysmal tor- inant disorder characterized by an aura that has more ticollis of infancy: four new cases and linkage to CACNA1A stroke-like qualities than typical aura. The aura con- mutation. Dev Med Child Neurol 44:490–493 sists of motor weakness, usually unilateral, along with 5. Kors EE, Haan J, Giffen NJ et al. (2003) Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a other neurological changes. These include positive description of 5 families with hemiplegic migraine. Arch Neu- visual changes (e.g. scintillating lights, colors or lines) rol 60:684–688 or vision loss, sensory changes (e.g. pins and nee- 6. Li BU, Balint JP (2000) Cyclic vomiting syndrome: evolution in dles sensation or numbness) or speech difficulties. our understanding of a brain-gut disorder. Adv Pediatr 47:117–60 7. Ophoff RA, Terwindt GM, Vergouwe MN et al. (1997) Familial The aura develops gradually, lasts between 5 minutes hemiplegic migraine: involvement of a calcium neuronal channel. and 24 hours and may or may not be associated with Neurologia 12:31–37 headache fulfilling the criteria for migraine. Identifi- 8. Proceedings of the 2nd International Scientific Symposium on cation of a first or second degree relative with similar Cyclic Vomiting Syndrome (1999) Dig Dis Sci 44:1S–119S 9. The International Classification of Headache Disorders: 2nd edn attacks completes the diagnostic criteria. While there is (2004) Cephalalgia 24:9–160 no diagnostic testing for familial hemiplegic migraine, 10. Thomsen L, Eriksen M, Roemer S et al. (2002) A population- specific causative gene mutations have been identified. based study of familial hemiplegic migraine suggests revised di- A missense mutation in P/Q type calcium channel agnostic criteria. Brain 125:1379–1391 gene (CACNA1A) on chromosome 19p13 is responsible for the disorder in about 50% of the families (Kors et al. 2003). Mutations in this gene are also responsible for acetazolamide responsive episodic ataxia and be- Migraine Epidemiology nign paroxysmal torticollis (Ducros et al. 2001). Other 1 2 families with familial hemiplegic migraine have been RICHARD B. LIPTON ,MARCELO E. BIGAL identified with mutations in the ATP1A2 gene, which is 1Departments of Neurology, Epidemiology and an ATP-dependent Na/K pump found on chromosome Population Health, Albert Einstein College of Medicine 1q31. This suggests that there may be multiple mech- and Montefiore Headache Unit, Bronx, NY, USA anisms for the neuronal instability that leads to these 2Department of Neurology, Albert Einstein College of unusual auras. Medicine, The New England Center for Headache, Migraine Epidemiology 1139

Stamford, CT, and Montefiore Headache Unit, Bronx, reported above (Stang et al. 1992). A second study NY, NY, USA using a linked medical records system showed a lower [email protected] incidence (probably because many people with migraine do not consult doctors or receive a medical Definition diagnosis) (Breslau et al. 1994). In this study, the av- Migraine is a prevalent under-diagnosed and under- erage annual incidence rate per 1,000 person-years treated medical disorder, associated with a severe was 3.4 (4.8 in women and 1.9 in men). In women, impact on the quality of life of the sufferers and their incidence rates were low at the extremes of age and families as well as an enormous economic impact on higher among those aged between 10 and 49 years, society. This essay reviews the epidemiology and bur- with a striking peak at the age of 20 to 29 years. In den of migraine in population studies. Epidemiological this study, incidence also peaked later than in other studies often focus on the incidence and prevalence studies, probably because medical diagnosis may oc- of disease in defined populations. cur long after the age of onset. Finally, in the Danish population, the annual incidence of migraine in those Characteristics aged 25 to 64 years old was 8 / 1,000, being 15 / 1,000 The Incidence of Migraine in males and 3 / 1,000 in females (Lyngberg et al. 2003). The incidence of migraine has been investigated in a limited number of studies (Fig. 1). Stewart et al found The Prevalence of Migraine that in females, the incidence of migraine with aura peaked between ages 12 and 13 (14.1 / 1000 person- The published estimates of migraine prevalence have years); migraine without aura peaked between ages varied broadly, probably because of differences in the 14 and 17 (18.9 / 1000 person-years). In males, the methodology. The studies presented herein primarily incidence of migraine with aura peaked several years used the IHS definition. M earlier, around 5 years of age at 6.6 / 1000 person- years; the peak for migraine without aura was 10 / 1000 Prevalence by Age person-years between 10 and 11 years. New onset of Before puberty, as suggested by the incidence data, migraine was uncommon in men in their twenties. This migraine prevalence is higher in boys than in girls; study suggests that migraine begins earlier in males than as adolescence approaches, incidence and prevalence in females and that migraine with aura begins earlier increase more rapidly. As a consequence, at all post- than migraine without aura (Stewart et al. 1993). pubertal ages, migraine is more common in girls than in Three other studies assessed the incidence of migraine. boys. The prevalence increases throughout childhood A study performed in a random sample of young adults and early adult life until approximately age 40, after (21–30 years), found that the incidence of migraine which it declines (Fig. 2) (Scher et al. 1999). Over- was 5.0 per 1,000 person-years in males and 22.0 in all, prevalence is highest from 25–55, the peak years females (Breslau et al. 1994), supporting the findings of economic productivity. The gap between peak inci-

Migraine Epidemiology, Figure 2 Adjusted prevalence of migraine bya Migraine Epidemiology, Figure 1 Incidence of migraine, by age and sex age from a meta-analysis of studies using IHS criteria. (from Scher et al. (from Stewart et al. 1993). 2001). 1140 Migraine Epidemiology

Migraine Epidemiology, Table 1 Prevalence of headache and migraine by age in selected community and school based-studies Author(Y) Type of Sample Age Time Migraine Headache Migraine Country Population Size Range Frame Deﬁnition Prevalence Prevalence (Years) Males Females Overall Males Females Overall

Ayatollahi School 1,868 11–18 ? IHS 6.1% (2002) Iran teenage girls

Al Jumah M School 1,400 6–18 ? IHS 6.4% 7.7% 7.1% (2002) Saudi Children Arabia

Abu-Arafeh 1,754 5–15 1 year IHS1 10.6 (1994)

Bille (1962) School 8,993 7–15 Lifetime Vahlquist1 58.0 59.3 - 3.3 4.4 - Sweden Children

Linet (1989) Community 10,132 12–29 1 year 2 of 90 95 - 5.3 14 - USA NV/U/VA

Mortimer General 1,083 3–11 1 year IHS1 40.6* 36.9* 38.8* 4.1 2.9 3.7 (1992) UK Practice

Raielli (1995) School 1,445 11–14 1 year IHS1 19.9 28.0 23.9 2.7 3.3 3.0 Italy Children

Sillanpaa School 4,825 3 ? Vahlquist1 4.3 3.2 3.2 3.2 (1976) Finland Children 7 ?

Sillanpaa School 3,784 13 1 year Vahlquist1 79.8 84.2 - 8.1 15.1 - (1983) Finland Children

* age adjusted N, nausea; U, unilateral, V, vomiting; VA, visual aura dence in adolescence and peak prevalence in middle life old boys than in 3–5 year old girls. Thus, the overall indicates that migraine is a condition of long duration. prevalence of headache increases from preschool age Despite suggestions to the contrary, the prevalence children to mid-adolescence, when examined using of migraine is probably not increasing. According to various cross-sectional studies (Bille 1989). the Centers for Disease Control, self-diagnosed mi- Recent studies report the prevalence of pediatric migraine prevalence in the U.S. increased 60%, from graine in the Asian Middle East. The ﬁrst one, per- 25.8 / 1000 to 41 / 1000 persons, between 1981 formed in the southern Iran, evaluated a random sample and 1989 (MMWR 1991). Because this study relies of 1868 teenaged girls (aged 11 to 18 years). The overall on self-reported migraine, an increase in diagno- prevalence rate for migraine was 6.1% (95% CI, 5.0 sis or disease awareness could be mistaken for an to 7.2). The second study evaluated 1,400 randomly increase in prevalence. Numerous population stud- selected Saudi children in grades 1 through 9. Overall, ies in the U.S. show that prevalence is stable, while the headache prevalence was 49.8%. The prevalence consultation and diagnosis have increased (Lipton of migraine was 7.1%. There was a sharp increase in et al. 2001). It may be that these increases in med- the prevalence rate (from around 2% to around 9%) ical consultation and diagnosis have caused an ap- at aged 10 to 11, in both boys and girls. Age adjusted parent rather than a real increase in migraine preva- prevalence for migraine between aged 6 and 15 was lence. 6.2% (for references on the original studies the reader is referred to Bigal et al. 2004). Prevalence in Children and Adolescents Another recent study evaluated the evolution of juve- The prevalence of headache in children, as investi- nile migraine without aura in adolescents over 5 years. gated in a number of school and population-based Sixty-four subjects out of 80 previously selected were studies shows that by age 3, headache occurs in 3-8% re-evaluated. Thirty two (50%) had migraine without of children. At age 5, 19.5% have headache and by aura. After 5 years, migraine without aura persisted age 7, 37 to 51.5% have headaches. In 7 to 15 year- in 56.2%, converted to migrainous disorder or non- olds, headache prevalence ranges from 57–82%. The classiﬁable headache respectively in 9.4% and 3.1% prevalence increases from ages 3–11 in both boys and of cases, changed to episodic tension-type headache in girls, with higher headache prevalence in 3–5 year 12.5% and remitted in 18.8%. Migraine Epidemiology 1141

Prevalence by Gender in Adults Estimates of migraine prevalence range from 3.3 to 21.9% for women and 0.7% to 16.1% for men. In the United States, the American Migraine Study II found that the prevalence of migraine was about 18% in women and 6% in men (Lipton et al. 2001). Table 1 summarizes several prevalence studies conducted in the last 12 years. The prevalence of migraine in different geographic locations, overall and by gender is presented. The female to male gender ratio is about 3 to 1 in most places where it has been studied.

Migraine Epidemiology, Figure 3 Adjusted prevalence of migraine by Prevalence of Migraine by Socioeconomic Status geographical area and gender in a meta-analysis of studies using IHS The relationship between migraine prevalence and criteria (from Scher et al. 2001). socioeconomic status is uncertain. In physician- and clinic-based studies, migraine appears to be associated with high intelligence and social class. In his studies The Burden of Migraine of children, Bille did not find an association between The Impact of Migraine on the Individual migraine prevalence and intelligence (Bille 1989). Sim- The burden of migraine is significant both to theindivid- ilarly, in adults, epidemiological studies do not sup- ual sufferer and to the society. In the American Migraine port a relationship between occupation and migraine Study II, 92%of womenand89%ofmen with severemi- prevalence (Lipton et al. 2001). In both the American grainehadsomeheadacherelateddisability(Liptonetal. Migraine Studies I and II, migraine prevalence was 2001). About half were severely disabled or needed bed M inversely related to household income (i.e. migraine rest. In addition to the attack related disability, many mi- prevalence fell as household income increased) (Lipton graineurs live in fear, knowing that at any time an attack et al. 2001). This inverse relationship between migraine could disrupt their ability to work, care for their families and socioeconomic status was confirmed in another or meet social obligations. Abundant evidence indicates U.S. study based on members of a managed care orga- that migraine reduces health related quality of life. nization and in the National Health Interview Study. In The World Health Organization (WHO) has recently Europe, results are contradictory. While one large study released a report on the burden of diseases (The World failed to demonstrate an association between migraine Health Report 2001). The WHO report defines the and socioeconomic status (Launer et al. 1999), a sec- “burden” of a disease to include the economic and ond recent study in England showed this relationship emotional difficulties that a family experiences as a (Steiner et al. 2003). result of migraine, as well as the lost opportunities – The higher prevalence in the lower socioeconomic the adjustments and compromises that prevent other groups may be a consequence of a circumstance as- family members from achieving their full potential sociated with low income and migraine, such as poor in work, social relationships and leisure. The global diet, poor medical care or stress. It may also reflect burden of disease (GBD) is an analysis of the onset of social selection, that is migraineurs may have lower disorders and the disability caused by them. Using the incomes because migraine interferes with educational GBD methodology, migraine is estimated to account for and occupational function, causing a loss of income 2.0% years of life lost due to a disability in women of all or the ability to rise from a low-income group. The ages. In both sexes of all ages, migraine is responsible relationship of migraine and socioeconomic status, for 1.4% of total years of life lost due to a disability and especially in children and adolescents, requires further ranks within the top 20 most disabled studied disorders study. (Table 2).

Prevalence of Migraine by Geographical Distribution The Impact of Migraine on the Family Migraine prevalence also varies by race and geography. The impact of migraine extends to household part- In the U.S., it is highest in Caucasians, intermediate ners and other family members. In a recent study, in African Americans and lowest in Asian Americans one half of the participants believed that, because of (Scher et al. 1999). Similarly, a meta-analysis of preva- their migraine, they were more likely to argue with lence studies suggests that migraine is most common in their partners (50%) and children (52%), while ma- North and South America, similar in Europe, but lower jorities (52–73%) reported other adverse consequences in Africa and often lowest in studies from Asia (Fig. 3) for their relationships with their partner and children (Scher et al. 1999). The data suggest that race related and at work. A third (36%) believed they would be differences in genetic risk may contribute. better partners but for their headaches. Participating 1142 Migraine Epidemiology

Migraine Epidemiology, Table 2 Gender-Speciﬁc Prevalence Estimates of Migraine from 25 Population-Based Studies Using IHS Diagnostic Criteria Author Country Source Method Sample Time Age Migraine Comments (Year of Size Frame Range Prevalence (%) Publication) Female Male Total

Abu-Arefeh Scotland School Clin Interview 1,754 1 Year 5–15 11.5 9.7 10.6 Prevalence is higher (1994) in boys prior to age 12 (1.14:1). After age 12, more common in girls (2.0:1).

al Rajeh Saudi Community Face to face/ 22,630 All 6.8 3.2 5.0 (1997) Arabia Clin Interview

Alders Malaysia Community Face to face 595 1 Year 5+ 11.3 6.7 9.0 (1996) Arregui Peru Community Clin Interview 2,257 All 12.2 4.5 8.4 (1991) Bank et al Hungary Community Questionnaire 813 1 Year 15–80 9.6 (2000) Barea Brazil School Clin Interview 538 1 Year 10–18 10.3 9.6 9.9 2-48 hour duration (1996) allowed

Breslau US Community Face to face/ 1,007 1 Year 21–30 12.9 3.4 9.2 (1991) Telephone

Cruz (1995) Ecuador Community Clin Interview 2,723 Lifetime All 7.9 5.6 6.9 Community endemic for cysticercosis

Cull (1992) UK Community Face to face 16,002 16+ 11.0 4.3 7.8 Without aura only

Dahlof et al Sweden Community Telephone 1,668 1 Year 18–74 16.7 9.5 13.2 (2003) interview

Deleu et al Saudi Community Face to face 1158 1 Year 10+ 5.6 4.5 (2002) Arabia

Göbel (1994) Germany Community Mail SAQ 4,061 Lifetime 18+ 15.0 7.0 11.0

Hagen et al Norway Community Clin Interview 51,833 1 Year 20+ 16.0 8.0 12.0 (2000) Haimanot Ethiopia Community Face to face/ 15,000 1 Year 20+ 4.2 1.7 3.0 (1995)[ Clin Interview

Henry, P France Community Face to face 4,204 1 Year 15+ 11.9 4.0 8.1 (1992) Henry et al France Community Face to face 10,585 1 Year 15+ 11.2 4.0 7.9 (2002) Jabbar, A Saudi Community Face to face 5,891 Lifetime 15+ 8.0 (1997) Arabia

Jaillard Peru Community Clin Interview 3,246 1 Year 15+ 7.8 2.3 5.3 (1997)[ Kececi et al Turkey Community Face to face‘ 1320 1 Year All 17.1 7.9 (2002) Lamp et al Sweden Community Fade to face 997 1 Year 15+ 13.8 6.1 10.2 (2003)

Lenore et al Nether- Community Questionnaire 6,491 Lifetime 18-65 33 13.3 (1999) lands and telephone 1 Year 25 7.5

Lipton et al United Community Telephone 29 727 1 Year 12+ 18.2 6.5 (2001) States

Lipton et al United Community Telephone 11,863 1 Year 18–65 17.2 6 (2002) States Migraine Epidemiology 1143

Migraine Epidemiology, Table 2 (continued) Author Country Source Method Sample Time Age Migraine Comments (Year of Size Frame Range Prevalence (%) Publication) Female Male Total

Merikangas Switzer- Community Clin Interview 379 1 Year 28–29 32.6 16.1 24.5 Weighted prevalence (1993) land

Michel France Community Mail SAQ 9,411 3 Month 18+ 18.0 8.0 13.0 (1995) Mirandaetal Puerto Community Telephone 1610 1 Year All 6 16.7 13.5 (2003) Rico

O’Brien Canada Community Telephone 2,922 1 Year 18+ 21.9 7.4 15.2 (1994) Raieli (1994) Italy School Clin Interview 1,445 1 Year 11–14 3.3 2.7 3.0

Rasmussen Denmark Community Clin Interview 740 1 Year 25–64 15.0 6.0 10.0 (1992) Russell Denmark Community Clin Interview 3,471 Lifetime 40 23.7 11.7 17.7 (1995) Sakai (1996) Japan Community Mail SAQ 4,029 1 Year 15+ 12.9 3.6 8.4 Female:Male prevalence ratio=3.6. Regional differences

Steiner et al England Community CATI 4,007 1 Year 18–65 14.3 7.6 18.3 (2003) M Stewart US Community Mail SAQ 20,468 1 Year 12–80 17.6 5.7 12.0 (1992) Stewart US Community Telephone 12,328 1 Year 18–65 19.0 8.2 14.7 Racial differences (1996) Takeshima Japan Community Questionnaires 5758 1 year 18+ 9.1 2.3 6 Study done in the et al (2004) and telephone rural area of western Japan

van Roijen Nether- Community Face-to-face 10,480 1−Year 12+ 12.0 5.0 9.0 (1995) lands

Wang (1997) China Community Clin Interview 1,533 1 Year 65+ 4.7 0.7 3.0

Wong (1995) Hong Community Telephone 7,356 1 Year 15+ 1.5 0.6 1.0 Kong

Zivadinov Croatia Community Telephone and 5173 Lifetime 15–65 22.9 14.8 19 et al (2001) face to face 1 Year 18 12.3 partners partly confirmed these findings; 29% felt that the direct costs (Lipton et al. 2001). Indirect costs in- arguments were more common because of headaches clude the aggregate effects of migraine on productivity and 20–60% reported other negative effects on rela- at work (paid employment), for household work and in tionships at home. Compared with subjects who did other roles. The largest componentsof indirect costs are not have migraine, regarding their work performance, a the productivity losses caused by absenteeism and re- statistically significantly higher proportion of migraine duced productivity while at work. Hu et al estimated that partners were unsatisfied with work demands placed productivity losses due to migraine cost American em- on them, with their level or responsibilities and duties ployers 13 billion dollars per year (Hu et al. 1999). In an and with their ability to perform (Lipton et al. 2003). UK study, 5.7 working days were lost per year for every Results from this study show that the impact of mi- working person or student with migraine, although the graine extends to household partners and other family most disabled 10% accounted for 85% of the total, pro- members (impact beyond the individual). jecting a lost 25 million days from work or school each year (Steiner et al. 2003). The Societal Impact of Migraine Migraine’s impact on healthcare utilization is marked as Migraine has an enormous impact on society. Studies well. Studies show that 4% of all visits to physicians’ of- have evaluated the indirect costs of migraine as well as fices are for headache (Bigal et al. 2004). Migraine also 1144 Migraine Epidemiology

Migraine Epidemiology, Table 3 Global burden of migraine. Leading causes of years of life lost due to a disability according to the global burden of disease initiative (modiﬁed from Lipton et al. 2003) Females All Ages % Total Both Sexes All Ages % Total

1 Unipolar depressive disorders 1 Unipolar depressive disorders 11.9

2 Iron-deﬁciency anemia 2 Hearing loss, adult onset 4.6

3 Hearing loss, adult onset 3 Iron-deﬁciency anemia 4.5

4 Osteoarthritis 4 Chronic obstructive pulmonary disease 3.3

5 Chronic obstructive pulmonary 5 Alcohol use disorders 3.1 disease

6 Schizophrenia 6 Osteoarthritis 3.0

7 Bipolar affective disorder 7 Schizophrenia 2.8

8 Falls 8 Falls 2.8

9 Alzheimer’s and other dementias 9 Bipolar affective disorder 2.5

10 Obstructed labor 10 Asthma 2.1

11 Cataracts 11 Congenital abnormalities 2.1

12 Migraine 12 Perinatal conditions 2.0

13 Congenital abnormalities 13 Alzheimer’s and other dementias 2.0

14 Asthma 14 Cataracts 1.9

15 Perinatal conditions 15 Road trafﬁc accidents 1.8

16 Chlamydia 16 Protein-energy malnutrition 1.7

17 Cerebrovascular disease 17 Cerebrovascular disease 1.7

18 Protein-energy malnutrition 18 HIV / AIDS 1.5

19 Abortion 19 Migraine 1.4

20 Panic disorder 20 Diabetes mellitus 1.4 results in major utilization of emergency rooms and ur- 7. Lipton RB, Bigal ME, Kolodner K et al. (2003) The family im- gent care centers (Bigal et al. 2004). Vast amounts of pact of migraine: population-based studies in the USA and UK. Cephalalgia 23:429–440 prescription and over the counter medications are taken 8. Lyngberg A, Jensen R, Rasmussen BK et al. (2003) Incidence for headache disorders. OTC sales of pain medication of migraine in a Danish population-based follow-up study. (ab- (for all conditions) were estimated to be 3.2 billion dol- stract). Cephalalgia 23:596 lars in 1999 (U.S.) and headache accounts for about one 9. MMWR (1991) Prevalence of chronic migraine headaches – United States, 1980–89. MMWR 40:331–338 third of OTC analgesic use (Bigal et al. 2004). 10. Ozge A, Bugdayci R, Sasmaz T et al. (2002) The sensitivity and specificity of the case definition criteria in diagnosis of headache: References a school-based epidemiological study of 5562 children in Mersin. 1. Bigal ME, Lipton RB, Stewart WF (2004) The epidemiology and Cephalalgia 22:791–798 impact of migraine. Curr Neurol Neurosci Rep 4:98–104 11. Scher AI, Stewart WF, Lipton RB (1999) Migraine and headache: 2. Bille B (1989) Migraine in children: prevalence, clinical features, a meta-analytic approach. In: Crombie IK (ed), Epidemiology and a 30-year follow-up. In: Ferrari MD, Lataste X (eds) Migraine of Pain. IASP Press, Seattle, Washington, pp 159–170 and other headaches. Parthenon, New Jersey 12. Stang PE, Yanagihara T, Swanson JW et al. (1992) Incidence 3. Breslau N, Davis GC, Schultz LR et al. (1994) Joint 1994 Wolff of migraine headaches: A population-based study in Olmstead Award Presentation. Migraine and major depression: a longitu- County, Minnesota. Neurology 42:1657–1662 dinal study. Headache 34:387–393 13. Stang PE, Sternfeld B, Sidney S (1996). Migraine headache in a 4. Hu XH, Markson LE, Lipton RB et al. (1999) Burden of migraine pre-paid health plan: ascertainment, demographics, physiologi- in the United States: disability and economic costs. Arch Intern cal and behavioral factors. Headache 36:69–76 Med 159: 813–818 14. Steiner T, Scher A, Stewart W et al. (2003)The prevalence 5. Launer LJ, Terwindt GM, Ferrari MD (1999) The prevalence and disability burden of adult migraine in England and and characteristics of migraine in a population-based cohort: the their relationships to age, gender and ethnicity. Cephalalgia GEM Study. Neurology 53:537–542 23:519–527 6. Lipton RB, Stewart WF, Diamond S et al. (2001) Prevalence and 15. Stewart WF, Linet MS, Celentano DD et al. (1993) Age and sex- Burden of migraine in the United States: data from the American specific incidence rates of migraine with and without visual aura. Migraine Study II. Headache 41:646–657 Am J Epidemiol 34:1111–1120 Migraine, Genetics 1145

16. The World Health Report 2001: Mental health, new understand- and for MA (Ulrich 1999), demonstrating the existence ing, new hope. Available at www.who.int/en/ of genetic factors in migraine that interact with environmental factors to produce the phenotype. Family studies provided further evidence in favor of the exis- Migraine, Genetics tence of genetic factors in MO and MA, those factors being more important in MA than in MO (Russell and ANNE DUCROS Olesen 1995). In addition, segregation analysis showed Headache EmergencyDepartment and Institut National that both MO and MA have a non-mendelian poly- de la Santé et de la Recherche Médicale (INSERM), genic mode of inheritance (Russell 1995). The possible Faculté de Médecine Lariboisière, Lariboisière number of genetic susceptibility loci is still unknown. Hospital, Paris, France FHM is the only variety of migraine in which a mono- [email protected] genic mendelian mode of inheritance has been clearly established. Two clinical forms of FHM have been Synonyms described: pure FHM (80% of the families), and FHM Inherited Factors Implicated in the Mechanisms of Mi- with permanent cerebellar symptoms in which some graine affected subjects have nystagmus and/or ataxia. In addition to usual attacks, patients may have severe attacks Definition with confusion, coma, fever and prolonged hemiple- Migraine is a primary headache disorder. It is a com- gia. Genetic tools are more powerful to identify the plexdiseaseinwhichenvironmentalfactorsinteractwith genes responsible for monogenic conditions than genes genetic factors. The major goal of genetic studies is the responsible for polygenic conditions. Thus, the only identification of susceptibility genes that may give clues known migraine genes have been identified in FHM. to the mechanisms underlying migraine, and may help FHM isgenetically heterogeneous, with atleastthree re- to identify new therapeutic targets. sponsible genes of which two have been identified. The M first gene, CACNA1A, located on chromosome 19p13, Characteristics was identified in 1996 (Ophoff 1996). CACNA1A en- Migraine is a primary headache disorder responsible for codes the pore-forming α1A-subunit of voltage-gated 2+ recurrent attacks of disabling pain lasting a few hours to neuronal Cav2.1 (P/Q type) Ca channels. CACNA1A a few days. This condition is characterized by the repeti- is implicated in about 50% of unselected FHM families tionofsuchattacksintheabsenceofanydisordercausing and in the vast majority of families with permanent cere- secondary headaches. TheInternationalHeadache Soci- bellar symptoms. The second gene, ATP1A2, located ety (IHS) classification distinguishes different varieties on chromosome 1q21-q23, was identified in 2003 (De of migraine attacks, the most frequent being migraine Fusco 2003). ATP1A2 is implicated in about 20–30% withoutaura(MO)andmigrainewithtypicalaura(MA). of unselected FHM families, and encodes the catalytic In MO attacks, the headache is the most prominent and α2-subunit of a transmembrane NA+/K+ ATPase. Both disabling symptom. In MA attacks, the headache phase known FHM genes encode proteins regulating ion is preceded or accompanied by transient neurological translocation, FHM is thus a channelopathy. signs including visual, sensory and language troubles. Cav2.1 channels are found exclusively in neurons Some patients have only MO, others have only MA, and including central and peripheral neurons at the neuro- some have both types of attacks. In addition, hemiplegic muscular junction. They play a major role in neurotrans- migraine is a rare variety of MA characterized by the mitter release (mainly glutamate) and in the control of presence of a motor deficit during the aura, in addition neuronal excitability. CACNA1A is a large gene con- to one or more of the typical aura symptoms. In famil- taining 47 exons. Thus far, a total of 17 CACNA1A ial hemiplegic migraine (FHM), the index case has at mutations have been identified in 41 FHM1 families least one first- or second-degree relative who also has (33 affected by FHM and cerebellar symptoms and 8 migraine with aura including motor weakness. In spo- by pure FHM), and in 4 sporadic cases affected by HM radic hemiplegic migraine, there is no such familial his- and cerebellar symptoms. Five of these mutations are tory. Migraine is a highly frequent condition affecting recurrent, i.e. they have been detected in two or more about 15% of the western population. Familial aggre- unrelated families. The most frequent mutation T666M gation has long been known, and was even classically has been detected in 19 families and 2 sporadic cases. used as a diagnosis criterion. Genetic epidemiological All mutations are missense mutations, changing only surveyshavedemonstratedthatthisfamilialaggregation one of the 2550 amino-acids of the predicted protein. was not observed purely by chance, but was due to the They are located in important functional domains of the existence of genetic factors. subunit, near the ionic pore or within the voltage sensor. Twin studies have shown that the ‘pairwise’ concor- Mutations causing FHM1 with cerebellar symptoms dance rates were significantly higher among monozy- are distinct from those causing pure FHM1, and all gous than dizigous twin pairs for MO (Gervil 1999) recurrent mutations are causing FHM1 with cerebellar 1146 Migraine, Genetics symptoms. Mutations have been detected in sporadic These mutations are missense mutations responsible cases, including a de novo mutation, demonstrating that for the substitution of one of the 1020 amino-acids of sporadic HM is due to CACNA1A mutations in at least the protein. Only one mutation (R763H) was found in a part of the cases. two unrelated families. In the family with the R689Q DifferentkindsofCACNA1Amutationshavebeeniden- mutation, FHM cosegregates with benign familial in- tified in two other autosomal dominant neurological dis- fantile convulsions. In another family with the T378N orders. Episodic ataxia type 2 is a paroxysmal neuro- mutation, the phenotypic spectrum includes features logical condition producing recurrent attacks of major characteristic of FHM and of alternating hemiplegia. cerebellar ataxia, which is due to CACNA1A mutations Electrophysiological studies initially suggested that (Ophoff 1996). Spinocerebellar ataxia type 6 (SCA6) ATP1A2 mutations are loss of function mutations lead- is a progressive cerebellar disease characterized by an ing to haploinsufficiency. Further studies suggest that adult onset ataxia, which is due to small expansions of the mutations are gain of function mutations leading to theCAGrepeatcontainedwithinexon47ofCACNA1A. an abnormal function of the pump. Electrophysiological studies of CACNA1A mutations FHM is characterized by an important clinical vari- causing FHM1 have shown that all mutations analyzed ability. The age of onset, the frequency and duration of so far modify the density and the gating properties attacks, the aura features and the headache characteris- of Cav2.1 currents (Pietrobon and Striessnig 2003). tics may vary from one patient to another, even among Mutated single Cav2.1 channels display lower activa- affected members from a given family who are carrying tion thresholds and increased opening probabilities. the same mutation in the same gene. Thisvariabilitysug- FHM1 mutations are thus gain-of-function mutations. gests complex interactions between the consequences On the contrary, EA2 mutations have been shown to of the FHM causing mutation and environmental fac- be loss-of-function mutations, the mutated allele gen- tors or modifying genetic factors. However, several erating no current when expressed in heterologous studies have shown that the various genotypes play a cells. role in producing this clinical variability. FHM1, due to Knockout mice that do not have the CACNA1A gene CACNA1A mutations, is characterized by a higher pen- are born with a severe ataxia and die within a few days. etrance of FHM and of permanent cerebellar symptoms, Mice carrying different spontaneous mutations within the vast majority of families with permanent cerebellar CACNA1A display distinct phenotypes called tottering, symptoms being linked to CACNA1A (Ducros 2001). leaner, or rocker, characterized by various paroxysmal FHM2, due to ATP1A2 mutations, is characterized by manifestations(absence epilepsy, motor attacks) always a lower penetrance of FHM. Cerebellar symptoms are associated with a permanent cerebellar ataxia of vari- rarely part of the clinical spectrum of FHM2 (2 families able severity. Leaner mice have lower levels of voltage- published). In addition, striking correlations between dependantglutamate release measurable bycerebralmi- genotype and phenotype have been shown in patients crodialysis. They also have an elevated threshold for ini- with CACNA1A mutations, including the fact that the tiating cortical spreading depression (CSD) anda slower most frequent FHM1 causing mutation, T666M, had velocityofCSDpropagation.Knockinmicecarryingthe the highest penetrance of hemiplegic migraine, severe human pure FHM1 mutation R192Q display multiple attacks with coma and nystagmus (Ducros 2001). The gain-of-function phenotypes: increased Cav2.1 current existence of different CACNA1A mutations partly density in cerebellar neurons, enhanced neurotransmis- accounts for the clinical variability. sion attheneuromuscular junction, and,in theintactani- The implication of CACNA1A in the more frequent mal, a reduced threshold and increased velocity of corti- varieties of migraine has been analyzed by the mean cal spreading depression (van den Maagdenberg 2004). of linkage and association studies with contradictory This mouse is the first animal model for FHM. These results, 3 studies concluding in favor and 5 against. variousabnormalitiesstronglysuggestthatFHM1muta- None of the positive studies provided a direct analysis tionsin the Cav2.1 channelmodify thecorticalexcitabil- of the CACNA1A gene in order to detect pathogenic ity and increase the susceptibility to CSD, which is the mutations. CACNA1A is thus probably not a suscepti- mechanism underlying the aura. bility gene for the more common varieties of migraine. ATP1A2 encodes the catalytic α-2subunit of a trans- Moreover, a subsequent study showed that the 19p13 membrane NA+/K+ ATPase. This protein hydrolysis region does indeed contains a susceptibility locus for ATP to extrude Na+ ions and pump K+ ions into the cell. MA that is distinct from CACNA1A. The same group This active pumping maintains the Na+ transmembrane showed an association between migraine and five poly- gradientthatisessentialforthetransportofamino-acids, morphisms within the insulin receptor (INSR) gene neurotransmitters (including glutamate) and Ca2+.In located in 19p13.3/2 (McCarthy 2001). These five neonates, the α-2subunit is mainly expressed in neu- polymorphisms had no effect on INSR transcription, rons. In adults, it is mainly expressed in astrocytes. translation, and protein expression, and INSR-mediated ATP1A2 contains 23 exons. So far, 14 mutations have functions. The nature of the implication of the INSR been identified in 14 families and one sporadic case. gene in migraine remains to be understood. Migraine Optical 1147

With regards to the FHM2 gene, a linkage analysis con- 2. CaderZM,Noble-TophamS,DymentDAet al.(2003)Significant ducted in a single family suggested the presence of a Linkage to Migraine with Aura on Chromosome 11q24. Hum Mol Genet 12:2511–2517 possible migraine susceptibility locus in 1q31, distinct 3. De Fusco M, Marconi R, Silvestri L et al. (2003) Haploinsuffi- from the ATP1A2 locus in 1q21-q23. An ATP1A2 mu- ciency of ATP1A2 Encoding the Na+/K+ Pump Alpha2 Subunit tation (R548H) was found in a small family in which Associated with Familial Hemiplegic Migraine Type 2. Nat Genet the two affected subjects had migraine with basilar, non- 33:192–196 hemiplegic, aura. This mutation was not found in 100 4. Ducros A, Denier C, Joutel A et al. (2001) The Clinical Spectrum of Familial Hemiplegic Migraine Associated with Mutations in healthy controls, or in 77 migrainous controls. Actual a Neuronal Calcium Channel. N Engl J Med 345:17–24 data do not permit a conclusion regarding the implica- 5. Estevez M, Gardner KL (2004) Update on the Genetics of Mi- tion of ATP1A2 in MO/MA. graine. Hum Genet 114:225–235 6. Gervil M, Ulrich V, Kaprio J, Olesen J, Russell MB (1999) The Three linkage analyses, each conducted in a large Relative Role of Genetic and Environmental Factors in Migraine panel of MA families, have permitted the mapping of without Aura. Neurology 53:995–999 three susceptibility loci for MA: the first on 4q24 (in 7. Maagdenberg AM van den, Pietrobon D, Pizzorusso T et al. 50 Finnish families) (Wessman 2002), the second on (2004) A Cacna1a Knockin Migraine Mouse Model with In- creased Susceptibility to Cortical Spreading Depression. Neuron 11q24 (in 43 Canadian families) (Cader 2003), and 41:701–710 the last on 15q11-q13 (in 10 Italian families) (Russo 8. McCarthy LC, Hosford DA, Riley JH et al. (2001) Single- 2004). An important linkage analysis in a group of Nucleotide Polymorphism Alleles in the Insulin Receptor Gene 289 Icelandic patients with MO identified a suscep- are Associated with Typical Migraine. Genomics 78:135–149 9. Ophoff RA, Terwindt GM, Vergouwe MN et al. (1996) Familial tibility locus on 4q21 (Bjornsson 2003). This genetic Hemiplegic Migraine and Episodic Ataxia Type-2 are Caused interval overlapped the genetic region identified in by Mutations in the Ca2+ Channel Gene CACNL1A4. Cell the Finnish families on 4q24, suggesting an implica- 87:543–552 tion of this chromosome 4q region both in MO and 10. Pietrobon D, Striessnig J (2003) Neurobiology of Migraine. Nat Rev Neurosci 4:386–398 MA. Finally, several linkage analyses, each conducted 11. Russell MB, Iselius L, Olesen J (1995) Inheritance of Migraine in a single family, suggested the existence of other Investigated by Complex Segregation Analysis. Hum Genet M migraine susceptibility loci on 1q21-q23, 6p12.2- 96:726–730 p21.1, 14q21.2-q22.3 and Xq24-q28 (Estevez and 12. Russell MB, Olesen J (1995) Increased Familial Risk and Evi- dence of Genetic Factor in Migraine. Bmj 311:541–544 Gardner 2004). None of the results have been repli- 13. Russo L, Mariotti P, Sangiorgi E et al. (2004) A New Suscepti- cated. bility Locus for Migraine with Aura in the 15q11-q13 Genomic Finally, numerous association studies have been per- Region Containing Three GABA-A Receptor Genes. Am J Hum formed in migraine. A wide range of candidate poly- Genet 76:2 14. Ulrich V,Gervil M, Kyvik KO et al. (1999) Evidence of a Genetic morphisms have been tested in migraine. Association Factor in Migraine with Aura: A Population-Based Danish Twin studies compare the frequency of alleles of a polymor- Study. Ann Neurol 45:242–246 phic genetic marker between cases and controls. In the 15. Wessman M, Kallela M, Kaunisto MA et al. (2002) A Suscep- absence of methodological shortcomings, a significant tibility Locus for Migraine with Aura, on Chromosome 4q24. Am J Hum Genet 70:652–662 difference means that the polymorphism is located within the susceptibility gene or is in linkage dise- quilibrium with the susceptibility gene. Association studies do not provide any demonstration of the impli- Migraine Hemiparesthetic cation of the tested gene, or of an abnormal function of the tested gene in the pathophysiology of the studied Clinical Migraine with Aura disease. Positive associations have been found between migraine and polymorphisms within the dopamine receptor D2 (DRD2) gene, the human serotonin trans- Migraine Hemiplegic porter gene, the catechol-o-methyltransferase gene, the endothelin type A gene, the dopamine beta-hydroxylase (DBH) gene, and the 5,10-methylenetetrahydrofolate Clinical Migraine with Aura reductase (MTHFR). These various candidate polymorphisms have been chosen based on the hypothesis that the genes containing them encode proteins that Migraine Ophthalmic are suspected to be involved in migraine. However, additional studies are needed to determine if the alleles Clinical Migraine with Aura associated with migraine have any biological effect.

References Migraine Optical 1. Bjornsson A, Gudmundsson G, Gudﬁnnsson E et al. (2003) Lo- calization of a Gene for Migraine without Aura to Chromosome 4q21. Am J Hum Genet 73:986–993 Clinical Migraine with Aura 1148 Migraine, Pathophysiology

example, it is useful to remember that migraine is not Migraine, Pathophysiology simply a pain problem. PETER J. GOADSBY Institute of Neurology, The National Hospital for Genetics of Migraine Neurology and Neurosurgery, London, UK One of the most important aspects of the pathophys- [email protected] iology of migraine is the inherited nature of the disorder. It is clear from clinical practice that many pa- Introduction tients have first degree relatives who also suffer from migraine (Lance and Goadsby 2005; Silberstein et al. An understanding of the pathophysiology of migraine 2002). Transmission of migraine from parents to chil- should be based upon the anatomy and physiology of dren has been reported as early as the seventeenth cen- the pain producing structures of the cranium integrated tury (Willis 1682) and numerous published studies with knowledgeof central nervous system modulation have reported a positive family history (Russell 1997). of these pathways. Headache in general,andin particu- larmigraine(Goadsbyetal.2002)andclusterheadache Genetic Epidemiology (Goadsby 2002b), is better understood now than has Studies of twin pairs are the classical method to in- been the case for the last four millennia (Lance and vestigate the relative importance of genetic and en- Goadsby 2005). This chapter will set out the current vironmental factors. A Danish study included 1,013 understanding of migraine. monozygotic and 1,667 dizygotic twin pairs of the same gender, obtained from a population based twin Migraine — Explaining the Clinical Features register (Ulrich et al. 1999). The pairwise concordance Migraine is in essence a familial episodic disorder rate was significantly higher among monozygotic than whose key marker is headache with certain associated dizygotic twin pairs (P < 0.05). Severalstudies have at- features (Table 1). It is these features that give clues to tempted to analyze the possible mode of inheritance in its migraine pathophysiology and will ultimately pro- migraine families and conflicting results have been ob- vide insights leading to new treatments. tained (Lalouel and Morton 1981; Mochi et al. 1993; The essential elements to be considered are: Russell et al. 1995). Both twin studies and population based epidemiological surveys strongly suggest • Genetics of migraine; that migraine without aura is a multifactorial disorder, • Physiological basis for the aura caused by a combination of genetic and environmental • Anatomy of head pain, particularly that of the factors. trigeminovascular system • Physiology and pharmacology of activation of the Familial Hemiplegic Migraine (FHM) peripheral branches of ophthalmic branch of the trigeminal nerve; In approximately 50% of the reported families, FHM • Physiology and pharmacology of the trigeminal has been assigned to chromosome 19p13 (Joutel et al. nucleus, in particular its caudal most part, the 1994;Ophoffetal.1994).Fewclinicaldifferenceshave trigeminocervical complex been found between chromosome 19 linked and un- • Brainstem and diencephalic modulatory systems linked FHM families. Indeed, the clinical phenotype that influence trigeminal pain transmission and does not associate particularly with the known muta- other sensory modality processing. tions (Ducros et al. 2001). The most striking excep- tioniscerebellarataxia,whichoccursinapproximately Migraine involves a form of sensory processing dis- 50% of the chromosome 19 linked, but in none of the turbance with wide ramifications within the central unlinked families (Haan et al. 1994; Joutel et al. 1993, nervoussystem, while pain pathwayswillbe used asan 1994; Ophoff et al. 1994; Teh et al. 1995). Another less striking difference includes the fact that patients from Migraine, Pathophysiology, Table 1 International Headache Society chromosome 19 linked families are more likely to have defined features of migraine (Headache Classification Committee of The attacks that can be triggered by minor head trauma or International Headache Society 2004) Repeated episodic headache (4– are that associated with coma (Terwindt et al. 1996). 72 h) with the following features: The biological basis for the linkage to chromosome19 Any two of Any one of is mutations (Ophoff et al. 1996) involving the Cav2.1 unilateral nausea / vomiting (P / Q) type voltage gated calcium channel (Ertel throbbing photophobia and phonophobia et al. 2000) CACNA1A gene. Now known as FHM-I, worsened by movement this mutation is responsible for about 50% of identified moderate or severe families. Mutations in the ATP1A2 gene (De Fusco et Migraine, Pathophysiology 1149 al. 2003; Marconi et al. 2003) have been identified to ments may shed even further light on these relation- be responsible for about 20% of FHM families. Inter- ships. estingly, the phenotype of some FHM-II families in- Tonabersat is a CSD inhibitor that has entered clin- volves epilepsy (Jurkat-Rott et al. 2004; Vanmolkot et ical trials in migraine. Tonabersat (SB-220453) inal. 2003), while it has also been suggested that alter- hibits CSD, CSD induced nitric oxide (NO) release nating hemiplegia of childhood can be due to ATP1A2 and cerebral vasodilation (Read et al. 1999; Smith et mutations (Swoboda et al. 2004). The latter cases are al. 2000). Tonabersat does not constrict isolated hu- most unconvincing for migraine. man blood vessels(MaassenVanDenBrink etal. 2000), Taken together, the known mutations suggest that mi- but does inhibit trigeminally induced craniovascu- graine, or at least the neurological manifestations cur- lar effects (Parsons et al. 2001). Remarkably, topira- rently called the aura, are caused by a channelopathy mate, a proven preventive agent in migraine (Bran- (Goadsby and Ferrari 2001). Linking the channel des et al. 2004; Diener et al. 2004; Silberstein et al. disturbance for the first time to the aura process 2004), also inhibits CSD in cat and rat (Akerman and has demonstrated that human mutations expressed in Goadsby 2004). Tonabersat is inactive in the human a knock-in mouse produce a reduced threshold for NO model of migraine (Tvedskov et al. 2004a) as cortical spreading depression (van den Maagden- is propranolol (Tvedskov et al. 2004c), although val- berg et al. 2004), which has some profound implica- proate showed some activity in that model (Tvedskov tions for understanding that process (Goadsby 2004). et al. 2004b). Topiramate inhibits trigeminal neurons activated by nociceptive intracranial afferents (Storer Migraine Aura andGoadsby2004),butnotbyamechanismlocaltothe Migraine aura is defined as a focal neurological dis- trigeminocervicalcomplex(StorerandGoadsby2005) turbance manifest as visual, sensory or motor symp- and thusCSD inhibition may be a model system to con- toms (Headache Classification Committee of The In- tribute to the development of preventive medicines. M ternational Headache Society 2004). It is seen in about 30% of patients (Rasmussen and Olesen 1992) and it is Headache Anatomy clearly neurally driven (Cutrer et al. 1998; Olesen et al. The Trigeminal Innervation 1990). The case for the aura being the human equiva- of Pain-Producing Intracranial Structures lentof the corticalspreading depression (CSD) ofLeao Surrounding the large cerebral vessels, pial vessels, (1944a, 1944b) has been well made (Lauritzen 1994). large venous sinuses and dura mater is a plexus of In humans, visual aura has been described as affect- largely unmyelinated fibers that arise from the oph- ing the visual field, suggesting the visual cortex and it thalmic division of the trigeminal ganglion (Liu-Chen starts at the centre of the visual field and propagates to et al. 1984) and in the posterior fossa from the up- the periphery at a speed of 3 mm / min (Lashley 1941). per cervical dorsal roots (Arbab et al. 1986). Trigemi- This is very similar to spreading depression described nal fibers innervating cerebral vessels arise from neu- in rabbits (Leao 1944b). Blood flow studies in patients rons in the trigeminal ganglion that contain substance have also shown that a focal hyperemia tends to pre- Pand calcitonin gene related peptide (CGRP) (Ud- cede the spreading oligemia (Olesen et al. 1981) and dman et al. 1985), both of which can be released again this is similar to what would be expected with when the trigeminal ganglion is stimulated either in spreading depression. After this passage of oligemia, humans or the cat (Goadsby et al. 1988). Stimulation thecerebrovascularresponsetohypercapniainpatients of the cranial vessels, such as the superior sagittal si- is blunted, while autoregulation remains intact (Harer nus (SSS), is certainly painful in humans (Feindel et and Kummer 1991; Lauritzen et al. 1983; Sakai and al. 1960; Wolff 1948). Human dural nerves that inner- Meyer 1979). Again this pattern is repeated with ex- vate the cranial vessels largely consist of small diame- perimental spreading depression (Kaube and Goadsby ter myelinated and unmyelinated fibers (Penfield and 1994; Kaube et al. 1999; Lambert et al. 1999). Hu- McNaughton 1940) that almost certainly subserve a man observations have rendered the arguments rea- nociceptive function. sonably sound that human aura has cortical spreading depression as its equivalent in animals (Hadjikhani et Headache Physiology — Peripheral Connections al. 2001). An area of controversy surrounds whether aura in fact triggers the rest of the attack and is indeed Plasma Protein Extravasation painful (Moskowitz et al. 2004). Based on the avail- Moskowitz(1990)hasprovidedaseriesofexperiments able experimental and clinical data this author is not to suggest that the pain of migraine may be a form of at all convinced that aura is painful (Goadsby 2001), sterile neurogenic inflammation. Although this seems but this does not diminish its interest, or the impor- clinicallyimplausible,themodelsystemhasbeenhelp- tance of understanding it. Indeed therapeutic develop- fulinunderstandingsomeaspectsoftrigeminovascular 1150 Migraine, Pathophysiology

physiology. Neurogenic plasma extravasation can be markers, which would certainly activate trigeminalno- seenduringelectricalstimulationofthetrigeminalgan- ciceptors (Strassman et al. 1996). More likely in mi- glionintherat(Markowitzetal.1987).Plasmaextrava- graine is a form of central sensitization, which may be sationcanbeblockedbyergotalkaloids,indomethacin, classicalcentralsensitization (Burstein etal. 1998) or a acetylsalicylic acid and the serotonin-5HT1B / 1D re- form of disinhibitory sensitization with dysfunction of ceptor agonist, sumatriptan (Moskowitz and Cutrer descending modulatory pathways (Knight et al. 2002). 1993). The pharmacology of abortive anti-migraine Neuropeptide Studies drugshasbeenreviewedindetail(Cutreretal.1997).In addition there are structural changes in the dura mater Electrical stimulation of the trigeminal ganglion in thatareobservedaftertrigeminalganglionstimulation. both humansand the catleadsto increasesin extracere- These include mast cell degranulation and changes in bral blood flow and local release of both CGRP and SP post-capillary venules including platelet aggregation (Edvinsson and Goadsby 1998). In the cat, trigeminal (Dimitriadou et al. 1991, 1992). While it is generally ganglionstimulationalsoincreasescerebralbloodflow accepted that such changes and particularly the initi- by a pathway traversing the greater superficial petrosal ation of a sterile inflammatory response would cause branch of the facial nerve, again releasing a power- pain (Burstein et al. 1998; Strassman et al. 1996), it is ful vasodilator peptide, vasoactive intestinal polypep- not clear whether this is sufficient of itself or requires tide (VIP) (May and Goadsby 1999). Interestingly, the other stimulatorsor promoters.Preclinicalstudiessug- VIPergic innervation of the cerebral vesselsispredom- gest that cortical spreading depression may be a suffi- inantly anterior rather than posterior (Matsuyama et cient stimulus to activate trigeminal neurons (Bolay et al. 1983) and this may contribute to this regions vul- al. 2002), although this has been a controversial area nerability to spreading depression, explaining why the (Ebersberger et al. 2001; Goadsby 2001; Ingvardsen aura is so very often seen to commence posteriorly. et al. 1997; Ingvardsen et al. 1998; Moskowitz et al. Stimulation of the more specifically vascular pain pro- 1993). ducing superior sagittal sinus increases cerebral blood Although plasma extravasation in the retina, which flow and jugular vein CGRP levels. Human evidence is blocked by sumatriptan can be seen after trigemi- that CGRP is elevated in the headache phase of mi- nal ganglion stimulation in experimental animals, no graine (Gallai et al. 1995; Goadsby et al. 1990), clus- changesare seen with retinalangiography during acute ter headache (Fanciullacci et al. 1995; Goadsby and attacks of migraine or cluster headache (May et al. Edvinsson 1994) and chronic paroxysmal hemicrania 1998b). Clearly, blockade of neurogenic plasma pro- (Goadsby and Edvinsson 1996) supports the view that tein extravasation is not completely predictive of anti- thetrigeminovascularsystemmaybeactivatedinapro- migraine efficacy in humans, as evidenced by the fail- tective role in these conditions. It is of interest in this ure in clinical trials of substance P,neurokinin-1 antag- regard that compounds which have not shown activity onists(Connoretal.1998;DienerandTheRPR100893 in human migraine, notably the conformationally re- Study Group 2003; Goldstein et al. 1997; Norman et stricted analogue of sumatriptan, CP122,288 (Knight al. 1998), specific PPE blockers, CP122,288 (Roon et et al. 1999), and the conformationally restricted ana- al. 1997) and 4991w93 (Earl et al. 1999), an endothelin logue of zolmitriptan, 4991w93 (Knight et al. 2001), antagonist (May et al. 1996) and a neurosteroid (Data were both ineffective inhibitors of CGRP release after et al. 1998). superior sagittal sinusstimulation in the cat. The recent developmentofnon-peptide,highlyspecificCGRPan- Sensitization and Migraine tagonists (Doods et al. 2000) and the announcementof proof of concept for a CGRP antagonist in acute mi- While it is highly doubtful that there is a significant graine (Olesen et al. 2004), firmly establishes this as a sterile inflammatory response in the dura mater dur- novel and important new emerging principle for acute ing migraine, it is clear that some form of sensitization migraine. takes place during migraine, since allodynia is common. About two-thirds of patients complain of pain Headache Physiology — Central Connections from non-noxious stimuli, allodynia (Burstein et al. 2000a, b; Selby and Lance 1960). A particularly in- The Trigeminocervical Complex teresting aspect is the demonstration of allodynia in Fos immunohistochemistry is a method for looking at the upper limbs ipsilateral and contralateral to thepain. activatedcellsbyplottingtheexpressionofFosprotein. This finding is consistent with at least third order neu- After meningeal irritation with blood, Fos expression ronal sensitization, such as sensitization of thalamic is noted in the trigeminal nucleus caudalis (Nozaki et neurons and firmly places the pathophysiology within al.1992),whileafterstimulationofthesuperiorsagittal the central nervous system. Sensitization in migraine sinus, Fos-like immunoreactivity is seen in the trigem- may be peripheral, with local release of inflammatory inal nucleus caudalis and in the dorsal horn at the C1 Migraine, Pathophysiology 1151

and C2 levels in the cat (Kaube et al. 1993c) and mon- 2001; Maneesi et al. 2004) offers a prospect of highly key (Goadsby and Hoskin 1997; Hoskin et al. 1999). anatomically localized treatment options. These latter findings are in accord with similar data us- ing2-deoxyglucosemeasurementswithsuperiorsagit- Higher Order Processing talsinusstimulation(GoadsbyandZagami1991).Sim- Following transmission in the caudal brain stem and ilarly, stimulation of a branch of C2, the greater occip- high cervical spinal cord information is relayed ros- ital nerve, increases metabolic activity in the same re- trally. gions, i.e. trigeminal nucleus caudalis and C1/2dor- sal horn (Goadsby et al. 1997). In experimental an- Thalamus imals, one can record directly from trigeminal neu- Processing of vascular nociceptive signals in the thala- rons with both supratentorial trigeminal input and in- mus occurs in the ventroposteromedial (VPM) thala- put from the greater occipital nerve, a branch of the mus,medialnucleusoftheposteriorcomplexandinthe C2 dorsal root (Bartsch and Goadsby 2002). Stim- intralaminar thalamus (Zagami and Goadsby 1991). ulation of the greater occipital nerve for 5 min re- ZagamiandLambert(1991)haveshownbyapplication sults in substantial increases in responses to supra- of capsaicin to the superior sagittal sinus that trigemi- tentorial dural stimulation, which can last for over an nal projections with a high degree of nociceptive input hour (Bartsch and Goadsby 2002). Conversely, stim- are processed in neurons particularly in the ventropos- ulation of the middle meningeal artery dura mater teromedial thalamus and in its ventral periphery. These with the C-fiber irritant mustard oil sensitizes re- neurons in the VPM can be modulated by activation of sponses to occipital muscle stimulation (Bartsch and GABAA inhibitory receptors (Shields et al. 2003) and, Goadsby 2003). Taken together these data suggest perhaps of more direct clinical relevance, by propra- convergence of cervical and ophthalmic inputs at the nolol through a β1-adrenoceptor mechanism (Shields level of the second order neuron. Moreover, stimula- and Goadsby 2005). Remarkably, triptans can also in- M tion of a lateralized structure, the middle meningeal hibit VPM neurons locally through 5-HT1B / 1D mech- artery, produces Fos expression bilaterally in both anisms, as demonstrated by microiontophoreticappli- cat and monkey brain (Hoskin et al. 1999), a find- cation (Shields and Goadsby 2004), suggesting a hith- ing that is consistent with the fact that up to one third erto unconsidered locus of action for triptans in acute of patients complain of bilateral pain. This group of migraine. Human imaging studies have confirmed ac- neurons from the superficial laminae of trigeminal tivation of the thalamus contralateral to pain in acute nucleus caudalis and C1/2 dorsal horns should be migraine(Afridietal.2005a;Bahraetal.2001),cluster regarded functionally as the trigeminocervical com- headache(Mayetal.1998a)andSUNCT(short-lasting plex. unilateral neuralgiform headache with conjunctival in- These data demonstrate that trigeminovascular noci- jection and tearing) (May et al. 1999). ceptive information comes by way of the most caudal cells. This concept provides an anatomical expla- Activation of Modulatory Regions nation for the referral of pain to the back of the head Stimulation of nociceptive afferents by stimulation of in migraine. Moreover, experimental pharmacological the superior sagittal sinus in the cat activates neurons evidence suggests that abortive anti-migraine drugs, in the ventrolateral periaqueductal grey matter (PAG) such as ergots (Hoskin et al. 1996), acetylsalicylic (Hoskin et al. 2001). PAG activation in turn feeds back acid (Kaube et al. 1993b), sumatriptan after blood- to the trigeminocervical complex with aninhibitory in- brain barrier disruption (Kaube et al. 1993a), eletrip- fluence (Knight and Goadsby 2001). PAG is clearly in- tan (Goadsby and Hoskin 1999; Lambert et al. 2002), cluded in the area of activation seen in PET studies in naratriptan (Cumberbatch et al. 1998; Goadsby and migraineurs (Weiller et al. 1995). This typical nega- Knight 1997), rizatriptan (Cumberbatch et al. 1997) tive feedback system will be further considered below and zolmitriptan (Goadsby and Hoskin 1996) can have as a possible mechanism for the symptomatic manifes- actions at these second order neurons that reduce cell tations of migraine. activity and suggest a further possible site for thera- Another potential modulatory region activated by peutic intervention in migraine. This action can be dis- stimulation of nociceptive trigeminovascular input sectedouttoinvolveeachofthe5-HT1B,5-HT1D and5- is the posterior hypothalamic grey (Benjamin et HT1F receptor subtypes (Goadsby and Classey 2003). al. 2004). This area is crucially involved in sev- Interestingly, triptans also influence the CGRP pro- eral primary headaches, notably cluster headache moter (Durham et al. 1997) and regulate CGRP secre- (Goadsby 2002b), short-lasting unilateral neuralgi- tionfromneuronsinculture(DurhamandRusso1999). form headache attacks with conjunctival injection and Furthermore, the demonstration that some part of this tearing (SUNCT) (May et al. 1999) and hemicrania action is post-synaptic with either 5-HT1B or 5-HT1D continua (Matharu etal. 2004b). Moreover,the clinical receptors located non-presynaptically (Goadsby et al. features of the premonitory phase (Giffin et al. 2003) 1152 Migraine, Pathophysiology

and other features of the disorder (Bes et al. 1982; Per- central noradrenergic nucleus, reduces cerebral blood outka 1997) suggest dopamine neuron involvement. flow in a frequency dependent manner (Goadsby et al. Orexinergicneuronsintheposteriorhypothalamuscan 1982) through an α2-adrenoceptor linked mechanism be both pro- and anti-nociceptive (Bartsch et al. 2004), (Goadsby et al. 1985). This reduction is maximal in offering a further possible region whose dysfunction the occipital cortex (Goadsby and Duckworth 1989). might involve the perception of head pain. While a 25% overall reduction in cerebral blood flow is seen, extracerebral vasodilatation occurs in paral- Central Modulation of Trigeminal Pain lel (Goadsby et al. 1982). In addition the main sero- Brain Imaging in Humans tonincontainingnucleusinthebrainstem,themidbrain Functional brain imaging with positron emission to- dorsal raphe nucleus can increase cerebral blood flow mography (PET) in studies during migraine without when activated (Goadsby et al. 1991). Furthermore, aura has demonstrated activation of the dorsal mid- stimulation of PAG will inhibit sagittal sinus evoked brain including the periaqueductal grey (PAG) and in trigeminal neuronal activity in the cat (Knight and Goadsby 2001), while blockade of P / Q-type voltage- the dorsal pons near the locus coeruleus (Weiller et 2+ al. 1995). Dorsolateral pontine activation is seen with gated Ca channels in the PAG facilitates trigemino- PET in spontaneous episodic (Afridi et al. 2005a) and vascular nociceptive processing (Knight et al. 2002) chronicmigraine(Matharuetal. 2004a)andwithnitro- with the local GABAergic system in the PAG still in- glycerin triggered attacks (Afridi et al. 2005b; Bahra tact (Knight et al. 2003). et al. 2001). These areas are active immediately after successful treatment of the headache but are not ac- Electrophysiology of Migraine in Humans tive interictally. The activation corresponds with the Studies of evoked potentials and event related poten- brain region that Raskin et al. (1987) initially reported tials provide some link between animal studies and and Veloso confirmed (Veloso et al. 1998) to cause human functional imaging (Kaube and Giffin 2002). migraine-like headache when stimulated in patients Authors have shown changes in neurophysiological with electrodes implanted for pain control. Similarly, measures of brain activation but there is much discus- Welch and colleagues (2001) have noted excess iron sion as to how to interpret such changes (Schoenen in the PAG of patients with episodic and chronic mi- et al. 2003). Perhaps the most reliable theme is that graine and chronic migraine can develop after a bleed the migrainous brain does not habituate to signals in into a cavernoma in the region of the PAG (Goadsby a normal way (Afra et al. 2000; Proietti-Cecchini et 2002a)orwithalesionofthepons(AfridiandGoadsby al. 1997; Schoenen et al. 1995; Wang and Schoenen 2003).Whatcoulddysfunctionofthesebrainareaslead 1998).Similarly,contingentnegativevariation(CNV), to? an event related potential, is abnormal in migraineurs compared to controls (Schoenen and Timsit-Berthier Animal Experimental Studies of Sensory Modulation 1993). Changes in CNV predict attacks (Kropp and It has been shown in the experimental animal that Gerber 1998) and preventive therapies alter and nor- stimulation of the nucleus locus coeruleus, the main malize such changes (Maertens de Noordhout et al.

Migraine, Pathophysiology, Table 2 Neuroanatomical processing of vascular head pain Structure Comments

Target innervation: Ophthalmic branch of trigeminal nerve Cranial vessels Dura mater

1st Trigeminal ganglion Middle cranial fossa nd 2 Trigeminal nucleus Trigeminal n. caudalis and C1 /C2 dorsal horns (quintothalamic tract)

3rd Thalamus Ventrobasal complex Medial n. of posterior group Intralaminar complex

Modulatory Midbrain Periaqueductal grey matter Hypothalamus Posterior and lateral nuclei

Final Cortex insulae frontal cortex anterior cingulate cortex basal ganglia Migraine, Pathophysiology 1153

1985). Attempts to correlate clinical phenotypes with why neck stiffness or pain is so common in primary electrophysiologicalchanges(Gantenbeinetal. 2004), headache. The genetics of channelopathies is opening may enhance further studies in this area. up a plausible way to think about the episodic nature of migraine. However, where is the lesion, what is ac- What Is Migraine? tually the pathology? Migraine is an inherited, episodic disorder involving Ifoneconsiderswhatpatientssay,thenperhapstheytell sensory sensitivity. Patients complain of pain in the us the answer to this question. Migraine aura cannot be head that is throbbing, but there is no reliable relation- the trigger, there is no evidence at all after 4,000 years ship between vessel diameter and the pain (Kruuse et that it occurs in more than 30% of migraine patients, al. 2003;Olesen etal. 1990) or itstreatment(Limmroth it can be experienced without pain at all and is seen in et al. 1996). They complain of discomfort from normal the other primary headaches. There is not a photon of lights and the unpleasantness of routine sounds. Some extra light that migraine patients receive over others, mention otherwise pleasant odors are unpleasant. Nor- so for that symptom and phonophobia and osmopho- mal movementof the head causes pain and many men- bia, the basis of the problem must be abnormal central tion a sense of unsteadiness as if they have just stepped processing of a normal signal. Perhaps electrophysio- off a boat, having been nowhere near the water! logical changes in the brain have been mislabeled as The anatomical connections of, for example, the pain hyperexcitability whereas dyshabituation might be a pathways are clear, the ophthalmic division of the simplerexplanation.Ifmigrainewasbasicallyanatten- trigeminal nerve subserves sensation within the cra- tional problem with changes in cortical synchroniza- nium and explains why the top of the head is headache tion (Niebur et al. 2002) or hypersynchronization (An- and the maxillary division is facial pain. The con- gelini et al. 2004), all its manifestations could be ac- vergence of cervical and trigeminal afferents explains counted for in a single over-arching pathophysiolog- M

Migraine, Pathophysiology, Figure 1 Illustration of some of the elements of migraine biology. Patients inherit a dysfunction in brain control systems for pain and other afferent stimuli, which can be triggered and are in turn capable of activating the trigeminovascular system as the initiating event in a positive feedback of neurally driven vasodilatation. Pain from cervical inputs that terminate in the trigeminocervical complex accounts for the non-trigeminal distribution of pain in many patients. Migraine has thus a pain system for its expression and brain centers and modulatory systems that deﬁne the associated symptoms and periodicity of the clinical syndrome. Brain stem changes after Bahra and colleague (2001). 1154 Migraine, Pathophysiology

ical hypothesis of a disturbance of sub-cortical sen- 17. Burstein R, Cutrer MF, Yarnitsky D (2000a) The develop- sory modulation systems (Goadsby 2003). While it ment of cutaneous allodynia during a migraine attack. Brain 123:1703–1709 seems likely that the trigeminovascular system and its 18. Burstein R, Yarnitsky D, Goor-Aryeh I et al. (2000b) An asso- cranial autonomic reflex connections, the trigeminal- ciation between migraine and cutaneous allodynia. Ann Neurol autonomic reflex (May and Goadsby 1999) act as a 47:614–624 feed-forward system to facilitate the acute attack, the 19. Connor HE, Bertin L, Gillies S et al. (1998) The GR205171 fundamental problem in migraine is in the brain. Un- Clinical Study Group. Clinical evaluation of a novel, potent, CNS penetrating NK1 receptor antagonist in the acute treat- raveling its basis will deliver great benefits to patients ment of migraine. Cephalalgia 18:392 and considerable understanding of some very funda- 20. 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• Acute medication overuse; Migraine, Preventive Therapy • Very frequent headaches (>2/week) (risk of medica- STEPHEN D. SILBERSTEIN tion overuse); Jefferson Medical College, Thomas Jefferson • Patient preference; University and Jefferson Headache Center, Thomas • Special circumstances, such as hemiplegic migraine Jefferson University Hospital, Philadelphia, PA, USA or attacks with a risk of permanent neurologicinjury. [email protected] Preventive medication groups include beta-adrenergic blockers, antidepressants, calcium channel an- Definition tagonists, serotonin antagonists, Anticonvulsant Migraine is a primary episodic headache disorder (Agent),and NSAIDs, Survey (NSAIDs). Choice is characterized by various combinations of neurologic, based on efficacy, AEs, and coexistent and comorbid gastrointestinal, and autonomic changes. Diagnosis is conditions (Table 5). The medication is started at a based on the headache’s characteristics and associated low dose and increased slowly until therapeutic effects symptoms (Silberstein et al. 2001). The International develop or the ceiling dose is reached. A full therapeutic Headache Society’s diagnostic criteria for headache trial may take 2–6 months. Acute headache medica- disorders were recently revised, and provide criteria tions should not be overused. If headaches are well for a total of seven subtypes of migraine (Headache controlled, medication can be tapered and discontin- Classification Committee 2004). This review relied on ued. Dose reduction may provide a better risk-to-benefit the Technical Reports of the Agency for Healthcare ratio. Women of childbearing potential should be on Policy and Research (Goslin et al. 1994; Gray et al. adequate contraception. 1999) and the US Headache Consortium Guidelines Behavioral and psychological interventions used for (Ramadan et al. 1999). prevention include relaxation training,thermal biofeedback combined with relaxation training, elec- Characteristics tromyography biofeedback, and cognitive-behavioral Treatment therapy (Silberstein 2004). These interventions are Migraine treatment begins with making a diagnosis effective as monotherapy, but are more effective when (Silberstein et al. 2001), explaining it to the patient, and used in conjunction with pharmacologic management. developing a treatment plan that considers coincidental or comorbid conditions. Headache calendars record Medication headache duration, severity, and treatment response. Beta(β) Blockers Propranolol, nadolol, ate- Comorbidity indicates an association between two nolol, metopropol,and timololareeffectivepreven- disorders that is more than coincidental. Conditions tive drugs (Gray et al. 1999). Their relative efficacy has that occur in migraineurs with a higher prevalence than not been established; choice is based on beta-selectivity, would be expected include stroke, epilepsy, Raynaud’s convenience, AEs, and patients’ reactions (Silberstein syndrome, and affective disorders, which include de- et al. 2001). Beta-blockers can produce behavioral AEs, pression, mania, anxiety, and panic disorder. Possible such as drowsiness, fatigue, lethargy, sleep disorders, associations include essential tremor, mitral valve pro- nightmares, depression, memory disturbance, and hal- lapse, and irritable bowel syndrome (Silberstein 2004). lucinations; they should be avoided when patients are Pharmacotherapy may be acute (abortive) or preven- depressed. Decreased exercise tolerance limits their use tive (prophylactic), and patients may require both ap- by athletes. Less common AEs include impotence, or- proaches. Acute treatment attemptsto reverse or stopthe thostatic hypotension, and bradycardia. Beta-blockers progression of a headache once it has started. It is appro- are useful for patients with angina or hypertension. priate for most attacks and should be limited to 2–3 days They are relatively contraindicated for patients with a week. Preventive therapy is designed to reduce at- congestive heart failure, asthma, Raynaud’s disease, tack frequency and severity. and insulin-dependent diabetes. Preventive Treatment Antidepressants Preventive medications reduce attack frequency, dura- Amitriptyline (a tricyclic antidepressant) is the only tion, or severity (Silberstein and Goadsby 2004; Silber- antidepressant with fairly consistent support for effi- stein et al. 2001). According to the US Headache Con- cacy (Gray et al. 1999). AEs include increased appetite, sortium Guidelines (Ramadan et al. 1999), indications weight gain, dry mouth, and sedation; cardiac toxi- for preventive treatment include: city and orthostatic hypotension occasionally occur • Migraine that significantly interferes with the pa- (Saper et al. 1994). There has been one positive trial tient’s daily routine despite acute treatment; for fluoxetine. Sexual dysfunction is a common AE. • Failure of, contraindication to, or troublesome ad- Antidepressants are especially useful for patients with verse events (AEs) from acute medications; comorbid depression and anxiety disorders. Migraine, Preventive Therapy 1159

Calcium-Channel Blockers increased appetite, and weight gain. It is not available in The Agency for Healthcare Policy and Research an- the US. alyzed 45 controlled trials (Gray et al. 1999). Flunar- Natural Products izine was effective, nimodipine had mixed results, and nifedipine was difficult to interpret. Verapamil was Feverfew (Tanacetum parthenium) is a medicinal herb more effective than placebo in two of three trials, but whose effectiveness has not been totally established. both positive trials had high dropout rates, rendering Riboflavin (400 mg) was effective in one placebo- the findings uncertain (Silberstein et al. 2001). Its most controlled, double-blind trial, with over half the pa- common AE is constipation. Flunarizine is the most tients responding. Petasites hybridus root (butterbur) effective drug of this class, but it is not available ev- is a perennial shrub. A standardized extract (75 mg erywhere. AEs include Parkinsonism, depression, and bid) was effective in a double-blind, placebo-controlled weight gain. study. The most common AE was belching (Silberstein 2004). Anticonvulsant Medications Newer Treatments Divalproex sodium (500–1000 mg) and sodium val- R proate are effective, as is the extended release for- Botulinum toxin type A (Botox 0, 25, or 75 U) showed promising results in one placebo-controlled, double- mulation (Gray et al. 1999). The most frequent AEs were nausea (42%), alopecia (31%), tremor (28%), blind trial. It was injected into glabellar, frontalis, and temporalis muscles. The 25 U treatment group was asthenia (25%), dyspepsia (25%), somnolence (25%), and weight gain (19%) (Silberstein and Collins1999). significantly better than the placebo group in reducing mean frequency of moderate to severe migraines during Hepatotoxicity and pancreatitis are the most serious AEs, but irreversible hepatic dysfunction is extremely days 31–60, incidence of 50% reduction in all migraine at days 61–90, and reduction in all migraine at days rare in adults. Baseline liver function studies should be 61–90 (Silberstein et al. 2000). obtained, but follow-up studies are probably not needed M in adults on monotherapy. Divalproex carries a high Setting Treatment Priorities (Table 1) risk of congenital abnormality. The preventive medications with the best documented Gabapentin (1800–2400 mg) showed efficacy in efficacy are the beta-blockers, amitriptyline, divalproex, a placebo-controlled, double-blind trial only when a and topiramate. Choiceismadebased onadrug’sproven modified intent to treat analysis was used. Migraine at- efficacy, the physician’s informed belief about medica- tack frequency was reduced by 50% in about one-third tions not yet evaluated in controlled trials, the drug’s of patients (Mathew et al. 2001). The most common AEs, the patient’s preferences and headache profile, and AEs were dizziness or giddiness and drowsiness. the presence or absence of coexisting disorders (Silber- Topiramate, a D-fructose derivative, has been asso- stein et al. 2001). Coexistent diseases have important ciated with weight loss, not weight gain. In two large, implications for treatment. In some instances, two or double-blind, placebo-controlled, multicenter trials, more conditions may be treated with a single drug. If in- topiramate, both 100 and 200 mg, was effective in re- dividuals have more than one disease, certain categories ducing migraine attack frequency by 50% in half of the of treatment may be relatively contraindicated. patients (Brandes et al. 2004; Silberstein et al. 2004). Dropouts due to AEs were common in the topiramate Summary groups, but did not affect statistical significance. Migraine is an extremely common neurobiologic Divalproex and topiramate are useful in patients with headache disorder that is due to increased CNS ex- epilepsy, anxiety disorder, or manic-depressive illness. citability. It ranks among the world’s most disabling They can be used in patients with depression, Raynaud’s medical illnesses. Diagnosis is based on the headache’s disease, asthma, and diabetes, circumventing the con- characteristicsand associated symptoms. The economic traindications to beta-blockers. and societal impact of migraine is substantial. It impacts Serotonin Antagonists on sufferers’ quality of life and impairs work, social activities, and family life. Increased headache frequency Methysergide is effective (Gray et al. 1999; Silber- is an indication for preventive treatment. Preventive stein 1998). AEs include transient muscle aching, clau- treatment decreases migraine frequency and improves dication, abdominal distress, nausea, weight gain, and quality of life. More treatments are being developed, hallucinations. The major complication is rare (1/2500) which provides hope to the many sufferers who are still retroperitoneal, pulmonary, or endocardial fibrosis (Sil- uncontrolled. berstein 1998). To prevent this, a 4-week medication- free interval is recommended after 6 months of continu- References ous treatment (Silberstein 1998; Silberstein et al. 2001). 1. Brandes JL, Saper JR, Diamond M et al. (2004) Topiramate for Pizotifen, a benzocycloheptathiophenederivative, is ef- Migraine Prevention: A Randomized Controlled Trial. JAMA fective (Ramadan et al. 1999). AEs include drowsiness, 291:965–973 1160 Migraine Type Headache

Migraine, Preventive Therapy, Table 1 Choices of Preventive Treatment in Migraine: Inﬂuence of Comorbid Conditions Drug Relative Contraindication Relative Indication

Beta–blockers Asthma, depression, CHF, Raynaud’s disease, diabetes HTN, angina

Antiserotonin Obesity Pizotifen

Methysergide Angina, PVD Orthostatic hypotension

Calcium channel blockers

Verapamil Constipation, hypotension Migraine with aura, HTN, angina, asthma Flunarizine Parkinson’s Hypertension, FHM

Antidepressants TCAs Mania, urinary retention, heart block Other pain disorders, depression, anxiety SSRIs Mania disorders, insomnia MAOIs Unreliable patient Depression, OCD Refractory depression

Anticonvulsants Divalproex/Valproate Liver disease, Mania, epilepsy, anxiety disorders Gabapentin bleeding disorders Mania, epilepsy, anxiety disorders Topiramate Liver disease, Mania, epilepsy, anxiety disorders bleeding disorders kidney stones

NSAIDs Naproxen Ulcer disease, gastritis Arthritis, other pain disorders

CHF, Congestive heart failure; OCD, Obsessive compulsive disorder; HTN, Hypertension; PVD, Peripheral vascular disease; MAOIs, Monoamine oxidase inhibitors; SSRI, Serotonin speciﬁc reuptake inhibitor; NSAIDs, Nonsteroidal anti-inﬂammatory drugs; TCA, Tricyclic antidepressants

2. Goslin R, Gray RN, McCrory DC (1999) Behavioral and Physi- 13. Silberstein SD, Goadsby PJ (2002) Migraine: Preventive Treat- cal Treatments for Migraine Headache. Prepared for the Agency ment. Cephalalgia 22:491–512 for Health Care Policy and Research, Contract No. 290-94-2025. 14. Silberstein SD, Neto W, Schmitt J et al. (2004) Topiramate in Available from the National Technical Information Service, Ac- the Prevention of Migraine Headache: A Randomized, Double- cession No. 127946, 1999 Blind, Placebo-Controlled, Multiple-Dose Study. For the MIGR- 3. Gray RN, Goslin RE, McCrory DC (1999) Drug Treatments for 001 Study Group. Arch Neurol 61:490–495 the Prevention of Migraine Headache. Prepared for the Agency for Health Care Policy and Research, Contract No. 290-94-2025. Available from the National Technical Information Service, Ac- cession No. 127953, 1999 4. Headache Classification Committee (2004) The International Migraine Type Headache Classification of Headache Disorders, 2nd edn. Cephalalgia 24:1–160 5. Mathew NT, Rapoport A, Saper J et al. (2001) Efficacy of Definition Gabapentin in Migraine Prophylaxis. Headache 41:119–128 6. Ramadan NM, Silberstein SD, Freitag FG (1999) Evidence- Manifestation of SLE, Sjögren’s syndrome or systemic Based Guidelines of the Pharmacological Management for vasculitides. Prevention of Migraine for the Primary Care Provider. Neurol- Headache Due to Arteritis ogy 7. Saper JR, Silberstein SD, Lake AE (1994) Double-Blind Trial of Fluoxetine: Chronic Daily Headache and Migraine. Headache 34:497–502 8. Silberstein SD (1998) Methysergide. Cephalalgia 18:421–435 Migraine Variants of Childhood 9. Silberstein SD (2004) Migraine. Lancet 363:391 10. Silberstein SD, Collins SD (1999) Safety of Divalproex Sodium in Migraine Prophylaxis: An Open-Label, Long-Term Study (for Migraine, Childhood Syndromes the Long-Term Safety of Depakote in Headache Prophylaxis Study Group). Headache 39:633–643 11. Silberstein SD, Mathew N, Saper J (2000) Botulinum Toxin Type A as a Migraine Preventive Treatment. Headache 40:445–450 12. Silberstein SD, Saper JR, Freitag F (2001) Migraine: Diagno- Migraine With Aura sis and Treatment. In: Silberstein SD, Lipton RB, Dalessio DJ (eds) Wolff’s Headache and Other Head Pain, 7th edn. Oxford University Press, New York, pp 121–237 Clinical Migraine with Aura Migraine Without Aura 1161

1 year period prevalence of migraine with or without Migraine With Pleocytosis, aura in adults is about 15% (7.6% among men and Pseudomigraine With Lymphocyctic 19.1% among women). The overall 1 year prevalence Pleocytosis of migraine with aura is about 5.8% (male 2.6%, female 7.7%). Studies in general populations agree that it is Transient Headache and CSF Lymphocytosis most common for migraineurs to have about one attack a month. In clinic samples the frequency is higher, since high frequency may be a compelling reason for referral. A large number of headache sufferers with features of Migraine Without Aura migraine fail to meet criteria for strict migraine but do meet criteria for probable migraine (attacks and / or ARNAUD FUMAL,JEAN SCHOENEN headache missing one of the features 1–4 needed to Departments of Neurology and Neuroanatomy, fulfill all criteria for migraine without aura, see above). University of Liège, CHR Citadelle, Liege, Belgium The 1 year prevalence for probable migraine was 14.6% [email protected] (15.9%in women, 12.6%in men) inarecentstudy (Patel et al. 2004). Synonyms Common Migraine; Clinical Migraine without Aura; Phenotype Hemicrania Simplex The heterogeneity of the clinical phenotype of migraine is underestimated. Despite a common diagnostic de- Definition nominator, some clinical features such as type of aura Migraine without aura (MO) is a recurrent headache symptoms, pain intensity, presence of prodromes, coex- manifesting in attacks lasting between 4 and 72 h. istence of migraine with and without aura or associated Typical features of this headache are unilateral loca- symptoms such as vertigo, may characterize subgroups M tion, pulsating quality, moderate or severe intensity, of patients bearing different underlying pathophysi- aggravation by routine physical activity and association ological and genetic mechanisms. Pain intensity can with nausea and / or photophobia and phonophobia help to distinguish migraine without aura from tension- (see Diagnostic criteria according to the International type headache (TTH); indeed among subjects in the Classification of Headache Disorders, 2nd edition or general population classified as TTH sufferers, clinical ICHD-II 2004). features suggestive of migraine, i.e. aggravation by routine physical exercise, pulsating quality, anorexia, Diagnostic Criteria of Migraine without Aura photophobia, unilateral headache and nausea may 1. At least 5 attacks fulfilling criteria 2–4 occur in non-negligible proportions. Trigger factors 2. Headache attacks lasting 4–72 h (untreated or unsuc- are manifold and may vary between patients and dur- cessfully treated) ing the disease course. The most common ones are 3. At least 2 of the following pain characteristics: stress, the perimenstrual period and alcohol. Overuse of acute anti-migraine drugs, in particular of combination a) Unilateral location analgesics and ergotamine is another underestimated b) Pulsating quality aggravating factor. There is a complex interrelation c) Moderate or severe intensity between migraine and depression, which are highly d) Aggravation by or causing avoidance of routine comorbid. It is not determined, however, whether the physical activity (e.g. walking or climbing stairs) increased prevalence of depression in patients with 4. During headache at least one of the following: frequent migraines is primary or secondary. Episodic vertigo without other signs of basilar migraine might a) Nausea and / or vomiting belong to the migraine phenotype. b) Photophobia and phonophobia 5. Not attributed to another disorder Genotype Thecommonmigrainephenotypesappeartobecomplex Characteristics genetic disorders, where additive genetic effects (susceptibility genes) and environmental factors are interre- Epidemiology lated (Stewart et al. 1997). Some studies suggest differ- The most recent population-based studies in adults, all ent liability loci for migraine headache (Estevez et al. using the diagnostic criteria of the IHS (International 2004). Migraine is characterized by recurrent attacks. Headache Society), have reached very similar preva- Geneticloadcanbeseenasdeterminingontheonehanda lence rates. Several European and American studies criticalthresholdformigraineattacks.Ontheotherhand, have reported somewhat congruent prevalence figures genetic abnormalities may induce incidental subclinical for migraine in adults (Steiner et al. 2003). The overall dysfunctions, such as, for instance, areducedneuromus- 1162 Migraine Without Aura cular junction safety factor (Ambrosini et al. 2001) or mined. Although not confirmed in every study, it may subtle cerebellar hypermetria (Sandor et al. 2001). Var- represent an endophenotypic vulnerability marker (see ious gene polymorphismswere found to be more preva- above). It could be due to low activity in raphe-cortical lent in migraineurs than in controls (Estevez et al. 2004). serotonergic pathways, which would reduce preac- Their precise role remains to be determined; some of tivation levels of sensory cortices, allowing a wider them may not be specific to migraine, but they could in- range for suprathreshold cortical activation and thus creasesusceptibilitytothedisorderandinduceendophe- enhancing intensity dependence and reducing habitua- notypic vulnerability markers (see below). tion. During the attack, when brain stem activation has been found (see above), electrophysiological methods Pathophysiology demonstrate a “normalization” of event-related and Thepresentconsensusisthatboth neuronalandvascular evoked potentials. components are relevant in migraine and most prob- Transcranial magnetic stimulation (TMS) studies to ably interrelated (Goadsby et al. 2002). The neuronal assess excitability of motor and visual cortices have structures involved are the cerebral cortex, the brain- yielded conflicting results, but taken together they stem (periaqueductal gray matter, aminergic nuclei) suggest normal or increased rather than decreased ex- and the peripheral as well as the central components citation thresholds between attacks (Schoenen et al. of the trigeminovascular system. The sequence of 2003). High frequency repetitive TMS (rTMS), which activation and the relative roles of these structures are activates the underlying cortex, is able to normalize still controversial. interictal VEPs in migraineurs, whereas low frequency rTMS, which has an inhibitory effect, induces in healthy Possible Role of the Brainstem volunteers a VEP potentiation similar to the one found During attacks of migraine without aura, an area of in- in migraine (Bohotin et al. 2002). These rTMS results creased blood flow has been identified contralaterally favor the hypothesis put forward to explain the habit- in the dorso-lateral part of the brainstem in a positron uation deficit found interictally in evoked potentials, emission tomography(PET) study (Weiller et al. 1995). i.e. that the preactivation level of sensory cortices is This led to the hypothesis of a “migraine generator” in reduced in migraineurs. the region of the dorsal raphe nucleus, locus coeruleus Metabolic studies using nuclear magnetic resonance and periaqueductal gray which would suggest that mi- spectroscopy (MRS) have shown a low mitochondrial graine is a central pain disorder and explain recurrence phosphorylation potential (Welch et al. 1989) in brain after acute antimigraine drug treatment. Consideringthe and muscles of migraineurs. Nevertheless, none of the well-knownprojectionsofsecondordertrigeminalnoci- known mutations of mitochondrial DNA has been found ceptors on the periaqueductal gray and the fact that acti- up to now in the common forms of migraine. It has been vations were found in a similar location after other spon- hypothesized that the conjunction of a decreased mi- taneous and experimental pains, it cannot be excluded tochondrial energy reserve and a deficit in habituation that the brain stem activations found in migraineurs re- of cortical information processing, known to protect flect secondary modulation of pain. against over-stimulation and lactate accumulation, Cutaneousallodyniahasbeen described during the at- might lead to activation of the trigeminovascular sys- tack, ipsilateral and contralateral to the hemicrania as tem (Schoenen 1994). Itisstillto be determined whether well as in the forearm, indicating central sensitization the mitochondrialabnormality is an independentpatho- at the level of 2nd and thereafter of 3rd order nocicep- physiological component or rather a consequence of tors (Burstein et al. 2000). This may justify the clinical other functional deficits. rule that early treatment of the attack is more effective (Burstein et al. 2004). Role of the Trigeminovascular System PossibleRoleoftheCortex The trigeminovascular system is the major pain signal- During the headache-free interval, an abnormal func- ing structure of the visceral organ brain, but there is tioning of the migrainous brain can be demonstrated still no definite proof that an activation of its peripheral by neurophysiological and metabolic studies. Neuro- components is necessary to produce a migraine attack. physiological methods show that cortical information Such activation is indeed suggested by the increase of processing in migraineurs is characterized by a defi- CGRP ( calcitonin gene related peptide) in external cient habituation during repetition of the stimulation jugular vein blood during the attack and by the effective- (see Schoenen et al. 2003 for a review). This has been ness of most acute anti-migraine medications including demonstrated for event-related and visual evoked triptans in the experimental neurogenic inflamma- potentials (VEPs). Moreover, intensity dependence tion model in the rat. It is not known what activates the of auditory evoked cortical potentials is increased in trigeminovascular nociceptive pathway in migraine. migraine patients compared to normal controls. The But a link between the migraine aura (probably due to cortical abnormality is likely to be genetically deter- a cortical spreading depression) and the headache Migraine Without Aura 1163 is suggested by the experimental finding that cortical is room for more efficient and safer oral acute migraine spreading depression is able to activate trigeminovascu- treatments, among which CGRP receptor antagonists lar afferents and to evoke a series of cortical, meningeal are at present most promising (Olesen et al. 2004). and brainstem events consistent with the development of headache (Bolay et al. 2002). Prophylactic Therapy in Migraine Prophylactic anti-migraine treatment has to be individ- Role of Nitric Oxide ually tailored to each patient taking into account the mi- Nitric oxide (NO) donors such as glyceryl trinitrate graine subtype, the ensuing disability, the patient’s his- (GTN) are able to induce attacks in patients suffering tory and demands and the associated disorders. A major from migraine with or without aura. The underlying drawback of mostclassicalprophylactics(beta-blockers mechanisms are not well established but there is clinical devoid of intrinsic sympathomimetic activity, valproic and experimental evidence that NO may favor central acid, Ca2+ antagonists, antiserotoninergics, tricyclics.), sensitization of trigeminal nociceptors. which have all on average a 50% efficacy score, is the occurrence of side effects. Treatment of Migraine In recent years some new prophylactics with fewer side Acute Treatment effects have been studied. High dose magnesium or cyclandelate are well-tolerated, but poorly effective During the last decade, the advent of highly effective in comparison to the classical prophylactics (Fig. 1). 5-HT agonists, the triptans, has been a major 1B / 1D A novel preventive treatment for migraine is high breakthrough in the attack treatment. Triptans are able dose (400 mg / d) riboflavin which has an excellent to act as vasoconstrictors via vascular 5-HT receptors 1B efficacy / side effect ratio and probably acts by improv- and to inhibit neurotransmitter release at the peripheral ing the mitochondrial phosphorylation potential (see as well as at the central terminal of trigeminal noci- above). Co-enzyme Q10 (100 mg t.i.d.), another actor ceptors via 5-HT receptors. The site of action M 1D / B in the mitochondrial respiratory chain, is also effective relevant for their efficacy in migraine is still a matter in migraine prophylaxis (see Sandor et al. 2005, also of controversy; possibly their high efficacy rate is due for review of therapeutic gain of different drugs used to their capacity to act at all three sites contrary to in migraine prophylaxis). Lisinopril (10 mg bid), an other anti-migraine drugs. Sumatriptan, the first triptan, inhibitor of angiotensin converting enzyme and, even was followed by several second-generation triptans more so, candesartan (16 mg bid) an angiotensin II (zolmi-, nara-, riza-, ele-, almo-, frova-triptan), which inhibitor well known for the treatment of hypertension, were thought to correct some of the shortcomings of were found useful in migraine. Recent preliminary sumatriptan. but encouraging results with novel antiepileptic com- A large meta-analysis of a number of randomized con- pounds like gabapentin need to be confirmed in large trolled trials performed with triptans (Ferrari et al. 2001) randomized controlled trials, whereas topiramate was confirms that the subcutaneous auto-injectable form of found to be effective in several placebo-controlled tri- sumatriptan (6 mg) has the best efficacy, whatever out- als. Non-pharmacological and herbal treatments are come measure is considered. Differences between oral increasingly subject to controlled studies and some, triptansdoexistforsomeoutcomemeasures,butinprac- like butterbur, are found to be clearly more effective tice each patient has to find the triptan that gives him the than placebo. best satisfaction. At present the major reason for not considering triptans as first choice treatments for migraine attacks is their high cost and, in some patients, their cardiovascular side effects. However, stratifying care by prescribing a triptan to the most disabled patients has been proven cost-effective. In severely disabled migraineurs, the efficacy rate of injectable sumatriptan for pain-free at 2 h is twice that of ergot derivatives or NSAIDs taken at high oral doses and of iv acetylsalicylic acid lysinate. The therapeutic gain tends to be clearly lower for simple analgesics or NSAIDs such as acetaminophen 1000 mg po, effervescent aspirin 1000 mg or ibuprofen 600 mg than for the oral triptans, when severe attacks are considered. Combining analgesics or NSAIDs to an antiemetic and / or to caffeine or administering them as Migraine Without Aura, Figure 1 Therapeutic gain in migraine preven- suppositories increases their efficacy. As expected, the tive treatment (% of “responders”, with a reduction of minimum 50% of triptans have not solved the patients’ problems. There attacks). 1164 Minimal Alveolar Concentration

References Minimal Clinical Important Difference 1. Ambrosini A, Maertens de Noordhout A, Schoenen J (2001) Neu- romuscular transmission in migraine: a single fiber EMG study in clinical subgroups. Neurology 56:1038–1043 Synonyms 2. Bohotin V, Fumal A, Vandenheede M et al. (2002) Effects of repetitive transcranial magnetic stimulation on visual evoked po- MCID tentials in migraine. Brain 125:912–922 3. Bolay H, Reuter U, Dunn AK et al. (2002) Intrinsic brain activity Definition triggers trigeminal meningeal afferents in a migraine model. Nat Med 8:136–142 The smallestdifference in score in the domain of interest 4. Burstein R, Cutrer MF, Yarnitsky (2000) The development of which patients perceive as beneficial. cutaneous allodynia during a migraine attack clinical evidence for Oswestry Disability Index the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 123:1703–1709 5. Burstein R, Jakubowski M, Collins B (2004) Defeating migraine pain with triptans: A race against the development of cutaneous allodynia. Ann Neurol 19–26 Minimal Sedation 6. Estevez M, Gardner K (2004) Update on the genetics of migraine. Hum Genet 114:225–235 Synonyms 7. Ferrarri MD, Roon KI, Lipton RB et al. (2001) Oral triptans (serotonin 5-HT(1B / 1D) agonists) in acute migraine treatment: Anxiolysis a meta-analysis of 53 trials. Lancet 358:1668–1675 8. Goadsby PJ, Lipton RB, Ferrarri MD (2002) Migraine-current Definition understanding and treatment. N Engl J Med 24:257–270 9. Olesen J, Diener HC, Husstedt IW et al. (2004) BIBN 4096 BS A drug-induced state in which the patient responds nor- Clinical Proof of Concept Study Group. Calcitonin gene-related mallytoverbalcommands.Ventilatoryandcardiovascu- peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110 lar functionsareunaffected, althoughcognitivefunction 10. Patel NV, Bigal ME, Kolodner KB et al. (2004) Prevalence and and coordination may be impaired. impact of migraine and probable migraine in a health plan. Neu- Pain and Sedation of Children in the Emergency Set- rology 63:1432–1438 11. Sándor PS, Mascia A, Seidel L et al. (2001) Subclinical cerebellar ting impairment in the common types of migraine: A 3-dimensional analysis of reaching movements. Ann Neurol 49:668–672 12. Sandor PS, Di Clemente L, Coppola G et al. (2005) Effective- ness of Coenzyme Q10 in migraine prophylaxis: A randomized Minimum Effective Analgesic Serum controlled trial. Neurology 64:713–715 13. Schoenen J (1994) Pathogenesis of migraine: the biobehavioural Concentrations of Fentanyl and hypoxia theories reconciled. Acta Neurol Belg 94:79–86 14. Schoenen J, Ambrosini A, Sandor PS et al. (2003) Evoked poten- Definition tials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin Minimum effective analgesic serum concentrations of Neurophysiol 114:955–972 fentanyl range from 0.3 – 1.5 ng/ml. 15. Steiner TJ, Scher AI, Stewart WF et al. (2003) The prevalence Postoperative Pain, Fentanyl and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia 23:519–527 16. Stewart WF, Staffa J, Lipton RB et al. (1997) Familial risk of migraine: a population-based study. Ann Neurol 41:166–172 17. The International Classification of Headache Disorders, 2nd edn Minimum Erythema Dose (ICHD-II) (2004) Cephalalgia 24:1–160 18. Weiller C, May A, Limmroth V et al. (1995) Brain stem activation MED in spontaneous human migraine attacks. Nat Med 1:658–660 19. Welch KM, Levine SR, D’Andrea G et al. (1989) Preliminary observations on brain energy metabolism in migraine studied by in vivo 31-phosphorus NMR spectroscopy. Neurology 39:538–541 Minocycline

Definition Minimal Alveolar Concentration Minocycline is used to pharmacologically block microglial activation without directly affecting neurons or Synonyms astrocytes. As a result, minocycline blocks the produc- MAC tion of microglial-derived proinflammatory cytokines. In neuropathic pain, administration of minocycline Definition disrupts exaggerated pain by inhibiting proinflamma- Alveolar concentration of a volatile anesthetic at 1 atm tory cytokines. Importantly, minocycline has revealed pressure, which abolishes motor response to a painful that microglia may be more important in the initiation, surgical stimulus in 50% of patients. rather than the maintenance, of exaggerated pain states. Alpha(α) 2-Adrenergic Agonists in Pain Treatment Cord Glial Activation Modalities 1165

Miss Rate Mnemonic Function

Deﬁnition Deﬁnition Miss rate is the probability of response „B“ when event The hippocampus plays a role in learning and mem- A has occurred. ory, especially declarative learning and memory that Statistical Decision Theory Application in Pain As- involves, at least partly, forming associations between sessment different stimuli. Nociceptive Processing in the Hippocampus and En- torhinal Cortex, Neurophysiology and Pharmacology Mitogen-Activated Protein Kinase

Synonyms Mobilisation/Mobilization MAPK Definition Definition Mobilization is the restoration of motion in a joint. MAPK mediate intracellular signal transduction in Chronic Pain in Children, Physical Medicine and Re- response to a variety of stimuli, including several hor- habilitation mones and growth factors. Among them, extracellular Passive Spinal Mobilisation signal-regulated protein kinase (ERK) is involved in cellular growth and differentiation, whereas p38 MAPK M and c-Jun N-terminal kinase (JNK) function as mediators of cellular stresses such as inflammation and Mobilisation Following Surgery apoptosis. ERK Regulation in Sensory Neurons during Inflam- mation Postoperative Pain, Importance of Mobilisation

Mittelschmerz Mobilisation With Impulse

Gynecological Pain, Neural Mechanisms Spinal Manipulation, Characteristics

Mixed-Acting Analgesics Mobilisation With Thrust

Drugswith Mixed Action and Combinations, Empha- Spinal Manipulation, Characteristics sis on Tramadol

Mixed Forms of Diabetic Neuropathy Modalities ALISON THOMAS Diabetic Neuropathies Lismore, NSW, Australia [email protected]

Synonyms MMP Electrotherapy; shortwave diathermy; therapeutic ultrasound; interferential therapy; pulsed electromagnetic Matrix Metalloproteinases therapy 1166 Modalities

Definition ers and stimulate further changes in carcinoma or infec- The term modalities is used, in practice, as a generic tion. It should not be used over a pregnant uterus (Baxter term to encompass a variety of treatments that share the and Barlos 2002). characteristic of requiring an electrical device to deliver some form of energy to the tissues of the body. That en- Indications ergymaybeanelectricalcurrent,intendedtostimulateor Based on current experimental evidence and efficacy inhibit nerve conduction, or electromagnetic or acoustic data, there are no indications for the therapeutic use of energy, intended to heat tissues by inducing agitation of shortwave diathermy. molecules within the tissue. Therapeutic Ultrasound Characteristics Mechanism Shortwave Diathermy High frequency sound waves (0.75 to 1.0 MHz) are gen- Mechanism eratedbyvibrationofapiezo-electriccrystalinthesound head of the machine. These are delivered to tissues by Application of a high frequency (27.12 MHz) electro- application of the sound head to the skin via a coupling magnetic current induces rapid movement of charged medium (a gel or water). The ultrasound head is moved ions in the target tissue. The current can be success- rhythmically over the area to be treated. There is rea- fully delivered to heat deep tissues (Mercer and Bog- sonable evidence that ultrasound heats deep tissues and duk 2004). Heating tissues results in the physiological produces a range of non-thermal effects such as cavi- reactions of increased blood flow, stimulation of pe- tation, acoustic streaming and standing waves (Mercer ripheral nerves and increased localized metabolic rate and Bogduk 2004). (Baxter and Barlos 2002). In vitro studies have identified effects on fibroblast and chondrocyte proliferation Applications in human tissue (Hill et al. 2002). Ultrasound therapy is commonly used to treat acute Applications and chronic musculoskeletal symptoms, including joint Common purported therapeutic effects are: acceleration inflammation or restriction, pain and related disability of the resolution of chronic inflammation, acceleration (Gam and Johannsen 1995; van der Windt et al. 1999). of healing, relief of pain, reduction of muscle spasm It is proposed that the underlying mechanisms include and increase in extensibility of fibrous tissue. Common increased blood flow, increased extensibility of col- applications for which shortwave diathermy is used are lagenous tissues, decreased pain and decreased muscle acute and chronic osteoarthritis, polyarthritis, rheuma- spasm (Mercer and Bogduk 2004).Ultrasound therapy toid arthritis, acute and chronic low back pain, acute is also used for the promotion of wound healing and and chronic soft tissue injuries including haematomas tissue-repair processes in both acute (soft tissue injury) and sinusitis. and chronic (ulcerative) conditions (Watson 2000). Efficacy Efficacy Experimental evidence has shown that the increase in There is evidence, from in vitro and cutaneous lesion heat in deep tissues by a shortwave diathermy does raise studies, that ultrasound has proinflammatory effects on the pain threshold in that region, but only for a period damagedtissue.Thismayjustifyoftheuseofultrasound of 30 minutes (Mercer and Bogduk 2004). It has also therapy for superficial wound healing and ulcers (Mer- been shown that the increase in heat is much less than cer and Bogduk 2004). that generated by moderate or gentle exercise (Mercer Early evidence that ultrasound therapy increases blood and Bogduk 2004), and that the effect on healing rate of flow, increasesextensibility of collagen tissue, increases wounds is equivocal. Clinical trials have generally been muscle strength and improves the strength and quality of relatively poor quality. of repair of injured tendons has not been confirmed In essence, there is little experimental or high qual- with subsequent studies (Mercer and Bogduk 2004). ity clinical data at this time to support the purported Experimental evidence of the physiological effect of therapeutic effects of shortwave diathermy. Temporary ultrasound on peripheral nerve conduction (Baxter and change in pain threshold due to heating of tissuesmay be Barlos 2002) has yet to be demonstrated to have an effected more safely and expeditiously through gentle analgesic effect. exercise. The resultsof three, recent, systematic reviewson the efficacy of ultrasound therapy for musculoskeletal disor- Side Effects dersconcluded that there waslittle or no evidence forthe Shortwave diathermy has the potential to cause burns clinical effectiveness of ultrasound therapy (Gam and (particularly in an area surrounding a metal implant or Johannsen 1995; van der Windt et al. 1999; Robertson vascular insufficiency), interfere with cardiac pacemak- and Baker 2001). Modalities 1167

Side Effects currents, which are therapeutic. It has been shown that Ultrasound has the potential to produce unstable cavita- the amplitude-modulated frequency was immaterial to tion and standing wave formation within the tissues. Un- the effects of interferential current on sensory or mo- stable cavitation occurs when the gas bubble collapses tor nerves (Palmer et al. 1999), and pain-relieving ef- and reforms. Standing wavesare createdwhenthe sound fects are not affected by different swing patterns (John- waves are reflected from a dense surface, and interfere son and Tabasam 2003a). This would indicate that the with incoming waves to produce a high concentration of medium frequency component is the main parameter in energy in the tissue. Both may result in tissue damage stimulation. It appears that interferential offers no ad- (Baxter and Barlos 2002). vantage over transcutaneous nerve stimulation for pain Ultrasound therapy should not be applied over areas of relief (Johnson and Tabasam 2003b). acute infection, artificial implants, fractures, air filled cavities, rapidly dividing tissues, bony prominences, Side Effects eyes, testicles and areas of impaired circulation or It is not recommended that interferential be used over sensation (Baxter and Barlos 2002). areas of compromised skin sensation, over the carotid sinus, pregnant uterus, cardiac pacemakers, eyes or go- Indications nads, or for the treatment of undiagnosed pain. Ultrasound may have a role in the healing of superficial Chemical burns may occur if an excessively high inten- tissues. There is no evidence to support the role of ul- sity of current is delivered. trasound in the healing of deep tissues. To date, there When suction cap electrodes are used to deliver the cur- is no conclusive evidence that ultrasound is efficacious rent, injury or bruising may result if the pressure is too in the treatment of pain associated with musculoskeletal high. injuries. Indications M Interferential Therapy On current available evidence, it appears that interfer- Mechanism ential therapy is no more efficacious in the treatment of pain than transcutaneous electrical nerve stimula- Interferential therapy is produced by two different, tion. medium-frequency currents delivered to the tissues in such a way as to produce a low frequency current in the target tissue. It is generally applied using two pairs References of electrodes, either plate (carbon-rubber) or circular 1. Baxter GD, Barlos P (2002) Electrophysical Agents in Pain suction electrodes. The suction electrodes provide a Management. In: Strong, Unrah, Wright, Baxter (eds) Pain: “massage-like” effect in addition to the current. The A Textbook for Therapists. Harcourt Publishers, Edinburgh, pp 207–226 rationale for this application has been that the medium 2. Gam AN, Johannsen F (1995) Ultrasound Therapy in Muscu- frequency currents overcome the high skin impedance loskeletal Disorders: A Meta-Analysis. Pain 63:85–91 encountered by low frequency currents. Low frequency 3. Hill J, Lewis M, Mills P, Kielty C (2002) Pulsed Short-Wave Diathermy Effects on Human Fibroblast Proliferation. Arch Phys currents can then be delivered to tissues at a greater Med Rehab 83:832–836. depth. 4. Johnson MI, Tabasam G (2003a) A Single-Blind Investigation into the Hypoalgesic Effects of Different Swing Patterns of Inter- Applications ferential Currents on Cold-Induced Pain in Healthy Volunteers. Arch Phys Med Rehabil 84:350–357 Common purported therapeutic effects include pain re- 5. Johnson MI, Tabasam G (2003b) An Investigation into the lief, stimulation of muscle fibres to produce contraction, Analgesic Effects of Interferential Currents and Transcuta- increase in blood flow and promotion of tissue healing neous Electrical Nerve Stimulation on Experimentally Induced Ischemic Pain in Otherwise Pain-Free Volunteers. Physical (Baxter and Barlos 2002). Interferential therapy has Therapy 83:208–223 been widely used for the treatment of pain and swelling 6. Mercer S, Bogduk N (2004). Selection and Application of Treat- in soft tissues injuries, and to enhance the healing of ment. In: Efshaugee RK, Gass E (eds) Musculoskeletal Phys- bone fractures. It is also one of the most commonly used iotherapy. Clinical Science and Practice, 2nd edn. Butterworth modalities for the management of back pain (Baxter Heinman (in press) 7. Palmer ST, Martin DJ, Steedman WM, Ravey J (1999) Alteration and Barlos 2002). of Interferential Current and Transcutaneous Nerve Stimulation Frequency: Effects on Nerve Excitation. Arch Phys Med Reha- Efficacy bil 80:1065–1071 8. Robertson VJ, Baker KG (2001) A Review of Therapeutic Ultra- To date, there has been little experimental data to sub- sound: Effectiveness Studies. Physical Therapy 81:1339–1358 stantiate the alleged physiological effects of interferen- 9. van der Windt DAWM, van der Heijden GJMG, van den Berg tial therapy (Watson 2000). SGM, ter Riet G, de Winter AF, Bouter LM (1999) Ultrasound The pivotal rationale in the use of interferential therapy Therapy for Musculoskeletal Disorders: A Systematic Review. Pain 81:257–271 isthatitistheeffectsofthelowfrequencycurrent,gener- 10. Watson T (2000) The Role of Electrotherapy in Contemporary atedbydifferentswingpatternsofthemediumfrequency Physiotherapy Practice. Manual Therapy 5:132–141 1168 Model of Neuropathic Pain

(Bandura 1986). Much of human behavior is presumed Model of Neuropathic Pain to be learned by modeling. This includes cognitive and motor skills, knowledge, attitudes and beliefs, values Definition and judgmental standards and emotional responses. For There are several models of neuropathic pain. Neuro- example, phobic fears can be acquired by vicarious pathic pain is induced by injury to a nerve and results instigation of emotional arousal when observing a in both mechanical and heat hyperalgesia. One model model’s fear response to an object. Social learning can involves tying loose ligatures around the sciatic nerve. serve to direct attention to stimuli that otherwise would Another model involves tying tight ligations around the be ignored. A child may increasingly become aware spinal nerves, L5 and/or L6. of bodily symptoms and interpret them as threatening TENS, Mechanisms of Action by repeated observations of a parent focusing and being preoccupied about somatic symptoms. Modeling can also exert an inhibiting or facilitating influence on previously learned behavior, since it entails learning Model of Spontaneous Neuropathic Pain about the functional value of behaviors. For example, by observing the mother receiving much attention and care from her spouse when she is verbally and nonver- Anesthesia Dolorosa Model, Autotomy bally expressing her pain, a child may as an adult be more likely to show high levels of pain behavior. It is a core characteristic of modeling that it is to be inferred Modeling, Social Learning in Pain primarily by its outcome, rather than being directly observable. Also, few learning trials are necessary for CHRISTIANE HERMANN social learning to occur. The effects of modeling are Department of Neuropsychology and Clinical not necessarily tangible in close temporal relationship Psychology, Central Institute of Mental Health, to the learning phase. Whether or not behaviors pre- Mannheim, Germany viously acquired by modeling are performed depends [email protected] on situational and motivational cues. Thus, modeling constitutes one facet of the social context in which pain Synonyms occurs. Observational Learning;modeling; Imitation Learning; Two main strategies have been followed to demonstrate Vicarious Learning the contribution of social learning in shaping pain responses, and as a risk factor for the development of Definition chronic pain. Correlational studies have focused on the co-occurrence of pain problems within families Social learning or learning by observation of others’ or, under naturalistic conditions have examined the reaction to pain, has been implicated as an important modulating impact of a positive family history of pain mechanism by which pain responses and complex pain on responses to acute pain and injury. Experimental behavior patterns are acquired (for a recent review see manipulations of modeling behavior have been used to Craig and Riddell 2003). By observing their parents delineate its direct influence on the observer’s reaction and other significant persons, children acquire attitudes to painful stimuli. about health and health care, learn to perceive and interpret physical symptoms and how to respond to Correlational Studies illness and injury (Baranowski and Nader 1985). From Since the late 1970s, several reports have noted that pain this perspective, a member in the immediate family problems tend to run in families. Studies have looked environment who suffers from chronic pain may act at the incidence of pain models within the families of as a pain model. Exposure to such a pain model at an adult and child pain patients, but also at the incidence of early age will shape the child’s future pain behavior and pain and illness in the offspring of pain patients. For ex- pain experience. Social learning of maladaptive pain ample, adult chronic pain patients as compared to pain- responses and pain behavior is then presumed to act free chronic patients indicated a greater number of fam- as a predisposing factor in the development of chronic ily members also suffering from pain (e.g. Violon and pain. Giurgea 1984). Similarly, parents of children with recurrent abdominal pain were more likely to report pain Characteristics and somatization than parents of healthy children. Fa- Learning by observing others, or modeling, enables milial aggregation of pain problems and the implied role the observer to acquire new patterns of behaviors and of modeling have also received support in non-clinical rules for regulating behavior, without having to rely samples. Among students, correlations between the re- on one’s own actions or trial and error experiences ported frequency of current pain episodes and the num- Modeling, Social Learning in Pain 1169 ber of familial pain models have been observed in sev- effects of modeling. It is well established that social eral studies (e.g. Edwards et al. 1985). In children of learning depends on the model’s attributes, and the chronic pain patients, a higher frequency of illness (but perceived similarity between observer and model. For not injuries), more days of school absence, more behav- example, sex-role information is conveyed by obser- ioral problems and greater somatic distress have been vational learning in a sex-selective manner (Bandura noted (e.g. Rickard 1988). The specific influence of a 1986). Since more women are affected by chronic pain, parental pain model on the frequency of pain in chil- girls may be more likely than boys to grow up with a drenhasnotbeenaddressedsystematically. Inonestudy, relevantpain model. Thepossiblesex-dependentimpact children of parents with chronic pain indicated a higher of social learning on pain behavior, and its interaction frequency of abdominal pain episodes than children of with sex-related genetically determined differences parentswithoutpain (Jamison and Walker 1992). Rather in pain susceptibility, certainly needs to be further little is known about whether a positive family history explored. of pain determines an individual’s response to naturally occurring or injury-related pain. Schrader et al. (1996) Experimental Studies questioned a cohort of individuals for the occurrence of The pioneering experimental work by Kenneth Craig neck and other pain 1–3 years after they had experienced has been most important in accruing empirical support a rear-end collision. A positive family history of pain for the hypothesis that social learning can account for emerged as an important risk factor for the evolution of individual differences in pain responding (for a review pain problems subsequent to the injury. see Craig 1986). Starting in the late 1960s, Craig has While being consistent with the proposed influence of conducted a series of experimental studies using varia- modeling, mere observation of the co-occurrence of tions of the following experimental paradigm. Students pain problems in families says little about the involved were exposed to a series of increasingly painful shocks learning processes. From a social learning perspective, starting with a noticeable, but not painful stimulus. one would expect at least some relationship between After each shock, the subject rated pain intensity and M the model’s and the observer’s pain behavior, coping then observed a confederate rating the same stimulus as behavior and reaction to the pain. Consistent with this either less (i.e. tolerant model) or more (i.e. intolerant assumption, students coming from families with a his- model) painful. This procedure continued for the whole tory of multiple pain problems did not only report more series of shocks. Across studies, subjects exposed to pain sites, but also indicated that their pains interfered a tolerant model as compared to those exposed to an more with their daily activities (Lester et al. 1994). intolerant model had a higher pain threshold, were less Similarly, in a group of mothers with chronic pain, autonomically aroused and indicated less subjective significant correlations were observed between the fre- stress. Moreover, signal detection analyses revealed quency of pain episodes in the child and the mother’s that subjects showed greater discrimination between perceived pain intensity, subjective pain-related inter- painful and non-painful stimuli when they had observed ference in every-day life and the level of emotional an intolerant model. As Turkat and Guise (1983) noted, distress (Jamison and Walker 1992). Altogether, these the model’s behavior served both as an antecedent and results are well in accordance with previous findings a consequence of the subject’s pain response in these on the impact of parental modeling of illness behavior studies, and therefore may have shaped the subject’s during childhood on later illness behavior. Growing up response. When this was controlled for, prior exposure with a familial pain model may increase the risk of later to a pain-tolerant or intolerant model again yielded a experiencing pain problems by learning maladaptive change of the subjects’ pain tolerance in the expected pain and illness behaviors and exacerbating responses to direction (Turkat and Guise 1983). Recently, first exper- pain. However, the social transmission of specific (mal- imental evidence for the influence of maternal modeling adaptive) pain behaviors, including coping responses, on children’s pain responses during a cold pressor test is yet to be clarified. Investigating the role of modeling was provided (Goodman and McGrath 2003). Mothers is complicated by the fact that familial pain models had been instructed to exaggerate their pain display may exert their influence in a sex-dependent manner. during a cold pressor task, while their children were Early on, pain models were found to have a greater watching. These children later had a significantly lower impact on females than on males (e.g. Edwards et al. pain threshold as compared to the control children. 1985). More recently, a higher incidence of familial Minimized maternal pain behavior did not increase the pain models in a female than a male student population children’s pain threshold. Maternal modeling also had has been noted (Koutantji et al. 1998). Moreover, in no impact on the children’s subjective pain intensity females a positive family history of pain was associated ratings during the task. with more frequent pain and an enhanced sensitivity to Overall, experimental studies have consistently demon- experimental pain stimuli (Fillingim et al. 2000). One strated that modeling can modulate the observer’s de- explanation has been that females may be more aware tection of a stimulus as painful. Whether social learn- of pain in others. Yet, it may also reflect sex-specific ing can also alter the perceived intensity and aversive- 1170 Moderate Sedation ness of a painful stimulus, is less clear. It should benoted 10. Lester N, Lefebvre BA, Keefe FJ (1994) Pain in Young Adults: that in all experimental studies, the observers could rely I. Relationship to Gender and Family Pain History. Clin J Pain 10:282–289 either on verbal responses or other overt behavioral re- 11. Prkachin KM, Craig KD (1986) Social Transmission of Natural sponses to infer that the model was detecting pain. Un- Variations in Pain Behaviour. Behav Res Ther 24:581–585 der natural conditions, however, the level of pain experi- 12. Rickard K (1988) The Occurrence of Maladaptive Health- enced by a model is less easily decoded by the observer. Related Behaviors and Teacher-Rated Conduct Problems in Children of Chronic Low Back Pain Patients. J Behav Med Whether vicariously induced emotional arousal in the 11:107–116 observer, when observing a person in pain, may shape 13. Schrader H, Obelieniene D, Bovim G et al. (1996) Natural Evolu- the intensity and quality of the observer’s later pain re- tion of Late Whiplash Syndrome Outside the Medicolegal Con- sponse, hasnotbeen studied systematically.Experimen- text. Lancet 347:1207–1211 14. Turkat ID, Guise BJ (1983) The Effects of Vicarious Experience tal studies further suggest that individual differences in and Stimulus Intensity on Pain Termination and Work Avoidance. pain sensitivity may impose constraints on the direction Behav Res Ther 21:241–245 and magnitude of the change of the pain response that 15. Violon A, Giurgea D (1984) Familial Models for Chronic Pain. can be induced by modeling influences. Moreover, the Pain 18:199–203 impact of a tolerant versus an intolerant model may not be symmetrical (e.g. Goodman and McGrath 2003). In one study (Prkachin and Craig 1986), female students were first selected based on whether they had a high or Moderate Sedation low pain threshold, and were then tested alone or in the presence of another participant with either a high or low Definition pain threshold. Results showed that only women with high pain thresholds lowered their pain threshold when Adrug-induced stateof depressed consciousnessduring exposed to a low-threshold model. Modeling had no ef- whichthepatientrespondspurposefullytoverbalorlight fect on the pain threshold in subjects with a low pain- tactile stimulation, while maintaining protective airway threshold. reflexes and airway patency. Cardiovascular function is Taken together, there is converging evidence from both usually maintained. correlational and experimental studies that social learn- Pain and Sedation of Children in the Emergency Set- ing is important in shaping an individual’s pain response ting and pain behavior, even though the exact mechanisms by which this occurs are not fully understood. Data suggest that the effects of social modeling may be modulated by the observer’s (and possibly the model’s) sex Modifications of Treatment for the Elderly and interindividual differences in pain sensitivity. Motivational Aspects of Pain Definition Psychology of Pain and Psychological Treatment The treatment protocol has to take functional, sensory and cognitive restrictions of elderly individuals into ac- References count, e.g. by facilitating comprehension and providing 1. Bandura A (1986) Social Foundations of Thought and Action: more time for a session. A Social Cognitive Theory. Prentice Hall, Englewood Cliffs, NJ PsychologicalTreatmentofPaininOlderPopulations 2. Baranowski T, Nader PR (1985) Family Health Behavior. In: Turk DC, Kerns RD (eds) Health, Illness, and Families: A Life-Span Perspective. Wiley, New York, pp 51–80 3. Craig KD (1986) Social Modeling Influences on Pain. In: Stern- bach RA (ed) Chronic Pain: Psychological Factors in Rehabil- itation. Williams and Wilkins, Baltimore, pp 73–109 Modifying Factors 4. Craig KD, Pillai Riddell RR (2003) Social Influences, Culture, and Ethnicity. In: McGrath PJ, Finley GA (eds) Pediatric Pain: Biological and Social Context. IASP Press, Seattle, pp 159–182 Definition 5. Edwards PW, Zeichner A, Kuczmierczyk AR et al. (1985) Famil- ial Pain Models: Relationship between Family History of Pain Pain related factors that may affect the assessment of and Current Pain Experience. Pain 21:379–384 pain in the newborn include gestational age (number of 6. Fillingim RB, Edwards RR, Powell T (2000) Sex-Dependent Ef- days since conception), post natal age (number of days fects of Reported Familial Pain History on Recent Pain Com- of life since birth), behavioral state (sleep/wake state), plaints and Experimental Pain Responses. Pain 86:87–94 7. Goodman JE, McGrath PJ (2003) Mothers’ Modeling Influences severity of illness, and gender. Pain expression in infants Children’s Pain During a Cold Pressor Task. Pain 104:559–565 may also be affected by developmental ability, consola- 8. Jamison RN, Walker LS (1992) Illness Behavior in Children of bility, chronic pain, environmental stimulation and re- Chronic Pain Patients. Int J Psychiatr Med 22:329–342 peated exposure to pain and stress events, medication, 9. Koutantji M, Pearce SA, Oakley DA (1998) The Relationship between Gender and Family History of Pain with Current Pain caregiving including direct parent involvement Experience and Awareness of Pain in Others. Pain 77:25–31 Pain Assessment in Neonates Molecular Contributions to the Mechanism of Central Pain 1171

sensory processing by changing the electrophysiologi- Molecular Contributions cal excitability and therefore output of sensory neurons. to the Mechanism of Central Pain Specific molecular changes shown to contribute to the development of central pain in animal models and BRYAN C. HAINS specifically to the development of pain following spinal The Center for Neuroscience and Regeneration cord injury (SCI) are described below. Research, Department of Neurology, Yale University School of Medicine, West Haven, CT, USA Ion Channels [email protected] At the most fundamental level, action potential generation and propagation by sensory neurons relies on Synonyms multiple isoforms of voltage gated sodium channels Central Pain Mechanisms, Molecular Contributions (termed Nav). The selective expression of ensembles of sodium channels tunes the biophysical properties of Definition each neuron. Within the normal nervous system, properties fundamentalto neuronal function such as activation Changes in ion channels, neurotransmitters, receptors, threshold, inactivation and refractory period, rates signaling pathways and gene expression represent im- of repriming and the ability to generate and conduct portant consequences of disease or ischemic and trau- high frequency trains of action potentials all depend maticinjuryofthecentralnervoussystemthatultimately on the type(s) of sodium channels expressed within a impact the functional state of neurons at different levels given neuron (Waxman 2000). Similarly, dysregula- of the neuraxis, leading to the development of central tion of channel expression can abnormally reconfigure pain. neuronal function in disease states. Ten genes encode The molecular organization of the structural and func- molecularly distinct voltage gated sodium channels, at tionalcomponentsofaneuronendowitwithcertainelec- least seven of which are expressed in the rat nervous M trophysiological properties. After injury to the central system. In the adult spinal cord dorsal horn, Nav1.1, nervous system, molecular reconfiguration of ion chan- Na 1.2 and Na 1.6 are strongly detectable, whereas nels, neurotransmitters and receptors takes place in no- v v Nav1.3 expression decreases with development and ciceptive neurons, leading to dysfunctional firing prop- is down-regulated in adults. In the adult spinal cord, erties and the development and maintenance of central Na 1.3 is expressed at very low levels (Fig. 1a) (Felts pain syndromes. v et al. 1997). Following SCI, expression of Nav1.3 is up-regulated in the dorsal horn (Fig. 1b) and colocalizes Characteristics 1- with NK R, a marker of nociceptive neurons. Nav1.3 Thespinalcorddorsalhorncontainstheprimarysynapse plays a role in maintaining hyperresponsiveness to pe- through which afferent somatosensory information re- ripheral stimulation as well as pain-related behaviors, lated to touch, pressure, brush, temperature and noxious as evidenced through selective knockdown of Nav1.3 stimuli is received from the periphery. Dorsal horn sen- expressionviaantisenseoligodeoxynucleotideadminis- sory neurons receive this information primarily from tration (Fig. 1c) (Hainsetal. 2003a). TheNav1.3 sodium the skin, perform a degree of processing and transmit channel produces a rapidly repriming tetrodotoxin sen- signals through distinct tracts within the spinal cord to sitive sodium current that permits neuronal firing at supraspinal structures where pain is perceived. Within higher than normal frequencies (Cummins et al. 2001). peripheral nerves and spinal cord, pain is thought to Since stimulus intensity is encoded in the dorsal horn exist simply as a signal and is subject to a degree of by the rate of firing, this change in how neurons pro- modulation by circuitry that it passes through. cess incoming sensory information serves to amplify Experimental spinal cord injury (SCI) induces electro- incoming signals, so that perceived pain thresholds are physiological changes in dorsal horn sensory neurons lowered. that contribute to pain-like behaviors in animals (Hains et al. 2003b). These include shifts in proportions of Neurotransmitters and Receptors cells responding to evoked noxious stimulation, in- Neurotransmitter molecules and their receptors produce creases and irregularity in spontaneous Background signals that cause depolarization of dorsal horn sensory Activity / Firing, increased evoked activity to (for- neurons. After SCI, neurotransmitter levels are altered merly) innocuous and noxious stimuli and increases in in a way that is facilitative to central pain. Serotonin afterdischarge activity following stimulation. Since (5-HT) is an important molecule that participates in the the nature of the applied stimuli does not change, other functional modulation of dorsal horn nociceptive neu- mechanisms must account for the alterations in stimulus rons. Released by terminals of fibers descending from processing that lead to central pain. Central changes in cell bodies located within the midline raphe nuclei of expression of molecules such as ion channels, neuro- the brain stem, 5-HT can act directly on ion channels or transmitters and their receptors, contribute to altered trigger intracellular cascades that cause neuronal depo- 1172 Molecular Contributions to the Mechanism of Central Pain

Molecular Contributions to the Mechanism of Central Pain, Figure 1 Nav1.3 mRNA is expressed at low levels in naïve animals, (a) but is upregulated in lumbar dorsal horn neurons after spinal cord injury (SCI). (b) Treatment with antisense oligodeoxynucleotides against Nav1.3 reduces Nav1.3 transcripts after SCI. (c) Corresponding unit recordings show evoked activity to peripheral stimulation (BR = brush, PR = press, PI = pinch, increasing strength von Frey filament stimulation and noxious thermal heating (47o C)), after SCI (b) compared to controls (a). After Nav1.3 antisense delivery, evoked activity of dorsal horn neurons resembles that found in naïve levels (c). larization and/or regulate intrinsic excitability. SCI re- support central pain after SCI by decreasing the in- sultsinalossofthesupplyof5-HTwithinthespinalcord hibitory influences within spinal circuitry (Drew et through interruption of descending sources (Hains et al. al. 2004). Synthesized locally, GABA is the major in- 2001). After SCI, replacement of interrupted 5-HT re- hibitory neurotransmitter and acts via ligand gated ion duces abnormal activity of dorsal horn neurons, as well channels (GABAA receptors) and G-protein coupled as pain-related behaviors. (GABAB) receptors. After SCI, reduced GABAergic Following SCI, 5-HT receptors also undergo changes inhibition results in abnormally exaggerated evoked in expression levels, a change thought to play a role and spontaneous neuronal firing through the impair- in the development of central pain. The major class of ment of GABA production or release and/or loss of 5-HT receptor found in the dorsal horn is the 5-HT1 GABA-releasing cells. family (Zemlan and Schwab 1991). Of this subset of Another mechanism for maintained hyperexcitability receptors, 5-HT1A represents a high percentage of all of dorsal horn neurons leading to central pain involves high affinity 5-HT binding sites, with highest receptor changes in the expression of metabotropic glutamate densities in laminae I and II. 5-HT1A couples an in- receptors ( mGluRs). mGluRs are G-protein coupled tracellular G-protein cascade and is up-regulated after receptors that have been subdivided into three groups, SCI (Giroux et al. 1999). Also highly represented in based on sequence similarity, pharmacology and in- the spinal cord, the 5-HT3 receptor, which gates a non- tracellular signaling mechanisms. Group I is made up selective monovalent cation channel, has been found in of mGluR1 and 5, Group II is made up of mGluR2 the substantia gelatinosa at all levels of the spinal cord and 3 and Group III is made up of mGluR4, 6, 7, and (Hamon et al. 1989). Following SCI, direct activation 8. mGluR1 is found primarily in deeper laminae of of both the 5-HT1A and 5-HT3 (Hains et al. 2002) re- the dorsal horn and mGluR5 is found at highest lev- ceptors reduces neuronal hyper-responsiveness and/or els in lamina II. mGluR2/3 is also expressed in high pain-related behaviors caudal to the injury site. 5-HT3 levels within lamina II. The differential distribution receptors are thought to be facilitatory to pain after SCI of mGluRs within laminae associated with sensory at levels rostral to the injury site (Oatway et al. 2004). processing implicates them in central pain after SCI. The 5-HT transporter protein, which regulates the ac- In the spinal cord, mGluRs directly modulate neuronal tivity level of 5-HT, undergoes up-regulated expression excitability; for example group I mGluRs decrease following SCI (Hains et al. 2001). thresholds of activation, inhibit afterhyperpolarization Reductions in spinal levels of the inhibitory neuro- and induce transient membrane depolarizations. Fol- transmitter gamma-aminobutyric acid ( GABA)also lowing SCI, mGluR1 expression increases at the level of Monosynaptic 1173 injury and mGluR2/3 expression levels are chronically 9. Hamon M, Gallissot MC, Menard F et al. (1989) 5-HT3 receptor decreased in and around the lesion site. There is also binding sites are on capsaicin-sensitive fibres in the rat spinal cord. Eur J Pharmacol 164:315–22 a chronic increase in mGluR1 in all laminae measured 10. Mills CD, Hulsebosch CE (2002) Increased expression of and a decrease in mGluR2/3 in laminae IIi, III, IV and V metabotropic glutamate receptor subtype 1 on spinothalamic (Mills et al. 2001). SCI produces an increase in mGluR1 tract neurons following spinal cord injury in the rat. Neurosci expression on spinothalamic tract neurons in both the Lett 319:59–62 11. Mills CD, Fullwood SD, Hulsebosch CE (2001) Changes in cervical enlargement and the spinal segment just rostral metabotropic glutamate receptor expression following spinal to the injury site (Mills et al. 2002). Treatment with ag- cord injury. Exp Neurol 70:244–247 onists to group II and III mGluRs affects pain responses 12. Nesic O, Svrakic NM, Xu GY et al. (2002) DNA microarray following SCI. analysis of the contused spinal cord: effect of NMDA receptor inhibition. J Neurosci Res 68:406–423 Genetic changes that may play a role in pain pathogen- 13. Oatway MA, Chen Y, Weaver LC (2004) The 5-HT3 receptor esis after SCI have been brought to light by microarray facilitates at-level mechanical allodynia following spinal cord analysis. SCI can lead to altered expression of genes injury. Pain 110:259–268 whose transcripts help to determine membrane ex- 14. Waxman SG (2000) The neuron as a dynamic electrogenic machine: modulation of sodium-channel expression as a basis for citability, including increases in mRNAs for ionotropic functional plasticity in neurons. Philos Trans R Soc Lond B Biol glutamate receptors and sodium and calcium channels Sci 355:199–213 and decreases in mRNAs for GABA receptors and 15. Zemlan FP, Schwab EF (1991) Characterization of a novel sero- potassium channels (Nesic et al. 2002). tonin receptor subtype (5-HT1S) in rat CNS: interaction with a GTP binding protein. J Neurochem 57:2092–2099 In summary, molecular events involved in the processing of afferent signals in spinal neurons significantly change following SCI. These changes endow affected neurons with maladaptive functional properties, and Monamine Oxidase Inhibitors provide the substrate to both generate and amplify incorrect signals that ultimately contribute to central M pain after SCI. Although the majority of studies re- Antidepressant Analgesics in Pain Management lated to molecular changes following central injury have focused on changes occurring at the level of the spinal cord (following spinal injury), similar changes are likely to be found at supraspinal levels. Monoamines References 1. Cummins TR, Aglieco F, Renganathan M et al. (2001) Nav1.3 Definition sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression Classification of neurochemicals based on their chem- in a mammalian cell line and in spinal sensory neurons. J ical structure (usually used to refer to serotonin, nore- Neurosci 21:5952–5961 pinephrine and dopamine). 2. Drew GM, Siddall PJ, Duggan AW (2004) Mechanical allody- Stimulation-Produced Analgesia nia following contusion injury of the rat spinal cord is associated with loss of GABAergic inhibition in the dorsal horn. Pain 109:379–388 3. Felts PA, Yokoyama S, Dib-Hajj S et al. (1997) Sodium channel alpha-subunit mRNAs I, II, III, NaG, Na6 and hNE (PN1): different expression patterns in developing rat nervous system. Monocyte/Macrophage Brain Res Mol Brain Res 45:71–82 4. Giroux N, Rossignol S, Reader TA (1999) Autoradiographic study of alpha1- and alpha2-noradrenergic and serotonin1A Definition receptors in the spinal cord of normal and chronically transected cats. J Comp Neurol 406:402–414 Monocytes are circulating immune/inflammatory cells 5. Hains BC, Fullwood SD, Eaton MJ et al. (2001) Subdural en- that originate in bone marrow and differentiate into graftment of serotonergic neurons following spinal hemisection macrophages after migrating through blood vessel restores spinal serotonin, downregulates serotonin transporter, walls into tissues. and increases BDNF tissue content in rat. Brain Res 913:35–46 6. Hains BC, Willis WD, Hulsebosch CE (2002) Serotonin recep- Wallerian Degeneration tors 5-HT1A and 5-HT3 reduce hyperexcitability of dorsal horn neurons after chronic spinal cord hemisection injury in rat. Exp Brain Res 149:174–186 7. Hains BC, Johnson KM, Eaton MJ et al. (2003a) Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability Monosynaptic of dorsal horn neurons after spinal hemisection in rat. Neuro- science 116:1097–1110 8. Hains BC, Klein JP, Saab CY et al. (2003b) Upregulation of Definition sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after Pertaining to a single synapse. spinal cord injury. J Neurosci 23:8881–8892 Amygdala, Pain Processing and Behavior in Animals 1174 Mood

Mood Morbus Sudeck

Definition Complex Regional Pain Syndromes, General Aspects DSM4 APA: Includes mood disorders associated with Sympathetically Maintained Pain in CRPS I, Human depression: depressive disorders, bipolar disorders, Experimentation mood disorders due to a general medical condition and substance-induced mood disorder, as well as anxiety: especially post traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety Morning Stiffness disorder due to a general medical condition, substance- induced anxiety disorder and anxiety disorder not otherwise specified. Other mood states may include anger, Definition frustration, fear and disappointment. In arthritis, morning stiffness of joints and muscles may Pain Assessment in the Elderly last for several hours. Muscle Pain in Systemic Inflammation (Polymyalgia Rheumatica, Giant Cell Arteritis, Rheumatoid Arthri- tis) MOP Receptor

Deﬁnition The term μ-opioid (μ from morphine) peptide receptor Morphine represents the G-protein coupled receptor that responds selectively to the majority of clinically useful opioid Deﬁnition drugs. It is expressed in areas of the nervous system that mediate therapeutic and adverse effects of most opioid Morphine is a strong (potent) naturally-occurring opi- drugs. The MOPreceptor protein isproducedby a single ate (a phenanterene derivative) produced from extracts gene. Several mRNA splice variants are known to exist of the poppy plant. Morphine undergoes extensive and produce receptor proteins that display different hepatic biotransformation by phase II reactions to Mor- properties when expressed in cells. When activated, phine – 3 – glucuronide (70%) and morphine – 6 – glu- the MOP receptor predominantly transduces actions curonide (5–10%) and the remainder undergoes sul- via inhibitory G-proteins. The electrophysiological phation. consequences of MOP receptor activation are usually Forebrain Modulation of the Periaqueductal Gray inhibitory. Postoperative Pain, Morphine Mu(μ)-Opioid Receptor Opioid Electrophysiology in PAG

Morphine and Muscle Pain MOR–1 Opioids and Muscle Pain Deﬁnition A clone encoding a mu opioid receptor. Opioid Receptors Morphine Sulphate

Postoperative Pain, Morphine Moral Hazard

Deﬁnition Morphine Tolerance When the presence of insurance changes a disability claimant’s or health care providers behavior. Disability Incentives Glutamate Homeostasis and Opioid Tolerance Morphology, Intraspinal Organization of Visceral Afferents 1175

with terminal swellings in the adjacent white mater of Morphology, Intraspinal Organization lateral and dorsal funiculi, in addition to terminal of Visceral Afferents branches in the spinal dorsal horn, revealing a distinctly different pattern of termination from somatic YASUO SUGIURA afferent C-fiber terminals (Fig. 1). Along the longitu- Nagoya University School of Medicine, Graduate dinal axis of the spinal cord, visceral afferent C-fibers School of Medicine, Department of Functional terminate with about 20 collateral branches, which Anatomy & Neuroscience, Nagoya, Japan are given off at 3–400μm spans in several spinal [email protected] segments from rostral and caudal branches. The rostral branch of the C-fiber shown in Figure 2 runs in Synonyms the surface of the dorsal funiculus, which may project Synaptic Organization of Afferent Fibers from Viscera to the dorsal column nucleus (Nucleus gracilis), part in the Spinal Cord of a new tract for visceral pain (Fig. 2) (Al-Chaer et al. 1998). Each collateral branch ramified in a relative Definition narrow sheet consisting of only one or two daughter Visceral afferent Aδ-and CFiberconvey sen- branches, which did not form a concentrated nest-like sory information from the viscera via vagal and spinal termination commonly seen with somatic C-fibers. The nerves. Intraspinal organization of visceral afferents is collateral branches have 250–300 terminal swellings, composed of the large number of sympathetic afferents forming an array arranged in the orientation of the which mediate pain, and a small number of the vagal neuropil of the spinal laminae (Sugiura et al. 1993). afferents. The afferent terminals make synapses with The number of terminal swellings is summarized in dendrite of the projecting or internuncial neurons or Table 1. About 5000 to 6000 enlargements (boutons) axons of inhibitory neurons in the spinal cord. were identified in visceral afferent C-fibers. Over 60% of visceral terminal swellings are found in the super- M Characteristics ficial dorsal horn, lamina I and adjacent area, which Terminal Distribution in the Spinal Cord seems to be the main region of termination. About 10% of terminal swellings are found in deeper dorsal horn Visceral afferent fibers terminate in the superficial (I, II) (laminae IV and V). A few visceral fiber boutons are in spinal laminae (see Spinal cord laminae) and deeper other laminae. (IV–V, X) spinal laminae (de Groat et al. 1978). A single visceral afferent C- fiber can project to the dorsal, superficial spinal cord and also in laminae V and X Synaptic Organization of the contralateral spinal cord (Sugiura et al. 1989). Light microscopic examination gives us some infor- Visceral afferent C-fibers have collateral branches mation about the terminal swellings (boutons). The

Morphology, Intraspinal Organization of Visceral Afferents, Figure 1 A transverse reconstruction of the central projection of a visceral afferent C-ﬁber. One of the collaterals could be traced to synaptic enlargements in lamina II. Broken lines indicate borders of Laminae I, II, and III; LF, Lateral funiculus; DF, dorsal funiculus; CC, central canal. (Sugiura et al. 1989) 1176 Morphology, Intraspinal Organization of Visceral Afferents

Morphology, Intraspinal Organization of Visceral Afferents, Figure 2 Saggital view of reconstructions of the arborization of visceral afferent C- ﬁbers. On entering the spinal cord (arrow head), the axon bifurcated into rostral and caudal main branches. The main branches ran on the dorsal surface of the dorsal funiculus or in Lissauer’s tract, as far rostrally as the 10th thoracic segment (top left) and as far caudally as the 2nd lumbar segment (bottom right). Many collaterals left these parent branches to terminate in laminae I(I) and II(II). Some collaterals also terminated in the lateral funiculus (LF) and the ipsilateral or contralateral laminae V(V, CV) and X(X, CX). The asterisk in a circle (bottom) shows the terminal proﬁles in lamina II, which is indicated by the circle in the upper view.

Morphology, Intraspinal Organization of Visceral Afferents, Table 1 Number of Terminal Swellings Visceral Fibers* Somatic Fibers Case Number 10588 30488 70887 72987

Number of swellings 6099(100) 5370(100) 1482 1450

Number of terminal areas 22 18 1 2

Mean number of areas 277 298 - 725

Dorsal funiculus 359(5.9) 1089(20.3)

Lamina I 3735(61.2) 2466(45.9)

Lamina II 240(3.9) 151(2.8)

Lamina IV and V 391(6.4) 553(10.3)

Lateral funiculus 276(4.5) 21(0.4)

Lamina X 171(2.8) 153(2.8)

Contralateral X 121(2.0) 61(1.1)

Contralateral VI and V 108(1.8) 142(2.6)

Total 5401(88.6) 4636(86.3)

*Number and (percentage). terminal swellings of visceral afferent C-ﬁbers ranged terminal swellings occupy a smaller fraction (one third 1.6 to 1.7μm in diameter and are 4.3 to 5.7μm2 in area to one half) of somatic terminal swellings. each, which is smaller than those of somatic afferents. In electron microscopy, primary afferent terminals in If presented graphically, the distribution of visceral the spinal cord generally show a central synaptic proﬁle Morphology, Intraspinal Organization of Visceral Afferents 1177

Morphology, Intraspinal Organization of Visceral Afferents, from C-fiber terminals of the somatic organ (skin and Table 2 Incidence of Central Terminals of Primary C Afferents muscle) (Ling et al. 2003). The laminar arrangement Fraction Percentage of visceral afferent C-fiber terminals suggests that somatovisceral convergence on neurons in lami- Somatic fiber: nae I and V arise from somatic myelinated and visceral High-threshold mechanoreceptor 24/32 75.0 unmyelinated fibers. This system may be committed Polymodal nociceptor 13/16 81.03 to referred pain, whereas some somatic unmyelinated afferents may only subserve the transmission of noci- Mechanical cold nociceptor 53/63 84.1 ceptive information to secondary neurons in the dorsal Warming receptor 12/38 31.5 horn. Visceral afferent fibers terminate in single or straight Visceral fiber: form of terminal branches. Compared with the concen- Superficial layer 3/29 10.3 trated focus of somatic terminations, visceral C afferents appear in thin sheets of termination having one or Deeper layer 10/38 26.3 two terminalbrancheswith severalenlargementsateach terminal focus. These terminal features may reveal the composed of axons and some dendritic spines. In so- morphological background for the poor localization and matic nociceptors, over 75% of terminals show central possibly vagueness of referred pain (Cervero 1994). synaptic profiles, but visceral afferent terminals show a The size of terminal boutons on visceral afferent C simple synapse and less than 30% of terminals show fibers is smaller than the boutons found on many kinds central synaptic profiles (Table 2) (reviewed in Sugiura of myelinated fiber terminals (Brown et al. 1981) and and Tonosaki 1995). those of somatic afferent C-fibers (Sugiura et al. 1995). A great number of visceral afferent cell bodies in dor- This difference in size may have relevance to the recep- sal root ganglia contain neuropeptides, especially sub- tor or to the nature of the synaptic transmission in the M stance P, calcitonin-gene related peptide, somatostatin dorsal horn. The size of terminal swellings of visceral andvasoactiveintestinalpeptide,andsomeareIB–4pos- afferent fibers seems to reflect the morphological vari- itive. ety of synaptic ultrastructural profiles (Ribeiro da Silva and Coimbra 1982, Alvarez et al. 1993). Functional Exploration from Morphological Organization Somatic C-fiber nociceptors make central terminal pro- Visceral afferent C-fibers terminate in spinal lam- files, which have various shapes according to the ade- ina I and V, similar to terminals thinly myelinated quate noxious stimulus: high threshold nociceptor, cold fibers from somatic nociceptors, which are different nociceptor or polymodal nociceptor. These ultrastruc-

Morphology, Intraspinal Organization of Visceral Afferents, Figure 3 An ultrastructural profile of a visceral afferent C-fiber. A visceral afferent terminal has simple synaptic contacts with post synaptic elements. To easily identify the synaptic relation, a schematic illustration is drawn (right bottom). Bar; 1 μm (modified from Sugiura et al. 1992, Sugiura & Tonosaki 1995). 1178 Morris Water Maze tural profiles may reveal the possibility of pain modula- Cingulate Cortex, Nociceptive Processing, Behav- tion at the synaptic site of central terminals (Wall 1989). ioral Studies in Animals Contrary to the somatic nociceptors, most visceral afferent C-fiber terminals show simple synaptic profiles. This means that these terminals transmit peripheral inputs to secondary neurons or elements, without modu- Morton’s Neuroma lating the information at the synaptic site. In this interpretation, somatic central terminals may be essential to Definition transmit pain from peripheral somatic tissues to the cen- tralnervoussystem,butvisceralpainmaybetransmitted Morton described a painful condition of the fourth toe by other mechanisms or mediated by small numbers of of the foot, which, over time, has been interpreted as being due to a neuroma of the interdigital nerve to the central terminals. If we presume that these central termi- rd th nals mainly mediate visceral pain, visceral pain would 3 /4 webspace of the foot. Tradition has called this a be a vague, strange feeling and not definitive for no- neuroma, and the traditional treatment has been to re- ciception. sect this nerve, which creates a true neuroma. Light and electron microscopy has demonstrated that the excised References nerve has chronic compression and not neuroma forma- 1. Al-Chaer ED, Feng Y, Willis WD (1998) A Role for the Dor- tion. Today, the approach includes a neurolysis, rather sal Column in Nociceptive Visceral Input into the Thalamus of than an excision, of this nerve. Primates. J Neurophysiol 70:3143–3150 Painful Scars 2. Alvarez FJ, Kavookjian AM, Light AR (1993) Ultrastructural Morphology, Synaptic Relationships, and CGRP Immunoreac- tivity of Physiologically Identified C-Fiber Terminals in the Mon- key Spinal Cord. J Comp Neurol 329:472–490 3. Brown AG (1981) Organization in the Spinal Cord: The Anatomy Motif and Physiology of Identified Neurons. Springer-Verlag, New York, pp 1–138 4. Cervero F (1994) Sensory Innervation of the Viscera: Peripheral Definition Basis of Visceral Pain, Physiol Rev7:495–138 5. de Groat WC, Nadelhaft I, Morgan C, Schauble T (1978) The motif is the region of a protein that is responsible Horseradish Peroxidase Tracing of Visceral Afferent and Pri- for binding or functional action, which is homologous mary Afferent Pathways in the Cat’s Sacral Spinal Cord using Benzidine Processing. Neurosci Lett 10:103–108 to other proteins of like function. 6. Ling L-J, Honda T, Shimada Y, Ozaki N, Shiraishi Y, Sugiura Y Trafficking and Localization of Ion Channels (2003) Central Projection of Unmyelinated (C) Primary Afferent Fibers from Gastrocunemus Muscle in the Guinea Pig. J Comp Neurol 461:140–150 7. Ribeiro da Silva A, Coimbra A (1982) Two Types of Synaptic Glomeruki and their Distribution in Laminae I–III of the Rat Motivation Spinal Cord. J Comp Neurol 209:176–186 8. Sugiura Y,Terui N, Hosoya Y (1989) Difference in Distribution of Central Terminals between Visceral and Somatic Unmyelinated Definition (C) Primary Afferent Fibers. J Neurophysiol 62:834–840 9. Sugiura Y,Terui N, Hosoya Y,Tonosaki Y,Nishiyama K, Honda T Motivation is that which contributes or leads to the ini- (1993) Quantitative Analysis of Central Terminals Projections of tiation, direction, persistence, intensity, or termination Visceral and Somatic Unmyelinated (C) Primary Afferent Fibers of behavior. in the Guinea Pig. J Comp Neurol 332:315–325 10. Sugiura Y, Tonosaki Y, Nishiyama K, Honda T, Oda S (1992) Motivational Aspects of Pain Organization of the central projections of unmyelinated primary Psychology of Pain and Psychological Treatment afferent fibers. In: Inoki R, Shigenaga Y, Tohyama M (eds) Pro- cessing and Inhibition of nociceptive information. Excerpta Med- ica, Amsterdam, pp 9–13 11. Sugiura Y, Tonosaki Y (1995) Spinal Organization of Unmyeli- nated Visceral Afferent Fibers in Comparison with Somatic Af- Motivational-Affective ferent Fibers. In: Gebhalt GF (ed) Visceral pain, Progress in Pain research and Management, vol 5. IASP Press, Seattle, pp 41–59 12. Wall PD (1989) Introduction. In: Wall PD, Merzack R (eds) Text Definition of Pain, 2nd edn. Churchill Livingstone, Edinburgh, pp 1–18 Responseto nociceptivestimuliinvolving theemotional (limbic)andvisceralcomponents,includingresponseby Morris Water Maze homeostatic systems responsible for regulation of blood pressure, respiration rate, and responses involving the hypothalamic-pituitary-adrenal axis. Definition Spinomesencephalic Tract Morris water maze is a behavioral test used to measure SpinothalamicTractNeurons,DescendingControlby spatial and working memory. Brainstem Neurons Motivational Aspects of Pain 1179

management strategies (such as pain-contingent rest Motivational-Affective and guarding) because such strategies are followed Aspects/Components of Pain by reinforcement. Motivation for change therefore results when the contingencies are changed; for example, Definition by encouraging and praising adaptive coping efforts and ignoring maladaptive ones. Cognitive-Behavioral The pain experience includes motivational and affec- Theory views behavior as a complex interaction of tive aspects/components, such as negative emotions cognitive structures, processes and their consequences. and arousal. Cognitive-Behavioral Therapy for chronic pain uses Parafascicular Nucleus, Pain Modulation various strategies for helping patients change maladap- Spinothalamic Input, Cells of Origin (Monkey) tivecognitionsthatcontributeto bothpainandsuffering, Thalamic Nuclei Involved in Pain, Cat and Rat and also integrates a number of other techniques for Motivational Aspects of Pain modifying, teaching, and encouraging adaptive coping skills ( positive reinforcement, biofeedback,self- control techniques) (Bradley 1996). Expectancy-value Motivational Aspects of Pain models of motivation and health behavior change posit that motivation for behavior and behavior change is MARK P. J ENSEN determined by patient beliefs (expectancies) and values Department of Rehabilitation Medicine, University of (incentives) (Bandura 1986; Janz and Becker 1984; Washington, Seattle, WA, USA Rogers 1983). According to these models, motiva- [email protected] tion for behavior change increases as people believe that the benefits of change outweigh the costs, and as Synonyms they increase their beliefs that change is possible. The Transtheoretical Model of behavior change (Prochaska M Incentive; drive and DiClemente 1984) emphasizes the fact that peo- Definition ple vary in their readiness (or motivation) to make change, and classify readiness into five distinct stages: Motivation refers to the initiation, direction, persis- precontemplation, contemplation, preparation, tence, intensity, and termination of behavior (Landy and action,and maintenance. This model argues that Backer 1987). According to most theories of motiva- different therapeutic responses may be used to help tion, the primary factorsthatlead to behaviorchange can patients move from one stage of readiness to the next, be classified as falling into two categories: (1) the per- until the patient is able to maintain the change for good. ceived importance of behavior change and (2) the be- Although there has been debate concerning whether lief that behavior change is possible (i.e. self-efficacy readiness to change is best thought of as a stage or Bandura 1986). continuous dimension, few researchers question the importance of the readiness construct, especially when Characteristics determining the approach best taken with a particular As the management of chronic pain depends more on patient (see Jensen et al. 2003). Finally, client-centered what patients do than on what is done to them, patient approaches to patient motivation, such as Motivational motivation for pain self-management represents an es- Interviewing and the Patient-Centered Counseling sential, yet under-studied aspect of clinical care (Jensen Model, have identified specific therapeutic responses et al. 2003). The more that clinicians understand moti- that increase patient motivation for adaptive behav- vation and the factors that contribute to motivation for ior change, including such responses as developing pain self-management, the better they will be at help- a collaborative (rather than confrontive) relationship, ing patients learn, practice, and use adaptive pain self- eliciting and reinforcing patient self-statements con- management coping strategies. sistent with adaptive change, and increasing patient awareness of the risks of maladaptive responses, while Theories of Health Behavior and Health Behavior Change at the same time encouraging patient beliefs that adap- A number of theories and models have been devel- tive change is possible (Miller and Rollnick 2002; oped that address the motivational issues that impact on Ockene et al. 1988). health behavior and health behavior change: the operant model, Cognitive-BehavioralTheory,expectancy-value Clinical Implications of the Motivation Models models, the Transtheoretical Model, and client-centered for Enhancing Patient Self-Management approaches. The operant learning theory of chronic pain Cliniciansmayusethemotivationalmodelsofhealthbe- emphasizesthe role thatenvironmental contingencies havior change as guides when helping motivate patients have on pain behavior (Fordyce 1976). According to with chronic pain make adaptive changes. For example, this model, patients continue to use maladaptive pain based on the transtheoretical model, clinicians would 1180 Motivational Aspects of Pain

Motivational Aspects of Pain, Figure 1 Motivational factors that contribute to pain self-management behaviors. be wise to assess a patient’s readiness to participate in ing them to argue against and therefore resist making whatever specific pain treatment(s) is/are being recom- adaptive changes (Miller and Rollnick 2002). A more mended (e.g. by stating “I think that this intervention is effectivestrategyistofirstprovideinformation,andthen worth trying.” and then asking, “What do you think?”). encourage the patient to discuss and think through the This is particularly important if the treatment involves implications of this information for his or her own pain active patient participation to be effective (such as keep- problem; that is, to elicit from the patient his or her own ing to a specific medication regimen, relaxation or self- thoughts concerning the information provided, and es- hypnosis training, and active physical or occupational pecially to pay attention to and reinforce patient state- therapy, etc.). If the patient expresses a clear disinterest ments indicating incorporation of the information. Pa- in the planned treatment approach (i.e. is in the “pre- tients are much more likely to believe what they them- contemplation stage” concerning this approach), then selves say than what is told to them (Miller and Roll- minimal participation can be expected, leading to few nick 2002). benefits. In this case, specific motivational interventions Theimportancethatpatientsplaceonanyparticularpain should be considered to help increase patient readiness coping responsecan also bechangedby altering thecon- to engage in treatment. However, motivational interven- tingencies surrounding that response (Fordyce 1976). tions can be useful at all readiness levels, to maximize Clinicians can, and should, praise and reinforce approx- patient commitment to active participation throughout imations towards adaptive coping, and seek to ignore treatment. coping responses associated with greater dysfunction. A variety of clinician behaviors and responses will in- Patients’ attention on their efforts towards adaptive crease patient motivation for engagement in active pain coping can be emphasized by asking questions about management. Most of these can be classified as inter- these efforts, and helping the patient come up with ventions that impact either the importance the patient solutions to problems associated with the use of new places on participating in treatment, and/or the beliefs adaptive coping strategies. Such discussion can help that participation is possible (see Fig. 1). focus patients’ attention on adaptive coping efforts. To increase the importance for engaging in regular ex- Patients, and the people who are close to the patient, ercise, for example, clinicians could start with provid- can also be taught operant principals, and be encour- ing patients with information concerning the long-term aged to integrate regular reinforcement for adaptive (negative) effects of inactivity and the benefits of regular coping (e.g. exercise contingent rest, praise for regular exercise. However, information alone is unlikely to pro- exercise) (Fordyce 1976). duceachangemotivationforexercise,oranyotheradap- Self-efficacy for adaptive coping can also be increased tive coping behavior, unless patients incorporatethis in- in a number of ways. One of these is to simply encourage formation into their belief system. Merely lecturing pa- patients to engage (slowly at first) in new adaptive cop- tients can, in fact, have a paradoxical effect of pushing ing efforts. As the patient sees himself/herself engage in patients into the position of defending their current maladaptive coping, he/she learns that such coping is possi- adaptive (e.g. inactivity, rest) coping responses, caus- ble. Such direct experience is perhaps the most powerful Motor Cortex, Effect on Pain-Related Behavior 1181 strategy for increasing self-efficacy (Bandura 1986). Self-efficacy can also be increased by observing others Motivational Reactions engage in the behavior ( modeling), such as occurs when pain treatment is provided in a group setting. Definition Eliciting from patients their past successes at chang- Motivational reactions are basic behaviors induced by ing behavior (Miller and Rollnick 2002), and directly a homeostatic necessity. Awakening, aggression, flight, addressing perceived barriers, can also increase self- freezing or hypotonic immobility in response to a nox- efficacy for adaptive pain self-management. ious event. By understanding that patient motivation is a state that Parabrachial Hypothalamic and Amydaloid Projec- can vary as a function of clinician responses, and by en- tions gaging in responses that increase the importance thatpa- tients place on adaptive coping and patient beliefs that adaptive coping is possible, clinicians can help patients increase their motivation for engagement in treatment Motor Cortex andadherencetotreatmentrecommendations.Totheex- tentthatthetreatmentiseffective,motivationalinterven- Definition tions can therefore lead to improved outcomes for many patients. Primate pre-central cortex receiving inputs from cerebellar receiving zones of thalamus and projecting to the spinal cord, striatum and pontine nuclei. Histologically References identifiedbythepresenceoflargepyramidalcellsindeep 1. Bandura A (1986) Social Foundations of Thought and Action: layers of cortex. A Social Cognitive Theory. Prentice Hall, Englewood Cliffs, NJ Pain Treatment, Motor Cortex Stimulation 2. Bradley L (1996) Cognitive-Behavioral Therapy for Chronic Pain. In: Gatchel R, Turk D (eds) Psychological Approaches to M Pain Management: A Practitioner’s Handbook. Guilford Press, New York, pp 131–147 3. Fordyce W (1976). Behavioral Methods for Chronic Pain and Motor Cortex, Effect Illness. Mosby, Saint Louis, MO 4. Janz N, Becker M (1984) The Health Belief Model: A Decade on Pain-Related Behavior Later. Health Educ Q 11:1–47 5. Jensen MP, Nielson WR, Kerns RD (2003). Toward the Devel- LUC JASMIN,PETER T. OHARA opment of a Motivational Model of Pain Self-Management. J Department of Anatomy, University of California San Pain 4: 477–492 Francisco, San Francisco, CA, USA 6. Landy F, Becker W (1987) Motivation Theory Reconsidered. [email protected], [email protected] Research in Organizational Behavior 9:1–38 7. Miller W, Rollnick S (2002) Motivational Interviewing: Prepar- ing People to Change, 2nd edn. Guilford Press, New York Definition 8. Ockene J, Quirk M, Goldberg R, Kristeller J, Donnelly G, Kalan K, Gould B, Greene H, Harrison-Atlas R, Pease J, Pick- Electrical stimulation of the primary motor cortex ens S, Williams J (1988) A Residents’ Training Program for (M1) is routinely used to relieve intractable pain in the Development of Smoking Intervention Skills. Arch Intern humans. Stimulating electrodes are placed over the Med 148: 1039–1045 9. Prochaska J, DiClemente C (1984) The Transtheoretical Ap- primary motor cortex and used to deliver an electrical proach: Crossing Traditional Boundaries of Therapy. Dow Jones current, which activates the underlying neurons. For Irwin, Homewood, IL reasons that are not yet well understood, this leads to 10. Rogers R (1983) Cognitive and Physiological Processes in Fear- a reduction in certain types of chronic pain without Based Attitude Change: A Revised Theory of Protection Motiva- tion. In: In Cacioppo J, Petty R (eds) Social Psychophysiology: affecting thoughts, mood, motor function or other sen- A Sourcebook. Guilford Press, New York, pp153–176 sation of any kind including acute pain perception. The electrodes can be left in placed and can be effective for years.

Characteristics Motivational Components Electrical stimulation of the motor cortex in humans results in the relief of chronic, intractable pain that is not responsiveto other therapies. Stimulating themotor cor- Definition tex for thispurposeseemscounterintuitive,asonewould Motivational components are a group of basic behaviors assume that the primary somatosensory cortex (SI) is a induced by a homeostatic survival necessity. Awaken- more logical target for interventions aimed at relieving ing, falling asleep, aggressive/defensive reaction, vocal- pain. However, large lesions of the primary somatosen- ization, flight, freezing, and hypotonic immobility. sory cortex in humans rarely disrupt pain sensation and Hypothalamus and Nociceptive Pathways direct electrical stimulation of the cortex in hundreds 1182 Motor Cortex, Effect on Pain-Related Behavior of cases of conscious surgery rarely produced pain sen- central or, occasionally, neuropathic pain has become a sations. Furthermore, from modern functional imaging standard procedure. In most cases, the motor cortex on studies, we know that the sensory, not the motor cortex, the side contralateral to the area of the body that hurts is often activated by nociceptive stimuli (Bushnell et al. is stimulated. Ipsilateral stimulation is usually reserved 1999). for patients in whom the contralateral motor cortex is If activation of the cerebral cortex is necessary for damaged, most often following an ischemic event. the perception of pain, changing the cortical activity Motor cortex stimulating electrodes are implanted using should alter its experience. Proof of this emerged in standard surgical techniques. The precise details vary the early 1990s, largely through the pioneering work according to the particular preferences of the surgeon of Tsubokawa and colleagues (Hirayama et al. 1990; but there islittle evidence that anydifferencehere affects Tsubokawa et al. 1991, 1993) who reported that stimu- the efficacy of the procedure as long as the localization lating the motor cortex is often successful in relieving of the electrodes is adequate. The surgery is carried central pain (i.e. pain due to lesion of the CNS). The out under general or local anesthesia and the cranium effectiveness of motor cortex stimulation might seem is opened exposing the dura mater (the thick opaque puzzling, particularly if one adopts a textbook view meningeal layer covering the brain). The bony open- of the nervous system and sees the motor and sensory ing consists of one or more small burr holes or a small systems as separate entities. However, it has long been cranial flap. The dura mater can be left intact or opened known that stimulation of the motor gyrus can produce to allow direct visualization of the cerebral cortex. The sensory responses and anatomical studies have shown cortical area to be stimulated is then localized. With connections between somatosensory and motor cortices the existing technology one cannot stimulate the entire providing support for interaction between the motor motor cortex, which means that for patients with pain and sensory systems. that extends to an entire hemibody, the neurosurgeon In a series of articles beginning in 1990, Tsubokawa and patient have to first agree on where the pain is and colleagues (Hirayama et al. 1990; Tsubokawa et al. maximal and if relieving that painful area leaving the 1991; Tsubokawa et al. 1993) described stimulating the others untouched would be worthwhile. For instance, motor cortex in humans as a means to relieve chronic in many patients the most bothersome pain is present central pain that was not responsive to other treatment in the face and hand. Because those two areas are im- and 70% of the patients in these studies reported pain mediately adjacent in the motor cortex it is possible to relief. The procedure has since gained wide acceptance concomitantly stimulated them and bring adequate re- and, inasmuch as any invasive surgical procedure can lief. Once the appropriate location of the electrode array be called routine, this form of treatment for chronic is determined (see below), it is fixed to the outer surface

Motor Cortex, Effect on Pain-Related Behavior, Figure 1 Post-operative lateral (a) and frontal (b) cranial X-rays of a patient with two stimulating electrodes (A) located over the primary motor cortex. The leads from the electrodes are tunneled subcutaneously via the neck to the extension wires (B), which connect it to the internal current generator (not seen). Motor Cortex, Effect on Pain-Related Behavior 1183 of the dura matter (most neurosurgeons prefer there also vary widely from continuously on to 10 min a to be no direct contact between the electrode and the day. The most usual is several hours at a time spread cortex because of risk of scar formation). The electrode evenly throughout the day or activated by the patient as array usually consists of 4 or 10 individual electrodes. required. As with other treatments for central or neu- The electrode wires are tunneled subcutaneously to the ropathic pain, it is some times the case that short-term anterior chest where they can be connected to a small treatment with the cortical stimulators results in long current generator (similar to a pacemaker) and the entire lasting and occasionally permanent pain relief. system is internalized under the skin. The reported success rate of this procedure runs the Although the actual implantation of the electrodes is gamut, with some patients reporting no relief while a relatively straightforward procedure, identifying the others experiencing complete (i.e. 100%) analgesia. motor cortex is not so easily achieved. Even if the motor Fifty to 80% pain relief seems to be the more usual re- cortex can be recognized on strictly anatomical grounds sult (Brown and Barbaro 2003; Canavero and Bonicalzi by its location anterior to the central (Rolandic) sul- 2001). In terms of numbers of patients helped, Canavero cus such identification is not straightforward. As the and Bonicalzi (Canavero and Bonicalzi 2001) conclude dura mater is not always opened and even when it is that approximately 50% of patients with central pain there is only a very limited exposure of the cortex, it is had satisfactory long-term results. The number finding often difficult to identify landmarks that would ensure relief from neuropathic pain (i.e. peripheral nerve injury proper location. Modern imaging techniques such as pain) is too limited to draw conclusions. It should be CT scans or preferably MRI can give high quality noted that these numbers are from reported studies and images in which it is possible to identify the central might not be completely representative of what happens sulcus and pre-central gyrus with good precision be- on a daily basis (there is no registry of all implanted fore any surgery is initiated. In addition to correctly patients). locating the motor cortex, one has to also determine the Motor cortex stimulation is clearly most applicable in somatotopical location. Functional MRI allows one central or neuropathic pain (recently it is also emerg- M to selectively locate the somatotopically relevant areas ing as a treatment for abnormal movement disorders). of the motor cortex by having the subject perform small However, the facts that the technique involves surgical movements of the hand or foot while in the magnet. The intervention and cannot be considered without risk and use of the images obtained pre-operatively combined thatsuccessisnotensuredarguesthatother,lessinvasive with an intraoperative computer-assisted 3D navigation therapy might be considered first. It would be useful if and guidance system ( neuronavigation) and direct there were some way to predict the success of the proce- electrical stimulation or recording of the cortex allows dure. Although there have been attempts to find predic- the surgeon to locate the appropriate parts of the motor tive factors there are not yet any reliable markers. Barbi- cortex in most cases. Additional methods to localize turate sensitivity and opioid insensitivity have been sug- the somatotopically relevant areas are to record the gested as possible predictors of response (Tsubokawa cortical potentials evoked in response to stimulating a et al. 1993; Yamamoto et al. 1997) as has transcranial peripheral nerve or to stimulate the motor cortex and magnetic stimulation (Migita et al. 1995). None of these locate the region of the body where muscle twitches indicators has been found to be infallible and exceptions or movements occur using standard electromyography. to these predictors have been reported. These latter techniques suffer some technical issues The mechanism by which cortical stimulation leads to that reduce their reliability. pain reduction is not clearly understood. In their original As soon as the electrodes are implanted, it is usually description, Tsubokawa and colleagues (Tsubokawa preferable to test the electrodes for placement and func- et al. 1991) considered that motor cortex stimulation tion. Although the anesthesia often precludes testing reduced somatosensory cortex and / or thalamic activity for pain relief, it is good confirmation of proper op- through inhibition evoked by non-nociceptive neuron eration of the electrodes if some muscle twitch of the activity. Although this might be a reasonable general targeted area is obtained on low frequency stimulation explanation, there is little detail on how or through ex- (< 5 cycle / s). Once in place and functioning correctly, actly what pathways the inhibition might occur. Cortical the stimulation parameters required for pain relief are stimulation might operate at the cortical level through below those that produce any muscle activation or some form of inhibition or gating of somatosensory seizures. A wide range of stimulation parameters that cortex or other cortical areas known to be associated have been reported as effective (Brown and Barbaro with pain (Ohara et al. 2005). Alternatively cortical 2003; Canavero and Bonicalzi 2001, 2002) as might be stimulation could activate subcortical sites directly or imagined from the large number of variables involved in indirectly and disrupt nociceptive signals. Currently each placement. The stimulation parameters that have there is no consensus on this question, although one been used and reported to provide relief range from can find individual studies and evidence in the literature 0.5–1.5 V with frequencies from 5–130 Hz and pulse to support almost any particular hypothesis. Although widths from 60–460 μs. The times used for stimulation we often speak of the motor and sensory systems as 1184 Movement Cycles though they were separate entities, in actuality we know 5. Giuffrida R, Sanderson P, Sapienza S (1985) Effect of micros- they are intimately linked functionally and anatomi- timulation of movement-evoking cortical foci on the activity of neurons on the dorsal column nuclei. Somatosens Res 2:237–247 cally. It has been thought for some time (Teuber 1966) 6. Hirayama T, Tsubokawa T, Katayama Y et al. (1990) Chronic that activity in the motor cortex directly influences the changes in activity of thalamic relay neurons following spinotha- somatosensory cortex and evidence has been steadily lamic tractotomy in cat. Effects of motor cortex stimulation. Pain accumulating to support the idea that activity in the Suppl 5:273 7. Migita K, Uozumi T, Arita K et al. (1995) Transcranial magnetic motor cortex alters somatosensory cortex activation by coil stimulation of motor cortex in patients with central pain. direct connections (Nelson 1996). Thus it is reasonable Neurosurgery 36:1037–1040 to postulate that stimulation of the motor cortex gates 8. Millan MJ (2002) Descending control of pain. Prog Neurobiol or damps down activity in the somatosensory cortex. It 66:355–474 9. Nelson RJ (1996) Interactions between motor commands and must be re-iterated that there is still a question over how somatic perception in sensorimotor cortex. Curr Opin Neurobiol much role the primary sensory cortex plays in noci- 6:801–810 ceptive processing, so even if motor cortex stimulation 10. Ohara PT, Vit JP, Jasmin L (2005) Cortical modulation of pain. does affect SI directly, it is not clear what, if any, the Cell Mol Life Sci 62:44–52 11. Teuber H-L (1966) Alterations of perception after brain injury. In: effect on pain would be. Eccles JC (ed) Brain and Concious Experience. Springer-Verlag, There is considerable anatomical and electrophysio- New York, pp 182–216 logical evidence from animal studies that the motor 12. Tsubokawa T, Katayama Y, Yamamoto T et al. (1991) Chronic cortex projects to and influences the responses of both motor cortex stimulation for the treatment of central pain. Acta Neurochir Suppl (Wien) 52:137–139 the dorsal column nuclei and the spinal cord dorsal horn 13. Tsubokawa T, Katayama Y, Yamamoto T et al. (1993) Chronic (Giuffrida et al. 1985; Zhang et al. 1991) both of which motor cortex stimulation in patients with thalamic pain. J Neu- are parts of the pathways transmitting sensory infor- rosurg 78:393–401 14. Yamamoto T, Katayama Y, Hirayama T et al. (1997) Pharma- mation to the thalamus. These, and other subcortical cological classification of central post-stroke pain: comparison sites such as the periaqueductal gray matter and raphe with the results of chronic motor cortex stimulation therapy. Pain nuclei, are known to be involved in pain modulation 72:5–12 circuits (Millan 2002) and are obvious sites where the 15. Zhang DX, Owens CM, Willis WD (1991) Short-latency excitatory postsynaptic potentials are evoked in primate spinothalamic motor cortex could exert sensory effects. Here it should tract neurons by corticospinal tract volleys. Pain 45:197–201 be emphasized that we are concerned specifically with stimulation of the motor cortex. There is substantial experimental evidence that lesion or stimulation of a number of cortical regions such as the cingulate, medial Movement Cycles prefrontal and insular cortices in animals (a majority of this work has been done on rats) can change the behavioral responses to noxious stimuli as well as the Definition activity of spinal nociceptive neurons. In this case, Units of behavior counted to program reinforcement. A most evidence suggests that descending projections to movementcycleissaidtohaveoccurredwhentheperson the regions including the hypothalamus, amygdala and isinapositiontorepeatit.Movingtheleftfootforwardis brainstem mediate the sensory changes. There is very not a movement cycle. Moving the left and then the right little data on stimulation specifically of motor cortex puts the person in a position to repeat; hence, left/right in animals and so there is little basic biological data to step is a movement cycle. Movement cycles can often be support or refute suggestions as to how motor cortex combined into more easily managed units. For example, stimulation might work in the clinical setting. A full left step/right step is a movement cycle. A 50- meter lap explanation of why motor cortex stimulation works containsmanysteps.Thosecanusuallybecombinedinto in terms of neural pathways, neurotransmitters and one lap and „lap“ becomes the unit of behavior. physiological and biochemical changes will depend Training by Quotas on development of an animal model and analysis with modern neurobiological experimental methods. Movement-Related Pain References 1. Brown JA, Barbaro NM (2003) Motor cortex stimulation for central and neuropathic pain: current status. Pain 104:431–435 Definition 2. Bushnell MC, Duncan GH, Hofbauer RK et al. (1999) Pain perception: is there a role for primary somatosensory cortex? Proc Movement-related pain is pain that occurs with move- Natl Acad Sci USA 96:7705–7709 ment. This term refers to both breakthrough pain, in 3. Canavero S, Bonicalzi V (2001) Motor cortex stimulation. J Neu- which background pain exists in addition to pain during rosurg 94:688–689 activity, and incident pain, in which background pain 4. Canavero S, Bonicalzi V (2002) Therapeutic extradural cortical stimulation for central and neuropathic pain: a review. Clin J Pain is absent or controlled. 18:48–55 Evoked and Movement-Related Neuropathic Pain Mucosa 1185

MPQ MSDs/MSPs

McGill Pain Questionnaire Disability, Upper Extremity

MPS MTrP

Myofascial Trigger Point Myofascial Pain Syndrome

MTrP Circuit MRI Deﬁnition Magnetic Resonance Imaging AnMTrPcircuitcomprisesoftheinter-neuronalconnec- tions in the spinal cord. The circuit cannot only transfer the nociceptive impulses to the brain, but may also con- MRS trol referred pain patterns via connections to other MTrP circuits. The occurrence of LTRsisalso mediated via the MTrP circuit. Synonyms Dry Needling Hydrogen Magnetic Resonance Spectroscopy M

Deﬁnition MTrP Locus 1H-MRS (Hydrogen Magnetic Resonance Spec- troscopy) is an NMR based technique for assessing Deﬁnition function in the brain. MRS takes advantage of the fact that protons (H) possess slightly different resonant There are multiple MTrP loci in an MTrP region. An properties depending upon the compound. For a given MTrP locus contains two components: the sensitive lo- volumeof brain (typically > 1 cubiccm), thedistribution cus, also known as the local-twitch-response locus (LTR of these H resonances can be displayed as a spectrum. locus), and the active locus, also known as the endplate- The area under the peak for each resonance provides a noisy locus (EPN locus). quantitative measure of the relative abundance of that Dry Needling compound. Thalamus, Clinical Pain, Human Imaging Mu(μ)- and Kappa(κ)-Opioids

MS Contin® Definition Opioids that selectively bind on mu- and kappa- recep- Definition tors. ® Endogenous Opioid Receptors MS Contin is a controlled (slow) release tablet formu- MOP Receptor lation of morphine that produces a peak morphine con- Nitrous Oxide Antinociception and Opioid Receptors centration 4-5 hours post dose, and therapeutic concen- Psychological Aspects of Pain in Women trations persist for about 12 hours. Postoperative Pain, Morphine Mucosa ® MS Contin Controlled (Slow) Definition Release Morphine Sulphate The smooth inner lining of the large intestine that se- cretes mucus to lubricate the waste materials. Postoperative Pain, Morphine Animal Models of Inflammatory Bowel Disease 1186 Mucosa of Sexual Organs, Nociception

Reports of pain severity and impact will vary depending Mucosa of Sexual Organs, Nociception onarangeofcontributions,andarenotsolelytheresultof physical pathology or perturbations within the nervous Nociception in Mucosa of Sexual Organs system. The biopsychosocial perspective forces an evaluator not only to consider the nature, cause, and characteristics of the noxious stimulation, but the presence of Mucositis the sensations reflected against a history that preceded symptom onset. The biopsychosocial model incorporates cognitive- Definition behavioral (CB) concepts (see Cognitive-Behavioral Mucousmembranetoxicityoftenoccursshortlyafterad- Perspective) in understanding chronic pain. For ex- ministration of chemotherapy or radiotherapy. Inflam- ample, proponents of this model propose that both the mation, ulceration, and infection can then occur on the person and the environment reciprocally determine oral and other mucus membranes. behavior. People not only respond to their environment Cancer Pain Management, Overall Strategy but elicit environmental responses by their behavior. The person who becomes aware of a physical event and decides the symptom requires attention from a health Mud Therapy care provider, initiates a set of circumstances different from the individual with the same symptom who chooses to self-manage symptoms. Another assumption Definition of the CB perspective is that people are active agents Mud therapy involves the application of heated mud and capable of change. The passive role many patients packs to parts of the body. have in traditional physician-patient relationships often Spa Treatment reinforces their beliefs that they have minimal ability to impact their own recovery. To understand and appropriately treat a patient whose primary symptom is pain should begin with a com- Multiaxial Assessment of Pain prehensive history and physical examination. Patients DENNIS C. TURK are usually asked to describe the characteristics (for Department of Anesthesiology, University of example, stabbing, burning), location, and severity Washington, Seattle, WA, USA of their pain. Physical examination procedures and [email protected] sophisticated laboratory and imaging techniques are readily available for use in detecting organic pathol- Synonyms ogy. Physical and laboratory abnormalities, however, correlate poorly with patients’ pain reports, and it is Comprehensive Assessment; Multidisciplinary Assess- often not possible to make any precise pathological ment diagnosis or even to identify an adequate anatomical Definition origin for the pain. Thus, an adequate pain assessment also requires clinical interviews and utilization of as- Multiaxial assessment refers to a comprehensive assess- sessment tools to assist in the evaluation of the myriad mentofchronicpainsufferersthataddressesbiomedical, Psychosocial Factors and behavioral factors that psychosocial, and behavioral domains, as each of these influence the subjective report. contribute to the chronic pain and disability (Turk and As there is no pain thermometer that can provide an ob- Rudy 1987). jective quantification of the amount or severity of pain experienced by a patient, it can only be assessed indi- Characteristics rectly based on a patient’s overt communication, both The biopsychosocial model of pain proposes that verbal and behavioral. However, even a patient’s com- dynamic and reciprocal interactions among biologi- munications make pain assessment difficult, as pain is a cal, psychological, and sociocultural variables shape complex, subjective phenomenon, comprised of a range the pain experience (Turk 1996; Turk et al. 2004). of factors, and is uniquely experienced by each individ- According to this model, the pain experience usually ual. Wide variability in pain severity, quality, and impact begins when peripheral nociceptive barrage produces maybenotedinreportsofpatientsattemptingtodescribe physiological changes, although there may be central what appear to be objectively identical phenomena. Pa- mechanisms involved in the initiation of pain, and the tient’s descriptions of pain are also colored by cultural experience is thoroughly modulated by the unique ge- and sociological influences. netic endowment, learning history, beliefs, affective A patient’s beliefs about the cause of symptoms, their state, and behavior. trajectory, and beneficial treatments will have impor- Multiaxial Assessment of Pain 1187 tant influences on emotional adjustment and adherence andexpectanciesaboutthemselves,theirsymptoms,and to therapeutic interventions. Clinical attention should the health care system have been developed. Standard- focus on the patient’s specific thoughts, behaviors, izedassessmentinstrumentshaveadvantagesoversemi- emotions, and physiological responses that precede, structured and unstructured interviews. They are easy to accompany, and follow pain episodes or exacerbations, administer, can suggest issues to be addressed in more including environmental and temporal conditions, and depth during an interview, require less time, and most consequences associated with the patient’s responses importantly, they can be submitted to analyses that per- (cognitive, emotional, and behavioral, including fre- mit determination of their reliability and validity. quency and specificity/generality across situations) in The poor reliability and questionable validity of physi- these situations. It is valuable to note any patterns of cal examination measures has led to the recent develop- maladaptive thoughts, as they may contribute to a ment of self-report functional status measures that seek sense of hopelessness, dysphoria, and unwillingness to quantify symptoms, function, and behavior directly, to engage in activity. Topics that can be covered in an rather than inferring them. Another advantage of self- assessment interview might include: asking what the report instruments is that they enable the assessment of patient thinks is wrong with him/her, what the patient a wide range of behaviors that are relevant to the patient, thinks about the pain (e.g. cause, impact), what worries someof which may beprivate(sexualrelations) or unob- the patient has (e.g. exacerbation of symptoms, impair- servable (thoughts, emotional arousal). Even traditional ment), problems the patient has experienced due to pain psychological measures have been used to identify psy- (e.g. marital, financial, occupational), how the patient chosocial characteristics of the pain experience. These lets others know when pain is present, what effect the measures, however, must be used with caution, as they patient believes the pain is having on others, in what were usually not developed for or standardized on sam- situations the patient experiences increased pain, what ples of medical patients. As a result, it is always best to others think about their pain, how others respond to corroborate information gathered from the instruments their pain, medications they are taking, strategies they with other sources, such as interviews with the patient M have used to alleviate pain, what treatments they have and significant others, and chart review. endured for pain management, and prior and current In addition to self-report instruments, more valid infor- stressful life events. mation may be obtained by asking about current levels TurkandMeichenbaum(1994)havesuggestedthatthree of pain or pain over the past week, and by having pa- centralquestionsshouldguideassessmentofpeoplewho tients maintain regular diaries of pain intensity with report pain: (1) What is the extent of the patient’s disease ratings recorded several times each day for several days or injury (physical impairment)? (2) What is the magni- or weeks. Through such diaries, patients can also record tude of the illness? That is, to what extent is the patient activities and the amount of time or the number of times suffering, disabled, and unable to enjoy usual activities? they perform specific behaviors such as reclining, sit- and (3) Does the individual’s behavior seem appropriate ting, standing, walking, and so forth. to the disease or injury, or is there any evidence of ampli- A third use of patient diaries is to record medication use fication of symptoms for any of a variety of psycholog- over a specified interval. Diaries not only provide infor- ical or social reasons or purposes? These three general mation about the frequency and quantity of medication, questions can be conceptualized and address three gen- but may also permit identification of the antecedent and eral domains or axes – biomedical, psychosocial, and consequent events of medication use. For example, a pa- behavioral. tient might note that he took medication after an argu- A thorough clinical assessment should also involve ment with his wife, and that when she saw him taking the gathering a detailed history from the patient, includ- medication she expressed sympathy. Antecedent events ing past medical history, drug/alcohol use, history of might include stress, boredom, or activity. Examination mental illness, and a list of current medications. It is of antecedents is useful in identifying patterns of medi- important for the clinician treating chronic pain patients cation use that may be associated with factors other than to understand the use of pain medications, in addition pain per se. Similarly, patterns of response to the use of to the side-effects associated with them, so as to avoid analgesic may be identified. Does the patient receive at- misinterpreting symptoms and potential misdiagnosis. tention and sympathy whenever he or she is observed by Patients may also make use of alcohol and illicit drugs significant others taking medication? That is, do signif- to palliate their symptoms. Patients with histories of icant others provide positive reinforcement for the tak- substance abuse may be at particular risk of becoming ing of analgesic medication, and thereby unwittingly independent on and abusing pain medications. Reviewing crease medication use? the chart and conducting a detailed history of previous The multiaxial approach to assessment isdesigned to as- and current prescription and substance use may help sess and integrate physical, psychosocial, and behavior ascertain whether this area warrants further inquiry. contributorstopainanddisability.Therearealargenum- In addition to interviews, a number of assessment instru- ber of measures and procedures that can be used to eval- ments designed to evaluate patients’ attitudes, beliefs, uate each axis. The multiaxial approach to assessment 1188 Multichannel CT does not specify any particular methods for assessment. 3. Turk DC, Meichenbaum D (1994) A Cognitive-Behavioural Ap- The evaluator will determine the appropriate methods proach to Pain Management. Wall PD, Melzack R (eds) Textbook nd based on his or her experience with chronic pain suf- of Pain, 2 edn. Churchill Livingstone, London, pp 1337–1338 4. Turk DC, Monarch ES, Williams AD (2004) Assessment of ferers, and specific questions that may be of particular Chronic Pain Sufferers. In: Hadjistavropoulos T, Craig KD (eds) importance for a given patient. Pain: Psychological Perspectives. Lawrence Erlbaum, Mahwah Components of the multiaxial assessment can be sum- NJ, pp 209–243 marized as follows: Biomedical Multichannel CT • Medical History • Co-morbid medical conditions • Pain (intensity, quality, duration, location, exacerbat- CT Scanning ing and alleviating factors) • Physical Examination • Laboratory Diagnostic Tests Multidimensional • Imagining Procedures • Responsetoprevioustreatment(bothpositiveandad- Definition verse) A pain assessment tool that includes measurement of Psychosocial two or more indicators of newborn pain (behavioral, physiological or biochemical (hormonal). Multidimen- • General history (family composition, education) sional approaches to pain assessment incorporate the • Living status (e.g. married, divorced, romantic rela- use of pain assessment tools that include measurement tionship) of two or more indicators of newborn pain, and con- • Quality of relationships with significant others current consideration of a variety of contextual and • Socioeconomic status modifying factors. • Work history Pain Assessment in Neonates • Substance abuse history and current use of drugs and alcohol to control pain as well as recreational. • Impact of pain on physical, emotional, and social functioning Multidimensional Model • Beliefs, attitudes, expectations, and fears about pain, treatment, their plight, and the future Diathesis-Stress Model of Chronic Pain • Prior and current psychiatric status, degree of emotional distress (fear, depression, anger), treatment of patient and family Multidimensional Scaling • Useofstetcopingmethods(e.g.problemsolving,dis- and Cluster Analysis Application traction) • Satisfaction with previous and current treatment(s) for Assessment of Pain W. CRAWFORD CLARK Behavioral College of Physicians and Surgeons, Columbia • Use of behavioral methods of coping with pain (e.g. University, New York, NY, USA medication, alcohol, exercise, withdrawal) [email protected] • Observation of pain behavior s (overt communica- tions of pain distress and suffering) Synonyms • Response to pain behaviors by significant others Multidimensional scaling; Factor Analysis; Pain Ques- • Physical, social, and recreational activities tionnaire; Cluster Analysis; pain; emotion • Vocational status • Adherence to treatment recommendations (e.g. med- Definition ication, exercise) Multivariate scaling (MVS), a subset of multivariate statistics, includes a large group of mathematical tech- References niques and data collection procedures. Of particular 1. Turk DC, Rudy TE (1987) Toward a Comprehensive Assessment interest here are multidimensional scaling (MDS), of Chronic Pain Patients. Behav Res Ther 25:237–249 cluster analysis and preference mapping (PREFMAP). 2. Turk DC (1996) Biopsychosocial Perspective on Chronic Pain. These models yield a geometric representation that In: Gatchel RJ, Turk DC (eds) Psychological Approaches to Chronic Pain Management: Clinical Handbook. Guilford Press, makes it easier for an investigator to uncover the “hid- New York, pp 3–33 den structure” of complex data bases. These techniques Multidimensional Scaling and Cluster Analysis Application for Assessment of Pain 1189 use similarity judgments or other measures of associa- imity measures may be obtained from other measures tion to generate proximities among a set of stimulus of association such as correlations, joint probabilities, objects as input. An object is a thing, or event; a stimulus or phi-coefficients. As the number of pairwise com- is the perceived object. Stimulus objects may be words, parisons rapidly increases with the number of stimulus physical stimuli or concepts. Just as a map yields far objects, less direct procedures, such as pile-sort where more information (distance, direction) than does a list the subject partitions the stimulus objects into groups of cities, so MVS procedures yield more information based on similarity, are used. than do scores on rating scales or questionnaires. These procedures yield the group stimulus space, a config- Interpreting Dimensions uration of points (stimulus objects) along dimensions Dimensions are interpreted by examining the stimulus in continuous space, or as clusters in discrete space. A objects at each pole (the remaining central stimulus dimension is a characteristic that serves to define a objects will usually be found at the poles of other di- point by its coordinates. Another advantage of these mensions). The stimulus objects at the poles of each models is that they also quantify individual differences dimension should share a common meaning, and the by providing subject weights in the source or weight two poleswillgenerally beoppositein nature. Theuseof space, which quantify the saliency or relative impor- PREFMAP in interpreting the meaning of a dimension tance that each individual attaches to each cluster or is described later. Interpretation of the spatial features dimension. The subject weight scores can be correlated is somewhat subjective, since, because the sampling with other test scores or used to distinguish subpop- distributions are unknown, there are no inferential sta- ulations in the sample. Information about individual tistical tests available for determining the number of differences promises to be useful in determining treat- dimensions. However, Weinberg and Carroll (1992) ment strategies for individual patients. An important describe a number of approaches to approximating the aspect of MVS procedures is that the subject is typically true space. asked to make similarity judgments between pairs of a M set of stimulus objects. Thus, the MVS procedures are Two-Way, Three-Way and Higher-Way Models more objective than commonly used procedures that assign scales determined by the investigator, because MVS clustering and multidimensional models are clas- the participant, not the investigator, determines the sified as two-way, three-way or higher-way (Carrolland dimensions or clusters. Chaturvedi 1995). In these models, the data are orga- nized into a half-matrix, in which rows and columns cor- Characteristics respond to stimulus objects and the cells contain some measure of similarity. As two-way models (e.g. KYST) Introduction to Multivariate Scaling are computed from a single group matrix in which the Multidimensional Scaling cells are means averaged over subjects, they yield only Introductions to INDSCAL and other spatial distance the group stimulus space. Three-way, or individual dif- models are provided by Carroll and Arabie (1998), ferences scaling, models (e.g. INDSCAL) treat matrices Kruskal and Wish (1978), Schiffman (1981), Weinberg that correspond to individual subjects, or, if desired, to and Carroll (1992), and Lattin et al. (2003). Introduc- subgroups. Three-way models assume that different in- tions and reviews of applications to pain and emotion dividuals perceive stimuli in terms of a common set of are available (Clark 2003). dimensions or clusters, but that these features differ in Of paramount importance to the investigation of sen- their saliency or importance to different individuals. In sory pain and emotional suffering is that the stimulus additiontothegroupstimulusspace,thethree-waymod- objects may be calibrated physical stimuli (e.g. heat, els provide a source space that yields individual subject cold, electrical) or they may be verbal descriptors (e.g. weights on each dimension or cluster. Subject weights moderate pain, stabbing, anxiety), or both. A variety of measure the importance ofeachdimensionto anindivid- data collection procedures and mathematical models ual. They can be used to distinguish among subgroups are used to obtain and analyze measures of proximity – in the sample population, and may be correlated with a number that represents the amount of similarity or psychologicaland physiologicalmeasures. Inmedicine, difference between a pair of stimulus objects. One of where knowledge about the individual patient is essen- the key ideas in MVS is that these subjective proximity tial, the three-way model is essential. measures, which represent psychological distance, can be used to scale physical distance. MVS models con- Cluster Analysis struct a configuration of points as on a map, so that the Clustermodelsrepresentthestructureofasetofstimulus distances in the group stimulus space systematically objects as subsets of clusters, where each cluster corre- model the judged proximities. To obtain direct proxim- sponds to a meaningful group of stimulus objects. De- ity data, pairs of stimuli are judged with respect to their pending upon the model used, the clusters may be non- degrees of similarity or dissimilarity. In general, prox- overlapping or overlapping. Two major types of clus- 1190 Multidimensional Scaling and Cluster Analysis Application for Assessment of Pain ter models are the hierarchical and the additive models quency along a Frequency dimension (Janal et al. 1993). (Latin et al. 2003). The interpretation of the dimensions in the group stimulus space was supported by PREFMAP analysis of sub- Relationship between Clustering jects’ ratings of each of the stimuli with respect to bipo- and Spatial Distance Models lar property scales (e.g. Faint Pain – Severe Pain). As Cluster and MDS (spatial distance) models are similar expected, the Pain Magnitude dimension was related to in many ways: the same pairwise similarity judgment property scales in the Sensory, Emotional and Arousal data can be analyzed by either procedure and both are domains, while the Frequency dimension was identified distance models. However, important differences exist. only with the Fast-Slow property scale. Cluster analysis groups stimulus objects that are most Studies with Descriptors of Pain and Emotion similar, while spatial distance models emphasize ways in which items are different. Cluster analysis is superior The number and composition of the dimensions un- to multidimensional scaling when the stimulus objects derlying the sensory, emotional, motivational, and are discrete and not readily placed on a continuum or other aspects of pain remain controversial in spite of when the number of descriptors is large. considerable speculation and some research. These various views concerning the number of dimensions Property or Preference Mapping (PREFMAP) and their composition are based entirely on subjective impressions. Clearly “armchair taxonomy” cannot Property or preference mapping (PREFMAP) models settle arguments over the number and nature of pain (Carroll and Chaturvedi 1995) provide an objective aid dimensions. Clark et al. (2001) used INDSCAL to to the interpretation of dimensions. Features, that is, the study this question. INDSCAL analysis of responses dimensions of the clusters in the group stimulus space, to 16 descriptors of sensations, negative and positive are usually interpreted by inspection. However, if the emotions and motivation yielded four dimensions (D) features are ambiguous, or if specific hypotheses are in the group stimulus space. Dimensions are defined being tested, it is useful to have additional information by the descriptors at the poles. D-1, Intense to Mod- that is objectively based on subjects’ judgments. The erate Experiences, contained two attributes: Strong PREFMAP model provides independent information Pain Sensations (Severe Pain to Slight Sensation) and that aids interpretation of the group stimulus. Strong Emotions (Upsetting to Comforting). D-2, Mod- erate to Weak Experiences, exhibited two attributes: Relation of MVS to Factor Analysis (i) moderate pain sensations (Faint Pain to No Sensa- Factor analysis, another multivariate procedure, has tion) and (ii) moderate emotions (Uncomfortable to proven useful for the study of responses to question- Comforting). D-3, Motivational State, possessed two naires by various pain patient populations. However, attributes: (i) pain (Severe Pain to Faint Pain) and (ii) because the investigator determines the response scales, arousal level (Startling to Indifferent). D-4, Sensory factor analysis cannot reveal in an unbiased manner the Qualities, exhibited two attributes: (i) pain (Severe number and types of dimensions that underlie patients’ Pain to Faint Pain) and (ii) somatosensory qualities sensory, emotional and other experiences. Schiffman (Hammering to Tingling). The interpretation of the et al. (1981) point out other advantages of the multi- dimensions was supported by PREFMAP and by cor- variate scaling approach over that of factor analysis. It relations between subject weights and psychological is easier to interpret the distances between points than tests. The results clearly demonstrated that pain and angles between vectors, and MVS provides more eas- other dimensions are not orthogonal to one another, ily interpretable solutions with fewer and much more for in each of the four dimensions the sensory pain homogeneous dimensions. attribute is inseparable from both the strong and weak emotional attributes, the motivational attribute and the Pain Studies with MVS Procedures somatosensory qualities attribute. It may be concluded MVS studies of responses to calibrated sensory stimuli that sensory pain does not exist as an independent di- offer a way to discover the dimensions of physical pain mension separate from other dimensions of pain. The and their relationship to pain descriptors. In the first ap- practical implication of this finding is that a score on plication of INDSCAL to the study of pain, Clark et al. a unidimensional pain intensity rating scale cannot be (1986) analyzed judgments made to various intensities a pure measure of the patient’s pain experience. That of noxious and non-noxious heat stimuli and obtained a a patient cannot separate these components of pain has two-dimensional solution. In a subsequent study, IND- been strongly supported by the finding that ratings of SCAL analysis of pairwise similarity ratings made to pain intense by patients experiencing postoperative electricalstimulioffiveintensities(milliwatts)andthree pain on a unidimensional numerical pain rating scale frequencies (hertz) yielded a two-dimensional solution are strongly influenced by the patients’ emotional state, with the stimuli ordered with respect to intensity along specifically depression, anxiety, anger and fear (Clark a Sensory Magnitude dimension and with respect to fre- et al. 2002). Multidimensional Scaling and Cluster Analysis Application for Assessment of Pain 1191

Quantifying the Relation between Physical Stimuli more patients than controls found the Pain Magnitude and Verbal Descriptors dimension to be the most salient. The wide individual What is the relationship between sensory experiences differences found suggest that the location of a patient induced by physical stimuli and the descriptors of these in the subject weight space might prove useful in tai- experiences? In the first study of its kind, we used IND- loring treatment. For example, a patient who finds the SCAL to study pairwise similarity responses for a set Pain Magnitude dimension to be most salient might of stimulus objects containing both electrical stimuli of profit from a higher analgesic dose, while a patient who various intensities, and sensory and emotional descrip- weights on the Emotional Quality dimension might ex- tors used to describe these sensory experiences (Janal perience relief following the addition of a psychoactive 1995). The subjects made pairwise similarity judgments medication and, perhaps, a reduction in the analgesic. to all possible pairings of 16 stimulus objects: 8 electro- In brief, the patient’s coordinates in the subject weight cutaneous stimuli ranging in intensity from innocuous space can help determine treatment. (3 mW) to noxious (235 mW), and 8 somatosensory and Other MDS Applications to Problems of Pain affective descriptors of these sensations which ranged from Slight Sensation, Tingling and Comforting to Se- A number of imaginative applications of various MVS vere Pain, Hammering and Upsetting. INDSCAL anal- procedures to problems in pain have been pursued: ysis revealed a 1-dimensional solution with a close rela- measurement of neural response patterns to noxious tionshipbetweentheperceivedintensitiesofthephysical stimulation using cluster analysis; pain during activities stimulus coordinates and the words describing them. of daily living; in post-operative myalgia patients by While preparing this paper, it occurred to this author that PREFMAP; facial expression of clinical pain and emo- a quantitative relation between the verbal and the phys- tion; cross cultural comparison of dental pain and emo- ical stimulus weights could be obtained, by plotting the tional attitudesin Chinese and Western patientsand den- INDSCAL stimulus coordinates of both the verbal and tists by cluster analysis and cross-cultural comparisons M the physical stimulus objects (ordinate) against a scale of cancer pain in various European and Asian groups of intensities in milliwatts (abscissa). A plot of the per- using MDS. Details appear in a review by Clark (2003). ceived stimulus coordinates (ordinate) against an objec- Questionnaire Construction by Cluster Analysis tive scale (abscissa) yielded two exponential functions that contain more information than found with magni- Another application of MVS is the construction of tude estimation procedures. questionnaires. Clark et al. (1995) used a hierarchical clustering model to analyze pile-sort similarity judg- Clinical Pain: Identifying Individual Differences ments made by seven experienced pain researchers to in the Saliency of Pain Dimensions 270 descriptors of sensory pain, negative and positive The results of the following study suggest how multidi- emotions, motivation, illness and health. Analysis by mensional scaling could be used to determine treatment the average-linkage-between-groups clustering model strategies. Clark et al. (1989) used INDSCAL to com- produced a dendrogram with 50 subclusters subsumed pare the group stimulus and subject weight spaces of within 18 primary clusters. No evidence was found to inpatients suffering cancer-related pain with those of support the homogeneous status claimed for descriptors healthy volunteers. The question was “Do patients and in the major Evaluative Class of the MPQ. A large num- volunteers differ in whether the emotional or the sen- ber of the descriptorsthatwere assigned to each of the 22 sory dimension is more salient?” The participants made subgroups of the MPQ were found to be dispersed over a pairwise similarity judgments between all possible number of different clusters in the dendrogram. In a sub- pairings of a set of nine descriptors of sensory pain, sequent study, described by Yang et al. (2000), healthy emotional pain and somatosensory qualities. The group male and female African-American, Euro-American stimulus spaces of patients and controls revealed simi- and Puerto Rican subjects sorted 189 descriptors into lar 3-dimensional solutions: Sensory Pain Magnitude, similar piles (pile-sort technique), and then sequentially Emotional Quality, and Somatosensory Quality. How- merged their piles on the basis of similarity (merge tech- ever, the subject weight space, which yields coordinates nique) until only two piles remained. The addition of for each individual on each dimension, demonstrated the merge technique greatly improved the hierarchical thatthesaliency of thevariousdimensionsvariedwidely structure of the dendrogram. Dendrograms for each among subjects. For some individuals the Pain Mag- of the six groups revealed striking gender and ethno- nitude dimension was most important in determining cultural differences in the language of pain. Men and their similarity judgments (high values on the abscissa, women and ethnocultural groups disagreed on the clus- low on ordinate); for others the Emotional Quality di- ter location, and hence the meaning, of 30 descriptors; mension was most salient, while for yet others the two 58 other descriptors were found to be very similar (re- dimensions were equally important. The coordinates dundant). The remaining 101 descriptors and clusters for each subject in the subject weight or source space determined the structure of the Multidimensional Af- revealed wide individual differences, but significantly fect and Pain Survey (MAPS). Thus, unlike the MPQ, 1192 Multidisciplinary the MAPS questionnaire is based on the structure of References the empirically derived dendrogram that emerged from 1. Carroll JD, Arabie P (1998) Multidimensional Scaling. In: Birn- subjects’ views of their sensory-emotional pain spaces. baum MH (ed) Handbook of Perception and Cognition. Vol 3: Measurements, Judgment and Decision. Academic Press, San Validation of MAPS Diego, pp 179–250 2. Carroll JD, Chaturvedi A (1995) A General Approach to Cluster- Factor analysis has demonstrated the validity of MAPS, ing and Multidimensional Scaling of Two-Way, Three-Way, or and hence, the advantage of the cluster analytic ap- Higher-Way Data. In: Luce RD, D’Zmura M, Hoffman DD (eds) proach to test construction (Clark et al. 2003). If MAPS Geometric Representation of Perceptual Phenomena. Erlbaum, is a valid questionnaire for the quantification of emotion Mahwah, pp 295–318 3. Clark WC (2003): Pain, Emotion, and Drug-Induced Subjective and pain, then factor analysis of cancer patients’ ratings States. In: Adelman G, Smith B (eds) Encyclopedia of Neuro- should produce factors that correspond uniquely to the sciences, 3rd edn. Elsevier, Amsterdam (CD-ROM) clusters and superclusters of the MAPS dendrogram. 4. Clark WC, Carroll JD, Yang JC et al. (1986): Multidimensional Almost all of the clusters in the MAPS Somatosen- Scaling Reveals Two Dimensions of Thermal Pain. J Exp Psychol (Hum Percept) 12:103–107 sory Pain Supercluster loaded on three sensory-pain 5. Clark WC, Ferrer-Brechner T, Janal MN et al. (1989) The Di- related factors. Most of the clusters in the Emotional mensions of Pain: A Multidimensional Scaling Comparison of Pain Supercluster loaded on emotional factors, and the Cancer Patients and Healthy Volunteers. Pain 37:23–32 Well-being Supercluster loaded on the good health fac- 6. Clark WC, Janal MN, Hoben EK et al. (2001) How Separate are the Sensory, Emotional, and Motivational Dimensions of tor. This correspondence between clusters and factors Pain? A Multidimensional Scaling Analysis. Somatosens Mot stands in sharp contrast with factor analytic studies of Res 18:31–39 the MPQ, where subclasses of its sensory, affective and 7. Clark WC, Kuhl JP, Keohan ML et al. (2003) Factor Analysis even evaluative classes often load on a single factor. Validates the Cluster Structures of the Dendrogram Underlying the Multidimensional Affect and Pain Survey (MAPS) and Chal- The meanings of such mixed factors are very difficult lenges the A Priori Classification of the Descriptors in the McGill to interpret. The cause of this factor heterogeneity and Pain Questionnaire (MPQ). Pain 106:357–363 the discrepant results obtained by various investigators 8. Clark WC, Yang JC, Tsui SL et al. (2002) Unidimensional Pain Rating Scales: A Multidimensional Affect and Pain Sur- is probably due to the a priori procedure used by in- vey (MAPS) Analysis of What They Really Measure. Pain vestigators of the MPQ to classify descriptors into its 98:241–247 major classes and subclasses. 9. Janal MN (1995) Concerning the Homology of Painful Experi- ences and Pain Descriptors: a Multidimensional Scaling Anal- Conclusions ysis. Pain 64:373–378 10. Janal MN, Clark WC, Carroll JD (1993) Multidimensional Scal- It is obvious that the MVS models, multidimensional ing of Painful Electrocutaneous Stimulation: INDSCAL Dimen- scaling, cluster analysis and PREFMAP, offer original sions, Signal Detection Theory Indices, and the McGill Pain approaches to many theoretical and practical questions Questionnaire. Somatosens Motor Res 10:31–39 in a variety of fields. They identify the underlying struc- 11. Kruskal JB, Wish M (1978) Multidimensional Scaling. Sage, Beverly Hills ture of the dimensions of the experienceand response to 12. Lattin JM, Carroll JD, Green PE (2003) Analyzing Multivariate pain and emotion, drug induced states, patterns of neu- Data. Duxbury Press, Belmont ral response and facial expressions. These methods can 13. Schiffman SS, Reynolds ML, Young FW (1981) Introduction to Multidimensional Scaling. Academic Press, New York be used to construct new questionnaires and to discover 14. Weinberg SL, Carroll JD (1992) Multidimensional Scaling: An the latent structure of existing questionnaires. In addi- Overview with Applications in Educational Research. Adv Soc tion, MDS of similarity responses to descriptors and to Sci Methodology 2:99–135 physical stimuli can be used to quantify the intensity of 15. Yang JC, Clark WC, Tsui SL et al. (2000): Preoperative Mul- tidimensional Affect and Pain Survey (MAPS) Scores Predict descriptorsataratioscalelevelofmeasurement.Consid- Post-Colectomy Analgesia Requirement. Clin J Pain 16:314–320 ering the widespread use of MDS, cluster analysis and PREFMAPinpsychologyandthesocialsciences(where it has been used to study visual, auditory and taste perception, language, consumer preferences, kinship pat- Multidisciplinary terns, the provenance of ancient pottery, etc.), it is as- tonishing thatthesemethodshavenotbeenapplied more extensively to complex medical problems. Definition Medical disciplines working with the same patient. Acknowledgements PhysicalMedicineandRehabilitation,Team-Oriented This essay and much of the research here was supported Approach by the Nathaniel Wharton Fund for Research and Edu- cation in Brain, Body and Behavior, NIDR 20248 and NICDR 12725. The author wishes to thank Dr. J.D. Car- roll, Board of Governor’s Professor, Rutgers University, Multidisciplinary Assessment for his many helpful comments, but theauthor is responsible for any errors that may remain. Multiaxial Assessment of Pain Multidisciplinary Pain Centers, Rehabilitation 1193

• Synthesize the diverse sets of information based on Multidisciplinary Pain Centers, their own evaluations, as well as those of outside con- Rehabilitation sultants, into a differential diagnosis and treatment plan customized to meet the specific need of each pa- DENNIS C. TURK tients Department of Anesthesiology, University of • Work together to formulate and implement a compre- Washington, Seattle, WA, USA hensive rehabilitation plan based on available data [email protected] • Share a common philosophy of disability management Synonyms • Act asa functional unit whose membersare willing to Multidisciplinary pain clinics, Interdisciplinary pain re- learn from each other and modify, when appropriate, habilitation programs, Functional restoration program, their own opinions based on the combined observa- Pain clinics tions and expertise of the entire group Definition In MPCs, patients are usually treated in groups. Patients work on at least 4 issues simultaneously: physical, phar- An organization of health care professionals and basic macological, psychological, and vocational. Programs and applied scientists that includes research, teach- usually emphasize helping patients to gain knowledge ing, and patient care related to acute and chronic pain. about pain and how the body functions, physical condi- It includes a wide array of health care professionals tioning, medication management, acquisition of coping including physicians, psychologists, nurses, physical and vocational skills. Individual and group counseling therapists, occupational therapist, and other specialty address patient‘s needs. In contrast to traditional West- healthcare providers. Multiple therapeutic modalities ern health care, the emphasis is upon what the patient ac- are available. These centers provide evaluation and complishes, not on what they say. The providers serve as treatment and are usually affiliated with major health M teachers, coaches, and sources of information and sup- science institutions. Multidisciplinary pain clinics are port (Loeser and Turk 2001). similartomultidisciplinarypaincenters(MPC),withthe Multidisciplinary pain management requires the collab- exception being that they do not include basic scientists orative efforts of many healthcare providers, including, and may not be involved in conducting research. but not limited to, physicians, nurses, psychologists, Characteristics physical therapists, occupational therapists, and vocational counselors. The healthcare providers act as Although there is no single format for multidisciplinary a team, with extensive interaction amongst the team pain management or the operations of an MPC, almost members. every treatment facility of thistypehasa generic concept Thefollowinglistitemizesthegoalsofmultidisciplinary and plan. pain management. Every patient will have a different Concepts of Treatment at Multidisciplinary Pain Clinics mixture of functional limitations, pain behaviors, affec- • Reconceptualization of the patient‘s pain and associ- tive disturbance, physical disability, and vocational dys- ated problems from uncontrollable to manageable function.Successfultreatmentwilladdresseachofthese • Overt or covert efforts are made to foster optimism general areas. and combat demoralization • Flexibility is the norm with attempts to individualize some aspectsof treatmentto patientneedsand unique Goals of Multidisciplinary Pain Management physical and psychological characteristics • Identify and treat unresolved medical issues • Emphasize active patient participation and responsi- • Symptomatic improvement bility • Eliminate inappropriate medications, institute desir- • Provide educational and training in the use of specific able medications skills such as exercise, relaxation, and problem solv- • Improve aerobic conditioning, endurance, strength ing and flexibility (restoration of physical functioning) • Encourage patient feelings of success, self-control, • Eliminate excessive guarding behaviorsthat interfere and self-efficacy with normal activities • Encourages patients to attribute success to their own • Improve coping skills and psychological well-being efforts • Alleviate depression • These treatment programs also share general features. Foster independence • Assess patient resources and identify vocational and General Features of Multidisciplinary Pain Treatment Teams recreational opportunities • Share a common conceptualization of chronic pain • Educate the patient about pain, anatomy, physiology patients and psychology, discriminating hurt from harm 1194 Multidisciplinary Pain Centers, Rehabilitation

• Educate the patient about prudent health care con- ment team to employ sound behavioral principles in sumption designing patient treatment activities (Turk and Gatchel • Assist the patient to establish realistic goals and to 2002). maintain treatment gains • Restoration of social and occupational functioning - Roles of the Nurse socialreintegration,returntoproductiveemployment The nurse is a key part of the treatment program, play- • Reduction in use of healthcare system ing a major role in patient education regardingsuch topics as medication, diet, sleep hygiene, and sexual activ- The original MPCs were inpatient-based. It is now ity. Another nursing function is assisting patients in the apparent that outpatient programs can be equally suc- practice of newly learned skills, assessing medication cessful if they have adequate intensity and duration (for responses, and acting as the focal point of the commu- a review see Turk et al. 1993). There are no controlled nication that keep such a program operational. The roles studies to determine the optimal duration of treatment of nurses vary with their skills and their interaction with and hours per day; nor does the literature reveal which other providers. Since the nurses tend to be with the pa- aspects of the various components are most important tients throughout their entire treatment course, they play for a treatment program. It is clear, however, that the a central role in maintaining continuity during the treat- effects of an MPC are greater than the sum of its parts. ment program. Common features of all programs include physical therapy, medication management, education about how the Roles of Physical and Occupational Therapists body functions, psychological treatments (e.g. learning Physicalandoccupationaltherapistsprovideassessment coping skills, problem solving, communication skills andactivephysicaltherapiesforpatientstoimprovetheir training), assessment, and therapies aimed at improving strength, endurance and flexibility. They do not provide function and the likelihood of return to work. Programs passive modalities of treatment. They assist the patient usually have a standard daily and weekly format that in developing proper body mechanics and strategies for providers can tailor to individual patient needs. The coping with the physical demands of a job and everyday overall length of a program depends, in part, upon life, and function mainly as teachers and coaches. unique patient requirements. Typical programs operate The occupational therapists review the patient’s work 8 hours per day, 5 days per week and last 3 to 4 weeks, history, disabilities, and factors that may play a role in although some programs meet less frequently and are determining who goes back to work and who does not. of longer duration. They help in the establishment of work hardening and training activities. Some programs heavily emphasize Roles of the Physician ergonomicissuesandutilizehightechnologyinphysical The physician is responsible for the initial history and therapies; however, the need for this type of treatment physical examination;review of outside records and de- is unclear. termination of the need for any further diagnostic tests. Role of the Vocational Counselor Detailed assessment of the patient’s medication history isalsoakeyphysiciancontribution.Theimplementation The vocationalcounselor playsa criticalrole inthe treat- of medication management, including drug tapering by ment of an individualfor whom return to work is a treat- meansof a pain cocktail technique (described below), mentgoal.Initialassessmentoccursaspartofthescreen- is also a physician role. Another important task for the ing process, but in-depth evaluation of interests, edu- physician is to review with the patient the medical issues cation, aptitude, physical capacities, learning capabili- and the findings of diagnostic tests and imaging studies. ties, work experience, transferable skills and vocational The physician also plays an essential role in the educa- goals occurs upon entry into the treatment program. The tion of the patient, and in legitimating all of the other goals are to identify vocational opportunities and barri- components of the treatment program. erstoeffectivereturntowork.Inadditiontooccupational counseling, counselors provide job seeking skills training,placementcounseling,workhardening,information Roles of the Psychologist about educational options and liaison services. Informa- The psychologist typically conducts the initial psy- tion obtained by the vocational counselor is critical for chological evaluation, monitors and implements the other team members to establish realistic goals for the cognitive and behavioral treatment strategies, teaches patient.Insomeorganizations,rehabilitationnursespro- the patient coping skills, and educates patients about vide this service. the relationship between thoughts, feelings, behavior, and physiology. The psychologist usually leads both Treatment Principles individual and group educational and counseling ses- The goals of multidisciplinary pain management are sions for the patients. In addition, the psychologist plays normally specific, definalble, operationalizable, and re- a critical role in helping other members of the treat- alistic in nature (see list ‘Goalsof Multidisciplinary Pain Multidisciplinary Pain Centers, Rehabilitation 1195

Multidisciplinary Pain Centers, Rehabilitation, Table 1 Issues Addressed by Psychologists

Impact of pain on life, signiﬁcant others Resourcefulness vs. helplessness

Communication Problem Solving

Reinforcement and pain behaviors Relationship between thoughts, feelings, behavior, and physiology

Goal setting, homework, adherence Coping Skills (relaxation, distraction, positive thoughts)

Self-reinforcement Fear of activity

Stress and Pain and Homework Generalization, maintenance, ﬂare-ups,Relapse

Multidisciplinary Pain Centers, Rehabilitation, Table 2 General Educational Topics Covered

Body mechanics, modiﬁcation of movement patterns Role of medication

Posture Sleep hygiene

Energy conservation Diet

Performance of activities of daily living Sexuality

Hurt vs. harm Anatomy &Physiology

Leisure activities Gate Control Theory

Vocational activities Home practice Active vs. passive exercises and modalities Progressive exercises M Adherence to recommendations Management of ﬂare-ups

Management’). As they have evolved, MPC treatments a method of converting all opioids to an equivalent dose have become performance based, goal-directed, and of methadone, delivered with a masking vehicle. The outcome driven. Integration of medical evidence related dose is then tapered over the period of treatment, always to patientt’s pain and physical impairment with infor- with the full knowledge of the patient. Most medica- mation concerning what patients are doing or failing to tions are discontinued; the common exceptions are do because of their pain, how these behaviors influence antidepressants, which often help chronic pain patients. patientt’s physical capacity, how others respond to the MPCs discourage long-term use of other medications, patient, the influence of psychosocial factots that con- both because of their potential side effects and because tribute directly and indirectly to patientt’s physical and their use undermines the philosophical concept that the emotional status, and the potential for rehabilitation patient must learn to control his or her pain, and not (i.e. disability) are essential. The treatment team must depend upon healthcare providers or their prescriptions. build an alliance with patients to instill a willingness to Psychological strategies generally target altering be- accept the need for self-management. havior rather than changing the patient’s personality. Physical therapy employs behavioral medicine prin- Patients learn coping skills because this is frequently a ciples (Turk et al. 2000) and, as noted, engages few, deficiency that has led to the patient’s many difficulties if any, passive modalities. The emphasis is upon im- (see following list). Couples therapy is sometimes ap- proving strength, endurance and flexibility through propriate. Issues that patients bring up receive attention the patient’s physical activities. The therapists pro- in either the group format or in individual therapy, as vide instruction, guidance, safety and encouragement. needed. As depression is so often a component of the Accomplishments, rather than pain behaviors, receive chronic pain problem, it warrants both psychological as rewards. Patients maintain graphs of their daily activity well as pharmacological interventions. Psychologists and track progress. As patients progress, they enroll in provide relaxation and consolidation sessions that al- more complex activities that simulate the workplace low the patients to work on newly acquired skills, and requirement. explore educational topics and new psychological skills Medications are given on a time contingent basis, so (see Table 1). as to uncouple the reinforcement of pain behaviors by medications. In general, patients in an MPC program do not derive adequate pain relief from analgesic medica- Coping Skills Taught tions, and this is why they are usually tapered by means • Relaxation of the pain cocktail technique. This technique is simply • Distraction (attention diversion) methods 1196 Multidisciplinary Pain Treatment for the Elderly

• Cognitive restructuring – identification and challeng- address the restoration of well-being and not just aim at ing maladaptive thoughts and feelings the alleviation of symptoms. Finally, the illness is not • Problem solving just chronic pain but is also the failure to work, often as- • Anger management cribed erroneously to the pain instead of the patient or • Desensitization the patient’s circumstances. • Rehearsal and home practice • Communication skills including assertiveness References • Goal setting • 1. Cutler RB, Fishbain DA, Rosomoff HL et al. (1994) Does Non- Pleasant activity planning surgical Pain Center Treatment of Chronic Pain Return Patients • Self-monitoring and Self-reinforcement to Work? A Review and Meta-Analysis of the Literature. Spine 19:643–652 An important aspect of MPCs is education. This is an 2. Guzman J, Esmail R, Karjalinen K et al. (2001) Multidisciplinary activity that is shared by physicians, psychologists and Rehabilitation for Chronic Low Back Pain: Systematic Review. nurses. Topics cover a wide array of the problems facing BMJ 322:1511–1516 3. Loeser JD, Turk DC (2001) Multidisciplinary Pain Management. those who suffer from chronic pain. Topic selection and In: Loeser JD, Butler SD, Chapman CR, Turk DC (eds) Bonica’s content is to some degree a function of the needs of each Management of Pain, 3rd edn. Lippincott Williams and Wilkins, group of patients, but content always includes a core set Philadelphia PA, pp 2069–2079 of issues (see Table 2). 4. Turk DC (2002) Clinical Effectiveness and Cost Effectiveness of Treatments for Chronic Pain Patients. Clin J Pain 18:355–365 An important issue is the maintaining of gains that have 5. Turk DC, Gatchel RJ (2002) Psychological Treatment of Chronic occurred during the treatment program. Surrounded by Pain: Clinical Handbook, 2nd edn. Guilford Press, New York a team of supportive healthcare providers and other pa- 6. Turk DC, Okifuji A, Sherman J (2000) Behavioral Aspects of tients, most patient see some gains by the end of treat- Low Back Pain. In: Taylor JR, Twomey L (eds) Physical Therapy ment. However, many are unable to maintain their gains of the Low Back, 3rd edn. Australia, pp 351–383 whentheyreturntotheirnormalfamilyandoccupational 7. Turk DC, Rudy T, Sorkin B (1993) Neglected Topics in Chronic Pain Treatment Outcome Studies: Determination of Success. Pain activities. Each patient must learn strategies for main- 53:3–16 taining his or her gains in a less supportive environment. Most programs have established brief follow-up interactions to try to assist patients to keep up their physical and psychological skills and to prevent relapses. Multidisciplinary Pain Treatment Outcomes for the Elderly A substantial body of literature supports the assertion that multidisciplinary pain treatment is effective in reducing pain, the use of opioid medication, the use Definition of health care services; it increases activity, returns The elderly are underrepresented in multidisciplinary people to work, and aids in the closing of disability programs, despite the fact that multimodal treatment is claims (e.g. Cutler et al. 1994, Guzman et al. 2001). a key to successful practice in geriatric medicine. Moreover, treatment at MPCs targets patients with the PsychologicalTreatmentofPaininOlderPopulations most recalcitrant problems, yet the benefits appear to exceed those for conventional treatments including surgery and, in contrast to surgery, there are no known iatrogenic complications of treatment at MPCs (Turk 2002). Not only do MPCs appear to be clinically ef- Multidisciplinary Treatment Program fective, they also appear to be cost-effective, with the potential to provide substantial savings in healthcare and disability payments (Turk 2002). Definition Physicians, nurses, physical therapists, and psycholo- Conclusions gists in one pain-management center. Treatment staff The team approach to complex chronic pain patients, as meet weekly to review patient progress in the profound in a multidisciplinary pain treatment facility, has gram, which emphasizes pain reduction and functional evolved with an underlying set of principles. These in- outcomes. clude the recognition that Cartesian mind-body dualism Complex Chronic Pain in Children, Interdisciplinary is a curse upon effective healthcare. Second, a biopsy- Treatment chosocial model is required to capture all of the relevant MultimodalRehabilitationTreatmentandPsychiatric factors. Third, the treatment must address the pain itself, Aspects of Multimodal Treatment for Pain and not just be a search for hidden causes and specific Psychological Treatment of Chronic Pain, Prediction remedies for these causes. Fourth, the treatment must of Outcome Multimodal Analgesia in Postoperative Pain 1197

Characteristics Multimodal Single analgesics, for example opioids or non-steroidal anti-inflammatory drugs (NSAIDs), are not able to Definition provide effective pain relief without side effects such Refers to treatment approaches that use more than one as nausea, vomiting, sedation, or bleeding (Jin and type of therapy (e.g. a combination of drug, psycholog- Chung 2001). The use of multi-drug therapy such as in ical and or physical therapies). neuraxial blocks, is a common and effective example Complex Chronic Pain in Children, Interdisciplinary of the multimodal approach, and may help to prevent Treatment rapid tolerance to individual medications. Studies of multimodal approaches for postoperative pain control have shown improvements in postoperative pain scores Multimodal Analgesia and similar reductionsin analgesic requirements(Shang and Gan 2003). Pharmacological pain relief can be markedly improved Synonyms by attention to choiceof drugs, positivedruginteraction, Balanced analgesia administration route, timing and dosing (Breivik 2002). Thismaybecarriedoutusingthe‘ AcutePainService’ Definition with anaesthetist-supervised pain nurses. Multimodal analgesia (also known as balanced anal- Commonly, acetaminophen (paracetamol) and NSAIDs gesia) occurs from a combination of analgesics (multi- are in routine use as components of multimodal anal- modal mixture). The rationale is that each drug exerts gesia, in combination with opioids or local anaesthetic its analgesic effect via a different mechanism. Thus, a techniques to modulate this (Power and Barratt 1999). low-dose combination might offer the best therapeu- Alpha 2 antagonists (e.g. clonidine) and N-Methyl- M tic effect, while minimizing the risk of the unwanted D-Aspartateantagonists(e.g. ketamine to reduce wound adverse effects seen with high doses of each of these secondary mechanicalhyperalgesia) canbeaddedeither drugs. intravenously (in patient controlled analgesia) or epidu- Epidural Infusions in Acute Pain rally (single shot, constant infusion or by patient con- Multimodal Analgesia in Postoperative Pain trolled epidural analgesia) (Potgatzki et al. 2003). The Postoperative Pain, Importance of Mobilisation use of spinal neostigmine and adenosine is currently be- Postoperative Pain, Transition fromParenteral to Oral ing investigated (Shipton 1999). Drugs Improved pain control includes the optimal use of acetaminophen (paracetamol) by mouth, rectally or intravenously (as the prodrug proparacetamol). Evi- dence is now sufficient to recommend that an NSAID be Multimodal Analgesia added to acetaminophen for short-term postoperative in Postoperative Pain pain relief, unless there are any known contraindications to NSAIDs (Breivik 2002). These include allergy, EDWARD A. SHIPTON gastro-intestinal ulcer disease, potential bleeding prob- Christchurch School of Medicine and Health Sciences, lems (due to its irreversible effects on platelet function), Department of Anaesthesia, University of Otago, renal functional impairment, asthma, hypovolaemia, Christchurch, Otago, New Zealand hyperkalaemia, severe liver disease, circulatory failure, [email protected] pre-eclampsia or certain drugs (ACE inhibitors, diuretics, beta blockers, cyclosporine, methotrexate) (Breivik Synonyms 2002). Balanced analgesia The new COX-2 inhibitor NSAIDs have relative gastric and platelet sparing effects, and can be Definition given orally (e.g. rofecoxib, celecoxib, etoricoxib, Multimodal analgesia is the technique of combining valdecoxib) and intravenously (e.g. paracoxib) as a multiple modalities of pain relief to provide more effec- component of multimodal analgesia (Shang and Gan tive analgesia and a lower incidence of adverse effects. 2003). Different analgesics act on different receptors, enzymes Where acetaminophen and NSAIDsresultin inadequate and ionic channels, creating an additive or synergistic pain relief, opioids can be given either orally, rectally, response. There is a concomitant reduction in adverse intramuscularly or intravenously (nurse administered or effects, owing to the lower dose of the individual drugs by patient controlled analgesia). Opioid adverse effects and differences between drugs in adverse effect profiles such as nausea, vomiting, pruritus and urinary retention (Shang and Gan 2003). are reduced by multimodal analgesia. 1198 Multimodal Analgesics

Local anaesthetic infiltration (in tissue, joints, peri- 3. Jin F, Chung F (2001) Multimodal Analgesia for Postoperative toneal cavity) as part of a multimodal regimen offers Pain Control. J Clin Anesth 13:524–539 4. Kehlet H (1999) Acute Pain Control and Accelerated Postoper- a simple, safe and inexpensive alternative to epidural ative Surgical Recovery. Surg Clin North Am 79:431–443 pain control (Schumann et al. 2003). Intra-articularly, 5. Kehlet H, Wilmore DW (2002) Multimodal Strategies to Improve local anaesthetics are often combined with opioids Surgical Outcome. Am J Surg 183:630–641 (morphine) (Menigaux 2001). Catheters can be used 6. Menigaux C, Guignard B, Fletcher D et al. (2001) Intraop- erative Small-Dose Ketamine Enhances Analgesia after Knee to provide constant infusions of local anaesthetics Arthroscopy. Anesth Analg 93:606–612 around peripheral nerves and plexuses (with or without 7. Pogatzki EM, Niemeier JS, Sorkin LS et al. (2003) Spinal a multimodal mixture). Glutamate Receptor Antagonists Differentiate Primary and Regional anaesthesia attenuates the endocrine- Secondary Mechanical Hyperalgesia Caused by Incision. Pain 105:970–1007 metabolic effects (the rise in cortisol, catecholamines, 8. Power I, Barratt S (1999) Analgesic Agents for the Postoperative glucagon, hyperglycaemia, insulin resistance and nega- Period. Nonopioids. Surg Clin North Am 79:275–295 tive nitrogen balance) on stress-induced organ dysfunc- 9. Schumann R, Shikora W, Weis JM et al. (2003) A Comparison of tion, and extends analgesia into the postoperative period Multimodal Perioperative Analgesia to Epidural Pain Manage- ment after Gastric Bypass Surgery. Anesth Analg 96:469–474 (Kehlet and Wilmore 2002). The inhibitory effects on 10. Shang AB, Gan TJ (2003) Optimising Postoperative Pain Man- catabolic responses are most pronounced when regional agement in the Ambulatory Patient. Drugs 63:855–867 anaesthesia is provided for up to 24–48 hours, prefer- 11. Shipton EA (1999) The Future. In: Shipton EA (ed) Pain – Acute ably as a continuous epidural analgesic technique. After and Chronic. Arnold, London, pp 326–365 12. Wu CL, Raja SN (2002) Optimising Postoperative Analgesia. major thoracic or abdominal surgery, patients at risk of Anesthesiology 97:533–534 postoperative respiratory and cardiac complications are offered optimal analgesia, with thoracic or thoracolum- bar epidural infusion of low doses of local anaesthetic (e.g. levobupivacaine, ropivacaine), a lipophilic opioid (e.g. fentanyl, sufentanil) and epinephrine (adrenaline) Multimodal Analgesics (Breivik 2002). Accelerated multimodal postoperative recovery pro- Drugswith Mixed Action and Combinations, Empha- grammes are being developed as a multidisciplinary sis on Tramadol effort, with the integration of postoperative pain management into a postoperative rehabilitation programme (Kehlet 1999). Multimodal intervention may reduce stress induced organ dysfunction and accompanying Multimodal Rehabilitation Treatment morbidity (Kehlet and Wilmore 2002). An integrated approach to perioperative care (com- and Psychiatric Aspects prising minimally invasive surgical access, optimal of Multimodal Treatment for Pain pain relief provided by epidural analgesia, early oral DAV I D A. FISHBAIN nutrition, avoidance of nasogastric tubes, and aggres- Department of Psychiatry and Department of sive active mobilization) decreases time to discharge, Neurological Surgery and Anesthesiology, University readmission rate, and postoperative morbidity with of Miami, School of Medicine and H. Rosomoff Pain increased patient satisfaction and safety after discharge Center at South Shore Hospital, Miami, FL, USA (Carli et al. 2002). After colonic surgery, as compared dfi[email protected] to intravenous opioids, epidural analgesia in a multimodal analgesic regimen results in significantly less deterioration in postoperative functional status (lower Synonyms pain and fatigue scores, earlier mobilization and return Multidisciplinary treatment; Psychiatric Aspects of of gastro-intestinal function), and health related quality Multimodal Treatment for Pain; Multimodal Treatment of life at six-week follow-up (Wu and Rajah 2002). The use of perioperative multimodal techniques may provide long-term benefits to patients. Definition a) Multimodal treatment is defined as applying several References treatments simultaneously / concurrently or sequentially (one after another) in order to improve pain and 1. Breivik H (2002) Postoperative Pain: Toward Optimal Phar- macological and Epidural Analgesia. In: Giamberardino MA facilitate rehabilitation. (ed) Pain 2002 – An Updated Review. IASP Press, Seattle, pp b) Multidisciplinary treatment is defined as treatment 337–349 involving more than one treatment discipline and as 2. Carli F, Mayo N, Klubien K et al. (2002) Epidural Analgesia En- different disciplines usually utilize different treat- hances Functional Exercise Capacity and Health-Related Quality of Life after Colonic Surgery: Results of a Randomized Trial. ments, multidisciplinary treatment is by definition Anesthesiology 97:540–549 multimodal. Multimodal Rehabilitation Treatment and Psychiatric Aspects of Multimodal Treatment for Pain 1199

Characteristics Multi-Disciplinary Pain Clinic Pain Treatment Facilities • Specializes in the multi-disciplinary diagnosis and Pain treatment facilities developed for a number of rea- management of patients with chronic pain or may sons. First, peoplein generalputavery high valueon liv- specialize in specific diagnoses or pain related to a specific region of the body. ing a pain-free life. Second, numerous epidemiological • studies determined that a large percentage (2–40%) of Staffed by physicians of different specialties and other health care providers. the general population suffered from chronic intractable • benign pain. And third, the experience of treating con- Differs from a multi-disciplinary pain center only be- tinuous severe pain in battle injured World War II sol- cause it does not include research and teaching. diersdetermined thata coordinatedteam wasrequired to managethedifferenttypesofpain(RosomoffandSteele- Multi-Disciplinary Pain Center Rosomoff 1991). • Organization of health care professionals and basic Multidisciplinary pain clinics or centers evolved from scientists that includes research, teaching and patient these concepts in the early 1970s. It was observed that care in acute and chronic pain. a significant percentage of low back pain and neck • Typicallya componentof a medicalschoolora teach- pain patients did not improve with traditional medi- ing hospital. cal treatment but remained disabled (Rosomoff and • Clinical programs supervised by an appropriately Steele-Rosomoff 1991). These patients demonstrated trained and licensed director. a host of behavioral and psychosocial problems in • Staffed by a minimum of physician, psychologist, oc- association with their chronic pain. These problems cupationaltherapist,physicaltherapistandregistered required the intervention of disciplines besides those of nurse. neurosurgery, orthopedic surgery and anesthesiology • Services provided integrated and based on interdis- (Rosomoff and Steele-Rosomoff 1991). In addition, ciplinary assessment and management. M these patients required a concurrent highly integrated • Offers both inpatient and outpatient program. multidisciplinary treatment approach that would address all the patient’s problems simultaneously, i.e. Inspection of the list above indicates that there is a clear multimodal treatment (Rosomoff and Steele-Rosomoff distinction between modality-oriented clinics, pain 1991). clinics and multidisciplinary facilities. Differences There were approximately 1500–2000 pain treatment between multidisciplinary pain clinics and multidis- facilities in the US (Rosomoff and Steele-Rosomoff ciplinary pain centers (MPC) include research and 1991). They differed in their staff composition, size, teaching in the MPCs. These definitions also indicate philosophy and most importantly, treatment approach. that the MPCs may be more likely to have inpatient and Because of this problem, the International Association outpatient treatment and to have larger and more diver- for the Study of Pain (IASP) developed definitions sified multi-disciplinary staffs, including more than one for four types of pain treatment facilities (see below) physician specialty. As a consequence, MPCs are likely (Loeser 1991). to offer a wider range of treatments than multidisci- IASP Classification of Pain Facilities plinary pain clinics and thus involve more multimodal (Adapted from Loeser 1991) treatment. Most of the pain facility treatment outcome studies involve MPCs. Modality-oriented Clinic • Provides specific type of treatment, e.g. nerve blocks, MPC Treatment Outcome Studies transcutaneous nerve stimulation, acupuncture, Because MPC developed in the 1970s and because they biofeedback. had to demonstrate treatment efficacy, there are now • May have one or more health care disciplines. close to three hundred treatment outcome studies in the • Does not provide an integrated, comprehensive ap- literature (Fishbain et al. 1993). As such, this literature proach. has been subjected to a number of meta-analyses (Table 1). It is interesting to note that these meta-analyses Pain Clinic (four) were consistent in indicating that MPC treatment • Focuses on the diagnosis and management of pa- or multimodal treatment is effective. This meta-analysis tients with chronic pain or may specialize in specific literature has recently been reviewed for meta-analytic diagnoses or pain related to a specific region of the procedure quality and found to be of acceptable qual- body. ity (Fishbain et al. 2000). It is also important to note • Does not provide comprehensiveassessment or treat- that this literature now indicates that multidisciplinary ment, an institution offering appropriate consultative (multimodal) treatment is superior to single treatment and therapeutic services would qualify but never an such as medical therapy or physical therapy (Flor et al. isolated solo practitioner. 1992). 1200 Multimodal Rehabilitation Treatment and Psychiatric Aspects of Multimodal Treatment for Pain

Multimodal Rehabilitation Treatment and Psychiatric Aspects of Multimodal Treatment for Pain, Table 1 MPC Chronic Pain Treatment Meta- Analyses Author / Year Treatment type and clinical Outcome measure Author clinical interpretation of condition meta-analysis data

Malone and Strube (1988) Pain facility, chronic pain Activity level. Frequency pain. Index Treatment effective, good effect sizes. pain. Intensity pain. Medication use. Mood.

Curtis (1992) Multi-disciplinary pain facility, Physical ﬁtness. Subjective distress. Multi-disciplinary treatment programs chronic low-back pain. Daily activity increase. Medication effective. decrease.

Flor et al. (1992) Multi-disciplinary pain facilities, Activity level. Pain behavior. Multi-disciplinary pain clinics effective chronic low-back pain. Medication use. Return to work. at returning chronic back pain patients to work.

Cutler et al. (1994) Multi-disciplinary pain facility, Return to work. Multi-disciplinary pain facilities return chronic low-back pain. chronic low-back pain patients to work.

Which Treatments or Combination Makes Clancy 1988) and outpatient group cognitive therapy, MPC Treatment Effective? relaxation training and cognitive therapy have all been For an exhaustive list of treatment by medical specialty demonstrated to be equally efficacious (Turner and available at MPCs, please refer to Fishbain DA et al. Jensen 1993). (1997). It is to be noted that some of these treatments, In addition, different treatments within one category ap- e.g. physical therapy, have been studied in a placebo pear not be additive. When a cognitive component was fashion, resulting in a significant number of studies added to operant pain treatment there was no decrease in the literature. There are meta-analysis results avail- in patient medical utilization costs or improvement in able for some of these (Fishbain et al. 2000). Of the patient quality of life scores (Goossens et al. 1998). non-pharmacological treatments having meta-analyses, However, treatments from different groups may have physical therapy, cognitive and behavior therapy and an additive effect. The combined package of cognitive- educational therapy appear to be effective. Of the behavioral group pain treatment with physical therapy psychopharmacological treatments, antidepressants, has been found to be superior to physical therapy alone topical NSAIDs, capsaicin and anticonvulsants are (Nicholas et al. 1992). This speaks to the apparent effective (Fishbain et al. 1997; Fishbain et al. 2000). advantage of multimodal treatment. Yet, in reality MPCs may or may not provide these treat- Atthistime,itisunclearwhatcombinationofMPCtreat- mentsormayprovideagreaterrangeoftreatments(Fish- ments delivered in a treatment package is effective. It is bain et al. 1997). Pain facilities generally use multiple thereforeunclearwhatcombinationoftreatmentsisnec- treatments simultaneously which are integrated into a essary for an effective package. It is also possible that treatment package (Fishbain et al. 1997). Thus, it is im- the effectiveness of MPCs rests in their ability to deliver possibletosaywhetherthepositiveMAresultsforMPCs this treatment package and an ability to integrate treat- related to the fact that the specific treatments shown to ments into a package (Rosomoff and Steele-Rosomoff be effective were provided or thatotherhitherto untested 1991). This last issue may influence an overall effective- treatmentswereutilized.Thisquestionawaitsfurtherre- ness that has not been explored in the literature. search. Another issue in relation to which treatments make Psychiatric Multimodal Treatment within MPCs MPC treatment effective is what outcome variables Early in the course of development of MPCs it became are examined (Fishbain et al. 1993). As an example, clear that the vast majority of chronic pain patients a specific treatment such as capsaicin may decrease suffered from associated psychiatric comorbidity (Fish- pain, but if used alone, it may not be enough to return bain 1999). In addition, it has recently become clear the patient to work. In other words, for the attainment that drugs commonly utilized by psychiatrists, e.g. of some outcome variables, such as return to work, a antidepressants, anticonvulsants, have strong analgesic combination of specific treatments may be required. properties (Fishbain et al. 2000). Finally, it has be- The evidence indicates that treatments under one cat- come recognized that many chronic pain patients have egory, such as behavior, may have equal efficacy. For neuropathic pain for which psychopharmacological example, operant conditioning has been found to be as treatment is becoming increasingly available (Fish- effective as cognitive-behavior treatment (Turner and bain et al. 2000). This confluence of factors and the Multimodal Treatment 1201 fact that psychiatrists by the nature of their specialty 5. Provide supportive counseling. have expertise in psychopharmacological treatment and 6. Lead behavior rehabilitation groups. detoxification (Fishbain 2002) has increased the poten- 7. Provide program patient education for his / her area tial impact of this medical specialty on pain treatment of expertise. outcome. 8. Participate in the behavior modification (reinforce- The list below presents the functions of the psychiatrist ment) aspects of the multidisciplinary program. within MPCs and the potential treatments that he / she 9. If within his / her area of expertise, perform proce- can initiate in a multimodal fashion. With reference to dures such as trigger point injections, acupuncture, treatments, it is to be noted that these now reflect the blocks, epidurals, etc. major issue of directing psychopharmacological treatment both at pain relief and at the same time psychiatric comorbidity. Thus, the psychiatrist working at an MPC References should be very familiar with the literature addressing the 1. Cutler RB, Fishbain DA, Rosomoff HL et al. (1994) Does non- psychopharmacologicaltreatment of pain in order to be surgical pain center treatment of chronic pain return patients to work? A review and meta-analysis of the literature. Spine able to choose an agent for pain, which will also have 19:643–652 impact on the psychiatric comorbidity. This concept is 2. Curtis JE (1992) The efficacy of multidisciplinary treatment pro- very different from 10–15 years ago, when psychiatrists grams for chronic low back pain: a meta-analysis. Dissertation treated psychiatric comorbidity exclusively. In addition, Abstracts International 53:4948 3. Fishbain DA (1999) Approaches to treatment decisions for psy- it is to be noted that as there is now a subspecialty psychiatric comorbidity in the management of the chronic pain pa- chiatry board in pain management, some psychiatrists tient. Med Clin North Am 83:737–759 are developing expertise in the procedure treatments of 4. Fishbain DA (2002) Opiate, hynopsedative, alcohol, and nicotine chronic pain. detoxification protocols. In: Tollison CD, Satterthwaite JR, Tol- lison JW (eds) Practical Pain Management, Lippincott Williams and Wilkins, Philadelphia, pp 314–329 Psychiatric Functions and Multimodal Treatments 5. Fishbain DA, Rosomoff HL, Goldberg M et al. (1993) The pre- M Potential Functions diction of return to the workplace after multidisciplinary pain center treatment. Clin J Pain 9:3–15 1. Diagnosis of psychiatric comorbidity per DSM- 6. Fishbain DA et al. (1997) Pain facilities: a review of their ef- system. fectiveness and referral selection criteria. Current Review Pain 1:107–115 2. Determination presence of psychological difficul- 7. Fishbain D, Cutler RB, Rosomoff HL et al. (2000) What is the ties, problems, etc., e.g. suicidal ideation, homicidal quality of the implemented meta-analytic procedures in chronic ideation, marital / system conflicts, etc. pain treatment meta-analyses? Clin J Pain 16:73–85 3. Determination presence of somatic comorbidities, 8. Flor H, Fydrich T, Turk DC (1992) Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain 49:221–230 e.g. sleep problems, headaches, dizziness, etc. 9. Goossens ME, Rutten-Van Molken MP, Kole-Snijders AM et al. 4. Develop a psychopharmacological and non-psycho- (1998) Health economic assessment of behavioural rehabilitation pharmacological treatment plan for #1–#3 above. in chronic low back pain: a randomised clinical trial. Health Econ 5. Administer behavioral rating scale testing if neces- 7:39–51 10. Loeser JD (1991) Desirable characteristics for pain treatment sary. facilities: reports of the IASP taskforce. In: Bond MR, Charlton 6. According to the history, physical examination and JE, Woolf CJ (eds) Proceedings of the VI th World congress on required laboratory workup determine whether the Pain. Elsevier, Amsterdam, pp 411–415 pain is nociceptive, neuropathic or both. 11. Malone MD, Strub MJ (1988) Meta-analysis of non-medical treatments for chronic pain. Pain 34:231–244 7. Participate in multidisciplinary case staffing in order 12. Nicholas MK, Wilson PH, Goyen J (1992) Comparison of to develop a multidisciplinary treatment plan that cognitive-behavioral group treatment and an alternative nonpsy- would encompass the psychiatric treatment plan. chological treatment for chronic low back pain. Pain 48:339–347 8. Act as consultant to other multidisciplinary staff. 13. Rosomoff HL, Steele-Rosomoff R (1991) Comprehensive multidisciplinary pain center approach to the treatment of low back 9. Educate members of multidisciplinary staff on psy- pain. Neurosurgical Clinics of North America 2:877–890 chiatric aspects of chronic pain. 14. Turner JA, Clancy S (1988) Comparison of operant behavioral 10.Perform clinical research on all aspects of pain. and cognitive-behavioral group treatment for chronic low back pain. Clin Psychol 56:261–266 11.Act as director of the multidisciplinary team. 15. Turner JA, Jensen MP (1993) Efficacy of cognitive therapy for chronic low back pain. Pain 52:169–177 Multimodal Treatments 1. Psychopharmacological treatment directed at nociceptive pain. 2. Psychopharmacologicaltreatment directed at neuro- Multimodal Treatment pathic pain. 3. Psychopharmacologicaltreatmentdirectedatpsychi- atric comorbidity. MultimodalRehabilitationTreatmentandPsychiatric 4. Detoxify patient if necessary. Aspects of Multimodal Treatment for Pain 1202 Multiple Sclerosis (MS)

Multiple Sclerosis (MS) Munchausen’s by Proxy

Deﬁnition Deﬁnition An idiopathic immune system disease of the central ner- Aseveretypeoffactitiousdisorderwheretheparentcon- vous system in which gradual destruction of myelin oc- sciouslycausesthechildtoassumethesickroletosatisfy curs in patches throughout the brain or spinal cord (or the parent’s psychological need. both), interfering with the nerve pathways and causing Somatization and Pain Disorders in Children muscular weakness, lossof coordination and speechand visual disturbances. Sometimes manifests as radiating pain in a similar distribution as the sciatic nerve. Central Pain, Outcome Measures in Clinical Trials Mu(μ)-Opioid Receptor Sciatica Trigeminal, Glossopharyngeal, and Geniculate Neu- Synonyms ralgias MOP

Definition Multipolar Cells Opioid receptors that preferentially bind endomorphins and morphine-likedrugs. Itwasoriginallynamed forthe Definition effects of morphine. Also known as OP3 receptors, they Neuron type whose cell body (soma) issues an axon and are the main sites of action for most opioid drugs. They several primary dendrites forming the dendritic tree. share the same distribution as kappa receptors with the Trigeminal Brainstem Nuclear Complex, Anatomy exception of the hypothalamus. Agonists are associated with analgesia, respiratory depression, euphoria bradycardia,miosis,reducedgutmotilityandnauseaandvom- Multiprofessional iting. Opiates During Development Opioid Receptors Definition Opioid Rotation in Cancer Pain Management Healthcare professionals working with the same patient Postoperative Pain, Appropriate Management PhysicalMedicineandRehabilitation,Team-Oriented Postoperative Pain, Transition from Parenteral toOral Approach

Multireceptive Neuron (MR) Muscle and Joint Pain

Deﬁnition Spinal Dorsal Horn Pathways, Muscle and Joint A neuron that is activated by a variety of innocuous and noxious mechanical and thermal stimuli applied to its receptive ﬁeld, which is typically widespread and com- Muscle Contraction Headache prises of cutaneous and deep tissue. ArthritisModel,Kaolin-CarrageenanInducedArthri- Headache, Episodic Tension Type tis (Knee) Chronic Pain Thalamic Bursting Activity Thalamus, Nociceptive Cells in VPI, Cat and Rat Muscle Cramp

Deﬁnition Multisensory Perceptions Involuntary sudden painful muscle contraction. During the cramp, the muscle is visibly and palpably taut and Deﬁnition painful, often with abnormal posture of the affected Perceptions of external objects based on more than one joint, condition which can be relieved by stretching or form of sensory input (e.g. sight and smell). massage. Amygdala, Pain Processing and Behavior in Animals Muscular Cramps Muscle Nociceptors, Neurochemistry 1203

an intracellular cascade of events that – among other ef- Muscle Discrimination fects–leadstotheactivationofenzymessuchaskinases.

Definition Characteristics This refers to a person’s ability to accurately sense the Morphology current level of tension within the muscles being mon- A nociceptor is an unencapsulated (“free”) nerve ending itored. that is connected to the CNS by thin myelinated (group Psychophysiological Assessment of Pain III) or unmyelinated (group IV) nerve fibers. These fibers have a slow conduction velocity, with group III fibers conducting between 2.5 and approximately Muscle Hyperactivity 20 m/s and group IV fibers between 0.5 and 1 m/s. Histologically, the nerve ending is not free in the strict Orofacial Pain, Movement Disorders sense but is surrounded by a single layer of Schwann cells. The Schwann cells leave small patches of the axonal membrane uncovered, the so-called exposed Muscle Nociceptor axon areas. These areas are assumed to be the sites of action for the chemical stimuli that are present in a pathologically altered muscle. Definition A free nerve ending with high thresholds to mainly Neuropeptide Content mechanical and chemical stimuli (nociceptive); also There is no neuropeptide that can be regarded as spe- high-intensity thermal stimuli may excite muscle noci- cific for sensory fibers from muscle or for muscle nociceptors. Their afferents are small-diameter myelinated ceptors. Nerve endings in skeletal muscle of the rat have M (Group III) or unmyelinated (Group IV) muscle nerve been reported to contain substance P (SP), calcitonin- fibers. Group IV corresponds to cutaneous C-fibers and gene related peptide ( CGRP), somatostatin (SOM), group III to Aδ-fibers. Conduction velocities for cat vasoactive intestinal polypeptide (VIP) as well as the muscle afferent fibers are below 2.5 m/s for group IV neurotrophin nerve growth factor (NGF), and thus and 2.5 to 30 m/s for group III fibers. presents a neuropeptide pattern similar to that of cuta- Exogenous Muscle Pain neous nerves. Of these neuropeptides, SP is of particular interest because, in experiments on fibers from the skin, SP has been shown to be predominantly present in no- Muscle Nociceptors, Neurochemistry ciceptive fibers (Lawson et al. 1997). The peptides are released during excitation of the ending and influence SIEGFRIED MENSE the chemical milieu of the tissue around the receptor. SP Institute for Anatomy and Cell Biology III, University has a strong dilating and permeability increasing action Heidelberg, Heidelberg, Germany on small blood vessels. By these effects, SP causes an [email protected] increase in local microcirculation and edema formation at the site of the lesion. In addition to that, SP has a Definitions sensitizing action on nociceptors.

A nociceptor is a receptive ending that specializes in Receptor Molecules in the Membrane of a Nociceptive Ending informing the central nervous system (CNS) about the Data concerning the presence of receptor molecules in presence of a tissue threatening stimulus. A nociceptor muscle nociceptors have not been reported. Based on has an elevated stimulation threshold just below the responsiveness of these endings to intramuscular and noxious level. (The receptor already has to respond intraarterial injections of Algesic Agent / Algesic to stimuli below the level that causes tissue damage, Chemical, and existing parallels with cutaneous noci- because it is supposed to fulfill the function of an alarm ceptors, the following types of receptor molecule are system and prevent tissue damage). In addition to an likely to be present (Caterina and David 1999; Mense elevated stimulation threshold, a nociceptor has to be and Meyer 1985; McCleskey and Gold 1999): able to encode the intensity of a stimulus within the noxious range, i.e. it must not saturate when a stimulus 1. Receptors for inflammatory substances. Among reaches noxious levels. these are receptors for bradykinin (BK; B1 A receptor molecule is a protein located within the ax- and B2 receptors), 5-hydroxytryptamine (5-HT, onalmembraneofareceptiveending.Itbindssensitizing serotonin;e.g.5-HT3receptor),andprostaglandins and stimulating substances in a highly specific manner (e.g. PGE2; EP2 receptor). In intact tissue, BK is andiseithercoupledtoanionchannel(whichopensafter known to influence the ending via the B2 receptor; the binding has occurred) or a G protein, which starts in inflamed tissue, the B1 receptor is synthesized in 1204 Muscle Nociceptors, Neurochemistry

the soma of the nociceptive neuron, transported to cle of the rat (U. Hoheisel and S. Mense, unpub- the receptive ending and inserted into its membrane. lished). This is an example of a neuroplastic change in the 4. Receptors for growth factors. In our group, nerve nociceptive ending. In contrast to the 5-HT3 recep- growth factor (NGF; TrkA receptor) proved to tor that controls an ion channel, the BKN receptors excite muscle nociceptors in concentrations that activate a G protein. caused cutaneous pain in humans. Brain-derived 2. Receptors for protons. Besides immunoreactivity neurotrophic factor (BDNF; TrkB receptor) had (IR) for acid-sensing ion channels (e.g. ASIC1), no excitatory effect on muscle nociceptors but de- IR for the transient receptor potential vanilloid re- sensitized the endings to mechanical stimuli (i.e. ceptor ( TRPV1) (Caterina and David 1999) is after i.m. injection of BDNF the response magni- present in somata of the dorsal root ganglion that tude of the ending to noxious pressure stimuli was supply receptive endings in skeletal muscle (U. reduced). Hoheisel and S. Mense, unpublished; Fig. 1). The 5. Receptors for excitatory amino acids. Reports in the receptor is sensitized by and responds to an increase literature indicate that nociceptors in the deep tissues in H+-concentration and to heat. The sensitivity around the temporomandibular joint are activated by of this receptor to protons is important under con- glutamate (Cairns et al. 1998). This means that gluta- ditions in which the pH of the tissue is lowered mate receptors must be present in nociceptors of deep (e.g. exhaustive muscle work, ischemia, inflam- somatic tissues. mation, tonic contraction). A specific stimulant 6. Opioid receptors. These receptors were found on Aδ- for this receptor molecule is capsaicin, the active and C fibers in cutaneous nerves (Stein et al. 1990). ingredient of chili peppers. In inflamed tissue, They are upregulated during tissue inflammation. TRPV1 receptors have been reported to be more frequent than under normal conditions (Carlton and Other algesic agents may activate muscle nociceptors Coggesshall 2001). without binding to specific receptor molecules An ex- 3. Purinergic receptors. These receptor molecules bind ample of this are potassium ions which might depolar- adenosine triphosphate (ATP) and the products ize and excite nociceptors following muscle trauma if of ATP degradation. The P2X3 receptor (Burn- the relatively high intracellular concentration of K+ is stock 2000; Cook and McCleskey 2002) has been released from muscle cells. High concentrations of Na+ demonstrated to be present in cutaneous nocicep- may likewise have an unspecific mechanism of action. tors; it has also been shown to exist in DRG A marked increase in extracellular Na+ does not occur cells supplying the gastrocnemius-soleus mus- under (patho)physiologic conditions, but is induced in

Muscle Nociceptors, Neurochemistry, Figure 1 Neurons in the rat spinal ganglion L5 exhibiting immunoreactivity (IR) for the acid-sensing ion channel 1 (ASIC 1) and the vanilloid receptor 1 (TRPV1), respectively. All evaluated neurons were retrogradely labelled from the gastrocnemius-soleus (GS) muscle with the fluorescent dye True blue. (a) the same neuron labelled with three different stains: Aa, retrograde labelling with True blue from the GS muscle; Ab, fluorescent staining with antibodies to TRPV1; Ac, fluorescent staining with antibodies to ASIC 1. (b) proportion of neurons with IR for ASIC 1 and/or TRPV1. The filled bar shows neurons exhibiting IR for both ASIC 1 and TRPV1 (ASIC 1-IR + TRPV1-IR). Without IR, neurons exhibiting neither ASIC 1-IR nor TRPV1-IR (J. Reinöhl, U. Hoheisel and S. Mense, unpublished). Muscle Nociceptors, Neurochemistry 1205 clinical studies on muscle pain mechanisms when hypertonic saline injections or infusions are injected i.m. (Graven-Nielsen et al. 1997). In these studies, the high Na+ concentration – and not the hypertonicity of the solution – appears to be the effective stimulus (see essay muscle pain model, ischemia-induced and hypertonic saline-induced). Response Properties Mechanical Stimulation Upon mechanical stimulation (e.g. by pressure stimuli), a muscle nociceptor has a high stimulation threshold and requires noxious (tissue-threatening, subjectively painful) intensities of stimulation for excitation. In intact muscle, a nociceptor does not respond to everyday stimuli such as physiologic movements or Muscle Nociceptors, Neurochemistry, Figure 2 Proportion of rat mus- muscle stretch (Mense 1997). Recordings of the ac- cle nociceptors responding to adenosine triphosphate (ATP), capsaicin tivity of single muscle afferent fibers in cats and rats (Caps.), acidic phosphate solution (pH 6), and hypertonic saline (NaCl, 5%). have shown that nociceptors as described in the above The data were obtained in electrophysiological experiments in which the impulses of single group IV afferent fibers from rat muscle were recorded. definition are present in skeletal muscle (Mense and The stimulating solutions (injection volume 25 μl) were injected intramus- Meyer 1985). Microneurographic recordings in humans cularly into the mechanosensitive receptive field of the ending. ATP*, ATP also demonstrated the existence of muscle nociceptors dissolved in tyrode. The solution had a pH of 5.5. ATP, ATP dissolved in (Marchettini et al. 1996). It is important to note that tyrode with the pH adjusted to neutral (7.4). NaCl 5% was the most effective stimulus and activated all of the units tested, the other agents excited M not all unencapsulated nerve endings in skeletal muscle at least 40% of the nociceptors (J. Reinöhl, U. Hoheisel and S. Mense, have nociceptive properties. Many of them can be ex- unpublished). cited by weak innocuous pressure stimuli and probably mediate subjective pressure sensations. ciceptors with moderate to high mechanical thresholds Chemical Stimulation were found that could be activated by intramuscular BK, 5-HT, and prostaglandin E2 have long been known injections of capsaicin (Marchettini et al. 1996). The to excite muscle nociceptors in concentrations that capsaicin injections were associated with strong muscle are likely to be present in an inflamed or ischemic pain. As capsaicin is assumed to be a specific stimulant muscle (Kumazawa and Mizumura 1977; Mense and for the TRPV1 receptor, these data show that TRPV1 Meyer 1985). 5-HT and PGE2 are ubiquitously present is present in human muscle nociceptors. in the body and are released under pathologic condi- Nociceptors of the gastrocnemius muscle in the rat tions. BK is cleaved by enzymatic action from kallidin, have been shown to respond to ATP in concentrations a plasma protein. Tissue ischemia is a potent stimulus that are present in muscle cells (Reinöhl et al. 2003). for inducing this cleavage. This means that every time a muscle cell is damaged, it In experiments by the author’s group, acidic solutions releases ATP in amounts that can excite muscle noci- were effective stimulants for muscle receptors with ceptors. Human muscle nociceptors also appear to be group IV afferent fibers in the rat. Approximately 60% equipped with purinergic receptors, since ATP causes of the tested receptors were excited by intramuscular pain when injected i.m (Mörk et al. 2003). In patients, injections of an acidic phosphate buffer (pH 6; Fig. 2). ATP may not only be involved in the pain of muscle Such a lowering in pH is known to occur in inflamed or trauma, but also in cases of sympathetically maintained ischemic tissue. The proton-sensitive nociceptors may pain. The underlying mechanism is that postganglionic be of particular importance for the induction of chronic sympathetic fibers release ATP as a co-transmitter of muscle pain. There is evidence indicating that repeated norepinephrine. intramuscular administration of acidic solutions results Among the growth factors studied so far, NGF is of in long-lasting hyperalgesia (Sluka et al. 2001). particular interest because data obtained in the author’s In patients, the pain during bruxism, chronic dys- group indicate that NGF excites nociceptive free nerve tonia, and some cases of tension-type headache may endings exclusively, i.e. the low-threshold mechanosen- be mediated by the TRPV1 receptor or other acid- sitive (presumably non-nociceptive) endings were not sensing ion channels, because these conditions are affected. NGF is the only substance known so far that likely to be associated with low tissue pH and ischemia. has such an exclusive action on nociceptive free nerve Due to the ischemia, BK acting on B2 or B1 receptors endings. An overview of most of the known receptor could also contribute to this pain. In microneurographic molecules in the membrane of a nociceptive ending is recordings from muscle nerves in humans, muscle no- given in Fig. 3. 1206 Muscle Nociceptors, Neurochemistry

Muscle Nociceptors, Neurochemistry, Figure 3 Receptor molecules in the membrane of a nociceptor. The scheme shows three branches of a free nerve ending. Not all of the receptor molecules included in the figure have been proven to exist in muscle nociceptors, some (e.g. the opioid receptor) are known from studies on nociceptors in the skin. The following processes are of practical importance. Branch (a), sensitization. Sensitization is caused by the binding of sensitizing substances (e.g. prostaglandin E2 (PG E2) or serotonin (5-HT)) to receptor molecules, which induce intracellular cascades of events that~– among other effects – increase the sensitivity of the Na+ channels by phosphorylation (addition of anorganic phosphate to the channel protein) through activated protein kinase A (PKA). Branch (b) , neuroplastic changes of the bradykinin (BKN) receptor. In intact tissue, BKN excites nociceptors by binding to the B2 receptor, in inflamed tissue, it does so by binding to the B1 receptor. Branch (c), other more recently detected receptors. Purinergic receptors (e.g. P2X3) bind adenosine triphosphate (ATP) and its degradation products, and vanilloid receptors (e.g. TRPV1-1) are sensitive to protons (H+), capsaicin, and heat. ASICs are acid-sensing ion channels (e.g ASIC 1) that can be opened by low pH. TrkA is the high-affinity receptor for nerve growth factor (NGF), TrkB for brain derived neurotrophic factor (BDNF). alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, receptor for glutamate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosin monophosphate; CGRP, calcitonin gene-related peptide; G, Glu, glutamate; G protein; KA, kainic acid; NMDA, N-methyl-D-aspartate, receptor for glutamate; NO, nitric oxide; PKC, protein kinase C; (PLC, IP3, and DAG are steps of the intracellular cascade that leads to the activation of PKC); SP, substance P; TTX, tetrodotoxin.

Interactions between Stimulants tions are of clinical significance, because the substances at the Receptive Nerve Ending are released together in damaged or pathologically al- Interactions between algesic agents have been mainly tered tissue. studied for BK on the one hand, and PGE2 or 5-HT The concentration of PGE2 and 5-HT required for po- on the other. PGE2 and 5-HT enhance the excitatory tentiating the action of BK is lower than that for exciting action of BK on slowly conducting muscle afferents the nociceptors. Therefore, in the course of a tissue in- (Mense 1981). The pain elicited in volunteers by i.m. flammation, the receptive endings will first be sensitized injection of a combination of BK and 5-HT is likewise and then excited. Clinical observations point in the same stronger than that caused by either stimulant alone direction; in the course of a pathologic alteration, the pa- (Babenko et al. 1999; Mörk et al. 2003). These interac- tient experiences tenderness first (because of nociceptor Muscle Pain, Fear-Avoidance Model 1207

sensitization) and then spontaneous pain (because of to Inhibit Nociception in Inﬂammation Proc Natl Acad Sci nociceptor excitation). USA 87:5935–5939

Polymodal Response Behavior Most of the muscle nociceptors studied in single fiber Muscle Pain recordings responded to noxious local pressure and injections of BKN (and some even additionally to thermal Definition stimuli), but receptors were also found that were acti- Pain originating from muscle and usually experienced vated by one type of noxious stimulation only (mechan- as dull, deep, diffuse and aching. ical or chemical). This finding indicates that different Myalgia types of nociceptors are present in skeletal muscle, simi- Spinothalamic Tract Neurons, Visceral Input lartotheskinwheremechano-,mechano-heat,andpoly- modal nociceptors are known to exist (Millan 1999). Muscle Pain, Fear-Avoidance Model References 1 2 1. Babenko V, Graven-Nielsen T, Svensson P et al. (1999) Experi- GEERT CROMBEZ ,JOHAN W.S. VLAEYEN , 1 mental Human Muscle Pain and Muscular Hyperalgesia Induced LIESBET GOUBERT by Combinations of Serotonin and Bradykinin. Pain 82:1–8 1Ghent University, Department of Experimental 2. Burnstock G (2000) P2X Receptors in Sensory Neurones. Br J Clinical and Health Psychology, Ghent, Belgium Anaesth 84:476–488 2 3. Cairns BE, Sessle BJ, Hu JW (1998) Evidence that Excitatory Maastricht University, Department of Medical, Amino Acid Receptors within the Temporomandibular Joint Re- Clinical and Experimental Psychology, Maastricht, gion are involved in the Reflex Activation of the Jaw Muscles. The Netherlands J Neurosci 18:8056–8064 4. Carlton SM, Coggesshall RE (2001) Peripheral Capsaicin Re- [email protected], [email protected], M ceptors Increase in the Inflamed Rat Hindpaw: A Possible Mech- [email protected] anism for Peripheral Sensitization. Neurosci Lett 310:53–56 5. Caterina MJ, David J (1999) Sense and Specificity: A Molecular Synonyms Identity for Nociceptors. Curr Opin Neurobiol 9:525–530 6. Cook SP, McCleskey EW (2002) Cell Damage Excites Nocicep- Kinesiophobia; pain-related fear; fear of pain; fear- tors through Release of Cytosolic ATP. Pain 95:41–47 avoidance model 7. Graven-Nielsen T, Arendt-Nielsen L, Svensson P et al. (1997) Ex- perimental Muscle Pain: A Quantitative Study of Local and Re- Definition ferred Pain in Humans following Injection of Hypertonic Saline. J Musculoskel Pain 5:49–69 Fear-avoidance models explain how and why patients 8. Kumazawa T, Mizumura K (1977) Thin-Fiber Receptors Re- sponding to Mechanical, Chemical, and Thermal Stimulation in experiencing acute pain may become chronic sufferers the Skeletal Muscle of the Dog. J Physiol 273:179–194 and become trapped into a vicious circle of more pain 9. Lawson SN, Crepps BA, Perl ER (1997) Relationship of Sub- and disability. Common in these models is their focus stance P to Afferent Characteristics of Dorsal Root Ganglion upon the role of pain-related fear (fear of pain, fear of Neurons in Guinea-Pig. J Physiol 505:177–191 10. Marchettini P,Simone DA, Caputi G, Ochoa JL (1996) Pain from movement / (re)injury) and dynamic learning processes Excitation of Identified Muscle Nociceptors in Humans. Brain (avoidance learning). Res 40:109–116 11. McCleskey EW, Gold MS (1999) Ion Channels of Nociception. Characteristics Ann Rev Physiol 61:835–856 12. Mense S (1981) Sensitization of Group IV Muscle Receptors Pain is more than an unpleasant perceptual and emo- to Bradykinin by 5–Hydroxytryptamine and Prostaglandin E2. tional experience. It elicits innate responses and action Brain Res 225:95–105 tendencies that prepare and facilitate escape from pain 13. Mense S (1997) Pathophysiologic Basis of Muscle Pain Syn- dromes. Phys Med Rehab Clin N Am 8:23–53 (Eccleston and Crombez 1999). Pain is an experi- 14. Mense S, Meyer H (1985) Different Types of Slowly Conduct- ence that drives learning. The relevance of learning in ing Afferent Units in Cat Skeletal Muscle and Tendon. J Phys- chronic pain has been recognised early on in the field iol 363:403–417 of pain (Fordyce 1976) and continues to play a role in 15. Millan MJ (1999) The Induction of Pain: An Integrative Review. Prog Neurobiol 57:1–164 more recent biopsychosocial accounts of chronic pain 16. Mörk H, Ashina M, Bendtsen L et al. (2003) Experimental Mus- (Asmundson et al. 2004; Vlaeyen and Linton 2000). cle Pain and Tenderness following Infusion of Endogenous Sub- Fordyce (1976) was the first to apply the principles stances in Humans. Eur J Pain 7:145–153 of operant conditioning to the problems of chronic 17. Reinöhl J, Hoheisel U, Unger T et al. (2003) Adenosine Triphos- phate as a Stimulant for Nociceptive and Non-Nociceptive Mus- pain patients. The central idea was that “pain be- cle Group IV Receptors in the Rat. Neurosci Lett 338:2528 haviour” (e.g. verbal complaints, medication use, bed 18. Sluka KA, Kalra A, Moore SA (2001) Unilateral Intramuscu- rest, avoidance of home and work responsibilities) lar Injections of Acidic Saline Produce a Bilateral Long-Lasting should be conceived of as behaviours that are learned Hyperalgesia. Muscle Nerve 24:37–46 19. Stein C, Hassan AHS, Przewlocki R et al. (1990) Opioids and maintained by their positive consequences (empa- from Immunocytes Interact with Receptors on Sensory Nerves thy from solicitous spouses, access to pain medications, 1208 Muscle Pain, Fear-Avoidance Model

financial compensation, avoidance of pain-worsening maladaptive response that initiates a vicious circle in activities or escape from distressing events). In the which fear of movement / (re)injury and the subsequent context of fear-avoidance models, the principles of avoidance of activities augment functional disability classical conditioning and operant conditioning are and the pain experience by means of hypervigilance, of paramount importance. Much behaviour is learned depression, and disuse (Vlaeyen and Linton 2000). The because it permits the person to avoid or postpone an latter response is also known as kinesiophobia. aversive experience. What exactly is avoided may vary Several empirical studies have provided support for considerably between persons. An obvious example of these central ideas. First, pain catastrophizing,an avoidance behaviour is that patients learn to avoid exaggerated negative orientation towards actual or pain. Some patients do not avoid activities because anticipated pain experiences, has been found to be of anticipated pain, but because they fear that these strongly related to pain-related fear (e.g. Goubert et activities may lead to (re)injury (Kori et al. 1990). It al. 2006b; Vlaeyen and Linton 2000). Second, fear of may also be true that pain behaviours are maintained movement / (re)injury has been found to be character- by the avoidance of aversive experiences that are not ized by escape and avoidance behaviours and to lower at all related to pain. A popular example is that pain the ability to accomplish daily living tasks. Patients who behaviour and, in particular sick leave, may be rein- are afraid of pain or of (re)injuring themselves during forced and maintained by the avoidance of aversive and physical activities tend to avoid physical activities or unsatisfying work conditions. Whenever these extra are reluctant to perform vigorously during standard benefits outweigh the costs of pain behaviour, one talks physical tests (Crombez et al. 1999, see video extract). about secondary gain. Although clinical practice sug- Because avoidance behaviours occur in anticipation gests that secondary gain does occur, its incidence is of pain rather than as a response to pain, opportunities probably overestimated. It is often overlooked that the are limited to correct (erroneous) beliefs about their presence of pain also creates distress and frustration at pain. As a consequence, pain-related fear and avoidance work. Patients, whose pain interferes with their valued may become resistant and persistent (e.g. Crombez et professional activities, may not resume work because al. 1999; Vlaeyen and Crombez 1999). Prospective they avoid these distressing and frustrating experiences. studies have further substantiated the important and Building upon the model of Lethem et al. (1983), unique role of pain-related fear and avoidance as pre- the cognitive-behavioural model of fear of move- dictors of chronic pain problems (Klenerman et al. ment / (re)injury was developed to explain the develop- 1995; Linton et al. 2000). Third, excessive avoidance ment of chronic suffering in non-specific low back pain. of physical activities may have detrimental physical Vlaeyen and Linton (2000) postulated two extreme re- and psychological consequences. A decrease in mo- sponses to pain, namely confrontation and avoidance. bility, decreased muscle strength, and loss of fitness As depicted in Figure 1, a gradual confrontation and can occur, possibly resulting in a ‘ disuse syndrome’ resumption of daily activities despite pain is consid- (Verbunt et al. 2003). Avoidance can also result in loss ered as an adaptive response that eventually leads to of self-esteem, deprivation of reinforcers, depression the reduction of fear, the encouragement of physical and worrying. Fourth, pain-related fear has been found recovery and functional rehabilitation. In contrast, a to be related to a hypervigilance for pain (Goubert et catastrophic interpretation of pain is considered as a al. 2004b) and a difficulty in switching attention away

Muscle Pain, Fear-Avoidance Model, Figure 1 Confrontation to pain. Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary) 1209 from pain (Eccleston and Crombez 1999). This pat- 7. Klenerman L, Slade PD, Stanley M et al. (1995) The prediction tern of hypervigilance in fearful chronic pain patients of chronicity in patients with an acute attack of low back pain in a general practice setting. Spine 20:478–484 may further diminish the ability to perform everyday 8. Kori SH, Miller RP, Todd DD (1990) Kinesiophobia: a new view activities and hamper the recruitment of pain coping of chronic pain behavior. Pain Manage Jan / Feb:35–43 strategies (Eccleston and Crombez 1999; McCracken 9. Lethem J, Slade PD, Troup JD et al. (1983) Outline of a fear- and Gross 1993). avoidance model of exaggerated pain perception: I. Behav Res Ther 21:401–408 Fear-avoidance models are dynamic in that both pain- 10. Linton SJ, Buer N, Vlaeyen JWS et al. (2000). Are fear-avoidance related fear and avoidance are not static or stable char- beliefs related to the inception of an episode of back pain? A acteristics of the individual (Goubert et al. 2006b), but prospective study. Psychol Health 14:1051–1059 are the result of complex interactions that are typical for 11. Linton SJ, Vlaeyen JWS, Ostelo RW (2002). The back pain beliefs of health care providers: are we fear-avoidant? J Occup Re- a biopsychosocial perspective. Catastrophic thinking habil 12:223–232 about pain and pain-related fear do not emerge within a 12. McCracken LM, Gross RT (1993) Does anxiety affect coping social and cultural vacuum. In Western cultures many – with chronic pain? Clin J Pain 9:253–259 even pain-free – persons hold a biomedical view of 13. Vlaeyen JWS, Crombez G (1999) Fear of movement / (re)injury, avoidance and pain disability in chronic low back pain patients. back pain. As a consequence, many believe that back Man Ther 4:187–195 pain is caused by an injury, that a wrong movement 14. Vlaeyen JWS, Linton SJ (2000) Fear-avoidance and its conse- can lead to serious problems if one has back pain, that quences in chronic musculoskeletal pain: a state of the art. Pain X-ray and imaging tests can always identify the cause 85:317–332 15. Vlaeyen JWS, de Jong JR, Sieben JM et al. (2002) Graded expo- of back pain and that bed rest is an important part of sure in vivo for pain-related fear. In: Turk DC, Gatchel RJ (eds) treatment (Goubert et al. 2004a). Health-care providers Psychological approaches to pain management: a practitioner’s may further reinforce these beliefs, inadvertently, fu- handbook. The Guilford Press, New York, pp 210–233 16. Verbunt JA, Seelen HA, Vlaeyen JWS et al. (2003) Disuse and elling pain-related fear and avoidance. Indeed, Linton deconditioning in chronic low back pain: concepts and hypothe- et al. (2002) have found that many health care providers ses on contributing mechanisms. Eur J Pain 7:9–21 still advise patients to avoid painful movements and M believe that pain-reduction is a necessary requirement for return to work or that sick-leave is an adequate treatment for back pain. Muscle Pain, Fibromyalgia Syndrome One of the clinical implications of the fear-avoidance (Primary, Secondary) models is that treatment should directly target pain- related fear and avoidance. Therefore, in analogy with I. JON RUSSELL phobia and anxiety disorders, exposure in vivo has Division of Clinical Immunology and Rheumatology, been proposed as a potentially effective treatment of Department of Medicine, The University of Texas pain-relatedfear(Vlaeyenetal.2002).Duringexposure, Health Science Center, San Antonio, TX, USA patients are gradually exposed to physical activities that [email protected] are feared or believed to be harmful, in order to correct erroneous cognitions and to extinguish fear and avoid- Synonyms ance. At present, the effectiveness of exposure in vivo Fibromyalgia Syndrome; Fibrositis Syndrome; FMS; has only been investigated in single case experimental chronic widespread allodynia designs. Results show remarkable improvements on self-report measures of pain-related fear, catastrophiz- Definition ing and disability (Vlaeyen et al. 2002). The Fibromyalgia Syndrome (FMS) is a common, References female gender-predominant, idiopathic clinical syndrome characterized by widespread musculoskeletal 1. Asmundson GJG, Vlaeyen JWS, Crombez G (2004) Understand- pain, and reproducible tenderness to deep palpation ing and treating fear of pain. Oxford University Press, Oxford, p 367 pressure at anatomically defined soft tissue structures, 2. Crombez G, Vlaeyen JWS, Heuts PHTG et al. (1999) Pain-related collectively called tender points (TePs) (Wolfe et fear is more disabling than pain itself: evidence on the role of al. 1990). The classification of soft tissue pain (STP) pain-related fear in chronic back pain disability. Pain 80:329–339 disorders, including the FMS, is shown below (Russell 3. Eccleston C, Crombez G (1999) Pain demands attention: a cognitive-affective model of interruptive function of pain. 1993). Psychol Bull 3:356–366 4. Fordyce W E (1976). Behavioral methods for chronic pain and Characteristics illness. The C.V. Mosby Company, Saint Louis 5. Goubert L, Crombez G, De Bourdeaudhuij I (2004a) Low back Taxonomically, FMS is classified among over 100 other pain, disability and back pain myths in a community sample: clinical conditions that cause pain in soft tissue struc- prevalence and interrelationships. European J Pain 8:385–394 tures (including nerve, muscle, ligament, tendon, and/or 6. Goubert L, Crombez G, Van Damme S (2004b) The role of neu- roticism, pain catastrophizing and pain-related fear in vigilance bursae) of the musculoskeletal system. The term “soft to pain: a structural equations approach. Pain 107:234–241 tissue pain” (STP) has been proposed (Russell 1993) 1210 Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary) as the generic heading for this long list of clinical dis- • Myofascial pain dysfunction syndrome [MPDS, re- orders. As such, the term STP replaces the antiquated places TMD] term “non-articular rheumatism”. The proposed classi- • Referred pain [angina or subphrenic abscesstoshoul- fication of STP as listed below is based on the typical der, hip to thigh] body distributions of the included conditions, rather • Complex regional pain syndrome [CRPS] than upon their pathogenesis. For example: • Type 1 – non-nerve injury [replaces reflex sympa- Localized STP is exemplified by tendinitis and thetic dystrophy] bursitis; Regionalized STP is exemplified by com- • Type 2 – nerve injury [replaces causalgia] plex regionalpain syndromeand myofascialpain syn- Generalized drome with trigger points (TrPs); and Generalized STP is exemplified by FMS with tender points (TePs) • Fibromyalgia syndrome and by chronic fatigue syndrome, when that condition • Chronic fatigue syndrome presents with musculoskeletal pain. As a member of • Hypermobility syndrome the generalized STP category, FMS is now viewed as the human model for chronic, widespread, allodynia The term ‘primary FMS’, has come into common usage (see Allodynia (Clinical, Experimental)). to identify a condition meeting the American College of Localized Rheumatology (ACR) classification criteria based upon widespread pain and TeP tenderness (Wolfe et al. 1990), • Bursitis [subacromial, olecranon, trochanteric, but lacking evidence for any associated painful condi- prepatellar, anserine] tion. • Tenosynovitis [biceps, supraspinatus, infrapatellar, It is apparent, however, that patients can exhibit the Achilles] same ACR classification criteria (Wolfe et al. 1990) in • Enthesopathies [lateral epicondylitis, medial epi- association with other painful conditions (see Table 2). condylitis] That seems to be the case in about 30 % of patients • Entrapment syndrome [carpal tunnel, tarsal tunnel, with rheumatoid arthritis, 40 % of patients with sys- cubital tunnel] temic lupus erythematosus and 50 % with Sjögren’s Regionalized syndrome. The FMS has been recognized in association with tuberculosis, syphilis, and Lyme disease. There • Myofascial pain syndrome [trapezius, piriformis, il- also seems to be a high prevalence of FMS among iopsoas] women having body pain in association with silicone breast implants. For want of better terminology, the FMS in such settings has been collectively referred to Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary), as ‘secondary FMS’. Table 1 American College of Rheumatology (ACR) Criteria for Classifi- The ACR classification criteria study (Wolfe et al. 1990) cation (Wolfe et al. 1990) History – Chronic, widespread (four quadrants) failed to disclose any clinical features in the secondary soft tissue pain for three months Examination – Pain (1+ or greater severity) induced by 4 kg of palpation pressure at 11 of 18 anatomically FMS patients that would clearly distinguish them from defined tender points ∗ primary FMS, so it was recommended that the term sec- Number Official ACR Bilateral Tender Point Sites ondary FMS be abandoned. Despite that, essentially all of the current and past FMS clinical trials, sponsored 1, 2 Occiput: suboccipital muscle insertions by industry or by government agencies, have specified 3, 4 Low cervical: anterior aspects of C5-7 inter-transverse enrollment of only primary FMS patients. They accom- spaces plishthatdistinctionbyexcludingallsubjectswithacon- comitant rheumatic disease or organ related abnormal- 5, 6 Trapezius: midpoint of upper border ities. 7, 8 Supraspinatus: origins, above the scapula spine, near In each of the secondary FMS situations, it has been un- medial border clear what pathogenic role the ‘other’ condition might 9,10 2nd rib: upper lateral surface of second costochondral havehad in thedevelopmentof theFMS. Thecurrentbe- jn lief is that the comorbid inflammatory conditions have 11,12 Lateral epicondyle: two cm distal to the epicondyles not developed from the FMS, nor has the FMS necessarily resulted from them, so the implication of causality 13,14 Gluteal: upper outer buttock, anterior fold of muscle in the term secondary FMS is likely to be a misnomer. 15,16 Greater trochanter: posterior to trochanteric prominence Despite that, the terminology serves a need, and has become entrenched, so it will probably endure, at least for 17,18 Knees: medial fat pad, just proximal to medial condyle the short term. Sensitivity and specificity are > 80 % Biochemical studies help to support this distinction of Anatomically Defined Tender Points in Fibromyalgia Syndrome (FMS). Note a single syndrome developing in two or more different that named sites are bilateral, even number refers to right side settings. Most people with FMS (both primary and sec- Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary) 1211

Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary), those conditions. This concept is important because it Table 2 Illnesses Concomitant with Secondary Fibromyalgia Syndrome. provides evidence that theremaybeafinalcommon With Tests Profile to Characterize the Diagnosis (Russell 1993)* pathway (related to the elevated CSF substance P) by Illness Tests which primary FMS and secondary FMS could exhibit Rheumatic disease the same clinical syndrome (i.e. FMS). a. Systemic lupus erythematosus ANA + ESR or CRP‡ Epidemiology b. Rheumatoid arthritis RF + ESR or CRP The FMS exhibitsa world-wide distribution.It isviewed asbeing common, because itaffects2–5%ofthegeneral c. Polymyositis Creatine phosphokinase population. It is female predominant, with 8 of 10 af- d. Sjögren’s syndrome Labial salivary gland fected individuals being female. It increases in preva- biopsy lence with age, such that about 10 % of women in the Infection/inflammation 50–60 years of age decade are affected. About one third of FMS patients are so severely affected by their symp- a. Tuberculosis PPD, ESR, Chest X-ray toms that they are unable to maintain their usual occu- b. Chronic syphilis VDRL, FTA, CSF pational activities (Wolfe et al. 1997c). The average annual direct cost of this condition in the United States was c. Subacute bacterial endocarditis Culture, ESR estimated to be about $2,250 (Wolfe et al. 1997a). The d. Lyme disease Serology natural history of FMS is to develop a pattern of severity over a relatively short period of time, and then remain e. Parvovirus Serology, Change relatively unchanged over a period of many years (Wolfe e. Acquiredimmunodeficiency syndrome Serology etal.1997b).Itdoesnotusuallybecomeanothermedical condition like a rheumatic disease. f. Breast implant Serology M g. Inflammatory bowel syndromes Colonoscopy Comorbidities

Endocrine disorders In addition to the defining widespread musculoskeletal pain and TePs, people with FMS typically exhibit a a. Hypothyroidism Thyroxine, TSH constellation of painful symptoms or syndromes that b. Hypopituitary Prolactin can include insomnia, which occurs in about 70 % (Smythe and Moldofsky 1977), nocturnal myoclonus, Obstructive myelopathy cognitive dysfunction, headache, depression in about a. Whiplash C1,2 or subaxial subluxation CT or MRI of CSpine 40 % (Ahles et al. 1991), anxiety, autonomic neuropathy (Martinez-Lavin 2003), nocturnal bruxism, b. Chiari malformation MRI foramen magnum myofascial pain dysfunction syndrome (the so-called c. Syringomyelia MRI of TMJ syndrome), myofascial pain syndrome (particu- brainstem/Cspine larly involving the piriformis muscles), hypermobility d. Spinal stenosis MRI of Cspine syndrome in about 30 % (Acasuso-Diaz and Collantes- Estevez 1998), biceps tendinitis, pes anserine bursitis, *Adapted with consent irritable bowel syndrome in about 40 % (Aaron and Abbreviations: Buchwald 2001), and irritable bladder syndrome (in- ANA=antinuclear antibody; ESR=Westergren erythrocyte sedimentation rate; CRP=C-reactive protein; RF =rheumatoid factor; PPD =purified pro- terstitial cystitis) in about 10 % (Clauw et al. 1997). tein derivative delayed cutaneous test for exposure to tuberculosis bacilli; Despite overlapping features and prevalence, FMS can VDRL =serologic screening test for syphilis; FTA =fluorescent treponemal be distinguished from rheumatic diseases, the complex antibody test for syphilis; CSF =cerebrospinal fluid tests; TSH =thyroid regional pain syndromes, the chronic fatigue syndrome, stimulating hormone; C1,2 =cervical spine level 1 and level 2 atlantioax- ial; CT =computerized tomography; CSpine =cervical spine; MRI =magnetic and the myofascial pain syndrome affecting a variety resonance tomography of muscles, on the basis of its clinical presentation, its consistent epidemiologic pattern, and its predictable prognosis. ondary) have elevated spinal fluid (CSF) substance P as an amplifier of afferent pain signals. The distinction Heterogeneity seems to be, that only primary FMS patients exhibit How should this heterogeneity of associated manifes- elevated concentrations of nerve growth factor as a tations be viewed? Should clinicians caring for FMS substance P inducing agent (Giovengo et al. 1999). patients be lumpers or splitters? It is worthy, in this In secondary FMS, associated with an inflammatory regard, to consider the established situation with sys- condition, the nerve growth factor levels were found temic lupus erythematosus (SLE). The ACR supports to be normal. The inflammation itself may be respon- the concept that 11 diagnostic criteria are important to sible for initiating the high CSF substance P levels in the clinical diagnosis of SLE, but only four of these cri- 1212 Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary) teria are required to diagnose SLE in a given individual fatigue, and muscle stiffness. That may have been what (Tan et al. 1982). Lupus subgroups are characterized prompted early FMS researchers to seek some specific by their patterns of major organ involvement, critical to pathology in affected muscles. Controlled histological the prognosis and management of the disorder (Hughes examination of FMS muscle tissue sections by light 1978). For example, in various combinations, about microscopy and electron microscopy have disclosed 50 % of SLE patients have renal involvement, 50 % minor mitochondrial abnormalities, atrophy of type exhibit lung involvement, cardiac involvement is seen 2 muscle fibers, ragged red fibers, or moth-eaten fibers in about 40 %, neuropsychiatric manifestations are (Yunuset al. 1989; Lindman et al. 1995), and lower than present in about 60 %, autoimmune hemolysis occurs normal capillary density, but the histological evidence in about 5 %, and about 30 % have concomitant FMS. did not support FMS specificity. In addition, lower ThefindingsfrompriorpsychologicalstudiesofFMS,in levels of ATP and phosphoryl creatine were found in whichtwoorthreedistinctclusters(subgroups?)ofFMS the trapezius and the tibialis anterior muscles of FMS patients had been identified, were reviewed by Walen patients compared with HNC (Bengtsson et al. 1986). and colleagues(Walen etal. 2002). They thenconducted Clearly, skeletal muscle that is at risk could serve as extensive evaluations on 600 FMS patients who were a peripheral pain generator in FMS patients who fail members of a health maintenance organization. Clus- to maintain physical fitness of the very muscle groups ter analysis on the data from those subjects confirmed needed for usual function, and for critical situations thepreviouslydescribeduniqueclustersofFMSpatients of physiological stress that cause the falling injuries thatdifferedfromeachotherwithrespecttomooddistur- observed to be common among people with FMS. bance,pain,physicalfunction,andsocialsupport.While these subgroup differences were statistically definable, Biochemistry all three subgroups were still much worse than healthy Biochemical analysis of fluid samples from patients normal controls in the general population. with FMS has also identified apparent subgroups. For Electrophysiological assessment methods, such as example, 84 % of FMS patients had elevated cere- combinations of quantitative electroencephalography brospinal fluid levels of substance P (Russell et al. (qEEG) and electromyography (sEMG) have also 1994). As noted earlier, patients with “primary” FMS helped to identify distinct FMS subgroups (Donaldson had elevated levels of nerve growth factor not seen in et al. 2002). Forty patients with FMS, off their usual normal controls, or in FMS patients with concomitant FMS medications for five half lives, were stratified rheumatic diseases (“secondary” FMS), or in rheumatic into three subgroups on the basis of their Symptom disease patients who do not have FMS (Giovengo et Checklist-90-Revised (SCL-90-R) Global Severity al. 1999). Similarly, blood samples from a subgroup Index (GSI) scores (Derogatis 1994). The subgroups of about 50 % of FMS patients exhibit an antibody to were then examined by qEEG activity patterns with an environmental polymer (Wilson et al. 1999), so the the subjects resting, eyes closed. By-subgroup dif- antipolymer antibody assay is being proposed as a way ferences in the quantity of the typical qEEG wave to distinguish these two unique subgroups. A genetic forms were found. Across the GSI-defined subgroups, predisposition appears to be a factor in a subgroup of from least to most distressed, alpha brainwave activity FMS (Iyengar et al. 2003). The current hope is that the (7.5–13 Hertz) progressively decreased, while theta findings from objective tests, which are now in active activity (3.5–7.5 Hertz) progressively increased. Beta development, can be leveraged to identify pathogenic activity (13 –22 Hertz) was highest in the middle group; mechanisms. while delta activity (0.5–3.5 Hertz) wasconsistently low across all three subgroups. The addition of sEMG data Medications in this study demonstrated widely dispersed skeletal Finally, attempts at diagnostic treatment regimens have muscle co-contractionin response to a distant volitional disclosed differences in the responses of FMS patients stimulus, but the magnitude of this abnormality did not to ketamine, suggesting that the N-methyl-D-aspartic differ among the three GSI-defined subgroups. receptor (which ketamine inhibits) in the spinal cord is important to the perceived pain in FMS (Graven- Muscle Nielsen et al. 2000). Patient volunteers in one key study The FMS is probably is a central neurological disor- (Sorensen et al. 1997) were treated (randomized serial der rather than a disorder of skeletal muscle, but there crossover) with brief intravenous infusions of ketamine, was a time in the history of the disorder when skeletal morphine sulfate, lidocaine, or saline placebo. Of the muscle was the focus of investigation into the patho- 18 FMS patients studied, two patients were placebo genesis of FMS. Indeed, the clinical complaint most responders (responded with improvement to all three consistently reported by FMS patients is deep, aching, agents and the placebo) and three were nonrespon- body pain. Whether spontaneously, or as learned from ders (no improvement with any of the administered their health care providers, FMS patients have tended agents). The majority (N = 13) responded to one or to interpret these symptoms as muscle pains, muscle more of the active medications but not to placebo. Four Muscle Pain, Fibromyalgia Syndrome (Primary, Secondary) 1213 patients responded to a single drug (morphine-one, ing opinions about it. The reasons for the resultant role ketamine-three), six responded to two drugs (lidocaine modeling are buried deep in the fabric of belief sys- and morphine-four, lidocaine and ketamine-two), and tem anchoring. Effective contemporary management of three responded to all three active drugs. Since all of the FMS requires each of the following (Russell 1996): The patients were clinically diagnosed as having FMS, this unequivocal recognition that pain is always subjective, study implies substantial heterogeneity in the response a willingness to accept FMS as a medical syndrome, of FMS patients to treatment. It may further help to ex- the effort to integrate a logical but increasingly complain why some patients fail to respond to a clinician’s plex pathogenesis, and empathetic individualization of favorite regimen. increasingly evidence-based therapy. The components From the preceding discussion, it seems likely that the of a practical regimen include: accurate diagnosis of the composite of FMS subjects, identified by the 1990 ACR FMS and associated conditions, education about FMS, criteria for the classification of FMS (Wolfe et al. 1990), physical modalities such as exercise, medications for are heterogeneous in several important respects. Walen the presenting symptoms, and follow-up assessment to and colleagues (Walen et al. 2002) concluded their as- monitor therapeutic progress. sessment by saying that: “People with FMS may fall into References distinct subgroups; ...(but) the utility of dividing participants into these (sub) groups in planning interven- 1. Aaron LA, Buchwald D (2001) A Review of the Evidence for Overlap among Unexplained Clinical Conditions. Ann Intern tions remains unclear.” On the other hand, they also sug- Med 134:868–881 gest that “the most helpful direction for future research 2. Acasuso-Diaz M, Collantes-Estevez E (1998) Joint Hypermobil- would involve comparing the effects of interventions de- ity in Patients with Fibromyalgia Syndrome. Arthritis Care Res signed especially for each cluster to a ‘nontaylored’ in- 11:39–42 3. Ahles TA, Khan SA, Yunus MB et al. (1991) Psychiatric Status of tervention.” Finally, It always comes back to the hopeful Patients with Primary Fibromyalgia, Patients with Rheumatoid prediction that the better we understand the mechanisms Arthritis, and Subjects without Pain: A Blind Comparison of of chronic FMS pain, the more likely we are to find spe- DSM-III Diagnoses. Am J Psychiat 148:1721–1726 M 4. Bengtsson A, Henriksson KG, Larsson J (1986) Reduced High cific and effective therapies. Energy Phosphate Levels in the Painful Muscles of Patients with Primary Fibromyalgia. Arthritis Rheum 29:817–821 Pathogenesis 5. Clauw DJ, Schmidt M, Radulovic D et al. 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J Rheumatol 26:1564–1569 FMS exhibit objective abnormalities in nociception 9. Graven-Nielsen T, Aspegren KS, Henriksson KG et al. (2000) Ketamine Reduces Muscle Pain, Temporal Summation, and Re- and in neuroendocrine functions, which undoubtedly ferred Pain in Fibromyalgia Patients. Pain 85:483–491 contribute substantially to their generalized symptoms. 10. Hughes GRV (1978) Systemic Lupus Erythematosus. In: Scott Some of the biological participants in this process in- JT (ed) Copeman’s Textbook of the Rheumatic Diseases. T & clude: unmyelinated dorsal horn neurons (like A-delta A Constable Ltd, Edinburgh, pp 901–922 11. Iyengar SK, Arnold LM, Khan MA et al. (2003) Genetic Linkage and C-fibers), excitatory amino acids, neuropeptides, of Fibromyalgia Syndrome to the Serotonin Receptor 2A Region zinc, biogenicamines, nitricoxide, wide-dynamicrange on Chromosome 13 and the HLA Region on Chromosome 6. In spinal neurons, the limbic system of the midbrain, and Preparation 12. Lindman R, Hagberg M, Bengtsson A et al. (1995) Capillary several regions of the cerebral cortex. A lowered pain Structure and Mitochondrial Volume Density in the Trapezius threshold (ie. allodynia) characterizes the examination Muscle of Chronic Trapezius Myalgia, Fibromyalgia and Healthy findings in FMS. Allodynia can be caused in animal Subjects. J Musculoske Pain 3:5–22 systems by strategic manipulation of nociceptive neu- 13. Martinez-Lavin M (2003) Use of the Leeds Assessment of Neu- ropathic Symptoms and Signs Questionnaire in Patients with Fi- rochemicals. Studies of the nociceptive neurochemicals bromyalgia. Seminars in Arthritis & Rheumatism 32:407–411 in FMS spinal fluid find them abnormal in concentration 14. Russell IJ (1993) A New Journal. J Musculoske Pain 1:1–7 and/or correlated with the symptoms. Those observa- 15. Russell IJ (1996) Fibromyalgia Syndrome: Approaches to Man- tions change the way FMS is viewed, and identify it as agement. Bull Rheum Dis 45(3):1–4 16. Russell IJ, Orr MD, Littman B et al. (1994) Elevated Cere- a remarkably interesting human syndrome of chronic brospinal Levels of Substance P Patients Fibromyalgia Syn- central neurochemical pain amplification. drome. Arthritis Rheum 37:1593–1601 17. Smythe HA, Moldofsky H (1977) Two Contributions to Un- Management derstanding of the “Fibrositis” Syndrome. Bull Rheum Dis 28:928–93l Dealing with FMS has been a complicated process for 18. Sorensen J, Bengtsson A, Ahlner J et al. (1997) Fibromyalgia twentieth century medicine, leading to widely conflict- – Are there Different Mechanisms in the Processing of Pain? 1214 Muscle Pain in Systemic Inflammation (Polymyalgia Rheumatica, Giant Cell Arteritis, Rheumatoid Arthritis)

A Double-Blind Crossover Comparison of Analgesic Drugs. J theseconditionsisaccompaniedbytirednessandanemia Rheumatol 24:1615–1621 due to systemic actionsof the cytokinesasin rheumatoid 19. Tan EM, Cohen AS, Fries JF et al. (1982) The 1992 Revised Criteria for the Classification of Systemic Lupus Erythematosus. cachexia (Walsmith and Roubenoff 2002). Arthritis Rheum 25:1271–1277 In the elderly, it may be very difficult to distinguish be- 20. Walen HR, Cronan TA, Serber ER et al. (2002) Subgroups of tween rheumatoid arthritis (RA) and polymyalgia Fibromyalgia Patients: Evidence for Heterogeneity and an Ex- rheumatica / giant cell arteritis(PMR/ GCA) with a pos- amination of Differential Effects Following a Community-Based Intervention. J Musculoske Pain 10:9–32 sible overlap between the diseases (Lange et al. 2000; 21. Wilson RB, Gluck OS, Tesser JR et al. (1999) Antipolymer An- Salvarani and Hunder 1999). tibody Reactivity in a Subset of Patients with Fibromyalgia Cor- PMR / GCA is associated with pain and muscle soreness relates with Severity. J Rheumatol 26:402–407 in the shoulder and head regions. The two diseases have 22. Wolfe F, Anderson J, Harkness D et al. (1997a) A Prospective, Longitudinal, Multicenter Study of Service Utilization and Costs similar symptoms from the muscles but may be distin- in Fibromyalgia. Arthritis Rheum 40:1560–1570 guished by the finding of vasculitis in a biopsy of the 23. Wolfe F, Anderson J, Harkness D et al. (1997b) Health Status temporal artery in the latter. PMR occurs in the elderly and Disease Severity in Fibromyalgia: Results of a Six Center populationwithanincidencerateofabout0.5per10,000 Longitudinal Study. Arthritis Rheum 40:1571–1579 24. Wolfe F, Anderson J, Harkness D et al. (1997c) Work and population aged more than 50, while GCA is consider- Disability Status of Persons with Fibromyalgia. J Rheumatol ably less frequent, although the incidence may vary over 24:1171–1178 the world. 25. Wolfe F, Smythe HA, Yunus MB et al. (1990) The American The muscle pain in PMR / GCA may resemble other College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Arthritis Rheum 33:160–172 conditions in the area and there are no pathognomonic 26. Yunus MB, Kalyan-Raman UP, Masi AT et al. (1989) Electron features of the head and neck pain with the possible Microscopic Studies of Muscle Biopsy in Primary Fibromyal- exception of jaw claudication present in about half of gia Syndrome: A Controlled and Blinded Study. J Rheumatol 16:97–101 the cases (Hall et al. 1983). The diagnosis must be suspected in any person above 50 years of age with unexplained changes in pain patterns in the proximal parts of the upper extremity and to some extent the lower ex- Muscle Pain in Systemic Inflammation tremity as well. In more than 2 / 3 of the patients, the (Polymyalgia Rheumatica, Giant Cell pain involves the shoulder region as well as headache. Arteritis, Rheumatoid Arthritis) The muscles of the shoulder girdle are sore and exhibit exercise intolerance and fatigue. There is often pain at HENNING BLIDDAL night and decreased range-of-motion of the joints in the The Parker Institute, Frederiksberg Hospital, affectedarea.Thefindingofanelevatederythrocytesed- Copenhagen, Denmark imentation rate substantiates the diagnosis. The signs of [email protected] systemic inflammatory action, e.g. light fever, malaise and weight loss may dominate pain as a secondary phe- Synonyms nomenon. Arthritogenic Pain; Immuno-Inflammatory Muscle Pain; polymyalgia rheumatica; giant cell arthritis; rheumatoid arthritis

Definition With the exception of some cases of myositis,thein- flammatory conditions of joints and muscles have muscle pain as a very prominent symptom. The pain may be caused by changes in the muscles per se, including possible referred pain, or be secondary to the inflammatory changes in the joints. Inflammation in both tendon sheaths and tendon insertions may contribute to the condition, which may be quite complex with regard to pain analysis. Due to its frequent involvement, giant cell arteritis is often called temporal arteritis.

Characteristics Muscle Pain in Systemic Inflammation (Polymyalgia Rheumatica, Gi- ant Cell Arteritis, Rheumatoid Arthritis), Figure 1 Arteritis temporalis. Theinflammatoryprocessinvolvesanincreasedproduc- The artery is abnormally swollen and sore on palpation due to immuno- inflammatory changes in the arterial wall. This may eventually lead to tion of cytokines e.g. the important pro-inflammatory obstruction of the lumen and as the process may involve other arteries in cytokines TNF-α and Il-1. These cytokines are involved the area, including the arteria to the optic nerve, a feared complication is inthepathogenesisofpain(Gotohetal.2002)andpainin blindness. Muscle Pain in Systemic Inflammation (Polymyalgia Rheumatica, Giant Cell Arteritis, Rheumatoid Arthritis) 1215

Rheumatoid Arthritis (RA) RA has a prevalence of about 1%, with maximum incidence among the 30–50 year olds and a female / male ratio of 2.5–3. The etiology is unknown, with autoimmune mechanismsinvolvedinthepathogenesis.Thediseaseis most often chronic with fluctuations of disease activity leading to agraduallossof function. Cardinalsymptoms are morning stiffness of joints, swollen and tender finger joints, symmetrical distribution of arthritis and, depending on severity, joint erosions. The symptoms and signs may differ with the age group. All patients suffer from inflammatory pain in synovial tissues including joints, tendon sheaths and bursae. In the elderly the muscle pain may be very prominent, while all patients have various degrees of muscle fatigue. Some of the medica- Muscle Pain in Systemic Inflammation (Polymyalgia Rheumatica, Gi- tions used for treatment of RA may induce myopathy ant Cell Arteritis, Rheumatoid Arthritis), Figure 2 Muscle wasting in (Le Quintrec and Le Quintrec 1991). The weakness and rheumatoid arthritis. The inflammation of the joints and the arthritogenic the associated activity induced pain in the muscles may pain affect the whole movement segment with pain-induced muscle wasting. The process is irreversible in cases of joint destruction as in this case not be a primary feature as indicated by the lack of corre- where subluxations and ulnar deviation is evident in both wrist joint and lation with the muscle strength (Schiottz-Christensen et fingers. al. 2001). A specific muscle weakness induced by treatment with steroidsiswelldescribed;itisprobable, but not fully established, that this may be accompanied by chronic pain conditions, there is less uncertainty M pain (Danneskiold-Samsoe and Grimby 1986). It is pos- associated with the origin or extent of the rheumatic sible for patients with RA to train in spite of their joint pain. disease (Bearne et al. 2002; Lyngberg et al. 1994) and 2. The rheumatic patient has unique possibilities of exercises to increase muscle strength should be encour- pain relief by anti-inflammatory agents. The most aged to maintain general functional abilities. pronounced effect is the well-documented, almost RA, in 20% of cases, coexists with Sjögren’s syn- immediate effect of glucocorticoids in polymyalgia drome, which, apartfrom the sicca-syndrome, ischar- rheumatica (PMR / GCA), which may even be used acterized by general muscle pain and fatigue. Myositis to substantiate the diagnosis. may occur in Sjögren’s as well and is unrelated to the By such procedures the pain may be explained and even pain, which is of unknown origin (Lindvall et al. 2002). documented to both patients and social contacts, which Finally, RA may – as do other immune-inflammatory may save the patients from a deterioration due to an diseases - induce a secondary fibromyalgia and the pain uncertainty of diagnosis, which is otherwise a definite quality in the two diseases may be indistinguishable psychological problem in muscle pain of the shoul- (Burckhardt et al. 1992). In the elderly, an overlap- ders (Dyrehag et al. 1998). Nevertheless, the patients syndrome exists, with muscle pain in the shoulder with inflammatory diseases may benefit from general region as a common sign between PMR / GCA and therapeutic measures against their pain, including non- RA. In younger women, a similar diagnostic problem medicinal pain management (Evers et al. 2003; Keefe arises in the lighter cases of RA, which may resemble et al. 2001). fibromyalgia for long periods before a certain diagnosis Combined muscle and joint pain in a patients involves can be given. a number of considerations in internal medicine and in There are aspects of the pain in inflammatory rheumatic unsettled diagnosis it must be suggested that both clin- diseases, which makes the arthritogenic pain differ from ical examination and blood tests including calcium and other chronic pain condition. thyroid hormones are performed (Table 1). 1. The rheumatic patient is typically well diagnosed with a clear explanation of the pain. Most often the References pain correlates with either obvious clinical changes 1. Bearne LM, Scott DL, Hurley MV (2002) Exercise can rein the joints, e.g. swelling, readily understandable verse quadriceps sensorimotor dysfunction that is associated blood tests, e.g. erythrocyte sedimentation rate, ESR with rheumatoid arthritis without exacerbating disease activity. Rheumatology 41:157–166 or imaging of the inflammatory changes in synovial 2. Burckhardt CS, Clark SR, Bennett RM (1992) A comparison of tissue, e.g. by ultrasound-Doppler or MRI (Terslev et pain perceptions in women with fibromyalgia and rheumatoid al. 2003). The patients will often have frequent con- arthritis: relationship to depression and pain extent. Arthritis Care tacts with a specialist, who can reassure them about Res 5:216–222 3. Danneskiold-Samsoe B, Grimby G (1986) The relationship be- the nature of the pain. In consequence, unlike other tween the leg muscle strength and physical capacity in patients 1216 Muscle Pain Model, Inflammatory Agents-Induced

Muscle Pain in Systemic Inﬂammation (Polymyalgia Rheumatica, Giant Cell Arteritis, Rheumatoid Arthritis), Table 1 Medical diseases, which may give rise to both joint and muscle pain Suspected disease Pain region Examination

Heart disease Neck / shoulder / arm Stethoscopy, EKG

Disease close to diaphragm (e.g. pneumonia, gall- Neck / shoulder / arm Stethoscopy, palpation of the abdomen bladder problems) Thyroid diseases Diffuse pain in muscles and joints Palpation of the thyroid –other signs of thyroid disease incl. eye changes

Calcium metabolism Diffuse pain in muscles and joints In severe cases, cramps and involuntary muscle contractions

with rheumatoid arthritis, with reference to the influence of cor- Synonyms ticosteroids. Clin Rheumatol 5:468–474 4. Dyrehag LE, Widerstrom-Noga EG, Carlsson SG et al. (1998) AnimalModelsofInflammatoryMyalgia;AnimalMod- Relations between self-rated musculoskeletal symptoms and els of Inflammatory Muscle Pain; Nocifensive Behav- signs and psychological distress in chronic neck and shoulder iors Evoked by Myositis pain. Scand J Rehabil Med 30:235–242 5. Evers AW, Kraaimaat FW, Geenen R et al. (2003) Stress- vulnerability factors as long-term predictors of disease activity Definition in early rheumatoid arthritis. J Psychosom Res 55:293–302 Animal models have been recently developed that may 6. Gotoh M, Hamada K, Yamakawa H et al. (2002) Interleukin- allow further elucidation of the underlying mechanisms 1-induced glenohumeral synovitis and shoulder pain in rotator cuff diseases. J Orthop Res 20:1365–1371 of pain associated with inflammation of muscle (i.e. 7. Hall S, Persellin S, Lie JT et al. (1983) The therapeutic impact myositis). A better understanding of these mecha- of temporal artery biopsy. Lancet 2:1217–1220 nisms may lead to the developmentof novel approaches 8. Keefe FJ, Affleck G, Lefebvre J et al. (2001) Living with rheumatoid arthritis: The role of daily spirituality and daily religious and to treating inflammatory myalgia (i.e. muscle pain). spiritual coping. J Pain 2:101–110 These animal models also provide methods by which 9. Lange U, Piegsa M, Teichmann J et al. (2000) Ultrasonography of the efficacy and potency of novel pharmaceutical agents the glenohumeral joints –a helpful instrument in differentiation in can be examined. elderly onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatol Int 19:185–189 Animal models of inflammatory muscle pain consist of 10. Le Quintrec JS, Le Quintrec JL (1991) Drug-induced myopathies. two parts: a method of inducing inflammation in mus- Baillieres Clin Rheumatol 5:21–38 cle,andamethodofevaluatingchangesin nocifensive 11. Lindvall B, Bengtsson A, Ernerudh J et al. (2002) Subclinical behaviors. Methods of inducing inflammation in muscle myositis is common in primary Sjogren’s syndrome and is not related to muscle pain. J Rheumatol 29:717–725 include intramuscular injection of substances, such as 12. Lyngberg KK, Ramsing BU, Nawrocki A et al. (1994) Safe and carrageenan (Kehl et al. 2000), or components of the ineffective isokinetic knee extension training in rheumatoid arthri- flammatory milieu, such as protons (i.e. acidity) (Sluka tis. Arthritis Rheum 37:623–628 etal. 2001). Changesin nocifensivebehaviorsexamined 13. Salvarani C, Hunder GG (1999) Musculoskeletal manifestations in a population-based cohort of patients with giant cell arteritis. bythesemodelsareusuallydescribedas hyperalgesia, Arthritis Rheum 42:1259–1266 becausetheyincreasetheresponsetostimulithatarenor- 14. Schiottz-Christensen B, Lyngberg K, Keiding N et al. (2001) Use mally considered nociceptive. One method of evaluat- of isokinetic muscle strength as a measure of severity of rheuma- ing changes in nocifensive behaviors involves measur- toid arthritis: a comparison of this assessment method for RA with other assessment methods for the disease. Clin Rheumatol ing the amount of force that an animal can produce with 20:423–427 the inflamed muscle (e.g. grip force). Another method 15. Terslev L, Torp-Pedersen S, Savnik A et al. (2003) Doppler ultra- examineschangesin withdrawalresponsesto controlled sound and magnetic resonance imaging of synovial inflammation of the hand in rheumatoid arthritis: a comparative study. Arthritis mechanical( vonFreymonofilaments)stimuliapplied Rheum 48:2434–2441 to areas of skin, often the hind paw, that are remote from 16. Walsmith J, Roubenoff R (2002) Cachexia in rheumatoid arthri- the inflamed muscle. tis. Int J Cardiol 85:89–99 Characteristics Protons Inflammation can result in decreased tissue pH (i.e. Muscle Pain Model, acidosis), which activates cutaneous nociceptors Inflammatory Agents-Induced (Steen et al. 1992) and increases withdrawal responses to mechanical stimuli in rats (Hamamoto et al. 2001). DARRYL T. HAMAMOTO,DONALD A. SIMONE In humans, constant infusion of acidic buffer into skin University of Minnesota, Minneapolis, MN, USA or muscle produces flow-dependent pain that has been [email protected] shown to correlate with decreased tissue pH, at least Muscle Pain Model, Inflammatory Agents-Induced 1217

Muscle Pain Model, Inflam- matory Agents-Induced, Figure 1 Decreased mechanical threshold following two injections of acidic saline into the gastrocnemius muscle of one hind limb of a rat. The injections were spaced 2 or 5 days apart. Decrease in the threshold force is expressed as area under the curve for the 6 weeks after the second injection. A significant decrease in mechanical withdrawal threshold occurred bilaterally for rats injected with pH 4 or pH 5 saline, but not for those injected with pH 6 or 7.2. Data are expressed as mean ± SEM, N=8 rats/group, *P < 0.05. Figure modified from Sluka et al. 2001. in the skin (Steen et al. 1995; Isseberner et al. 1996). such as fibromyalgia, experience areas of tenderness Thus, decreased tissue pH may contribute to pain as- called tender points (Sluka et al. 2001). This model sociated with muscle inflammation. Two injections of has subsequently been used to examine the role of M acidic saline (pH 4.0 – 6.0) administered 2 days apart excitatory amino acid receptors in the development into the gastrocnemius muscle of one hind limb of a and maintenance of mechanical hyperalgesia induced rat, produced cutaneous mechanical hyperalgesia that by intramuscular injection of acidic saline (Skyba et persisted for up to 4 weeks (Fig. 1) (Sluka et al. 2001). al. 2002). In this model, mechanical hyperalgesia was examined by applying von Frey monofilaments to the plantar Carrageenan surface of the hind paw, a site remote from the site Injection of carrageenan into muscle evokes a localized were the acidic saline was injected. The contralateral myositis, as demonstrated by accumulation of leuko- hind paw also exhibited mechanical hyperalgesia. After cytes around the site of injection (Diehl et al. 1988). In mechanical hyperalgesia had developed, neither phar- electrophysiological studies, injection of carrageenan macological (i.e. intramuscular injection of lidocaine into muscle sensitizes nociceptors, both increasing their into the site of acidic saline injection) nor physical spontaneous activity and lowering their threshold to (i.e. dorsal rhizotomy) interruption of input from activation by mechanical stimuli (Berberich et al. 1988; primary afferent innervating the gastrocnemius muscle Diehl et al. 1988). Thus, when inflamed muscle is con- abolished the contralateral mechanical hyperalgesia. tracted, nociceptors in the muscle would be activated by These results suggest that central sensitization fol- lower than normal magnitudes of mechanical stimuli. lowing nociceptive input from muscle may underlie the The animal might then react to this nociceptive input secondary hyperalgesia in this model. Interestingly, by decreasing contraction of the muscle, in order to injection of acidic saline produced histologic evidence decrease mechanical activation of muscle nociceptors. of only mild injury and inflammation of the muscle This reduction in effort would reduce the force pro- fibers in some rats, which was attributed to the needle duced by the muscle. Thus, Kehl and colleagues have penetration and not to the acidic solution. Thus, this developed a model of inflammatory muscle pain that model appears to isolate the effects of one component involves bilateral injections of carrageenan into the tri- of inflammation, which is tissue acidity. Of interest is ceps muscles, and examines the grip force produced by the long lasting (i.e. 4 weeks) hyperalgesia produced by the inflamed muscle in rats and mice (Kehl et al. 2000; two injections of acidic saline. Also, the mechanical hy- Wacnik et al. 2003). This appears to be a clinically rel- peralgesia was exhibited in a different tissue (i.e. skin) evant model, because patients with muscle pain exhibit and at a site remote from the acidified muscle tissue. reduced grip force (Norsdenskiold and Grimby 1993). This pattern of referral from deep structures to remote In this model, grip force is measured using a strain cutaneous sites has been shown in humans (Marchettini gauge attached to a wire mesh upon which the rodent is et al. 1990). Thus, this model of acid-induced muscle allowed to grab with its fore paws (Fig. 2). The rodent is pain may help to determine the mechanisms by which held by the tail and gently pulled until it releases the wire patients with chronic generalized musculoskeletal pain, mesh and the maximum force produced by the rodent is 1218 Muscle Pain Model, Inflammatory Agents-Induced

Muscle Pain Model, Inflammatory Agents-Induced, Figure 2 Measurement of grip force in mice. Mice are posi- tioned and allowed to grasp a wire mesh with their fore paws. Mice are Muscle Pain Model, Inflammatory Agents-Induced, Figure 3 Time- held by the tail and gently moved in a rostral-caudal direction. The wire response curve for the reduction in fore limb grip force in rats following mesh is attached to a strain gauge and the peak grip force produced by injection of carrageenan (4 mg) or an equal volume (75 μl) of PBS into the mouse is determined. the triceps muscles both fore limbs. Intramuscular carrageenan (Carra) produced a significant treatment- and time-dependent reduction in grip force. Data are expressed as mean ± SEM, N=15 rats/group, **P<0.01. Figure modified from Kehl et al. 2000. recorded. Grip force is subject to factors, such as hyperalgesia, that influence the behavioral performance of the rodent. Kehl and colleagues have shown that intramus- as paw withdrawal from mechanical or thermal stim- cular injection of carrageenan into the triceps muscle in uli, are based on the assumption that an animal that rodents produces a dose– and time-dependent reduction withdraws less or withdraws at a higher threshold is in grip force (Fig. 3). This reduction in grip force was exhibiting antihyperalgesia. However, drug-induced specific to the inflamed triceps muscles, because the motor dysfunction and sedation may produce the same force produced by the hind limbs was not affected. behavioral response. That is, it may take a more intense Furthermore, injection of carrageenan into one triceps mechanical or thermal stimulus to elicit a withdrawal muscle did not affect the grip force in the contralateral response. In contrast, if a drug produces motor dysfunc- fore limb. Additional support for the clinical relevance tion or sedates an animal then it will produce less grip of this model of inflammatory muscle pain is the fact force, which will not be misinterpreted as antihyperal- that carrageenan-induced reduction in grip force is gesia. Thus, the carrageenan model appears to be useful attenuated by the opioid levorphanol, the nonsteroidal for further elucidation of the mechanisms associated anti-inflammatory drug indomethacin and the steroid with inflammatory muscle pain. Furthermore, the grip dexamethasone. These drugs represent three classes of force assay provides a method by which the analgesic analgesic agents used clinically to treat muscle pain. efficacy and potency of novel pharmaceutical agents Additionally, experimental analgesic agents such as the can be examined in models of inflammatory muscle non-competitive NMDA antagonist MK801 and the pain. cannabinoid agonist WIN 55,212–2 have been shown to have attenuated inflammatory muscle hyperalgesia using this model. References The carrageenan-induced model of muscle pain has 1. Berberich P, Hoheisel U, Mense S (1988) Effects of a several advantages over the model of acidic saline Carrageenan-Induced Myositis on the Discharge Properties induced hyperalgesia. First, the carrageenan-induced of Group III and IV Muscle Receptors in the Cat. J Neurophys- model of muscle pain is a model of pain produced by iol 59:1395–1409 2. Diehl B, Hoheisel U, Mense S (1988) Histological and Neuro- inflammation in muscle, whereas injection of individ- physiological Changes Induced by Carrageenan in Skeletal Mus- ual or multiple inflammatory mediators may not be. cle of Cat and Rat. Agents Actions 25:210–213 Second, the carrageenan model is a model of primary 3. Hamamoto DT, Ortiz-Gonzalez XR, Honda JM, Kajander KC hyperalgesia, because it examines the function of the (2001) Intraplantar Injection of Hyaluronic Acid at Low pH into the Rat Hindpaw Produces Tissue Acidosis and Enhances With- inflamed muscle. In contrast, models in which the site drawal Responses to Mechanical Stimuli. Pain 74:225–234 of hyperalgesia is remote from the site of inflammation 4. Issberner U, Reeh PW, Steen KH (1996) Pain due to Tissue Aci- or injury are models of secondary hyperalgesia. Third, dosis: A Mechanism for Inflammatory and Ischemic Myalgia? the grip force assay avoids the potential of misinter- Neurosci Lett 208:191–194 5. Kehl LJ, Trempe TM, Hargreaves KM (2000) A New Animal preting drug-induced motor dysfunction or sedation Model for Assessing Mechanisms and Management of Muscle with antihyperalgesia. Many behavioral assays, such Hyperalgesia. Pain 85: 333–343 Muscle Pain Model, Ischemia-Induced and Hypertonic Saline-Induced 1219

6. Marchettini P, Cline M, Ochoa J (1990) Innervation Territories pressure exerted on the nerve by the tourniquet, and not for Touch and Pain Afferents of Single Fascicles of the Human by the ischemia. Ulnar Nerve. Brain 113:1491–1500 7. Norsdenskiold UM, Grimby, G (1993) Grip Force in Patients Clinical Findings and Results from Studies with Rheumatoid Arthritis and Fibromyalgia and in Healthy Sub- jects: A Study with the Grippit Instrument. Scand J Rheuma- on Human Subjects tol 22:14–19 Oneof theclinically importanttypesof ischemicmuscle 8. Skyba DA, King EW, Sluka KA (2002) Effects of NMDA and Non-NMDA Ionotropic Glutamate Receptor Antagonists on the pain is the pain of intermittent claudication. It occurs Development and Maintenance of Hyperalgesia Induced by Re- during walking in patients with sclerotic narrowing of peated Intramuscular Injection of Acidic Saline. Pain 98:69–78 the arteries of the lower leg and foot. In earlier clinical 9. Sluka KA, Kalra A, Moore SA (2001) Unilateral Intramuscular studies, a multitude of factors were discussed as being Injections of Acidic Saline Produce a Bilateral, Long-Lasting Hyperalgesia. Muscle Nerve 24:37–46 the cause of the pain, e.g. chemical metabolites, accu- + 10. Steen KH, Reeh PW, Anton F, Handwerker HO (1992) Protons mulation of potassium ions (K ), and reduced pH due Selectively Induce Lasting Excitation and Sensitization to Me- to release of lactic acid. Lactic acid was soon ruled out, chanical Stimulation of Nociceptors in Rat Skin, In Vitro.JNeu- because patients with McArdle’s disease – who are un- rosci 12:86–95 11. Steen KH, Issberner U, Reeh PW (1995) Pain due to Experimental able to produce lactic acid due to a gene defect – often Acidosis in Human Skin: Evidence for Non-Adapting Nociceptor present with pain of intermittent claudication or angina Excitation. Neurosci Lett 199:29–32 pectoris. Another candidate substance was the nonapep- 12. Wacnik PW, Kehl LJ, Trempe TM, Ramnaraine ML, Beitz tide bradykinin (BKN) that is cleaved by kallikrein – a AJ, Wilcox GL (2003) Tumor Implantation in Mouse Humerus Evokes Movement-Related Hyperalgesia Exceeding that Evoked proteinase – from plasma proteins. The importance of by Intramuscular Carrageenan. Pain 101:175–186 BKN for the pain of intermittent claudication was supported by the finding that administration of a proteinase inhibitor in claudication patients extended the distance Muscle Pain Model, Ischemia-Induced the patients were able to walk without pain (Digiesi et al. 1975). Electron microscopicinvestigationsof bioptic M and Hypertonic Saline-Induced material of claudication patients showed that the mus- SIEGFRIED MENSE cle exhibited signs of inflammation with infiltration by Institute of Anatomy and Cell Biology III, University inflammatory cells and muscle fiber necrosis. The lat- Heidelberg, Heidelberg, Germany ter finding adds adenosine triphosphate (ATP) to the list [email protected] of candidate substances, because muscle cells contain high concentrations of ATP, which are released into the Synonyms interstitial space when a muscle fiber is damaged (see below). Ischemia-induced muscle pain: Ischemic muscle pain Definitions Data from Animal Experiments Theresultsobtainedfromanimalstudiesindicatethatthe Ischemia-induced muscle pain: muscle pain during following agents or factors may be involved in ischemic and following muscle exercise under ischemic con- pain: ditions. In clinical studies, ischemic conditions were induced by occlusion of blood vessels of an entire limb 1. Potassium ions. The potassium concentration is in- (e.g. by a tourniquet, or by administration of adrenalin creasedinmusclesofexperimentalanimalsfollowing to study pain mechanisms in the tooth pulp). In animal contractions with and without occlusion of the blood experiments, the blood flow was interrupted by occlu- supply. sion of arteries using a ligature or clamp, by a tourniquet 2. Proton concentration (pH). The interstitial pH is low- around the tail or by circulatory arrest. ered to approximately 6.5 during prolonged ischemia Hypertonic saline-induced pain: muscle pain induced plus exercise. by intramuscular or intraarterial (into the muscle artery) 3. Kinins such as BKN and kallidin. The kinin-forming injection of hypertonic saline (NaCl) at a concentration activity of muscle tissue is increased after prolonged of 5–10% (5.6–11.1 times hypertonic). ischemia. 4. Degeneration and necrosis of muscle fibers. If necro- Characteristics sis is present in a chronically ischemic muscle, the Ischemia-Induced Pain ATP concentrations released from the muscle cells are sufficient to activate muscle nociceptors (Reinöhl Data from clinical studies and animal experiments indi- et al. 2003). cate that ischemia alone (without muscle contractions) is not an effective stimulus for muscle nociceptors. In Electrophysiological recordings from single muscle af- clinical studies where a tourniquet was used to induce ferentfibershaveshownthatinskeletalmuscleofcatand ischemia in a limb, the pain that occurred after approx- rat, receptive endings are present that respond specifi- imately half an hour appeared to be mostly due to the callytoischemiccontractions,inthattheyarenotexcited 1220 Muscle Pain Model, Ischemia-Induced and Hypertonic Saline-Induced

Muscle Pain Model, Ischemia- Induced and Hypertonic Saline-Induced, Figure 1 Impulse activity of single cat muscle receptors with unmyelinated afferent fibers showing exclusive or predominant activation during ischemic contractions. In both panels, the upper trace indicates the force of the contraction of the gastrocnemius-soleus muscle in percent of maximal contraction (M.c.) induced by electrical stimulation of the muscle nerve, the middle trace shows the temperature inside the muscle, and the lower trace is a histogram of the fiber’s activity (bin width 4s). Periods of contractions are marked by filled bars underneath the abscissa; occlusion of the muscle artery is marked by open bars. In (a), the force of contraction was adjusted to approximately 50% M.c., and in (b) to 100%. Under the latter condition, the muscle could not maintain the contraction force during occlusion of the muscle artery. Note that in both panels the discharge frequency drops markedly at the end of the contraction period. This indicates that in addition to chemical factors a mechanical component is involved in the activation of the receptors during ischemic contractions. From Mense and Stahnke 1983. byshort-lastingischemiaalonebutrequireischemiaplus for a review on ASICs as channels mediating the contractions for activation (Bessou and Laporte 1958; pain of angina pectoris, see Sutherland et al. 2000). Mense and Stahnke 1983; Fig 1). This behavior was in- Capsaicin is assumed to be a specific ligand for terpreted as indicating that the units were nociceptors the VR 1 receptor. The fact that intramuscular in- and may mediate the pain of intermittent claudication, jection of capsaicin causes strong pain in humans but other authors emphasized a possible function in the by exciting group IV units (Marchettini et al. 1996) adjustment of respiration and circulation to the require- indicates that VR 1 receptors are present in human ments during muscle work (Kaufman et al. 1984). skeletal muscle. 3. as muscle fibers of claudication patients exhibit What Factors Cause the Pain of Intermittent Claudication? necrosis, another likely factor for the activation of muscle nociceptors is ATP, which binds to The available data suggest that it is not a single factor purinergic receptors (e.g. the P2X3 receptor) that is responsible for ischemic muscle pain but that sev- (Burnstock 2000) and activates muscle group IV no- eral stimuli act in combination. Recent findings regard- ciceptors in concentrationsthat are present in muscle ing receptor molecules that are present in the membrane fibers (Reinöhl et al. 2003). of nociceptors suggest that the following agents could be involved in the induction of ischemic pain: In conclusion, a possible mechanism of activation of 1. BKNactingontheB2 bradykininreceptors(unless muscle nociceptors, in a muscle that contracts under the nociceptor is sensitized, then BKN stimulates the acute ischemic conditions, is that first, BKN or low ending by binding to the B1 receptor). pH sensitize the high-threshold mechanosensitive 2. the low pH in an ischemic muscle is likely to sensi- muscle receptors (putative nociceptors) (Mense and tize the vanilloid receptor subtype VR 1 (now called Meyer 1985), and subsequently, in the sensitized state, TRPV1), and to activate other acid sensing ion nociceptors are activated by the mechanical force of the channels (ASICs) (Immke and McCleskey 2003; contractions. Such a mechanism issuggested bythetime Muscle Pain Model, Ischemia-Induced and Hypertonic Saline-Induced 1221

Muscle Pain Model, Ischemia-Induced and Hypertonic Saline-Induced, Figure 2 Effects of hypertonic saline on a single high-threshold mechanosensitive (presumably nociceptive) group IV afferent fiber from rat gastrocnemius-soleus (GS) muscle. (a) Experimental set-up. The impulse activity ofa single unmyelinated afferent fiber was recorded from a thin nerve filament dissected from the sciatic nerve. (b) Response of the unit to 5% NaCl injected into that region of the muscle where the receptive ending was located with mechanical stimuli (receptive field, RF). The same NaCl solution that had evoked the strong response when injected i.m. was later put on the nerve filament to show that the axonal membrane was not the site of action of the hypertonic saline. Inset: original recording showing the high mechanical threshold of the receptive ending. Mod.p., moderate, innocuous pressure; Nox.p., noxious, painful pressure. course of activation of the single group IV unit shown do not exhibit abscesses. In clinical studies, hyper- in Figure 1a: the unit was not activated by ischemia or tonic saline has been extensively used to induce pain contractions alone, but gave a strong response during in human subjects. One of the pioneers in this field ischemic contractions. Moreover, the activity dropped was Kellgren, who induced pain in muscles and liga- markedly when the contractions were discontinued but ments of volunteers by injecting 0.1 to 0.3 ml of 6% the ischemia maintained. The unit in Figure 1b was NaCl (Kellgren 1938). Presently, several groups in- weakly activated at the end of the contraction period ject or infuse hypertonic NaCl (5–10%) into muscles without ischemia (in this case the force of contraction in healthy subjects and patients to study the mecha- was higher: close to 100% maximal voluntary contrac- nisms of muscle pain in humans. With this method, tion), but likewise showed a much stronger excitation muscle pain of moderate to strong intensity (values when the contractions were repeated with the muscle around 7 on a VAS with a range from 1 to 10) can artery occluded. be induced. The injected volume is of importance, The release of ATPfrom damaged muscle fibers appears because the innervation density of muscle with no- to occur more under chronic ischemic conditions, but ciceptors is low. Therefore, small injection volumes ATP might also be involved in cases of acute ischemic are likely to yield variable or ill-reproducible pain pain, because ATP is a product of any anaerobic gly- responses. The results obtained with intramuscular colysis (Sutherland et al. 2000). injections of hypertonic saline, suggest that the receptor population mediating ischemia-induced muscle Hypertonic Saline-Induced Muscle Pain pain is distinct from that mediating hypertonic saline- Studies in human subjects . There are few condi- induced pain (Graven-Nielsen et al. 2003). In human tions in which muscle pain is induced by hypertonicity subjects, hypertonic saline appears to excite predom- of the tissue in patients. Abscess formation is one inantly group IV muscle afferent units (as opposed to of them (Schade 1924), but most cases of myositis group III units). 1222 Muscle Pain, Referred Pain

Data from animal experiments . Many authors who 4. Garland A, Jordan JE, Necheles J, Alger LE, Scully MM, Miller recorded the activity of single muscle nociceptors used RJ, Ray DW, White SR, Solway J (1995) Hypertonicity, but not Hyperthermia, Elicits Substance P Release from Rat C-Fiber injections of hypertonic saline for receptor activation. Neurons in Primary Culture. J Clin Invest 95:2359–2366 Interestingly, 5% NaCl proved to be the only chemical 5. Graven-Nielsen T, Jansson Y, Segerdahl M, Kristensen JD, stimulus that excited all of the nociceptors tested, in a re- Mense S, Arendt-Nielsen L, Sollevi A (2003) Experimental centstudy(HoheiselandMense,unpublished)(Fig.2)in Pain by Ischaemic Contractions Compared with Pain by Intra- muscular Infusions of Adenosine and Hypertonic Saline. Eur J whichthestimulantswereinjectedintothemechanosen- Pain 7:93–102 sitive receptive field of rat group IV receptors. The other 6. Immke DC, McCleskey EW (2003) Protons Open Acid-Sensing agents excited only a fraction of the receptors. Ion Channels by Catalyzing Relief of Ca2+ Blockade. Neu- ron 37:75–84 Mechanisms of Nociceptor Activation 7. Kaufman MP, Rybicki KJ, Waldrop TG, Ordway GA (1984) Ef- by Hypertonic Saline fect of Ischemia on Responses of Group III and IV Afferents to Contraction. J Appl Physiol 57:644–650 The mechanisms by which muscle nociceptors are ex- 8. Kellgren JH (1938) Observations on Referred Pain Arising from cited by hypertonic saline are obscure. Several possibil- Muscle. Clin Sci 3:175–190 ities exist (for an overview see Kress and Reeh 1996): 9. Kress M, Reeh P (1996). Chemical Excitation and Sensitization in Nociceptors. In: Belmonte C, Cervero F (eds) Neurobiology 1. activation by increased tonicity in the intersti- of Nociceptors. Oxford University Press, Oxford, pp 259–297 tial space. The receptive ending might shrink in 10. Marchettini P, Simone DA, Caputi G, Ochoa JL (1996) Pain from Excitation of Identified Muscle Nociceptors in Humans. Brain the hypertonic environment, and stretch-sensitive Res 40:109–116 + Na –channels could be opened. However, nothing 11. Mense S, Stahnke M (1983) Responses in Muscle Afferent Fibres is known about the water permeability of nocicep- of Slow Conduction Velocity to Contractions and Ischaemia in tive endings, and the high mechanical stimulation the Cat. J Physiol 342:383–397 12. Mense S Meyer H (1985) Different Types of Slowly Conduct- threshold of muscle nociceptors speaks against this ing Afferent Units in Cat Skeletal Muscle and Tendon. J Phys- mechanism. iol 363:403–417 2. activation by ionic changes. The high Na+ concen- 13. Reinöhl J, Hoheisel U, Unger T, Mense S (2003) Adeno- tration in the interstitial fluid should have only lit- sine Triphosphate as a Stimulant for Nociceptive and Non- Nociceptive Muscle Group IV Receptors in the Rat. Neurosci tle influence on the membrane potential of the noci- Lett 338:25–28 ceptive ending, because the Na+ conductance of an 14. Schade H (1924) Die Molekularpathologie in ihrem Verhältnis axon is normally low. However, there is evidence in- zur Zellularpathologie und zum klinischen Krankheitsbild am dicating that the Na+ conductance of receptive end- Beispiel der Entzündung. Münch Med Woschr 71:1–4 + 15. Sutherland SP, Cook SP, McCleskey EW (2000) Chemical Me- ingsishigher,andthereforethehighextracellularNa diators of Pain due to Tissue Damage and Ischemia. Prog Brain concentration could cause aneffective depolarization Res 129:21–38 with ensuing excitation of the ending. Thus, the high 16. Svensson P, Cairns BE, Wang K, Hu JW, Graven-Nielsen T, + Arendt-Nielsen L, Sessle BJ (2003) Glutamate-Evoked Pain Na concentration could be the decisive factor for hy- and Mechanical Allodynia in the Human Masseter Muscle. – pertonic saline-induced muscle pain. The high Cl Pain 101:221–227 concentration appears not to be a stimulus, because 17. Tegeder L, Zimmermann J, Meller ST, Geisslinger G (2002) Re- in peripheral nerve fibers Cl– channels are rare. An lease of Algesic Substances in Human Experimental Muscle Pain. Inflamm Res 51:393–402 additional unknown factor is that – if shrinking of the ending occurs – the intraaxonal concentrations of all ions increase to an unknown extent. 3. indirect activation of the nociceptor by other algesic Muscle Pain, Referred Pain agents released from muscle tissue or the nociceptive MARIA ADELE GIAMBERARDINO ending itself. The injection of hypertonic saline has Department of Medicine and Science of Aging, G. beenreportedtoreleaseglutamatefrommuscletissue D‘Annunzio University of Chieti, Chieti Scalo, Italy (Tegeder et al. 2002). Glutamate excites muscle no- [email protected] ciceptors and causes muscle pain in humans (Svens- son et al. 2003). Hypertonic solutions have also been Synonyms shown to release substance P from airway sensory Musculoskeletal Transferred Pain; referred muscle pain cells in vitro (Garland et al. 1995). Definition References Painperceivedatmusclelevelduetoaprimaryalgogenic 1. Bessou P, Laporte Y (1958) Activation des Fibres Afférentes Amyéliniques d’Origine Musculaire. Compt Rend Soc Biol process located at a distance, either in a visceral organ (Paris) 152:1587–1590 or in a deep somatic structure. 2. Burnstock G (2000) P2X Receptors in Sensory Neurones Br J Anaesth 84:476–488 Characteristics 3. Digiesi V, Bartoli V, Dorigo B (1975) Effect of a Proteinase In- hibitor on Intermittent Claudication or on Pain at Rest in Patients Referred muscle pain can result from an algogenic with Peripheral Arterial Disease. Pain 1:385–389 process in internal organs or in deep somatic structures, Muscle Pain, Referred Pain 1223

Hyperalgesia is accentuated by the repetition of the visceral episodes; although decreasing as they stop, it usually remains signiﬁcant after cessation of the spontaneous pain and sometimes even after removal of the primary visceral focus. Trophic changes are even more persistent than the hyperalgesia, often remaining unaltered for a long time after extinction of the visceral trigger (Giamberardino et al. 2005).

Clinical Examples Muscle Pain, Referred Pain, Figure 1 Classification of referred muscle In myocardial infarction, pain is referred to the tho- pain. racic region, anteriorly or posteriorly, often extending to the left arm. Hyperalgesia almost always affects the pectoralis major and muscles of the interscapular e.g., another muscle or a joint (referred muscle pain region and forearm. Trapezius and deltoid muscles are from viscera or from deep somatic structures) (Fig. 1). less frequently involved. Dystrophic muscle changes In both cases, it may or may not be accompanied by may also occur at the same level. In a low percentage secondary hyperalgesia, i.e. increased local sensitivity of cases, pain is also referred to the skin, within der- to pain / decreased pain threshold (referred muscle pain matomes C8-T1 on the ulnar side of the arm and forearm with or without hyperalgesia) (Vecchiet et al. 1999). and hyperalgesia is found at the same level (Giamber- When present, hyperalgesia is proportional in extent to ardino 2000; Procacci et al. 1986). In urinary colics the degree of activity of the primary algogenic focus from calculosis, referred pain is perceived in the lum- and is often accompanied by local trophic changes, bar region of the affected side, with radiation towards i.e. decreased thickness / sectional area of the muscle the ipsilateral flank and anteriorly towards the groin. M (Galletti et al. 1990; Giamberardino 2000; Simons Hyperalgesia and trophic changes characteristically and Mense 2003; Vecchiet et al. 1991). Both central affect muscles of the lumbar and flank area (quadratus (neuronal sensitization) and peripheral (reflex arc ac- lumborum, oblique muscles) (Vecchiet et al. 1989). In tivation) mechanisms are likely to be involved in the biliary calculosis, pain is referred to the upper right pathophysiologyof referred phenomenaat muscle level quadrant of the abdomen with radiation towards the (Arendt-Nielsen and Svensson 2001; Cervero and Laird back. Hyperalgesia and reduced trophism of the rectus 2004; Mense 1994; Procacci et al. 1986). abdominis at the cystic point (junction of 10th rib with outer margin of the same muscle) are typical findings Referred Muscle Pain from Viscera (Giamberardino et al. 2005). In dysmenorrhea, pain is Pain referral occurs constantly in visceral nociception referred to the lower abdomen, perineum and sacral (Cervero and Laird 2004). After the transitory phase region, with radiation towards the groin and upper part of “true visceral pain” (midline, vague and poorly of the thighs. Hyperalgesia and trophic changes can defined), the sensation is “transferred” to somatic ar- be detected in the lowest part of the rectus abdominis eas neuromerically connected to the specific viscus and muscles of the pelvic region (Giamberardino et al. (Procacci et al. 1986). Secondary hyperalgesia most 1997). often arises at this level, especially if pain episodes Referred muscle pain and hyperalgesia are typically are recurrent and / or prolonged; this may involve all enhanced in the case of “viscero-visceral hyperal- three body wall tissues – skin, subcutis and muscle – gesia”, when concurrent algogenic conditions affect but is most frequently confined to muscle, often ac- two viscera which share part of their central sensory companied by sustained contraction (referred muscle projection (Giamberardino 2000). Women suffering pain from viscera without and with hyperalgesia) (Vec- from both dysmenorrhea and irritable bowel syndrome chiet et al. 1989). Trophic changes may also occur in (IBS) (common projection for uterus and colon, T10- the same sites, i.e. increased thickness of subcutis but L1), for instance, frequently report more menstrual mostly decreased thickness of muscle (Procacci et al. pain, intestinal pain and abdominal / pelvic muscle 1986; Vecchiet et al. 1989). In patients with algogenic hyperalgesia (in areas of referral from uterus and in- conditions from a number of internal organs, muscle testine) than women with dysmenorrhea or IBS only hyperalgesia in referred zones has been detected clin- (unpublished observation). Patients with dysmenor- ically (hypersensitivity to digital compression) and rhea / endometriosis plus urinary calculosis (common quantified instrumentally (decrease in pain thresholds projection for uterus and upper urinary tract, T10-L1) to different stimuli); in a minor percentage of visceral present with more menstrual pain, urinary colic pain pain patients, muscle trophic changes have also been and abdomino-pelvic / lumbar muscle hyperalgesia (in measured, using ultrasounds (Giamberardino et al. areas of referred pain from uterus and urinary tract) 1997; Giamberardino et al. 2005; Vecchiet et al. 1989). than patients with one condition only (Giamberardino 1224 Muscle Pain, Referred Pain et al. 2001). The phenomenon of “viscero-visceral Mechanisms underlying enhancement of referred phe- hyperalgesia” has therapeutic implications. In fact, nomena in “viscero-visceral hyperalgesia” are still hy- effective treatment of one condition may significantly pothetical, butprobably involve sensitization of viscero- improve typical symptoms from the other, e.g. decrease viscero-somatic convergent neurons. Along with the in urinary pain and referred lumbar hyperalgesia af- well-documented viscero-somaticconvergenceonto the ter hormonal treatment of dysmenorrhea or decrease same sensory neurons, extensive viscero-visceral con- in menstrual pain and referred abdomino-pelvic hy- vergence has also been found in the CNS, for instance peralgesia after urinary stone elimination following between the colon / rectum, bladder, vagina and uterine lithotripsy (Giamberardino 2000; Giamberardino et al. cervix (refs. in Vecchietetal. 1999). The increasedaffer- 2001). ent barrage from one visceral organ would thus enhance the afferent signal from the second organ projecting to Pathophysiology the same neuron and also from the referred area. This “Referred muscle pain from viscera without hyperal- hypothesis needs to be verified in electrophysiological gesia” is explained on the basis of the convergence of studies on animal models of the condition, such as the visceral and somatic afferent fibers upon the same cen- model of endometriosis plus ureteral calculosis in the tral neurons (convergence-projection theory) (Cervero female rat in which an enhancement is observed of both and Laird 2004; Procacci et al. 1986). Messages from spontaneous pain behavior and referred lumbar muscle the viscus are “interpreted” by higher brain centers hyperalgesia (Giamberardino 2000). as coming from muscles due to mnemonic traces of Referred Muscle Pain from Deep Somatic Structures previous experiences of somatic pain, more numerous than those of visceral pain in life. “Referred muscle Clinical Examples pain from viscera with hyperalgesia” is contributed to Myofascial pain syndromes (MPSs) are classical exam- by central mechanisms, i.e. a process of sensitization ples of “referred muscle pain from muscles”. An MPS in the central nervous system (CNS), triggered by the is characterized by regional muscle pain and dysfunc- massive afferent visceral barrage involving hyperactiv- tion due to the presence, in muscles or their fascia, of ity and hyperexcitability of viscero-somatic convergent active trigger points (TrPs). A trigger point is a site of neurons, as shown by the results of electrophysio- tissue hyperirritability included in a taut, palpable band logical studies on animal models of referred muscle of muscle fibers. When stimulated, it gives rise to pain hyperalgesia from viscera (Cervero and Laird 2004; not only locally, but also at a distance, in an area called Giamberardino 2000). This process would facilitate the “target” because it is often remote from its location (Si- central effect of the normal input coming from the mus- monsand Mense 2003). The targetzone (area of referred cle (convergence-facilitation theory). NMDA receptors pain) is typical and characteristic for each muscle and is have been suggested to play an important role in the the site not only of spontaneous pain, but also of sensory generation of these central hyperexcitability changes changes. These consist of hyperalgesia, which is a func- (Cervero and Laird 2004). tion of the degree of hyperirritability of the trigger point, In addition to central changes, the afferent visceral bar- i.e. the more irritable the TrP, the greater the degree of rage probably activates a number of viscero-somatic re- hyperalgesia in the targetandthegreatertheextensionof flex arcs, whose afferent branch is represented by sen- the tissues involved. Latent trigger points (pre-clinical sory fibers from the internal organ and whose efferent phase of MPSs) only give rise to muscle hyperalgesia branch is represented by sympathetic efferences to the in the target, while active TrPs give rise to hyperalgesia, skin / subcutis and somatic efferences to the muscle of which extendsfrom themuscleto theoverlyingsubcuta- the referred area (Procaccietal. 1986). Activationof this neous / cutaneous tissues also. The dependence of these arc would produce sustained contraction in the skeletal changes on the presence of the TrPs is testified by their muscle, this, in turn, being responsible for sensitization regression after the TrP is extinguished through local in- of nociceptors locally. Studies in a rat model of referred filtration (Vecchiet et al. 1991). muscle hyperalgesia from artificial ureteric calculosis A typical example of “referred muscle pain from joints” provide experimentalsupport for this mechanism. Posi- isrepresentedbythepainfulsymptomatologyinpatients tivitywasfoundforanumberofultrastructuralindicesof withosteoarthritisoftheknee(Vecchietetal.1999).Pain contraction in the hyperalgesic muscle ipsilateral to the from this condition is deep, fairly well localized and of affectedureteratlumbarlevelbutnotinthecontralateral, varying intensity, sometimes making walking difficult. non-hyperalgesicmuscle and the extent of these indices Itspreadsupwardtothelowerpartofthethighanddown- was proportional to the degree of visceral pain behav- ward asfar asthemiddleof thecalf.Itbeginswhen walk- ior and referred hyperalgesia recorded in the animals. In ing,increasesaswalkingcontinuesanddecreasesatrest. the same model, c-Fos activation was found in the spinal The skin appears pale and hypothermic to touch in an cord not only in sensory neurons but also motoneurons, area covering the anterior surface of the knee. The un- significantly more on the affected side (refs. in Giamber- derlying subcutis is tender and thickened at pincer pal- ardino et al. 2005). pation; the skeletal muscles connected to the joint are Muscle Pain, Referred Pain 1225 tender and tense. Pain thresholds to electrical stimula- via both somatic (towards the muscle) and sympathetic tion of all three tissuesof the parietalwall (but mostly the (towards subcutis and skin) efferent fibers, responsible muscle) in the painful area are decreased (hyperalgesia). for the local referred changes (Vecchiet et al. 1999). The sectional area of periarticular muscles (mostly the vastus medialis), measured via ultrasounds, is reduced. Diagnosing Referred Muscle Pain The sensory changes in the referred area are reversible Detection and interpretation of simple referred pain when the intraarticular focus is extinguished, testifying (withouthyperalgesia)arerelativelyeasy,astheabsence their referred nature (Galletti et al. 1990). of tenderness at the site of the symptom immediately Patients with osteoarthritis of the knee have also been points out a site of origin of the algogenic impulses at shown to present increased pain intensity and larger a distance. Correct diagnosis of referred muscle pain referred and radiating pain areas after infusion of hy- with hyperalgesia is, however, much more difficult and pertonic saline into the leg muscles (tibialis anterior) as represents a major clinical problem, since this form is compared to controls, a finding suggesting the setting up far more frequent than that of simple referred pain. The of central sensitization by painful osteoarthritis (Bajaj problem concerns differentiation from primary muscle et al. 2001). pain, i.e. that arising in relation to an algogenic pathol- Pathophysiology ogy primarily affecting the tissue. Only careful study of the clinical history, accurate physical examination and As deducible from the two clinical examples provided complete sensory evaluation of the painful areas can (MPS and osteoarthritis), referred muscle pain from help towards diagnostic orientation, an indispensable somatic structures is almost exclusively of the type step in the institution of a therapeutic strategy that is “referred with hyperalgesia” Similar to what has been not merely symptomatic (Vecchiet et al. 1999). described for visceral nociception, referred pain from somatic structures has been attributed mainly to phenomena of central hyperexcitability triggered by the References M primary algogenic focus (Arendt-Nielsen and Svensson 1. Arendt-Nilesen L, Svensson P (2001) Referred Muscle Pain: Ba- 2001). Animal studies have indeed provided good evi- sic and Clinical Findings. Clin J Pain 17:11–19 dence that dorsal horn neurons become hyperexcitable 2. Bajaj P, Bajaj P, Graven-Nielsen T et al. (2001) Osteoarthritis in response to noxious stimulation of deep tissues (and and its association with muscle hyperalgesia: an experimental controlled study. Pain 93:107–114 that NMDA receptors and neurokinin receptors are most 3. Cervero F, Laird JM (2004) Understanding the signaling probably involved in this mechanism) (Hoheisel et al. and transmission of visceral nociceptive events. J Neurobiol 1993; Mense 1994). To account for the phenomenon 61:45–54 of referral, however, central hyperexcitability should 4. Galletti R, Obletter M, Giamberardino MA et al. (1990) Pain from osteoarthitis of the knee. Adv Pain Res Ther 13:183–191 involve neurons receiving convergent input from the 5. Giamberardino MA (2000) Visceral Hyperalgesia. In: Devor M, site of injury and the referred zone, whereas it is known Rowbotham MC, Wiesenfeld-Hallin Z (eds) Progress in Pain Re- that in dorsal horn neurons there is little convergence search and Management, vol 16. IASP Press, Seattle, pp 523–550 from deep tissues (Mense 1994). Thus, referred pain 6. Giamberardino MA, Berkley KJ, Iezzi S et al. (1997) Pain threshold variations in somatic wall tissues as a function of menstrual from somatic structures is not easily explained by the cycle, segmental site and tissue depth in non-dysmenorrheic “convergence-facilitation” theory in its original form. women, dysmenorrheic women and men. Pain 71:187–197 A modified theory has therefore been suggested, es- 7. Giamberardino MA, De Laurentis S, Affaitati G et al. (2001) pecially for referred pain from one muscle to another, Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neu- based on animal studies. Recordings from dorsal horn rosci Lett 304: 61–64 neurons reveal that noxious stimuli to a specific re- 8. Giamberardino MA, Affaitati G, Lerza R et al. (2005) Re- ceptive field in a muscle generate within minutes new lationship between pain symptoms and referred sensory and trophic changes in patients with gallbladder pathology. Pain muscle receptive fields at a distance from the original 114:239–249 one (Hoheisel et al. 1993). On this basis, the explana- 9. Hoheisel U, Mense S, Simons DG et al. (1993) Appearance of tion proposed is that convergent connections from deep new receptive fields in rat dorsal horn neurons following noxious tissues to dorsal horn neurons are not present from the stimulation of skeletal muscle: a model for referral of muscle pain? Neurosci Lett 153:9–12 beginning, but are opened by nociceptive input from 10. Mense S (1994) Referral of muscle pain. APS J 3:1–9 skeletal muscle. Referral to myotomes outside the le- 11. Procacci P, Zoppi M, Maresca M (1986) Clinical approach to vis- sion is due to spread of central sensitization to adjacent ceral sensation. In: Cervero F, Morrison JFB (eds) Visceral Sensa- spinal segments (Mense 1994). Central mechanisms tion, Progress in Brain Research. Elsevier, Amsterdam, pp 21–28 12. Simons DG, Mense S (2003) Diagnosis and therapy of myofascial alone, however, are not adequate to account for all trigger points. Schmerz 17:419–424 referred phenomena, especially the trophic changes. 13. Vecchiet L, Giamberardino MA, Dragani L et al. (1989) Pain Thus, like the hypothesis for visceral nociception, it from renal / ureteral calculosis: evaluation of sensory thresholds has been suggested that the afferent barrage from the in the lumbar area. Pain 36:289–295 14. Vecchiet L, Giamberardino MA, Saggini R (1991) Myofascial deep focus (in muscle or joint) triggers the activation pain syndromes: clinical and pathophysiological aspects. Clin J of reflex arcs towards the periphery (area of referral) Pain 7:16–22 1226 Muscle Relaxants

15. VecchietL, VecchietJ, Giamberardino MA (1999) Referred Mus- A low quality study found diazepam to be more effec- cle Pain: Clinical and Pathophysiologic Aspects. Curr Rev Pain tive than placebo at day 5, but a high quality study found 3:489–498 it to be no more effective than placebo (Bogduk 2004). Dantrolene was considered more effective than placebo onthegroundsthatitreducedpainduringmaximumvol- Muscle Relaxants untary movement to a greater extent, but not at other times (Bogduk 2004). MARK JOHNSON,NIKOLAI BOGDUK Carisoprodol was considered effective because it re- Musculoskeletal Physician, Hibiscus Coast Highway, duced pain to a greater extent than placebo at four days Orewa, New Zealand (Bogduk 2004). Methocarbamol was as effective as [email protected], [email protected] chlormezanone, but chlormezanone was as effective as an NSAID (Bogduk 2004). Definition Conflicting data concerning tizanidine have been reported by the same investigators in two separate studies. Muscle relaxants are drugs ostensibly designed to re- One found no differences in outcome at three and at lieve pain by reducing painful muscle spasm. seven days between patients treated with tizanidine and those treated with placebo (Bogduk 2004). The Characteristics other study compared tizanidine plus ibuprofen with Muscle relaxantshave been largely used in the treatment tizanidine plus placebo (Bogduk 2004). It found no of spinal pain, for it is believed that spasm of the spinal differences in pain scores between the two groups at muscles occurs in response to pain, but is itself painful. three days and at seven days. The success attributed to Most of the literature describes their use for low back tizanidine was based on a larger proportion of patients pain, but they have also been used and tested for neck having no pain or only mild pain at night, at three days pain. but not at seven days; and a larger proportion of patients having no pain or only mild pain at rest, both at three Rationale days and at seven days. The respective proportions in The rationale for the use of muscle relaxants is that if the latter instance were 90% vs. 72% at three days, and they can relieve the spasm, they serve as analgesics by 93% vs. 77% at seven days. Two other studies found no relieving at least part of the pain caused by the muscle differences from placebo (Bogduk 2004). spasm. This rationale, however, is not vindicated by the Baclofen is significantly more effective than placebo evidence. in reducing pain, but the magnitude of the difference There is no evidence that spasm of the back muscles is is about 10% in absolute terms, and 20% in relative painful or contributes to the patient’s pain. There is no terms, but applies only to assessment at ten days after evidence that so-called muscle spasm can be reliably di- treatment (Bogduk 2004). agnosed. There is no correlation between clinical mus- Cyclobenzaprine is more effective than placebo in so cle spasm and any biological parameter such as EMG. far as it achieved a reduction in pain, nine days after Indeed, eminent authorities have decried the wisdom of treatment, of 5.5 points on a 10-point scale, compared belief in muscle spasm (Johnson 1989) or lamented its with 4 points for placebo (Bogduk 2004). However, lack of validity (Andersson et al. 1989). cyclobenzaprine is not more effective than NSAIDs (Bogduk 2004). For relieving pain and improving daily Efficacy activities, it was slightly more effective than placebo at The most recent, systematic review (Van Tulder et al. day 7 but not at day 14 (Bogduk 2004). A meta-analysis 2003) concluded that there was strong evidence that of studies that compared cyclobenzaprine with placebo muscle relaxants are more effective than placebo for (Browning et al. 2003) found that cyclobenzaprine short-term relief of acute low back pain. Inspection of substantially improved local pain and global symptoms the review revealed that studies included in the tables when used for four days, but the effect declined con- were not included in the narrative, where the conclu- siderably after the first week, and was associated with sions were drawn. Inspection of the original studies a 25% increase in side-effects such as drowsiness, dry suggests that this conclusion may have been overly mouth and dizziness compared to placebo. That meta- generous (Bogduk 2004). analysis, however, included studies that were rejected The data are conflicting for orphenadrine (Bogduk by a systematic review on the grounds that they did 2004). One study found that only nine out of 20 patients not explicitly address low back pain (Van Tulder et al. treated with orphenadrine had reduced pain at 48 h 2003). after treatment, compared to four out of 20 patients Thesedataindicatethatfororphenadrine,diazepam,and treated with placebo. No other, or better, measure of tizanidine, the evidence is conflicting as to whether the outcome was reported. In contrast, another study found drugs are more effective than placebo, with the balance no superiority over placebo. favouring no superiority over placebo. Methacarbamol Muscular Cramps 1227 has not been shown to be more effective than placebo. Biofeedback in the Treatment of Pain Carisoprodol is more effective than placebo but only Psychophysiological Assessment of Pain at four days. Baclofen and cyclobenzprine are each only slightly more effective than placebo but only for a few days, but not thereafter. Meanwhile, the evidence Muscle Spasm is strong that muscle relaxants have consistently been associated with a greater incidence of central nervous Chronic Back Pain and Spinal Instability system side-effects (Van Tulder et al. 2003). This factor, Muscle Cramps balanced against their limited attributable effect, gives cause to question the propriety of their use for acute low back pain, especially when other interventions are no less effective, or even more effective, with far less Muscle Tension risk of troublesome side-effects. For the treatment of chronic low back pain, the data on Definition muscle relaxants are limited to only a few studies of a Muscle tension refers to the level of tension in a mus- fewagents. Agentsused for acute lowbackpainhave not cle that is usually measured by electromyography and been studied for chronic low back pain. Those that have is related to the amount of contraction in muscle fibers. been studied, show limited or no superiority of placebo Muscle Cramps (Bogduk 2004). Respondent Conditioning of Chronic Pain Two studies each showed that tetrazepam was significantly more effective than placebo in reducing pain at seven days, but not subsequently (Bogduk 2004). Muscular Cramps Flupirtin was perceived by physicians as achieving M better overall improvement than placebo at seven days, MARIANO SERRAO but improvements in pain or muscle spasm were not Department of Neurology and Otorinolaringoiatry, significantly better (Bogduk 2004). In terms of global University of Rome La Sapienza, Rome, Italy impression of efficacy, tolperisone was not significantly [email protected] better than placebo (Bogduk 2004). For the treatment of neck pain, diazepam and phenobar- Synonym bitalhavebeentested,andfoundtohavenogreatereffect than placebo for the treatment of acute neck pain (Bas- Muscle cramps majian 1983). Definition References Muscle cramps are “spasmodic, painful, involuntary, 1. Andersson G, Bogduk N, Deluca C et al. (1989) Muscle: Clinical contractions of the skeletal muscle” (Layzer and Row- Perspectives. In: Frymoyer JW, Gordon SL (eds) New Perspec- land 1971). They represent one of the most common tives On Low Back Pain. American Academy Of Orthopaedic medical complaints. Cramps sometimes occur spon- Surgeons, Park Ridge, Illinois, pp 293–334 2. Basmajian JV (1983) Reflex Cervical Muscle Spasm: Treatment taneously at rest, especially when the muscle is slack by Diazepam, Phenobarbital or Placebo. Arch Phys Med Rehabil (i.e. relaxed and shortened). More often, cramps are 64:121–124 triggered by a brief contraction or during exercise of a 3. Bogduk N (2004) Pharmacological Alternatives for the Allevi- susceptible muscle (Layzer and Rowland 1971). They ation of Back Pain. Expert Opin Phamacother 5:2091–2098 4. Browning R, Jackson JL, O’Malley PG (2001) Cyclobenzaprine can occur in any muscle of the body, though the foot and Back Pain: A Meta-Analysis. Arch Int Med 161:1613–1620 and calf muscles are more frequently involved (Jansen 5. Johnson EW (1989) The Myth of Skeletal Muscle Spasm (edi- et al. 1991). During the cramp, the muscle is visibly and torial). Am J Phys Med 68:1 palpably taut and painful, often with abnormal posture 6. Van Tulder MW, Touray T, Furlan AD et al. (2003) Muscle Relaxants for Nonspecific Low Back Pain: A Systematic Review of the affected joint, a condition which can be relieved within the Framework of the Cochrane Collaboration. Spine by stretching or massage (Rowland 1985). 28:1978–1992 Characteristics The mechanism of muscle cramps is still speculative, Muscle Scanning because both their expression and their association with numerous diseases vary. Thus, their pathophysiology awaits clarification. A clear etiological distinction Definition should be made between cramps generically named Aform of psychophysiologicalassessmentthatinvolves “ contractures”, present in metabolic myopathies making multiple bilateral recordings of muscle tension (e.g. McArdle’s disease) and cramps associated with levels from varied locations. most other pathologies, usually named “ ordinary 1228 Muscular Cramps cramps”. The former type of cramp is characterized by fasciculation syndrome, myokymia-cramp syn- an absence of activity (“electrical silence”) on EMG drome) recordings, suggesting amuscularorigin (Layzer 1994); – Syndrome of progressive muscle spasm, alope- in most cramps, however, the EMG shows brief periodic cia, and diarrhea (Sathoyoshi’s syndrome) bursts of high-frequency,high-voltage action potentials – Idiopathic nocturnal cramps (Norris et al. 1957), suggesting a neural origin. – Idiopathic generalized myokymia The origin of the pain associated with muscle cramps is – Myokymia-hyperhidrosis syndrome not known and there are no consistent studies that have investigatedthisaspect.Thepainpresentduringthemus- • Others (familial insulin resistance with acanthocyto- clecrampseemstobestrikinglyassociatedtothemuscu- sis nigricans and acral hypertrophy, muscle cramps lar contraction, which probably produces a mechanical in cancer patients) stimulation of the group III or IV intramuscular fibers (Layzer 1985). Other factors such as an ischemia pro- ducedduringthemusclecontraction,anincreaseinmus- Symptomatic Cramps cular metabolites or a direct lesion of the muscular fibers • Central and Peripheral Nervous System Diseases have been hypothesized as well. Muscle cramps have been classified according to their – Motor neuron disease anatomicsiteoforigin,causeorclinicalfeatures(Layzer – Occupational dystonias and Rowland 1971; McGee 1990; Rowland 1985). Re- – Parkinson’s disease cently we have proposed a new classification (Parisi et – Tetanus al. 2003) based primarily on their site of pathogenesis – Multiple sclerosis and on Layzer’s definition of muscle cramp (see below). – Radiculopathies In accordance with such a definition, the muscle con- – Plexopathies traction of the cramp must be painful, which therefore – Peripheral neuropathies (inherited, endocrine- excludesinvoluntary musclecontractionsof variousori- metabolic, infectious, toxic, inflammatory, de- gins which are not painful, such as myotonia, stiffness, myelinating) dystonia and various movement disorders, e.g. myoclo- – Others rare (neurolathyrism, familial paroxysmal nias, chorea, tremors, tics. Furthermore, the muscle con- dystonic choreoathetosis) tractionmustbesuddenandsustainedforaperiodoftime ranging from a few second to a few minutes. Any patho- • Muscular Diseases logical conditions such as antalgic contractures, which develop after a muscle injury and last for several days or – Metabolic myopathy (deficiency of myophos- weeks, should be excluded from this classification be- phorylase, phosphofructokinase, phosphoglyc- cause they, unlike cramps, are neither sudden nor tran- eromutase, phosphoglycerokinase, lactate dehy- sient. In addition, muscular, articular or nervous disor- drogenase (LDH), adenylate deaminase, G6PDH, ders that induce strong, localized pain but are not associ- phosphorylase b-kinase) ated with a real muscle contraction (e.g. neuralgia, con- – Mitochondrial myopathy (carnitine deficiency, tusion, myalgia) should be distinguished from cramps. CPT1 e 2 deficiency) – Endocrine myopathy (Hoffman’s syndrome etc) Classification of Muscle Cramps – Dystrophinopathies (Duchenne, Becker, others) Paraphysiological Cramps – Myotonia (Thomsen, Becker, rippling syndrome) • – Inflammatory myopathies (myositis, myopathy Occasional cramps with tubular aggregates, rheumatic polymyalgia) • Cramps during sporting activity • – Others rare (Lambert-Brody’s diseases, Swartz- Cramps during pregnancy Jampel syndrome, eosinophilia-myalgia syndrome, type two muscle fiber myopathy) Idiopathic Cramps • Familial • Cardiovascular Diseases – Autosomal dominant cramping disease – Venous diseases – Familial nocturnal cramps – Arterial diseases – Continuous muscle fibers activity syndrome – Heart diseases – Hypertension • Sporadic • Endocrine-metabolic Disease – Continuous muscle fiber activity syndrome (Isaac’s syndrome, Stiffman syndrome, cramp- – Hypo-hyperthyroidism Muscular Cramps 1229

– Hypo-hyperparathyroidism Muscular Cramps, Table 1 Drugs inducing muscle cramps – Cirrhosis Hypocholesterolemics Clofibrate – IsolateddeficiencyofACTHaccompaniedbygen- Fenofibrate eralized painful muscle cramp Bezafibrate – Bartter’s syndrome Antiblastics Vincristine – Gitelman’s syndrome – Conn’s disease Antihypertensive Diuretics – Addison’s disease Beta-blockers Angiotensin-converting enzyme inhibitors, – Uremia and dialysis calcium channel blockers

• Hydro-electrolyte Disorders Hormones Medroxyprogesterone acetate Testosterone – Dehydration with or without electrolytes imbal- Estrogens and progesterone ance (diarrhea, vomiting etc) Beta agonist Terbutaline – Hypo-hypernatremia Salbutamol – Hypo-hypercalcemia Pindolol – Hypo-hyperkalemia Others Penicillamine – Hypomagnesemia Insulin – Heat cramps

• Toxic and Pharmacological Causes system pathologies as well as numerous muscular diseases are associated with muscle cramps (Parisi et al. – Drugs 2003). Moreover, muscular cramps are frequent in pa- – Pesticides tients affected by vascular diseases, endocrinopathies, M – Black widow bite electrolyte imbalance and psychiatric disorders. Fur- – Toxic oil syndrome thermore, toxic and pharmacological causes (Table 1) – Malignant hyperthermia can induce muscle cramps (Parisi et al. 2003). Psychiatric Disorders By contrast, allthetrue“sudden, involuntaryandpainful References muscular contractions” are included in the definition of 1. Arimura K, Watanabe O, Kitajima I et al. (1997) Antibodies muscle cramps. Thus, many diseases in which the cramp to potassium channels of PC12 in serum of Isaacs’ syndrome: is not well recognized or in which the cramp is not the Western blot and immunohistochemical studies. Muscle Nerve 20:299–305 principal symptom, such as multiple sclerosis, Parkin- 2. Jacobsen JH, Rosenberg RS, Huttenlocher PR et al. (1986) Fa- son’s disease and myotonia with painful spasms, have milial nocturnal cramping. Sleep 9:54–60 been recognized as causes of muscle cramps. 3. Jansen PHP, Joosten EM, Van Dijck J et al. (1991) The incidence Paraphysiological cramps are characterized by the of muscle cramps. J Neurol Neurosurg Psychiat 54:1124–1125 4. Layzer RB, Rowland LP (1971) Cramps. N Engl J Med occurrence of cramps in healthy subjects during par- 285:31–40 ticular conditions such as pregnancy or exercising. We 5. Layzer RB (1985) Diagnosis of neuromuscular disorders. In: have named occasional cramps (Parisi et al. 2003) those Layzer RB (ed) Neuromuscular manifestation of systemic dis- cramps that occasionally occur in healthy subjects in ease. Davis, Philadelphia, pp 19–22 6. Layzer RB (1994) Muscle pains, cramps and fatigue. In: Engel the absence of exercising or pregnancy. In this case, a AG, Franzini Armstrong C (eds) Myology. McGraw-Hill, New strong muscular contraction or a sustained abnormal York, pp 3462–3497 posture may lead to muscle cramps. 7. Lazaro RP, Rollinson RD, Fenichel GM (1981) Familial cramps and muscle pain. Arch Neurol 38:22–24 Idiopathic cramp is the main symptom of a disease 8. McGeeSR(1990)Musclecramps. ArchIntern Med 150:511–518 about which little is known, the cause of the cramp being 9. Norris FH, Gasteiger EL, Chatfield PO (1957) An electromyo- obscure or speculative. Idiopathic cramps can be either graphic study of induced and spontaneous muscle cramps. Elec- sporadic or inherited and are not usually associated with troencephalogr Clin Neurophysiol 9:139–147 10. Parisi L, Amabile G, Valente G et al. (2003) Muscular cramps: a any cognitive, pyramidal, cerebellar or sensory abnor- new proposal of classification. Acta Neurol Scand 107:176–186 malities.Inthecaseofthefamilialforms,severalauthors 11. Ricker K, Moxley RT (1990) Autosomal dominant cramping dis- have described an autosomic dominant cramping disease. Arch Neurol 47:810–812 ease (Jacobsen et al. 1986; Lazaro et al. 1981; Ricker 12. Rowland LP (1985) Cramps, spasms and muscle stiffness. Rev Neurol 141:261–273 and Moxley 1990; Van den Bergh et al. 1980). Among 13. Solimena M, Folli F, Denis-Donini S et al. (1988) Autoantibod- the idiopathic forms, continuous muscle fiber activity ies to glutamic acid decarboxylase in a patient with stiff-man syndrome and other rare diseases show frequent mus- syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med cle cramps (Arimura et al. 1997; Solimena et al. 1988). 318:1012–1020 14. Van den Bergh P, Bulcke JA, Dom R (1980) Familial muscle Symptomatic cramps include cramps due to several cramps with autosomal dominant transmission. Eur Neurol types of diseases. Both central and peripheral nervous 19:207–212 1230 Muscular Nociceptors, Sensitization

15. Whiteley AM (1982) Cramps, stiffness and restless legs. Prac- Palpation titioner 226:1085–1087 Tendernessisthemainfindingonpalpation.Itmaybefo- cal or diffuse. Other palpatory signs include alterations Muscular Nociceptors, Sensitization of skin sensitivity and apparent alteration of bony landmarks or soft tissue conformation. Sensitization of Muscular and Articular Nociceptors Movement Testing.Movementsareassessedbytesting active,passiveandaccessoryranges,andchallengingre- straints. Muscular Rheumatism Ranges of Movement. Active ranges are assessed by the patient assuming a neutral position and then moving Fibromyalgia the body part in question in each direction as far as Myalgia they can. For the spine the standard movements are extension, flexion, sidebending to left and right, and rotation to left and right. For peripheral joints they are extension, flexion, abduction, adduction, external ro- Musculoskeletal Disorders tation and internal rotation. Conventions have been set (Greene and Heckman 1994, Russe et al. 1976) for these Definition tests. Ranges are estimated visually or measured with a Musculoskeletal disorders is a descriptive term used to goniometer (an instrument like a protractor with arms) label pain associated with repetitive activities. or inclinometer (a device with gravitational reference Disability, Upper Extremity and a dial showing degrees). The examiner records any limitation of range and any association with pain. Passive movements are tested through the same ranges Musculoskeletal Examination with the patient relaxed and the examiner supplying the effort instead of the patient. WADE KING Accessory movements are movements that cannot typi- Department of Clinical Research, Royal Newcastle cally be executed in isolation by a patient, but which can Hospital, University of Newcastle, Newcastle, NSW, be elicited by an examiner. They can be translations or Australia rotations, and their ranges are usually small. They are [email protected] tested by fixing one body part and moving the other as required. The accessory movements of a joint all con- Definition tribute to “joint play”. Musculoskeletal examination means the physical exam- ChallengingRestraints. Restraintstomovementinclude ination of the musculoskeletal system. By tradition, ex- bones, joint capsules, ligaments, tendons and muscles. amination complements the history in clinical assess- They are tested actively by the patient moving a body ment. Its main purpose is to elicit objective information segment as far as possible. They are tested passively by about the index condition. It can also foster rapport and the examiner moving a joint through its ranges and ac- enhance the doctor-patient relationship. cessory movements.During testing,theexaminermakes a judgment as to what may be limiting the movement. Characteristics This may be the onset of pain, an obstruction by bone The three elements of physical examination are de- or soft tissue, tethering by tight ligaments or fascia, or scribed in an aphorism by Apley (Apley and Solo- tension in antagonist muscles. mon 1993) as “look, feel, move” or: Movements may be limited or impeded before terminal restraints are engaged, if structures adjacent to the • inspection moving one produce pain or interfere with movement. • palpation A “painful arc” is part of a range through which move- • movement testing ment is associated with pain (Kessell and Watson 1977). The“impingementsign”relatestotheshoulder.Thesign Inspection is considered positive if, during flexion of the shoulder, Observationsmadebyvisualinspectionofthepatientare movement is limited by pain as the humeral head and general and specific. General observations include dy- acromion move closer and impinge on tissues between namic posture (gait and other gross movements), static them, but the pain and limitation is abolished after sub- posture(standingandsitting)andbodilydeformity.Spe- acromial injection of lignocaine (Neer 1972).The “ap- cific observations of the affected region include skin dis- prehensionsign”occurswhenthepatientexhibitsappre- colouration, scars, swelling and other local abnormali- hensionastheexaminerstartstotestrestraintstoapartic- ties of form or shape. ular movement. It is said to signify instability, in particu- Musculoskeletal Examination 1231 lar of a glenohumeral joint (Blazina and Satzman 1969) Pain Guidelines Group 2003). Goniometry confers or a patella (Hughston 1972). no advantage (Australian Acute Musculoskeletal Pain Many other tests of restraints have been developed for Guidelines Group 2003). Inclinometry seems better if spinal segments and peripheral joints. They are de- done by trained practitioners but is not uniformly reli- scribed in articles and textbooks dealing with disorders able(AustralianAcuteMusculoskeletalPainGuidelines of various regions of the musculoskeletal system. Group 2003). Movement Testing–Challenging Restraints. For various Application joints and regions of the body, some tests have reason- Musculoskeletal examination is often overlooked. able reliability, but for others reliability is poor or lack- A study of patients in a teaching hospital (Ahern et ing (Australian Acute Musculoskeletal Pain Guidelines al. 1991) showed 55% had musculoskeletal symptoms Group 2003). This means clinicians can be trained to and18%significantmusculoskeletaldisorders,yetmus- perform physical tests in similar ways and sometimes culoskeletal examination was performed on only 15%, achieve consistent results, but it does not mean that the compared to examination of the respiratory system findings have diagnostic significance. That depends on on 100%, and cardiovascular examination on 99%. validity of data. Although musculoskeletal examination is often not done, many clinicians perform a neurological exam- Evidence of Validity ination to assess musculoskeletal problems, probably Inspection.Therearenodataonthevalidityofinspection because of confusion about mechanisms of pain. Low of any part of the musculoskeletal system (Australian back pain and neck pain in particular are widely consid- Acute Musculoskeletal Pain Guidelines Group 2003). ered due to impingement on spinal nerves, even though Palpation. There are no data showing the validity of ten- such beliefs are at variance with the evidence base. dernessinanymusculoskeletalregion(AustralianAcute There is no good reason for neurological examination Musculoskeletal Pain Guidelines Group 2003). of a patient with musculoskeletal pain unless they also Movement Testing–Ranges of Movement. There are no M have neurological symptoms. If so, the neurological data on the validity of ranges of movement of any part of condition should be addressed first, and the pain dealt the musculoskeletal system, so the utility of these tests with when the neurological issues have been clarified. is unknown too (Australian Acute Musculoskeletal Pain Guidelines Group 2003). Clinical Utility Movement Testing–Challenging Restraints. Evidence The diagnostic utility of physical tests depends on data on the validity of challenging restraints is also exempli- from well-designed studies, of which there have been fied by data relating to the shoulder, on which there have many in recent years. In general, despite the traditional been many studies. useofmusculoskeletalexamination,formalstudieshave One study (Çali et al. 2000) of physical examination of shown that few tests have reliability and validity the shoulder found “the highly sensitive tests seem to (Australian Acute Musculoskeletal Pain Guidelines have low specificity values and the highly specific ones Group 2003). Space permits only a few examples to be to have low sensitivity”. This is reflected in the low pos- outlined here. itive likelihood ratios of all individual tests. Other investigators (MacDonald et al. 2000; Naredo et al. 2002) Evidence of Reliability have reported similarly, even for combinations of tests. Inspection. The reliability of inspection of any musculoskeletal region is unknown as there are no relevant References data. Palpation. Studies have shown high reliability (kap- 1. Ahern MJ, Soden M, Schulz D, Clark M (1991) The Musculo- Skeletal Examination: A Neglected Skill. Aust NZ J Med pa 0.80–1.0) of tenderness elicited at non-specific sites 21:303–306 around a painful shoulder or lower back, but the validity 2. Apley AG, Solomon L (eds.) (1993) Apley’s System of Or- of such non-specific tenderness is unknown (Australian thopaedics and Fractures. 7th edn. Butterworth-Heinemann, Acute Musculoskeletal Pain Guidelines Group 2003). Oxford, pp 8–12, 261–263 3. Australian Acute Musculoskeletal Pain Guidelines Group (2003) Much lower reliability (kappa 0.11–0.38) has been Evidence-Based Management of Acute Musculoskeletal Pain. shown for finding focal tenderness in the lumbar region Australian Academic Press, Brisbane, [Online. available at (Australian Acute Musculoskeletal Pain Guidelines http://www.nhmrc.gov.au ] Group 2003), and its significance is also uncertain. 4. Blazina ME, Satzman JS (1969) Recurrent Anterior Subluxation of the Shoulder in Athletics: A Distinct Entity. J Bone Joint Surg There are no data on the reliability of focal tenderness 51A:1037–1038 in other regions (Australian Acute Musculoskeletal 5. Çali M, Akgün K, Birtane M, Karacan I, Çali H, Tüzün F (2000) Pain Guidelines Group 2003). Diagnostic Values of Clinical Diagnostic Tests in Subacromial Movement Testing–Ranges of Movement. Visual es- Impingement Syndrome. Ann Rheum Dis 59:44–47 6. Greene WB, Heckman JD (1994) The Clinical Measurement timations of ranges of shoulder movement seem of of Joint Motion. American Academy of Orthopaedic Surgeons, varying reliability (Australian Acute Musculoskeletal Rosemont 1232 Musculoskeletal Transferred Pain

7. Hughston JC (1972) Subluxation of the Patella in Athletes. In: Characteristics Symposium on Sports Medicine. CV Mosby, St. Louis, p 162 8. Kessell L, Watson M (1977) The Painful Arc Syndrome: Clini- Introduction cal Classiﬁcation as a Guide to Management. J Bone Joint Surg Myalgia can be a primary chronic pain state in which 59B:166 9. MacDonald PB, Clark P, Sutherland K (2000) An Analysis of there are no laboratory abnormalities. Pain can be dis- the Diagnostic Accuracy of the Hawkins and Neer Subacromial abling and isoften associated with debilitatingfatigue as Impingement Signs. J Shoulder Elbow Surg 9:299–301 inFMS.Myalgiacanbeco-morbidwithotherconditions 10. Naredo E, Aguado P,De Miguel E, Uson J, Mayordomo L, Gijon- as in secondary FMS. Myalgia is considered chronic Baños J, Martin-Mola E (2002) Painful Shoulder: Comparison of Physical Examination and Ultrasonographic Findings. Ann when it has been present for at least 3 months. The most Rheum Dis 61:132–136 common myalgic syndromes are FMS and MPS. These 11. Neer CS (1972) Anterior Acromioplasty for the Chronic Im- two conditions both give rise to muscle tenderness, pingement Syndrome of the Shoulder. J Bone Joint Surg 54A:41 but otherwise, they form two distinct entities. FMS is 12. Russe O, Gerhardt JJ, King PS (1976) An Atlas of Examina- tion, Standard Measurements and Diagnosis in Orthopaedics and a syndrome of central sensitization and augmentation Traumatology, 2nd edn. Hans Huber, Bern that results in widespread musculoskeletal tenderness and pain. MPS is the result of local muscle metabolic stress that is thought to produce an energy crisis. MPS Musculoskeletal Transferred Pain is associated with discrete, linear band-like hardness or tautness within one or more muscles, leading to the release of nociceptive substances such as substance Muscle Pain, Referred Pain P, potassium and histamine that activate peripheral nociceptive receptors and dorsal horn nociceptive neurons. The region of a taut band is exquisitely tender Musculoskeletal Type of Pain and can refer pain to another, usually distal, region. Non-restorative sleep in addition to chronic myalgia Deﬁnition is characteristic of FMS. Exercise intolerance can be This refers to types of pain that involve the musculature. seen with either FMS or MPS. However, muscle pain Respondent Conditioning of Chronic Pain associated with exercise intolerance and fatigue can be due to an entirely different problem, such as a mutation in the cytochrome b geneof mtDNA (Hanna et al. 1999), Lyme disease or hypothyroidism. Consideration of the MVD differential diagnosis in myalgia is essential.

Microvascular Decompression Fibromyalgia: Characteristics FMS is a chronic, widespread myalgia that involves 3 or 4 quadrants of the body, the American College Myalgia of Rheumatology criteria (ACR) (Wolfe et al. 1990). Using the ACR criteria, 3.5% of women and 0.5% of ROBERT D. GERWIN men in the United States are estimated to have FMS. Department of Neurology, Johns Hopkins University, Bethesda, MD, USA The ACR criteria, intended to provide a uniform definition of fibromyalgia for research studies, require that 1) [email protected] symptoms have been present for at least 3 months and Synonyms 2) that 11 of 18 specified sites be tender. The clinical diagnosisof FMSin clinicalpractice wasnever intended Fibromyalgia; myofascial pain syndrome; muscle to be as strict. The ACR criteria do not distinguish FMS pain; Myofibrositis; Myogelosis; fibrositis; Muscular from chronic, widespread MPS or any other chronic Rheumatism; idiopathic myalgia; fibrositis syndrome condition where there is widespread muscle tenderness. MPS is the most common condition that must Definition be considered in the differential diagnosis (Gerwin). Myalgia is muscle pain or pain of muscular origin, Consequently, the physical examination performed for without regard to cause. Fibromyalgia (FMS) is a the evaluation of myalgia must include palpation for syndrome in which there is chronic, widespread mus- the taut bands of MPS trigger points as well as for cle tenderness related to central hypersensitization. the tender points of FMS. A comprehensive medical Myofascial pain syndrome (MPS) is a condition in evaluation is necessary in order to identify conditions which there are discrete taut bands of hardened muscle in which diffuse muscle pain occurs secondarily. The that contain zones of exquisite muscle tenderness and diagnosis of FMS is based on the history and physical which generate pain referred to another, usually distal, examination. Laboratory tests and imaging procedures site. are not useful for making a positive diagnosis, but Musculoskeletal Pain 1233

tonin, histamine, bradykinin and prostaglandins. Thus Musculoskeletal Pain they are most probably nociceptors. LARS ARENDT-NIELSEN Little is known about the peripheral transduction Laboratory for Experimental Pain Research, Center and encoding apparatus for muscle-, ligament-, for Sensory-Motor Interaction, Aalborg University, periosteum- and joint-nociceptive afferents and only Aalborg, Denmark very few human microneurographicstudies have been [email protected] published. It seems more difficult to obtain stable recordings from muscle / joint nociceptive afferents Theleadingcausesofdisabilityinpeopleintheirwork- than cutaneous nociceptors. The nociceptors can be ing years are musculoskeletal conditions, which areal- sensitised by release of neuropeptides from the nerve most exclusively associated with pain. Moreover, the endings. This may also lead to peripheral sensitisa- efficacy of treatment of many musculoskeletal pain tion of the nociceptors and central hyperexcitability of conditions by currently available pharmacological and dorsal horn neurones resulting in prolonged neuronal non-pharmacological interventions is often less than discharges, increased responses to defined noxious optimal. Musculoskeletal diseases are one of the most stimuli, response to non-noxious stimuli and expan- expensive areas for the health system and hence have sion of the receptive field. A variety of inputsfollowing a substantial socio-economic impact, which leads to intense and / or prolonged noxious stimuli and con- suffering for many patients. Musculoskeletal pain is sequent activation of group III and IV fibres increase more frequent in the elderly than in the young popu- spinal excitability. Three different pathophysiological lation with a predominance among females for many processes in the spinal cord can account for the above of the disorders e.g. joint pain, neck pain, shoulder alterations. pain, low back pain, temporomandibular disorders, fibromyalgia, whiplash and tension type headache. Structural Re-organisation M Although musculoskeletal pain is an important factor The synaptic connections between afferent fibres and in many disorders such as injuries, degenerative dis- central (spinal) neurons can be changed structurally eases and cancer, the peripheral and central mecha- and physiologically (or pathophysiologically) in re- nisms underlying muscle pain are poorly understood. sponse to a variety of influences (nerve damage, Musculoskeletal disorders can be classified as articu- inflammation,etc.). lar (e.g. rheumatoid arthritis, osteoarthritis) or non- articular (e.g. low back pain, myofascial pain syn- Decreased Inhibition drome, fibromyalgia) (Mense and Simons 2001). In particular in peripheral neuropathy, the inhibition normally suppressing transmission of nociceptive sig- Basis for Musculoskeletal Pain nals in the spinal cord could be decreased (Woolf and In animal studies two major types of Aδ- (type III) Doubell 1994). and C-fibre (type IV) muscle nociceptors (free nerve endings) have been found, chemo-nociceptors and Increased Excitability (Central Sensitisation) mechano-nociceptors (Mense 1993). The stimuli for The increased excitability of postsynaptic neurones nociceptors are mechanical (e.g. strong pressure, etc.) may in part be due to an increased efficacy of synap- or chemical(e.g. bradykinin, serotonin, potassium, hy- tic transmission from afferent nerve fibres onto post- pertonic saline and capsaicin) and some of the latter synaptic neurones. Long-term changes in synaptic areexcitedonlywithparticularstimulusconfigurations efficacy can be increases or decreases. Wall and like long-lasting contractions during ischaemia. Many Woolf(1984)showedthatmusclenociceptiveafferents of these receptors are notably polymodal, i.e. they re- seemparticularlyeffectiveatinducingneurofunctional spond to stimuli of different modalities (mechanical, changes in the spinal cord. Peripheral and central mus- thermal,chemical,etc.)ortheycanbesensitisedbyone cular related hyperalgesia is assumed to play an impor- stimulus (e.g. chemical) in order to respond to another tant role in musculoskeletal pain disorders. stimulus (e.g. mechanical). Free nerve endings are widely distributed through- Manifestations of Musculoskeletal Pain out most of the articular structures. The majority remains silent during normal conditions, but become ac- Musculoskeletal pain is manifested by four main com- tive when the articular tissue is subjected to damaging ponents(1)theeffectonthemotorsystem,(2)localand mechanical deformations and to certain chemical sub- referred pain, (3) increased or decreased muscle sen- stances. These chemosensitive units are activated by sitivity and (4) somatosensory changes in the referred certain ions and inflammatory mediators, such as sero- pain area (Fig. 1). 1234 Musculoskeletal Pain

Musculoskeletal Pain, Figure 3 Examples of local and referred pain Musculoskeletal Pain, Figure 1 A sketch of how musculoskeletal pain patterns in volunteers following intramuscular injections of hypertonic can be manifested. (1) Muscle pain has effects on the motor system. saline (6%, 0.5 ml) into the anterior tibialis muscle. If the area of referred This involves effects on voluntary contractions, endurance and muscle pain is completely blocked by anaesthetic procedures (e.g. a regional coordination and on reflex mediated pathways (e.g. stretch reflexes, pro- block), the referred pain can still be elicited, indicating that referred pain prioception, and motor unit firing characteristics). (2) Muscle pain may is a central phenomenon. The size of the referred pain area depends on result in local as well as referred pain areas. (3) In the local muscle pain the intensity and duration of the actual muscle stimulus. area, the muscle may have changed sensibility (e.g. hypersensitive to pressure). (4) In the referred area, various somatosensory changes can take place. referredpain pattern was initially observed by Kell- gren (1938), who injected hypertonic saline into many In contrast to the localised sharp, burning charac- skeletal muscles and ligaments and characterised the teristics of cutaneous pain, muscle pain is described referred pain patterns (Fig. 3). Similar characterisa- as diffuse aching and cramping. Furthermore, mus- tion has been performed clinically when activating culoskeletal pain is more complicated to investigate trigger points in various muscles (Travell and Si- than cutaneous and visceral pain, as muscle pain mons 1992). can consists of both localised pain and referred pain It is obviously important to distinguish the painful tis- (Fig. 2). sue, but it may be very difficult, due to poor localisa- Pain localisation is poor in skeletal muscles and pation and referred pain. Examples can be pain from tients may be unable to differentiate it from pain aris- an arthritic hip, which may refer to the thigh muscles ing from tendons, ligaments and bones as well as or knee joint, a carpal tunnel syndrome may refer to from joints and their capsules. The characteristically forearm muscles and cervical spondylosis may refer to

Musculoskeletal Pain, Figure 2 A simple sketch to illustrate the different characteristics and manifestations of cutaneous, muscle and visceral pain. Cutaneous pain is sharp and localised, whereas pain from deep structures is more diffuse. Pain from muscles can be localised to a specific muscle, but can also be referred to another somatic structure. In this referred structure, changes in somatosensibility can occur. Visceral pain is always referred either to somatic structures or via viscero-visceral convergent neurones. Musculoskeletal Pain 1235 arm muscles. Pain from joints and their capsules tends in patients with painful musculoskeletal disorders (fi- to be more localised than myalgia and arthralgia is bromyalgia, whiplash, low back pain and osteoarthri- often worsened by passive joint movements. Capsu- tis) (Arendt-Nielsen and Svensson 2001; Koelbaek Jo- lar pain may be present only in specific joint positions. hansenetal.1999;Sorensenetal.1998).Recentlyithas Bone pain also tends to be poorly localised but, unlike been emphasised that referred pain and central sensiti- myalgia, usually has a deep, boring quality. Further- sation are closely related (Arendt-Nielsen and Graven- more, bone pain is usually worse at night and tends to Nielsen 2002; Giamberardino 2003). be unaffected by either movement or muscle activity Somatosensory changes in referred muscle pain areas (Newham et al. 1994). The manifestations related to have been reported – and it seems that the duration musculoskeletal pain can be projected pain, spread of and intensity of pain are important for such manifesta- pain and referred pain, somatosensory changes in re- tions. Hypoalgesia as well as hyperalgesia has been referred pain areas (Vecchietet al. 1999) and interaction ported in referred muscle pain areas. The most consis- with the motor system (e.g. muscle coordination and tentfindingismusclehyperalgesiainthereferredareas. activation, postural stability, movement initiation and Referred muscle hyperalgesia can also be a result of reflex pathways). Projected muscle pain is normally visceral pain due to the viscero-somatic convergence. used as terminology in relationship to nerve fibre dam- This may occur in e.g. gastrointestinal, gynaecologi- age (e.g. compression) and felt in the innervation ter- cal/urologicalorinchronicvisceralpainfulconditions ritory / myotome of the damaged nerve. without known aetiology (e.g. irritable bowel diseases Spread of muscle pain is not clearly defined, but best and endometriosis). It has been shown that the degree described by phenomena related to experimental stud- of referred muscle hyperalgesia is related to the sever- ies. If the muscle nociceptive afferent is repetitively, ity of the visceral pathology and hence the degree of electrically stimulated by an intramuscular electrode, visceral pain. Persistent referred muscle hyperalgesia the area where the muscle pain is experiencedexpands can be manifested not only by chronic conditions, but M or spreads as the stimulation progresses (Laursen et also after recurrent painful visceral attacks, such as in al. 1997). A similar manifestation is seen after repeti- dysmenorrheic women where lumbar muscles are hy- tive visceral electrical stimulation (Arendt-Nielsen et peralgesic to pressure or after colic attacks following al. 1997). calculosis of the upper urinary tract, where hyperalge- Referred muscle pain has been known and described sia to pressure is found in muscles in the left lumbar for more than a century and is used extensively as a region (Giamberardino 1999). diagnostic tool. Substantial clinical knowledge exists concerning the patterns of referral from various skele- Exercise-related Painful Musculoskeletal Conditions tal muscles and after activation of trigger points (Trav- Muscle pain in relation to exercise may increase in in- ell and Simons 1992). The referred pain pattern fol- tensity until the exercise / contractions stop and the lowsthedistributionofsclerotomes(muscle,fasciaand blood flow is restored. This is termed ischaemic pain bone) more frequently than the classical dermatomes. and is the cause of well-known clinical presentations A clear distinction between spread of pain and referred such as intermittent claudication and angina pectoris. pain is not possible and these phenomena may also Hypoxia was thought to be the cause of ischaemic share common pathophysiological mechanisms. Firm pain, but it now seems more likely that accumulation neurophysiologically based explanations for referred of metabolites is responsible, at least in part. Lactic pain do not exist, but it has been shown that wide dy- acid was assumed to be the prime algesic substance, namic range neurones and nociceptive specific neu- but since patients with myophosphorylase deficiency rones in the spinal cord and in the brain stem of an- (patients with McArdle’s disease do not produce lac- imals receive convergent afferent input from the mu- tic acid) also experience ischaemic muscle pain during cosa, skin, muscles, joints and viscera. This may cause exercise, other substances such as histamine, acetyl- a misinterpretation of the afferent information coming choline, serotonin, bradykinin, potassium and adeno- from muscle afferents and reaching high levels in the sine are most likely involved. central nervous system and hence be one reason for the Another manifestation of exercise may be muscle diffuse and referred characteristics. cramps. Muscle cramps are involuntary, painful, sud- Referred pain is mainly a central phenomenon as it is den contractions of the skeletal muscles and may also possible to induce referred pain to limbs with com- appear after overuse of a muscle. Cramps can oc- plete sensory loss due to spinal injury or anaesthetic cur in normal subjects under a variety of conditions blockade. The size of the referred area to experimen- (during a strong voluntary contraction, sleep, sports tal muscle pain stimulation depends on the intensity and pregnancy) and in several pathologies such as and duration of the nociceptive musculoskeletal input myopathies, neuropathies, motoneurone diseases, in and the evoked referred area is significantly enlarged tetanus, metabolic disorders, hydroelectrolyte imbal- 1236 Musculoskeletal Pain

ances or endocrine pathologies (e.g. glycolytic disor- includes classes of syndromes such fibromyalgia, ders) or as a side effect after certain drugs (salbutamol, chronic fatigue syndrome and exposure syndromes phenothiazine, vincristine, lithium, cimetidine and (e.g. Gulf War Illnesses). Fibromyalgia is a chronic bumetanide). Considerable uncertainty is found in the painful musculoskeletal disorder of unknown aetiol- literature regarding the classification and nomencla- ogy and is defined by chronic widespread pain, involv- ture of muscle cramps, both because the term “cramp” ing three or more segments of the body plus the finding is used to indicate a variety of clinical features of mus- of at least 11 out of 18 designated tender points. Physi- cles leading to its use as an imprecise “umbrella” term calor emotionaltrauma, infectionor surgeryhave been that includes stiffness, contractures and local pain and reported anecdotally to be precipitating factors in fi- becausethespectrumofthediseasesinwhichitappears bromyalgia and it is not uncommon for the patients to is wide. report the onset of the syndrome in relation to an ac- If a muscle is exposed to heavy and unaccustomed cident or an injury. Fibromyalgia and the whiplash and especially eccentric exercise, delayed onset mus- syndrome therefore share some common features. cle pain may peak 1–2 days later. Delayed onset mus- Studies of the endocrine profile of fibromyalgia pa- cle pain / soreness (post exercise soreness) is associ- tients have indicated elevated activity of corticotropin ated with tenderness to pressure and pain during move- releasing hormone (CRH) neurones, which could not ment / contraction. The mechanisms underlying post- only explain some symptoms of fibromyalgia, but may exercise muscle pain seem different from those of is- also explain alterations observed in the hormonal axes. chaemic muscle pain, as considerable damage such as HypothalamicCRH neurones may play a role not only structural, biochemical, and radioisotopic changes are in resetting the various endocrine loops, but possi- found (Friden 1984). Post-exercise pain can be inhib- bly also nociceptive and psychological mechanisms as ited and treated by NSAIDs suggesting that inflamma- well. tory mediators belonging to the arachidonic cycle may Thewhiplashsyndromeisnormallyassociatedwithcar be involved in this kind of muscle pain. accidents where the car has been hit from the rear or the side and the persistent chronic pain is localised in the neck, shoulder and back. Patients with fibromyal- Selected Painful Musculoskeletal Disorders gia and whiplash show accentuated reactions to a vari- Myofascial pain syndromes are regional muscle pain ety of stimulus modalities and in general they are hy- disorders characterised by localised tenderness and peralgesic to experimental muscle stimulation (pres- pain and are common causesof persistentregionalpain sure and infusion of algogenic substances). A feature such as back pain, neck pain, shoulder pain, headaches in many of the chronic musculoskeletal disorders is and orofacial pain. The affected muscles often display that the referred pain areas to experimentally induced an increased fatigability, stiffness, subjective weak- muscle pain are significantly larger than in pain-free ness, pain in movement and slightly restricted range volunteers. Both fibromyalgia (Carli et al. 2002) and of motion that is unrelated to joint restrictions. The whiplash (Curatolo et al. 2001) patients show differ- exact aetiology of myofascial pain syndromes is un- entiated hyperalgesia to different sensory stimuli in- clear.Themajorcharacteristicsofmyofascialpainsyn- dicating that only specific parts of the sensory and dromes include tenderness in muscles (trigger points) nociceptive systems are influenced and that the sen- and local and referred pain. A trigger point is an up sorydisturbancesareaccentuatedasthesyndromepro- to 0.5 cm diameter point of hypersensitivity to pres- gresses (Carli et al. 2002). In recent years these gen- sure in a palpable taut band of skeletal muscle, ten- eralised chronic musculoskeletal disorders together don and ligament. Active trigger points are hypersen- with work-related muscle-related disorders have be- sitive and display continuous pain in the zone of refer- come an increasing challenge for the health care sys- ence that can be altered with specific palpation. Latent tem with an increased socio-economic burden on so- trigger points display only hypersensitivity to pressure cieties. with no continuous pain. Tender points differ from Myalgia can be related to a variety of medical condi- trigger points in the sense that they are tender to pres- tions (see list below) and common terms for the symp- sure, do not cause referred pain by activation and can tom are stiffness, soreness, aching, spasms or cramps. be identified as one of 18 designated soft tissue body The associated pain is often described as having a sites. dull, aching quality and can be exacerbated by mus- Widespread pain is defined as pain lasting for longer cle contractions. The manifestation of pain is, how- than 3 months, presenting in both sides of the body, ever, in some of the myalgias not the most prominent above and below the waist. In addition, axial skele- problem, as in myositis (e.g. polymyositis and tal pain (cervical spine, anterior chest, thoracic spine dermatomyositis) where muscle weakness is often or low back pain) must be present. Widespread pain the prominent feature. Musculoskeletal Pain 1237

Clinical Conditions Associated with Myalgia tion) showed an effect. Unfortunately only a few of (Newham et al. 1994) the physical therapies commonly used in the clinic for the management of musculoskeletal pain are scien- • Trauma and sports injuries tifically validated. However, exercise with instruction • Primary infective myositis from physical therapists seems to be the modality most • Inflammatory myopathies often resulting in good outcome. – Polymyositis with and without connective tissue disease Gender Differences in Musculoskeletal Pain – Dermatomyositis with and without connective Many musculoskeletal disorders and pains are more tissue disease prevalent in females than males. Sex (referring to bio- – Viral myositis logically determined aspects of femaleness and male- – Polymyalgia rheumatica ness) and / or gender (referring to modifiable, socio- • culturally shaped behaviour and traits such as femi- Myalgia of neurogenic origin ninity and masculinity) differences are present, with • Muscle cramp • female predominance in painful musculoskeletal syn- Impaired muscle energy metabolism dromes such as widespread pain, temporomandibular • Drug induced myalgia • disorders, neck pain, shoulder pain, back pain, joint Myalgic encephalomyelitis / chronic fatigue syn- pain, fibromyalgia, whiplash and headache. Psycho- drome • logical factors operative in chronic painful muscu- Muscle pain of uncertain cause (repetitive strain in- loskeletal disorders cannot be understood within any jury, fibromyalgia) single frame of reference. It is appropriate to exam- Myalgiaofneurogenicorigincanbedifficulttodissoci- ine emotional, interpersonal pain behaviour and in- ate from other manifestations of neuropathic pain. Ex- terpersonal relationships in parallel, not as dichoto- M amples can be cervical radiculopathy with pain radiat- mousconcepts.Highratesofcomorbidityhavebeenre- ing into the myotomal distribution of the roots or nerve ported between e.g. temporomandibular dysfunctions compressions (e.g. carpal tunnel syndrome) where the and other clinical musculoskeletal disorders (e.g. fi- pain radiates into the muscles in the region. Little is bromyalgia) and are again more common in women known specifically related to muscle sensitisation in than men. relation to neuropathic pain, as normally only the cuta- Fluctuations in hormonal levels have been implicated neous manifestations (allodynia, hyperalgesia) are in- in symptom severity in women with rheumatoid arthri- vestigated. tis, temporomandibular disorders and fibromyalgia. One mechanism by which hormones may affect mus- Physical Therapies for the Management cle nociceptors sensitisation could be related to nerve of Musculoskeletal Pain growth factor (NGF) and one of its high-affinity re- A wide range of physical therapies are traditionally ceptors (trkA). The trkA receptor expression is influ- used in the repertoire of management regimes of- enced by gonadal hormones (Liuzzi et al. 1999). In- fered to patients with chronic musculoskeletal disor- jection of NGF into the muscle tissue causes muscle ders. Such therapies include e.g. ice, heat, massage, tenderness to pressure which lasts for weeks (Svens- acupuncture and transcutaneous electrical nerve son et al. 2003). There has been some speculation that stimulation. The efficacy of these therapies is not hormonereplacementtherapymayincreaseawoman’s known and has rarely been compared in controlled risk of developing musculoskeletal pain (LeResche et studies. Acupuncture, electro acupuncture and tran- al. 1997). Numerous studies indicate that women have scutaneous electrical nerve stimulation have been ap- greater sensitivity to experimental muscle pain stimuli plied in order to inactivate e.g. trigger points, but again than men and the pressure pain threshold is generally the efficacy is not known. The advantage of e.g. tran- lower in females. There are indications in the literature scutaneous nerve stimulation is that the patients feel thatmalesandfemaleshavedifferentresultsfromsome that they have some control when they can take the de- drugs.Formusculoskeletalpain,thenon-steroidalanti- vice home and switch it on when needed. inflammatorydrugs(NSAIDs)arecommonlyusedand A variety of physiotherapeutic management regimes some studies have indicated that females experience are developed for different musculoskeletal disorders less pain alleviating effect than males. and,forexample,theQuebectaskforcereviewedavail- able literature on the treatment employed by physi- Techniques to Assess Sensitivity of Musculoskeletal Structures cal therapists in the management of whiplash injuries (Spitzer et al. 1995). Only two of the commonly em- Several methods exist to assess the sensitivity of mus- ployed physiotherapy modalities (exercise, mobilisa- culoskeletal structures. The methods are based on 1238 Musculoskeletal Pain

standardised application or induction of standardised eas are dependent on stimulus intensity and duration pain to musculoskeletal structuresto evaluate how sen- (Laursen et al. 1997). sitive the structure is to that specific stimulus modal- Intramuscular infusion of algogenic substances (e.g. ity. Such procedures can be applied to healthy vol- hypertonic saline, capsaicin, bradykinin) causes local unteers in the laboratory for basic experimental stud- andreferredpain. Inmostexperimentalhumanstudies, ies or to patients for clinical examinations (Arendt- manual bolus infusions of hypertonic saline are used, Nielsen 1997; Arendt-Nielsen et al. 1997). The stan- but more advanced models such as standardised infu- dardised pain stimulus can be classified as endogenous sionofsmallvolumesbycomputer-controlledinfusion pain models (the pain arises from muscles without the pumps have been used. When this advanced model is involvement of external stimuli) or exogenous models used, the infusion rate can be controlled by the pain in- (the pain is evoked by external stimuli) (see list below). tensityratingfeedbacksoconstantpainintensitycanbe achievedbycontinuousadjustmentoftheinfusionrate. Classification of Experimental Stimulus Modalities Muscle pain induced experimentally by intramuscu- That Can Be Used to Induce Muscle Pain Experimentally lar infusion of algogenic substances causes cutaneous Endogenous and muscular sensibility changes in referred pain areas. It is not entirely conclusive which somato-sensory • Ischaemic changes occur as both hypo- and hyper-aesthesia have • Exercise-induced been reported. Furthermore, these changes are stimulus modality specific (Graven-Nielsen et al. 1997). – Dynamic concentric contraction Pressure algometry is the most commonly used tech- – Isometric contraction nique to induce muscle pain and hence assess tender- – Dynamic eccentric contraction ness in myofascial tissues and joints such as e.g. ten- Exogenous der points, fibromyalgia, work-related myalgia, my- • Electrical ofascial pain, strain injuries, myositis, chronic fatigue • Mechanical syndrome, arthritis / orthoses and other muscle / ten- • Chemical don / joint inflammatory conditions (Fischer 1987a; • Focused ultrasound Fischer 1987b). The technique is adequate to quantify and follow the development of given diseases, but has Endogenous Models also proven to be instrumental for the documentation of treatment outcome such as local / systemic admin- Ischaemic muscle pain is a classically experimental istration of drugs. Pressure algometry is also suitable pain model and has been used as an unspecified pain for the assessment of joint tenderness. stimulus. A tourniquet is applied and after a period of voluntary muscle contractions a very unpleasant tonic Assessing Sensory Aspects of Musculoskeletal Pain pain sensation develops. The number of contractions, Assessing the sensory aspects of musculoskeletal pain the level of force and the duration are important deter- involves both evaluation of the muscle pain and of minants for the resulting pain. This is a very efficient the somatic structures related to the referred pain area model to induce pain in muscles, but skin, periosteum (Fig. 1). Clinical and experimentally induced muscle and other tissues will contribute. The model is appli- pain intensity and the implications on e.g. physical cable in experimental studies requiring a general tonic performance can be assessed quantitatively by various painstimulusfore.g.PETandfMRIexperimentalstud- measures (see list below). ies. Delayed Muscle Soreness is another model used experimentally to investigate endogenous muscle pain Techniques for Assessment of Experimentally Induced and this model is useful for e.g. evaluating drug effect. Musculoskeletal Pain and for Assessing Clinical Musculoskeletal Pain Exogenous Models Sensory Characterisation Intraneuralmicrostimulationofmusclenociceptiveaf- Muscle Sensitivity ferents can be performed in laboratory studies and can selectively elicit muscle pain accompanied by referred • Verbal assessment pain, which is dependenton the stimulation time (temporal summation) and the number of stimulated af- – Visual analogue scales ferents (spatial summation). Repetitive intramuscular – Verbal descriptor scales electrical stimulation can evoke localised and referred – McGill Pain Questionnaire muscle pain. The local and referred pain areas develop • Psychophysical tests during stimulation with the referred area slightly delayed as compared with the local pain area. The ar- – Pain thresholds Musculoskeletal Pain 1239

• Referred pain A simple and useful technique is pain drawings where – Distribution of pain e.g. tender points, trigger points, localised and referred – Area (size) pain areas, hyper- and hypo-algesia are marked. Dif- – Somatosensory changes ferent colours can eventually be used to characterise different manifestations. Motor Effects The psychophysical parameters used for the quan- tiﬁcation of musculoskeletal pain sensitivity to ex- • Electromyography perimentally applied pressure (pressure algometry) are pain detection, pain tolerance thresholds (Fig. 4) – Surface electrodes – Needle electrodes and stimulus-response functions. Stimulus-response functions can provide more information than just a – Indwelling wire electrodes threshold, as sensitisation to low as well as high in- • Kinetics and kinematics tensities can be assessed and a shift in parallel of the curve towards the left together with an increased – Sirognathograph (jaw movements) slope as has been found in patients with myofascial – Optoelectronic devices pain. For monitoring purposes quantitative parameters are • Force advantageousascomparedwithmanualpalpation.The – Dynamometers essence of pressure algometry is that standardised in- – Force platforms crease in pressure is applied to the part of the body – Bite force meters that is being investigated and the outcome is the patient’s or volunteer’s reaction to the pressure (Fischer Musculoskeletal pain has implications in many as- 1987a; Fischer 1987b). Pressure rate and pressure area M pects of daily life and questionnaires for assess- have been shown to be important factors for reliable re- ment of different dimensions have been developed sults. The pressure pain thresholds vary substantially for general and regional (e.g. back pain and neck between regions. In some of the commercially avail- pain) pain problems (general function score, Roland able pressure algometers, the pressure application rate and Morris disability scale, Oswestry disability in- can be monitored, which is important for the reliability dex, West Haven-Yale multidimensional pain inven- of the results. For research purposes, advanced com- tory, Bournemouth questionnaire, fear avoidance puter controlled devices are available where the pres- beliefs, life satisfaction) (Turk and Melzack 1992). sure rate can be pre-deﬁned.

Musculoskeletal Pain, Figure 4 A schematic ﬁgure indicating how the psychophysical thresholds related to pressure pain (pressure algometry) are measured. Using a pressure algometer it is possible to control the rate of force increase (e.g. 30 kPa / s to a 1 cm2probe) and determine when the volunteer / patient experience the pressure as just painful (pain detection threshold) and when he / she will not tolerate any further increase in stimulus intensity (pain tolerance threshold). 1240 Musculoskeletal Pain

Thresholds from various clinical pressure pain stud- adaptation and is not a cause of pain. This pain adap- ies are difficult to compare, as different instrumenta- tation model has also been verified in experimental tionshavebeenusedwithdifferentprobediametersand studies, where motor strategies have been investigated shapes and different force increase rates. The probe di- before and after experimentally induced muscle pain. ameter is of utmost importance as there is not necessar- It seemshowever that the adaptation patternmainly oc- ily a simple relation between diameter and threshold curs in relation to gross, high force movements and to a since spatial summation plays an important role. The lesser extent for high precision, low force movements. shape and contour of the probe are important, as sharp Johansson and Sojka (1991) suggested another patho- edgesmay excite more cutaneousreceptorsdue to high physiological model for chronic muscle pain and ten- shear forces compared with blunt probes. sion disorders. The model suggests that, under cir- Verbal assessments of the musculoskeletal pain inten- cumstances when chemosensitive group III-IV mus- sity and other subjective characteristics of the pain cle afferents, joint afferents or certain descending are obviously needed in any clinical and experimen- pathways are activated, the activity of both primary tal muscle pain studies. Visual analogue scales (VAS), and secondary muscle spindle afferents would be in- verbal descriptor scales (VDS), McGill pain question- creased via fusimotor reflexes. This would have sev- naire(MPQ)andsimilarscalesandquestionnairesmay eral consequences. Initially, an increased activity in be very helpful for the assessment of perceived pain γ-motoneurons would reduce the information trans- intensity and quality (Turk and Melzack 1992). Mus- mission capacity of muscle spindles. Secondly, an al- culoskeletal pain is most frequently characterised by tered activity in the primary muscle spindle afferents descriptors as “drilling” “aching” “boring” and “taut” would influence proprioception and thereby sensori- The intensity of musculoskeletal pain is easily mea- motor control at higher levels. This influence could sured using visual analogue scales (VAS). However, possibly lead to unfavourablework techniques, suchas thisisonlyaone-dimensionalaspectoftheexperienced increased co-contractions and insufficient rest periods, pain and additional VAS should be applied to moni- which might further increase the interstitial concen- tor e.g. unpleasantness and soreness. Word descriptors tration of substances exciting group III–IV afferents. on the VAS are important, as muscle tenderness and Thirdly, increased levels of these substances might muscle pain may not reflect the same mechanisms. In also excite, via chemosensitivegroup III–IV afferents, addition to verbal assessments, psychophysical tests the sympathetic outflow to skeletal muscles, which are valuable adjuncts for the examination of muscu- may change the balance between sympathetic vaso- loskeletal pain (Turk and Melzack 1992). constriction and metabolic vasodilation and thus entail a deficiency in oxygen and nutrients with the conse- Interaction between Musculoskeletal Pain quences. and Motor Performance There is so far little clinical evidence to support this model. Experimental human studies have to some de- Musculoskeletal pain has implications for motor greeverifiedtheinteractionbetweenγ-motoneuronex- performance and different electrophysiological and citabilityandtheactivationofgroupIII–IVnociceptive biomechanical methods and disability questionnaires afferents. Experimentally induced muscle pain causes (e.g. Oswestry pain disability index) have been devel- excitation of the human stretch reflex, which may in- oped to assess this interaction. dicate such facilitatory interaction (Matre et al. 1998). After reviewing articles describing motor function in In chronic muscle pain conditions where group III–IV five chronic musculoskeletal pain conditions (tem- muscle nociceptors are assumed to be active, muscle poromandibular disorders, muscle tension headache, spindle responses and hence proprioception, should fibromyalgia, chronic lower back pain and post- be affected. Indeed, patients suffering from work re- exercise muscle soreness), Lund et al. (1991) con- lated myalgia often exhibit reduced proprioception, cluded that the activity of agonist muscles is often disturbed motor control and impaired balance. reduced and the activity of the antagonist is slightly Disability, Upper Extremity increased by musculoskeletal pain. As a consequence Opioids and Muscle Pain of these changes, force production and the range and velocity of movement of the affected body part are References often reduced. To explain such changes motor con- 1. Arendt-Nielsen L (1997) Induction and assessment of experi- trol, Lund et al. (1991) proposed a neurophysiological mental pain from human skin, muscle and viscera. In: Jensen model based on the phasic modulation of excitatory TS, Turner JA, Wiesenfeld-Hallin Z (eds) Proceedings of the and inhibitory interneurones supplied by high thresh- 8th World Congress on Pain. IASP Press, Seattle, pp 393–425 old sensory afferents. They suggested that the ’’dys- 2. Arendt-Nielsen L, Graven-Nielsen T (2002) Deep tissue hyperalgesia. J Musculoskel Pain 10:97–119 function’’, which is characteristic of several types of 3. Arendt-Nielsen L, Svensson P (2001) Referred muscle pain: chronic musculoskeletal pain, is a normal protective basic and clinical findings. Clin J Pain 17:11–19 Myalgia 1241

4. Arendt-Nielsen L, Svensson P, Graven-Nielsen T (1997) How 18. Liuzzi FJ, Scoville SA, Bufton SM (1999) Long term estrogen to assess muscle pain experimentally and clinically. Eur J Pain replacement co-ordinately decreases trkA and beta-PPT mRNA 1:64–65 levelsindorsalroot ganglion neurons. Exp Neurol 155:260–267 5. Carli G, Suman AL, Biasi G et al. (2002) Reactivity to superfi- 19. Lund JP, Donga R, Widmer CG et al. (1991) The pain- cial and deep stimuli in patients with chronic musculoskeletal adaptation model: a discussion of the relationship between pain. Pain 100:259–269 chronic musculoskeletal pain and motor activity. Can J Physiol 6. Curatolo M, Petersen-Felix S, Arendt-Nielsen L et al. (2001) Pharmacol 69:683–694 Central hypersensitivity in chronic pain after whiplash injury. 20. Matre D, Sinkjr T, Svensson P et al. (1998) Experimental mus- Clin J Pain 17:306–315 cle pain increases the human stretch reflex. Pain 75:331–339 7. Fischer AA (1987a) Pressure algometry over normal muscles. 21. Mense S (1993) Nociception from skeletal muscle in relation Standard values, validity and reproducibility of pressure thresh- to clinical muscle pain. Pain 54:241–289 old. Pain 30:115–126 22. Mense S, Simons DG (2001) Muscle pain: Understanding 8. Fischer AA (1987b) Reliability of the pressure algometer its nature, diagnosis and treatment. Lippincott Williams & as a measure of myofascial trigger point sensitivity. Pain Wilkins, Baltimore 28:411–414 23. Newham DJ, Edwards RHT, Mills KR (1994) Skeletal muscle 9. Friden J (1984) Muscle soreness after exercise: implications pain. In: Wall PD, Melzack R (eds) Textbook of Pain, 3rd edn. of morphological changes. Int J Sport Med 5:57–66 Churchill Livingstone, UK, pp 423–440 10. Giamberardino MA (1999) Recent and forgotten aspects of vis- 24. Sorensen J, Graven-Nielsen T, Henriksson KG et al. (1998) ceral pain. Eur J Pain 3:77–92 Hyperexcitability in fibromyalgia. J Rheumatol 25:152–1555 11. Giamberardino MA (2003) Referred muscle pain / hyperalgesia 25. Spitzer WO, Skovron ML, Salmi LR et al. (1995) Scientific and central sensitisation. J Rehabil Med 41:85–88 monograph of the Quebec Task Force on Whiplash-Associated 12. Graven-Nielsen T, Arendt-Nielsen L, Svensson P et al. (1997) Disorders: redefining “whiplash” and its management. Spine Stimulus-response functions in areas with experimentally in- 20:1–73 duced referred muscle pain –a psychophysical study. Brain Res 26. Svensson P, Cairns BE, Wang K et al. (2003) Injection of nerve 2:121–128 growth factor into human masseter muscle evokes long-lasting 13. Johansson H, Sojka P (1991) Pathophysiological mechanisms mechanical allodynia and hyperalgesia. Pain 104:241–247 involved in genesis and spread of muscular tension in occupa- 27. Travell JG, Simons DG (1992) Myofascial Pain and Dysfunc- tional muscle pain and in chronic musculoskeletal pain syn- tion: The Trigger Point Manual, vol 1, 2. Williams & Wilkins, dromes: A hypothesis. Medical Hypotheses 35:196–203 Baltimore M 14. Kellgren JH (1938) Observations on referred pain arising from 28. Turk DC, Melzack R (eds) (1992) Handbook of pain assess- muscle. Clin Sci 3:175–190 ment. Guilford, New York 15. Koelbaek Johansen M, Graven-Nielsen T, Schou Olesen A et al. 29. Vecchiet L, Vecchiet J, Giamberardino MA (1999) Referred (1999) Generalised muscular hyperalgesia in chronic whiplash Muscle Pain: Clinical and Pathophysiologic Aspects. Curr Rev syndrome. Pain 83:229–234 Pain 3:489–498 16. Laursen RJ, Graven-Nielsen T, Jensen TS et al. (1997) Quan- 30. Wall PD, Woolf CJ (1984) Muscle but not cutaneous C-afferent tification of local and referred pain in humans induced by in- input produces prolonged increases in the excitability of the tramuscular electrical stimulation. Eur J Pain 1:105–113 flexion reflex in the rat. J Physiol 356:443–458 17. LeResche L, Saunders K, Von Korff MR et al. (1997) Use of 31. Woolf CJ, Doubell TP (1994) The pathophysiology of chronic exogenous hormones and risk of temporomandibular disorder pain–increased sensitivity to low threshold A beta-fibre inputs. pain. Pain 69:153–160 Curr Opin Neurobiol 4:525–534

are required to identify co-morbid conditions or other broad array of stimuli perceived as being more painful causes of chronic myalgia. among FMS patients than they are in control subjects (Russell 2001). Alterations in cardiovascular auto- Associated Symptoms of FMS nomic nervous system function cause orthostatic hy- FMS is associated with sleep disturbance, fatigue, potension or neurally mediated orthostatic tachypnea headache, morning stiffness, irritable bowel syndrome (Martinez-Lavin 1997). Neuroendocrine abnormali- (IBS), interstitial cystitis (IC), dyspareunia and mood ties in the hypothalamic-pituitary-adrenal system and disturbance. Some of these symptoms are manifesta- growth hormone deficiency are hormonal deficiency tions of referred muscle pain from myofascial trigger states that may tie together the symptoms of fatigue, points (headache, dyspareunia, morning stiffness) pain and sleep and mood disturbances (Dessein et al. and others, such as IBS and IC are viscerosomatic 2000). pain syndromes (Gerwin) that occur in up to 70% of FMS patients. They are by no means unique to FMS Fibromyalgia: Treatment and are usually associated with pelvic floor MPS syn- Treatment of fibromyalgia includes a wide variety dromes. Depression may occur in as many as 30% of of pharmacologic, nutritional, hormonal, behavioral, FMS patients, but is no more common in FMS than in cognitive, exercise and physical modalities (Gold- the general population. enberg et al. 2004). The long-term prognosis for FMS is more favorable than initially thought. Symp- Fibromyalgia: Etiology toms may persist for years, but patients either learn Tenderness in FMS is related to central sensitiza- to cope with the chronic pain or the pain does not tion with amplification of nociception, resulting in a progress. 1242 Myalgia

Myofascial Pain Syndrome: Characteristics skull and the trapezius and levator scapulae muscles). MPS is a muscular pain syndrome that arises from a pri- Posterior cervical muscle and shoulder muscle myalgic mary dysfunction in muscle. It is associated with central syndromes are thus frequently associated with head sensitization and a segmental spread within the spinal pain and headache. cord to give rise to the phenomenon of referred pain or Pelvic Torsion-related Pain pain that is felt at a distance (Mense 2001). The clinical picture of MPS is one of musculoskeletal pain, lim- Pelvic torsion-related pain is associated with pseudo- ited mobility, weakness and referred pain (Simons et al. leg-length-inequality or with trigger point muscular 1999). The trigger point has both a motor abnormality in shortening (pseudoscoliosis). It can be caused by, and which an abnormal hardness in muscle (the taut band) is in turn either cause or aggravate, myalgia in lumbar felt on palpation, and a sensory abnormality of exquisite muscles and in the pelvic floor muscles. tenderness in the taut band. Identification of the trigger SI joint Dysfunction point by physical examination has good interrater reli- Sacroiliac joint dysfunction, or sacro-iliac joint hypo- ability (Gerwin et al. 1997). The specifics of a MPS de- mobility can cause pelvic and spine dysfunction that re- pend on which muscles are involved. For example, TrPs sults in painful, widespread axial muscle trigger points. in the muscles of the head, neck and shoulders can cause Pain may be felt in the sacroiliac joint region (on either headache. Local or regional myofascial syndrome can the hypomobile or the normal side), referred to the low spread through the body and become a widespread my- back or occur because of the secondary development of ofascial syndrome, but does not become fibromyalgia. paraspinal trigger point up the axial spine to the shoul- Treatment ders and neck. Treatment of myofascial pain requires the inactivation Static Overload of MTrPs by manual trigger point compression or by Static overload occurs when mechanically stressful po- needling, the restoration of normal muscle length and sitions are held for prolonged periods of time, causing the elimination or correction of the factors that created fatigue and pain in the persistently activated muscles. orperpetuatedthetriggerpointsinthefirstplace.Aware- ness of ergonomic and postural factors is important in Nerve Root Compression developing a treatment plan. Trigger point needling is Nerve root compression can present with acute or done with or with out the injection of local anesthetic chronic myofascial trigger points. Trigger point pain (Cummings 2001). Injection of other materials such as syndromes can develop acutely when there is an acute steroidsorketorolacisinappropriate.Triggerpointinac- disc herniation. Muscle pain is in the distribution of tivation must be accompanied by correction of mechan- the affected nerve root. It can precede any neurological ical or structural stresses and of psychological and med- impairment such as weakness, sensory loss, paresthesia ical contributing factors. or reflex loss. Mechanical Causes Delayed Onset Muscle Soreness (DOMS) Mechanicalcausesofmyalgiaincludeergonomic,struc- Delayed onset muscle soreness (DOMS), as is well tural and postural pain syndromes. known, occurs after eccentric exercise, but has been shown to occur after ischemic exercise as well (Barlas et Hypermobility Syndromes al. 2000). Exercise under these conditions causes injury Hypermobility syndromes produce multiple mechani- to the muscle fiber and consequent pain or soreness. cal stresses. Structural stress occurs as ligamentous lax- The second major category is systemic medical illness. ity results in poor joint stabilization, muscles then be- The relationship of some of these conditions to myal- ing recruited to maintain joint integrity. This can result gia has been difficult to confirm. Yet when such an ill- in a seemingly disproportionate number of hypermobile ness is identified and treated and muscle pain improves persons, mostly women, who have focal or generalized or resolves, it is tempting to equate the treatment with a myalgia. The affected muscles always have myofascial successful outcome. Nonetheless, one must be cautious trigger points. The mechanism of injury appears to be about assuming a causal relationship. The conditions of muscular stress or overload that arises from the effort interest include autoimmune disorders, infectious dis- required to maintain joint integrity. The most effective eases, allergies, hormonal and nutritional deficiencies, treatment is strengthening. viscerosomatic pain syndromes and iatrogenic drug induced myalgic pain syndromes. Forward Head Posture Forward head posture places stress on the extensor Autoimmune Disorders muscles of the neck and shoulder (longissimus cervicis, Muscle pain is a common accompanying symptom of semispinalis capitis and cervicis, splenius capitis and many autoimmune disorders, particularly connective cervicis, the suboccipital muscles at the base of the tissue diseases like lupus and Sjögren’s syndrome. Myalgia 1243

Polymyalgia rheumatica (PMR) must certainly be 2003). This is an astounding figure that indicates that considered in any head, neck and shoulder regional vitamin Ddeficiency isextremely commonamongthose muscular pain syndrome in an older (>50 years of with myalgia. age) individual. Chewing-induced pain is an important Iron Deficiency component of both PMR and MPS, the latter when the temporomandibular joint is involved. Muscle pain may This causes a metabolic stress that produces fatigue precede other signs of Sjögren’s syndrome by several and muscle pain. Muscle is depleted of iron available years. for energy-producing enzymatic reactions when serum ferritin levels are 15 ng / ml or less. Treatment with iron Infectious Diseases supplements in women whose serum ferritin level is Lyme disease is perhaps the most prevalent of the 20 ng / ml or less results in less fatigue, less coldness and infectious diseases associated with myalgia and arthral- less muscle pain. Iron insufficiency is also associated gia. Post-Lyme disease syndrome is characterized with restless leg syndrome (RLS), a cause of sleep dis- by diffuse arthralgia, myalgia, fatigue and subjective turbance. Sleep deprivation also causes myalgia. Thus, cognitive difficulty (Weinstein and Britchkov 2002). iron deficiency can aggravate muscle pain secondarily Patients diagnosed with this condition do not show by causing RLS. evidence of chronic borrelial infection and they do not Drug Induced Myalgia respond to a 3 month course of antibiotics any better This is widespread and diffuse, rather than regional. than a control group treated with placebo. Chronic Drug-induced myalgia may or may not be associated infections that look like Lyme disease and that may with trigger points. Elevation of CK is a marker of mus- co-infect with Lyme disease are babesiosis, ehrlichiosis cle tissue breakdown. However, CK is not necessarily and Bartonella. Other infectious diseases thought to elevated when there is drug-induced myalgia. Drugs be related to myalgia are Mycoplasma pneumonia and known to produce myalgia, regardless of whether or not Chlamydia pneumonia. Interest in these two diseases M CK is elevated, include propoxyphene and the statin arises because of a putative association with arthralgia family of cholesterol lowering drugs (Thompson et or synovitis and with chronic fatigue. A number of pa- al. 2003). The risk of acquiring myalgia is increased tients with widespread myalgia have parasitic disease, when a statin drug is taken concomitantly with fibric most commonly amebiasis and Giardia. acid derivatives like gemfibrozil, niacin, cyclosporin, Allergies azole B antifungal and macrolide antibiotics, protease Cases of widespread myalgia (myofascial pain syn- inhibitors, nefazodone, verapamil, diltiazem, amio- drome) have been associated with persons who have darone or grapefruit juice (> 1 qt / day). had untreated allergies. When the myalgic syndrome is Conclusion limited to the head, neck and shoulders, forward head Muscle pain can be the result of a wide array of clinical posture as described above may be related to allergies conditions. The inflammatory diseases of muscle, such and obstruction of the nasal passages may play a role. as polymyositis or the inherited myopathies, can also Viscero-somatic Pain Syndromes present with pain. Myoadenylate deaminase deficiency Internal organs are associated with somatic segmental is the most common inherited muscle enzyme disorder, referred pain syndromes. Endometriosis, for example, but the role that it plays in muscle pain is still no clearer is associated with abdominal myofascial pain (Jarrell today than it was 10 years ago. In order to treat patients and Robert 2003). Interstitial cystitis and irritable bowel well, the conditions that produce muscle pain must be syndrome are associated with chronic pelvic pain syn- identified in order to be specifically addressed. dromes (Hetrick et al. 2003; Weiss 2001). Liver disease Guillain-Barré Syndrome can cause local abdominal and referred shoulder my- Muscle Pain Model, Inflammatory Agents-Induced ofascial pain syndromes that present as a regional pain References syndrome responsive to treatment of the trigger points 1. Andreu AL, Hanna MG, Reichman H et al. (1999) Exercise in- by needling or by manual therapy. tolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Eng J Med 341:1037–1044 Brain Tumor and Base of Skull Pain 2. Barlas P, Walsh DM, Baxter GD et al. (2000) Delayed onset Posterior fossa mass lesions (primary and metastatic tu- muscle soreness: effect ofa n ischemic block upon mechanical allodynia in humans. Pain 87:221–225 mors) can present as focal base of skull or upper cervi- 3. Cummings T, White A (2001) Needling therapies in the man- cal pain with identifiable myofascial trigger points that agement of myofascial trigger point pain: a systematic review. transiently respond to trigger point inactivation. Arch Phys Med Rehabil 82: 986–992 4. Dessein PH, Shipton EA, Joffe BI et al. (2000) Neuroendocrine Nutritional Deficiencies deficiency-mediated development and persistence of pain in fibromyalgia: a promising paradigm? Pain 86:213–215 Vitamin D deficiency was found in 89% of the persons 5. Gerwin RD (1999) Differential diagnosis of myofascial pain syn- in a group with chronic musculoskeletal pain (Plotnikof drome and fibromyalgia. J Musculoskeletal Pain 7:209–215 1244 Mycobacterium Leprae

6. Gerwin RD (2002) Myofascial and visceral pain syndromes: visceral-somatic pain representations. J Musculoskelet Pain Myelin 10:165–175 7. Gerwin RD, Shannon S, Hong C-Z et al. (1997) Interrater reliability in myofascial trigger point examination. Pain 69:65–73 Definition 8. Goldenberg DL, Burckhardt C, Crofford L (2004) Management of fibromyalgia syndrome. JAMA 292:2388–2395 Myelin is a specialized cell membrane composed of 9. Hetrick DC, Ciol MA, Rothman I et al. (2003) Musculoskeletal lipids and proteins that ensheathes axons and fosters dysfunction in men with chronic pelvic pain syndrome type III: rapid electrical conduction. a case-control study. J Urology 170:828–831 10. Jarrell J, Robert M (2003) Myofascial dysfunction and pelvic Demyelination pain. Canadian J CME Feb:107–116 Hereditary Neuropathies 11. Martinez-Lavin MA, Hermosilla AG, Mendoza C (1997) Ortho- Postsynaptic Dorsal Column Projection, Anatomical static sympathetic derangement in subjects with fibromyalgia. J Organization Rheumatology 24:714–718 12. Mense S, Simons DG (2001) Muscle Pain. Lippincott Williams Spinothalamic Tract Neurons, Morphology & Wilkins, Baltimore, pp 205–288 Toxic Neuropathies 13. Plotnikoff GA, Quigley JM (2003) Prevalence of severe hypovita- minosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 78:1463–1470 14. Russell IJ (2001) Fibromyalgia Syndrome. In: Mense S, Simons DG (eds) Muscle Pain. Lippincott Williams & Wilkins, Balti- Myelinated more, pp 289–337 15. Simons DG, Travell JG, Simons LS (1999) Myofascial Pain and Dysfunction: The Trigger Point Manual. Williams and Wilkins, Definition Baltimore 16. Thompson PD, Clarkson P, Karas RH (2003) Statin-associated Medium and large nerve fibers can be wrapped in a vari- myopathy. JAMA 289:1681–1690 able number of concentric layers of glial membrane that 17. Weinstein A, Britchkov M (2002) Lyme arthritis and post-Lyme provide for rapid neurotransmission. disease syndrome. Curr Opin Rheumatol 14:383–387 18. Weiss JM (2001) Pelvic floor myofascial trigger points: manual Postsynaptic Dorsal Column Projection, Anatomical therapy for interstitial cystitis and the urgency-frequency syn- Organization drome. J Urology 166:2226–2231 19. Wolfe F, Smythe H, YunusMB et al (1990) The American College of Rheumatolgy criteria for the classification of Fibromyalgia. Arthritis Rheum 33:160–172 Myelination

Deﬁnition Mycobacterium Leprae Myelinationisaprocessbywhicholigodendroglialcells wrap axons with multiple layers of glial cell membrane formingmyelin,whichelectricallyinsulatestheaxonin- Deﬁnition creasing axonal conduction velocity. Mycobacterium Leprae is the causative agent of Mechanonociceptors Hansen’s disease. The bacterium was discovered in 1873 by a Norwegian physician named Gerhard Ar- mauer Hansen. Hansen’s Disease Myelitis

Deﬁnition Myelitis is the inﬂammation of the spinal cord. Mycobacterium Species Viral Neuropathies

Deﬁnition Mycobacteria are a large genus of class of bacteria that Myelopathy are responsible for a multitude of diseases of many species. The most common mycobacterium used in Deﬁnition Freund’s complete adjuvant is mycobacterium tuberculosis, the organism responsible for tuberculosis in Myelopathy is the manifestation of systemic vasculi- humans. Mycobacterium butyricum has also been used tides and the isolated angiitis of the central nervous in FCA. system. Arthritis Model, Adjuvant-induced Arthritis Headache Due to Arteritis Myofascial Pain 1245

Myelotomy Myofascial Manipulation

Definition Definition Myofascial manipulation is the forceful, passive move- Myelotomy or midline or commissural myelotomy is mentofthemusculofascialcomponentsthroughtheirre- useful for the treatment of bilateral pain syndromes strictive direction. Treatment is initiated in the superfi- caused by cancer and other illnesses. Second order cial layers and moves into the deeper layers while con- spinalothalamic tract nociceptive track fibers cross the sidering the relationship to the joints involved. spinal cord, and a myelotomy is intended to cut these Chronic Pelvic Pain, Physical Therapy Approaches fibers as they decussate in the spinal cord. and Myofascial Abnormalities Cancer Pain Management, Overall Strategy Midline Myelotomy Myofascial Pain

ROBERT BENNETT Department of Medicine, Oregon Health and Science Myenteric Plexus University, Portland, OR, USA [email protected]

Definition Synonyms The myenteric plexus consists of unmyelinated nerve Trigger Point Pain; Soft Tissue Rheumatism; Myotomal fibers that are spread out in the muscular part of the in- Pain; Localized Muscle Pain testinal wall of the esophagus, stomach, and intestines. M The plexus is involved in the regulation of gut motility. Definitions Opioid Therapy in Cancer Pain Management, Route Myofascial pain: Pain arising from muscles or related of Administration fascia. ActiveTrigger point:Thisisatrigger pointthatresultsin pain at rest with increased pain on contraction or stretching of the involved muscle. Myocardial Ischemia Latent trigger point: A latent trigger point is a focal area of tenderness and tightness in a muscle that does not result in spontaneous pain. However, a latent trigger point Visceral Pain Model, Angina Pain may restrict range of movement and cause weakness of the involved muscle. Characteristics Prevalence Myoclonus Myofascialpainisauniversaloccurrencecommonlyde- veloping as a result of muscle injuries, overuse or repeti- Definition tive strain. In most instancesthe problemresolveswithin a few days without any need for medical intervention. Myoclonus refers to Irregular, involuntary contraction When pain persists or worsens, necessitating a medical of a muscle. consultation, it is referred to as a myofascial pain syn- Opioids and Reflexes drome (Travell and Simons 1983). There have not been any epidemiological studies of myofascial pain problems in the general population. Rather, physicians have reportedprevalencefiguresinspecializedsituations.For instance, in one internal medicine practice, 30% of pa- Myofascial tients presenting with pain complaints were diagnosed as having a myofascial pain origin for their symptoms. A report from a clinic specializing in head and neck pain Definition reported a myofascial etiology in 55% of cases. A report The fascia (the sheath around a muscle). from one pain management center attributed a myofas- Lower Back Pain, Physical Examination cialorigin to thesymptomatologyin 85%of patients. On Myofascial Pain the other hand, latent trigger points have been found in 1246 Myofascial Pain theshouldergirdlemusclesof54%offemaleand45%of fibromyalgia (Arendt-Nielsen and Graven-Nielsen male subjects who were completely asymptomatic (Si- 2003). mons 2001). Low Back Pain Diagnosis Acute low back pain has many causes. Some are potentially serious, such as cancer metastases, osteomyeli- The clinical diagnosis of myofascial pain is criti- tis, massive disk herniations (e.g. cauda equina syn- cally dependent on the physician being aware of this drome), vertebral fractures, pancreatic cancer and aortic diagnosis as a possible cause for the patient’s pain aneurysms. However, the commonest cause of acute complaint (Travell and Simons 1983). Myofascial pain back pain is so-called lumbosacral strain. In 95% of syndromes may mimic a large number of other disor- cases this resolves within three months. In those cases ders, thus there is a necessity to perform a thorough that do not resolve, the development of a chronic low physical examination, with appropriate investigations. back pain syndrome is usually accompanied by the Myofascial pain characteristically presents as a dull finding of active myofascial trigger points. Simons de- deep aching sensation, which is aggravated by use of scribes 15 torso and pelvic muscles that may be involved the involved muscles as well as psychological stres- in low back pain (Simons 2001). The most commonly sors that cause increased muscle tension (Alvarez and involved muscle group is the quadratus lumborum; pain Rockwell 2002). The defining clinical characteristic of emanating from trigger points in these muscles is felt in myofascial pain is the finding of a trigger point. This the low back with occasional radiation in a sciatic dis- is a well-defined point of focal tenderness within a tribution or into the testicles. Trigger points involving muscle. Sometimes firm palpation of this focus elic- the iliopsoas are also a common cause of chronic low its pain in a referred distribution that reproduces the back pain. The typical distribution of iliopsoas pain is patient’s symptoms. Importantly, referred pain from a a vertical band in the low back region and the upper trigger point does not follow a nerve root distribution portion of the anterior thigh. Trigger points at the origin (i.e. it is not dermatomal). Palpation usually reveals of the gluteus medius from the iliac crest are a common a ropelike induration of the associated muscle fibers, cause for low back pain in the sacral and buttock, with often referred to as the “taut band”. Sometimes, snap- a referral pattern to the outer hip region. ping this band or needling the trigger point produces a localized twitch response of the involved muscle. This Neck and Shoulder Pain twitch response can only be reproducibly elicited in Latent trigger points are universal findings in many of fairly superficial muscles. Importantly, trigger points the muscles of the posterior neck and upper back. Active produce functional consequences in terms of a restric- trigger points commonly involve the upper portion of tion of range of movement and weakness (probably thetrapeziusandlevatorscapula.Uppertrapeziustrigger a reflex inhibition secondary to pain), which is usu- points refer pain to the back of the neck and not uncom- ally associated with easy fatigability of the involved monly to the angle of jaw. Levator scapula trigger points muscle. causepain attheangleof theneck andshoulder;thispain isoftendescribedaslancinating,especiallyonactiveuse Clinical Syndromes of this muscle. As many of the muscles in this area have A myofascial pain syndrome may be due to just one trig- an important postural function, they are commonly ac- ger point, but more commonly there are several trigger tivated in office workers and developmental problems points responsible for any given regional pain problem. causing spinal malalignment (e.g. short leg syndrome, It is not uncommon for the problem to be initiated with hemipelvis and scoliosis). As the upper trapezius and a single trigger point, with the subsequent development levator scapulae act synergistically with several other of satellite trigger points, which evolve over time due to musclesinelevationandfixationofthescapula,itiscom- the mechanical imbalance resulting from reduced range mon for a single trigger point in this region to initiate a of movement and pseudo-weakness. The persistence of spread of satellite trigger points through adjacent mus- a trigger point may lead to neuroplastic changes at the cles that are part of the same functional unit. level of the dorsal horn, which results in amplification of the pain sensation (i.e. central sensitization) with Hip Pain a tendency to spread beyond its original boundaries Pain arising from disorders of the hip joint is felt in the (i.e. expansion of receptive fields) (Graven-Nielsen and groin and the lower medial aspect of the anterior thigh. Arendt-Nielsen 2002). In some instances segmental This distribution is uncommon in myofascial pain syn- central sensitization leads to the phenomena of mirror dromes except for iliopsoas pain. The great majority of image pain (i.e. pain on the opposite side of the body in patients complain of hip pain, and in fact localize their the same segmental distribution), and in other instances pain to the outer aspect of the hip. In some patients this a progressive spread of segmental central sensitization is due to a trochanteric bursitis, but in the majority of gives rise to the widespread pain that characterizes cases it is related to myofascial trigger points in the ad- Myofascial Pain 1247 jacent muscles. By far the commonest trigger pointsgiv- musculature. Posterior knee pain can result from trig- ing rise to outer hip pain are those in the attachments of ger points in the hamstring muscles and popliteus. Trig- the gluteusmediusand minimusmusclesintothe greater ger points in the anterior tibialis and the peroneus longus trochanter. musclesmay cause pain in the anterior leg and lateralan- kle, respectively. Myofascial pain syndromes involving Pelvic Pain these muscles are often associated with ankle injuries The pelvic floor musculature is a common sight for my- or an excessively pronated foot. Sciatica pain may be ofascial trigger points. There is increasing recognition mimicked by a trigger point in the posterior portion of by gynecologists and urologists that pain syndromes the gluteus minimus muscle. described in terms of prostatitis, coccydnia, vulvodynia and endometriosis are often accompanied by active Chest and Abdominal Pain myofascial trigger points. One of the most commonly Disorders affecting intrathoracic and intra-abdominal involved intrapelvic muscles is the levator ani; its pain organs are some of the commonest problems encoun- distribution is central low buttock. tered in internal medicine. For instance, anterior chest pain isa frequentcause for emergencyroom admissions, Headaches but in the majority of patients a myocardial infarction Active myofascial trigger points in the muscles of is not found. In some cases, the chest pain is caused by the shoulder, neck, and face, are a common source of trigger points in the anterior chest wall muscles (Trav- headaches (Borg-Stein 2002). In many instances, the ell and Simons 1992). Pectoralis major trigger points headache has the features of so-called tension headache, cause ipsilateral anterior chest pain with radiation down but there is increasing acceptance that myofascial trig- the ulnar side of the arm – thus mimicking cardiac is- ger points may initiate classical migraine headaches or chemic pain. A trigger point in the sternalis muscle be part of a mixed tension/migraine headache complex. typically causes a deep substernal aching sensation. For instance, sterno-cleido mastoid trigger points refer Trigger points at the upper and lower insertions of the M pain to the anterior face and supraorbital area. Upper rectus abdominus muscles may mimic the discomfort trapezius trigger points refer pain to the vertex forehead of gall bladder and bladder infections, respectively. and temple. Trigger points in the deep cervical muscles It is important to note that myofascial trigger points of the neck may cause post occipital and retro-orbital may accompany disorders of intrathoracic and intra- pain. abdominal viscera, and thus a diagnosis of an isolated myofascial cause for symptoms should never be made Jaw Pain without an appropriate workup. There is a complex interrelationship between temporomandibular joint dysfunction and myofascial trigger Pathogenesis points (Fricton et al. 1985) Common trigger points The precise pathophysiological basis for the trigger involved in jaw pain syndromes are the massetters, point phenomena is still not fully understood. There is pterygoids, upper trapezius and upper sterno-cleido a general agreement that electromyographic recordings mastoid. from trigger points show low voltage spontaneous activity resembling endplate spike potentials (Rivner 2001). Upper Limb Pain Simons envisions a myofascial trigger point to be “a The muscles attached to the scapula are common sites cluster of numerous microscopic loci of intense abnor- for trigger points that can cause upper limb pain (Ger- mality that are scattered throughout the tender nodule” win 1997). These include the subscapularis, infraspina- (Simons 2001). It is thought that these loci result from a tus, teresmajor and serratusanterior. Itisnotuncommon focal energy crisis (from injury or repetitive use), which for trigger points in these locations to refer pain to the results in contraction of focal sarcomeric units due to wrist, hand, and fingers. Extension flexion injuries to the calcium release from the sarcoplasmic reticulum. A neck often activate a trigger point in the pectoralis minor more detailed coverage of this topic is provided in the with a radiating pain, or down the ulnar side of the arm essay myofascial trigger point. Factors commonly and into the little finger. Myofascial pain syndromes of cited as predisposing to trigger point formation include the upper limbs are often misdiagnosed as frozen shoul- deconditioning, poor posture, repetitive mechanical der, cervical radiculopathy or thoracic outlet syndrome stress, mechanical imbalance (e.g. leg length inequal- (Simons 2001). ity), joint disorders, non-restorative sleep and vitamin deficiencies. Lower Limb Pain Trigger pointsin the tensor fascia lata and ilio tibial band Prognosis may be responsible for lateralthigh pain and lateralknee Uncomplicated myofascial pain syndromes usually re- pain, respectively. Anterior knee pain may result from solve with appropriate correction of predisposing fac- trigger points in various components of the quadriceps tors and myofascial treatment (Alvarez and Rockwell 1248 Myofascial Pain

2002). If the symptoms are persistent, due to ineffec- provides any enhanced effect. A beneficial role for bo- tive management, the developmentof segmental central tulinum toxin in trigger point injections has not so far sensitization may lead to a stubbornly recalcitrant pain been conclusively demonstrated. disorder. In some such cases, the spread of central sensitization leads to the widespread pain syndrome of fi- Medications bromyalgia. There is currently no evidence that any form of drug treatment of men eighths myofascial trigger points Treatment (Rudin 2003). NSAIDs and other analgesics usually For effective management of myofascial pain, syn- provide moderate symptomatic relief. Tricyclic an- dromes require attention to the following issues (Al- tidepressant drugs, which modulate pain at the central varez and Rockwell 2002; Rudin 2003): level, are often of benefit, especially in those patients Postural and Ergonomic with an associated sleep disturbance. In the author’s experience, tizanidine (a muscle relaxant that also ame- The most critical element in the effective management liorates pain by activating alpha 2 adrenergic receptors) of myofascial pain syndromes is the correction of pre- is often a useful adjunct in difficult to treat myofascial disposing factors (see above). These interfere with the pain syndromes. ability of the muscle to fully recover and are the commonest reason for treatment failures. Psychological Techniques Stretching In severe myofascial pain syndromes that are not responding to treatment, patients often become anxious The muscles involved in myofascial pain syndromes and depressed. These mood disorders need to be rec- are shortened due to the aforementioned focal contrac- ognized and appropriately treated. Persistent muscle tions of sarcomeric units. It is thought that these focal tension exacerbates the pain of myofascial trigger contractions result in a prolonged ATP consumption, points and can often be effectively managed with EMG and that the restoration of a muscle to its full stretch biofeedback, cognitive behavioral therapy and hyp- length breaks the link between the energy crisis and notic/meditation relaxation techniques. contraction of sarcomeric units. Effective stretching is most commonly achieved through the technique of spray and stretch (Rudin 2003). This involves the cu- References taneous application, along the axis of the muscle, of ethyl chloride spray, while at the same time passively 1. Alvarez DJ, Rockwell PG (2002) Trigger Points: Diagnosis and Management. Am Fam Physician 65:653–660 stretching the involved muscle. Other techniques to 2. Arendt-Nielsen L, Graven-Nielsen T (2003) Central Sensitiza- enhance effective stretching include trigger point to tion in Fibromyalgia and Other Musculoskeletal Disorders. Curr pressure release, post isometric relaxation, reciprocal Pain Headache Rep 7:355–361 inhibition and deep stroking massage (Simons 2001). 3. Borg-Stein J (2002) Cervical Myofascial Pain and Headache: Curr Pain Headache Rep 6:324–330 Strengthening 4. Fricton JR, Kroening R, Haley D et al. (1985) Myofascial Pain Syndrome of the Head and Neck: A Review of Clinical Character- Muscles harboring trigger points usually become weak istics of 164 Patients. Oral Surg Oral Med Oral Pathol 60:615–623 due to the inhibitory effects of pain. A program of 5. Graven-Nielsen T, Arendt-Nielsen L (2002) Peripheral and Cen- slowly progressive strengthening is essential to restore tral Sensitization in Musculoskeletal Pain Disorders: An Exper- imental Approach. Curr Rheumatol Rep 4: 313–321 full function and minimize the risk of recurrence and 6. Gerwin RD (1997) Myofascial Pain Syndromes in the Upper perpetuation of satellite trigger points. Extremity. J Hand Ther 10:130–136 7. Hong C-Z (1994) Considerations and Recommendations Regard- Trigger Point Injections ing Myofascial Trigger Point Injection. J Musculoskeletal Pain 2:29–59 Injection of trigger points is generally considered to be 8. Hong C-Z (1994) Lidocaine Injection versus Dry Needling to the most effective means of direct inactivation. A pep- Myofascial Trigger Point. The Importance of the Local Twitch pering technique using a fine needle to inactivate all the Response. Am J Phys Med Rehabil 73:256–263 foci within a trigger point locus is the critical element of 9. Rivner, MH (2001) The Neurophysiology of Myofascial Pain Syndrome. Curr Pain Headache Rep 5:432–440 successful trigger point therapy (Hong 1994). Accurate 10. Rudin NJ (2003) Evaluation of Treatments for Myofascial localization of the trigger point is confirmed if a local Pain Syndrome and Fibromyalgia. Curr Pain Headache Rep twitch response is obtained; however, this may not be 7:433–442 obvious when needling deeply lying muscles. Success- 11. Simons DG (2001) Myofascial Pain Caused by Trigger Points In: Mense S, Simons DG, Russel IJ (eds) Muscle Pain: Understand- ful elimination of the trigger point usually results in a ing its Nature, Diagnosis, and Treatment. Lippincott Williams relaxation of the taut band. Although dry needling is ef- and Wilkins, Philadelphia, pp 205–288 fective, the use of a local anesthetic (1% lidocaine or 1% 12. Travell JG, Simons DG (1983) Myofascial Pain and Dysfunction: procaine)helpsconfirmtheaccuracyoftheinjectionand The Trigger Point Manual. Williams and Wilkins, Baltimore 13. Travell J, Simons D (1992) Myofascial Pain and Dysfunction: provides instant gratification for patients (Hong 1994). The Trigger Point Manual, vol 2. Williams and Wilkins, Balti- There is no evidence that the injection of corticosteroids more Myofascial Trigger Points 1249

Myofascial Pain Syndrome

Synonyms MPS

Definition Myofascial pain syndrome is a muscle disorder charac- terizedbythepresenceoftriggerpoints(TrPs)withinthe muscle. There is also pain, muscle spasm, tenderness, stiffness, limited range of motion, weakness and/or au- tonomicdysfunction. Pressureonthetrigger pointrefers pain to an area distant from the trigger point. However, Myofascial Trigger Points, Figure 1 This schematic longitudinal view the trigger point itself could and usually is painful. of muscle illustrates key clinical features of a myofascial trigger point. Chronic Back Pain and Spinal Instability The central trigger point (CTrP), which is located near the mid-muscle fiber, exhibits outstanding spot tenderness in a palpable taut band and Chronic Pelvic Pain, Musculoskeletal Syndromes refers pain to a distance. The taut band extends the length of the muscle Chronic Pelvic Pain, Physical Therapy Approaches fibers to its attachments, where the sustained tension of the taut band and Myofascial Abnormalities induces an attachment trigger point (ATrP) enthesopathy (that is sensitive to applied pressure and increased muscle tension). Adapted from Simons Muscle Pain, Fibromyalgia Syndrome (Primary, Sec- et al. (1999). ondary) Myalgia Nocifensive Behaviors (Muscle and Joint) Definition M Opioids and Muscle Pain Clinically,acentral myofascialtriggerpoint(MTrP)is Sacroiliac Joint Pain characteristically a very tender, circumscribed, nodule- Stretching like spot that is located in the mid-portion of a taut Trigger Point band of skeletal muscle fibers and can cause referred pain. Application of digital pressure to the spot typically induces referred pain that is characteristic of that muscle, and is familiar to the subject if the MTrP is active. Myofascial Release The indurated tender attachments of taut-band muscle fibers are identified as attachment trigger points (see Fig. 1). Definition Etiologically, the central MTrP is associated with endplate noise, which originates from a motor end- Myofascial release can be described as a manual soft plate thatisreleasing abnormalamountsof acetylcho- tissue technique that can be either direct or indirect, and line. Shortened sarcomeres, in the region of end- is frequently combined. As a treatment technique, it plates, are associated with local release of sensitizing utilizes the principles of biomechanical loading of soft substances (Shah et al. 2005) that cause pain and ten- tissue, and the neural reflex changes by stimulation of derness. mechanoreceptors in the fascia. Chronic Pelvic Pain, Physical Therapy Approaches Characteristics and Myofascial Abnormalities Myofascial trigger points (MTrPs) are only one part of the complex neuromusculoskeletal pain picture, however,thatpartisprobablyasimportantasthenervoussys- tem and is certainly the most neglected and overlooked Myofascial Trigger Points part. The term myofascial pain is often used with two different meanings. Myofascial pain caused by MTrPs DAV I D G. SIMONS is a specific etiological diagnosis, whereas myofascial Department of Rehabilitation Medicine, Emory pain,usedinthegeneralsenseofregionalpainofuniden- University, Atlanta, GA, USA tified etiology in myofascial structures, is only a symp- [email protected] tom, not a diagnosis. Musculoskeletal pain is one of the major causes of common human aches and pains such as low back pain and tension type headache. Synonyms In one study, of the 32.5 % of the unselected population MTrP who were experiencing chronic pain, 94.5 % identified 1250 Myofascial Trigger Points it as musculoskeletal (Wolfe et al. 1998). Myofascial verification. If this study is representative, the natural trigger points (MTrPs) are often the major cause of the history of MTrPs could be that we are born with the pain, or a major component in association with well- tendency to develop latent MTrPs upon reading adoles- recognized sources of pain. Any of the approximately cence and, during adulthood, life stresses can convert 500 skeletal muscles can develop MTrPs. For more them into active MTrPs. A simple study, by reasonably detailed information on this subject, consult the two skilled investigators, could resolve this issue. latest volumes of The Trigger Point Manual (Simons et The diagnosis of MTrPs can firstly be approached by anal. 1999; Travell and Simons 1992), or the german or swering three questions, which require limited manual spanish editions, and the Muscle Pain book (Mense et skill to determine if MTrPs are a viable differential dial. 2001). agnosis. Could MTrPs of muscle be causing the pain? If Active MTrPs cause a clinical pain complaint but la- so, which muscle(s) should be examined? Doesaninitial tent MTrPs do not – an important clinical distinction. screening exam identify active MTrPs? If so, the patient One well-designed article (Hsieh et al. 2000) described needs further examination and testing by a skilled prac- 520 muscle examinations of muscles commonly caus- titioner who can also treat the MTrPs as listed below. ing low back pain (LBP), both in subjects with LBP Diagnosis of myofascial trigger points (MTrPs) and in normal pain-free controls. The authors found • Could MTrPs of muscle be causing the pain? MTrPs (some active) in 90 % of low back pain subjects’ muscles, and found latent MTrPs (not producing a pain – Other possibilities: nerves (radiculopathy), joints complaint) in 70 % of the control subjects’ muscles. (somatic dysfunction), central nervous system (fi- Latent MTrPs were common in control subjects. bromyalgia), viscera (renal calculi), etc. The natural history of MTrPs is unknown; however, a re- – Trigger point pain is initiated by: Sudden, unex- cent study provided a valuable lead. Among 13 healthy, pected overload (acute onsetfrom fallor motor ve- normal, pain-free hospital personnel, only one subject hicle accident)Chronic overload (insidious onset had no latent MTrPs in the eight muscles examined. from poor posture, poor ergonomic arrangement, Two subjects had MTrPs in seven of the eight muscles repetitive strain) (see Table 1). Age was not a significant factor. Note subjects 1 and 2. This small sample suggests that most • Which muscle(s) should be examined? adults have at least some latent MTrPs; a few adults have many and a few have almost none. This needs – Whichmuscleswereoverloaded(historyabove)— based on knowledge of muscle functions – Distorted posture or movements Myofascial Trigger Points, Table 1 Distribution of latent myofascial trig- – Pain pattern that fits known patterns of suspected ger points (MTrPs) in eight muscles of 13 pain-free, healthy normal control muscle(s). subjects. Subjects were numbered to correspond to their relative ages, which ranged between 23 and 59 years. Number 1 was the youngest. Age – Painful restriction in stretch range of motion does not appear to be an important factor among these adults and showed of involved muscle(s). Involved muscle shows no linear regression. increased stiffness and tension. Subject Number Number of muscles with MTrPs in each subject • What is a simple initial muscle examination (differ- 27 ential diagnosis screening)? 67 – Localized very tender spot in skeletal muscle+ 10 6 – Pressure-evokedreferredpainthatischaracteristic of that muscle= a likely latent myofascial trigger 85 point+ 35 – Patients’ recognition of evoked pain as part or all of the primary pain complaint= a likely active my- 12 5 ofascial trigger point 54 11 3 • Confirmatory myofascial trigger point examination (training and skill required) 13 3

42 – Tender spot feels nodular (if located sufﬁciently superﬁcial) 92 – Tenderspotlocatedinapalpabletautband,seeFig. 71 1 – Tender attachment TrP (enthesopathy) at attach- 10 ment of taut band. Myofascial Trigger Points 1251

– Favorable response to speciﬁc MTrP treatment a conﬁrmatory examination and, if indicated, treatment – Occurrence of a local twitch response evoked in- by a skilled practitioner. Referral may be necessary. La- cidentally by palpation of, or purposely by needle tent MTrPs can cause muscle inhibition, imbalance, and insertion into, the TrP. other motor problems.

The diagnostic process is complicated by the complex Confirmatory Myofascial Trigger Point Examination neuromusculoskeletal nature of musculoskeletal pain This examination demands skills that usually require and the lack of a diagnostic gold standard for MTrPs, considerable training and clinical practice, and are of- which are not identifiable by available laboratory or ten critical for effective treatment of MTrPs. Clinically, imaging testing. In addition, the appropriate examina- the taut band is considered by skilled and experienced tion depends on the amount and texture of overlying clinicians to be the most distinctive feature of MTrPs, tissue and the skills of the examiner. Different muscles but was one of the most difficult exams in credible in- may require quite different examinations. terrater reliability studies because of the skill required Initially, the diagnosis depends on medical history, (Gerwin et al. 1997; Sciotti et al. 2001). Fortunately, knowledge of MTrP characteristics, and knowledge of confusingly, similar fascial structures are rarely tender. muscle anatomy and function. Effective confirmatory Taut bands are usually indistinguishable in muscle that examination and treatment depend on clinical skill. A lies beneath thick layers of fat, firm subcutaneous tissue growing body of research studies and clinical experi- and/or overlying muscle tissue. Figure 1 schematically ence increasingly substantiates the guidelines presented illustrates the relationship between the taut band and here. its central and attachment trigger points. The localtwitchresponseisasensory-motorspinalre- Could MTrPs of Muscle be Causing the Pain? flex that induces a series of motor unit activations only in Commonly,inpatientswithchronicmyofascialpain,the tautband fibers. Ithashigh specificity butrelativelypoor M likely diagnoses, except MTrPs, have already been ruled reliability in most hands and can be extremely painful out,oftenbynumerousexpensivetests.Chronicprogres- to the patient. sive MTrP symptoms are perpetuated by mechanical or The pathophysiology of MTrPs is not totally unknown, systemic factors, which need identification and correc- but it is not firmly established and has been contro- tion – factors that alone, without the activated MTrPs, versial. An integrated hypothesis (Simons et al. 1999; often do not cause enough symptoms to demand atten- Mense et al. 2001; Simons 2004) incorporates the avail- tion. Without a perpetuating factor, acute onset active able research studies and explains the clinical features MTrPs tend to subside to asymptomatic latent MTrPs of MTrPs. The hypothesis helps to identify what we do with gentle, normal, muscle-stretching daily activities. know with confidence and what remains to be clarified. Figure 2 outlines and summarizes the hypothesis. Which Muscle(s) Should be Examined? Clinically, compression (radiculopathy) of the motor nerve can facilitate conversion of latent MTrPs to active Patient posture and modified movements is often a key. ones, which are associated with electromyographic Special attention should be paid to problems in the feet evidence of increased acetylcholine (ACh) release. that commonly reflect dysfunctions, which extend up Excessive spontaneous release can be identified by the body to the head. Active MTrPs of each muscle endplate noise (Simons 2001), which is mistakenly project a characteristic referred pain pattern that is vari- considered a normal finding by many electromyog- able in time and among individuals. Critically important raphers – a source of controversy. Endplate noise is referred pain patterns from active MTrPs throughout significantly associated with MTrPs – a fact not gen- the body are described in books (Travell and Simons erally recognized by electromyographers – but it is 1992; Simons et al. 1999; Dejung et al. 2003), also not uniquely diagnostic of MTrPs (Couppe et al. 2001; on wall charts and flip charts, and have been updated Simons et al. 2002). for masticatory muscles in a journal article (Wright Microscopic changes in muscle fibers in the region of 2000). The pain patterns help greatly to identify the the endplate include localized regions of severe sarcom- MTrP cause of the pain. The pain that limits stretch is ereshortening(contractiondisksandcontractionknots), usually located in the involved muscle, rather than in with evidence of increased tension of some fibers. The the referred pain zone. microscopic picture also suggests the possibility of abnormal calcium permeability of the muscle fiber mem- Simple Initial Examination brane (sarcolemma). Increased tension of many fibers If palpation with about 3 kilograms of calibrated con- can account for the taut band. The pathological changes sistent pressure on a spot of localized tenderness in a and natural history of MTrPs, suggest the possibility of a suspected muscle elicits referred pain that is familiar to genetic aberration of calcium channels of variable pen- the patient, that spot is likely an active MTrP. MTrPs etrance in the sarcolemma, and or neurolemma of the are then ruled in as a differential diagnosis that requires nerve terminal. 1252 Myofascial Trigger Points

pain relief helps to convince them that muscles are causing the pain, gives them a sense of control, and improves compliance for the important home stretching exercises. When the patient receives only dry needling or injection, treatment becomes the clinician’s responsibility, not the patient’s. A close physician-therapist relationship permits the physician to concentrate on injections when indicated, while the therapist teaches the patient home stretch exercises specific to the involved muscles. Treatments may cause slight discomfort, but should always be pain-free (not over about 2 or 3 on a 10 point visual analog scale) to avoid plasticity changes in the central nervous system, which enhances and prolongs pain perception. Myofascial Trigger Points, Figure 2 The integrated hypothesis postu- Treatment of myofascial trigger points (MTrPs) lates a positive feedback cycle, which characteristically involves excessive • spontaneous release of acetylcholine in a number of motor endplates asso- Manual techniques ciated with a myofascial trigger point. Mechanical stress (muscle overload) and increased autonomic activity can cause or increase abnormal spon- – Trigger point pressure release—finger pressure taneous acetylcholine release. The strong spontaneous local contractile applied to the MTrP activity increases fiber tension producing the palpable taut band, increased – Contract release—alternate voluntary contraction energy demand and local hypoxia. Together, they deplete the supply of and passive or active stretching of the muscle with adenosine triphosphate (ATP) and produce tissue distress, which releases substances that sensitize nociceptors causing MTrP pain. Shortage of ATP the MTrPs could reduce recovery of calcium into the sarcoplasmic reticulum sustain- – Vapocoolant spray and stretch—application of a ing contractile activity and increased fiber tension. See text for alternate stream of vapocoolant, or use of a covered edge of pathway (broken arrows). ice, to facilitate release

• Mechanisms by which the sensitizing substances pro- Needling techniques (require diagnostic skill) duce local tenderness and referred pain has been de- – Dry needling (as effective as injection, but leaves scribed in detail (Mense et al. 2001) (see Fig. 2). Many more post injection soreness) substances have been demonstrated histochemically (Shah et al. 2005). An alternate route to complete the feedback cycle (broken arrows) is presented, because several kinds of studies indicate that increased sympathetic nervous system activity increases the endplate noise (or endplate spikes) of a trigger point. Speciﬁc mediators have not been adequately identiﬁed for locally modulating autonomic effects, which include release of ACh packets from the nerve terminal. Both routes may occur.

Treatment Three manual treatments of MTrPs – contract-release, trigger point pressure release, and vapocoolant spray and release – are usually effective (Simons 2002). In addition, injection or dry needling provides another valuable approach (Simons et al. 1999). A quite new and remarkably effective modality that operates on a poorly explored mechanism is frequency specific microcurrent therapy (www.frequentcyspecific.com). This has been Myofascial Trigger Points, Figure 3 This schematic illustrates the demonstrated to be effective for MTrPs (McMakin mechanism by which trigger point pressure release can relieve the ten- 2004) and in patients who developed fibromyalgia fol- sion of the taut band by elongating the shortened sarcomeres, which has lowing a whiplash injury (McMakin 2005) as listed the effect of localized stretching of the muscle fibers. Like the balloon, a below. The patient benefits when treatment begins with sarcomere has a nearly constant volume, so flattening elongates it. The contracted fibers in the nodular swelling of muscle fibers represent either manual therapy rather than dry needling or injection. a contraction knot or contraction disc. The effect of trigger point pressure When patients are shown how to perform the manual release is enhanced by including a gentle voluntary contraction of that therapy on themselves, the experience of immediate muscle, while holding it at positions of progressive gentle passive stretch. Myofascial Trigger Points 1253

– Injection of 1% lidocaine (reduces post-injection vapocoolant spray and stretch, dry needling, injection soreness) of the MTrP with 1% lidocaine (to reduce post-injection – InjectionofBotulinumtoxin(specificallyformus- soreness) or with reciprocal inhibition. Following treat- cles with spasticity and MTrPs using electromyo- ment, three full cycles of active range of motion help to graphic guidance for endplate noise). normalize function of the treated muscle. If relief is still temporary,perpetuatingfactorsmustbeinvestigatedand resolved. • New possibilities Effective injection or dry needling require precise lo- – Frequency specific microcurrent therapy cation of the MTrP to enter it with the needle. Elicited – Shockwave therapy pain and local twitch responses assure a more effective treatment. Concentration on just injection encourages Figure 3 shows how trigger point pressure release neglect of home exercises and perpetuating factors, and can be effective. Shortened sarcomeres are a key part the patient usually does not understand the cause of the of the cause of MTrP symptoms. The constant-volume pain as well. balloon is analogous to a sarcomere, showing how SinceBotulinumtoxininactivatesAChreleaseatthemo- gentle but firm pressure on contraction knots (or con- tor endplate, it should be a specific therapy for MTrPs traction discs) will flatten and lengthen (normalize) the and has been effective. However, it is very expensive, shortened sarcomeres. As their tension releases, digital lasts about 3 months, can induce an immune reaction, pressure is increased. This local stretch reduces actin and is unlikely to be more effective than the other tech- and myosin overlap, which reduces contractile activity, niques described when they are skillfully applied. It is energy consumption, and ischemia – all of which tend specifically indicated in musclesthat are spastic and also to break the TrP feedback cycle. havepainfulMTrPs. Botulinum toxin ismosteffectively Contract-release (also post-isometric relaxation) re- injected under electromyographic guidance. quiresonly recognition of the painfully restricted stretch Application of shockwave technology for the localiza- M range of motion to which this treatment is then applied tion and treatment of MTrPs looks promising. (Bauer- (see Fig. 4). This can be learned and used by patients. If meister 2005; Müller-Ehrenberg and Licht 2005). necessary, additional release can often be obtained with OnereasonfortheneglectofMTrPsasamuscularsource of pain is that no medical specialty takes responsibility for research and training in allmedicalaspectsof muscle as an organ. As a result, clinical and basic research on MTrPsisconspicuousfor itsscarcity, and MTrPtraining of medical practitioners is rarely adequately covered in schools. It can be very difficult for patients to find practitioners adequately skilled in the diagnosis and treatment of MTrPs.

Myofascial Trigger Points, Table 2 Number of MEDLINE citations (main- stream medical literature) that were indexed in the past 7 years under low back pain compared to the number of trigger point citations retrieved by combining low back pain and trigger points with a low back pain and myofascial trigger point search. Year of Low Back Trigger Point Percent Publication Pain Citations Trigger Myofascial Trigger Points, Figure 4 Schematic showing effect of com- Citations Point (%) bining trigger pointpressurerelease(Finger Pressure) and contract-release, which takes advantage of the reduction in muscle tightness following a 1996 552 2 0,4 gentle (about 10 % of maximum effort) voluntary contraction. Treatment slowly alternates between gentle voluntary contractions held for several 1997 312 2 0,5 seconds,immediatelyfollowed bypassiveor activestretching ofthemuscle. This takes up slack that developed following contraction. The contraction- 1998 459 2 0,4 release cycles can be repeated rhythmically, as long as each cycle brings 1999 561 0 0 progress. The graph of a characteristic length-tension curve for one sarcomere shows that the strongly shortened sarcomeres produce much less 2000 527 3 0,6 tension than the mid-length sarcomeres throughout the rest of the muscle ﬁber. The mid-length sarcomeres are both stronger and far outnumber the 2001 537 3 0,6 shortened sarcomeres, so a gentle contraction temporarily increases the length of the shortened sarcomeres. Several cycles of full range of motion 2002 553 5 0,9 help to consolidate treatment gains. The two techniques are combined for increased therapeutic effectiveness. 1996–2002 3601 17 0,5 1254 Myoﬁbrositis

Unfortunately, many practitioners were not trained to 13. Travell JG, Simons DG (1992) Myofascial Pain and Dysfunc- include MTrPs as a differential diagnosis for muscu- tion: The Trigger Point Manual, vol 2. The Lower Extremities. Williams & Wilkins, Baltimore loskeletal pain. Low back pain (LBP) causes much 14. Wolfe F, Ross K, Anderson J et al. (1998) The Prevalence human suffering and health care costs. However, of the and Characteristics of Fibromyalgia in the General Population. 3,501 LBP citations retrieved from MEDLINE covering Arthritis Rheum 38:19–28 the past seven years, less than 1% were also indexed as 15. Wright EF (2000) Referred Craniofacial Pain Patterns in Patients including MTrPs (see Table 2). Moreover, much LBP with Temporomandibular Disorder. JADA 131:1307–1315 is either caused by MTrPs or has a significant MTrP component. A number of papers that do relate MTrPs and LBP describe MTrPs, but do not identify them in Myofibrositis the title or abstract. A few articles that identified MTrPs in LBP were published in journals that are not listed Myalgia by MEDLINE. Most authors writing about LBP do not include MTrPs as part of their routine differential diagnosis. A recent series of papers by César Fernández of spain Myogelosis and collegues is now appearing in the scientific literature that indicate a strong relationship between MTrPs Myalgia and several kinds of headache (Fernández et. Al 2005; Fernández et al. 2006). Central Trigger Point Chronic Pelvic Pain, Physical Therapy Approaches Myositis and Myofascial Abnormalities DIETER PONGRATZ Dry Needling Friedrich Baur Institute, Medical Faculty at Myalgia the Neurological Clinic and Policlinic, Ludwig References Maximilians University, Munich, Germany [email protected] 1. Bauermeister W (2005) Diagnose und Therapie des My- ofaszialen Triggerpunk Syndroms durch Lokalisierung und Stimulation Sensibilisierter Nozizeptoren mit Focussierten Synonyms Elektrohydraulischen Stosswellen. MOT 5:65–74 2. Couppé C, Midttun A, Hilden J et al. (2001) Spontaneous Needle Inflammatory Myopathies Electromyographic Activity in Myofascial Trigger Points in the Infraspinatus Muscle: A Blinded Assessment. J Musculoske Pain Definition 9:7–16 3. Dejung B, Gröbli C, Colla F et al. (2003) Triggerpunkt-Therapie Inflammatory Myopathies represent a small, but from a (Trigger Point Therapy). Hans Huber Verlag, Bern therapeutical point of view, important group of acquired 4. Gerwin RD, Shannon S, Hong C-Z et al. (1997) Interrater Reli- muscular disorders. With the exception of infectious ability in Myofascial Trigger Point Examination.Pain 69: 65–73 causes (viral myositis, bacterial myositis, and parasitic 5. Hsieh C-Y, Hong C-Z, Adams AH et al. (2000) Interexaminer Reliability of the Palpation of Trigger Points in the Trunk and myositis) immunogenic forms have to be considered. Lower Limb Muscles. Arch Phys Med Rehabil 81:258–264 There are 4 different forms: 6. Mense S, Simons DG, Russell IJ (2001) Muscle Pain: Its Na- ture, Diagnosis, and Treatment. Lippincott, Williams & Wilkins, 1. Dermatomyostis Philadelphia 2. Overlap Syndromes 7. Sciotti VM, Mittak VL, DiMarco L et al. (2001) Clinical Pre- 3. Polymyositis cision of Myofascial Trigger Point Location in the Trapezius Muscle. Pain 93:259–266 4. Inclusion Body Myositis 8. Shah JP, Phillips T, Danoff J et al. (2004) Novel Microanalytical Technique Distinguishes Three Clinically Distinct Groups: 1) Subjects without Pain and without a Myofascial Trigger Point; Characteristics 2) Subjects without Pain with a Myofascial Trigger Point; 3) The most prominent clinical symptoms of all immuno- Subjects with Pain and a Myofascial Trigger Point. Am J Phys Med Rehabil 83:231 genic inflammatory myopathies are muscle weak- 9. Simons DG (2001) Do Endplate Noise and Spikes Arise from ness and muscle atrophy. Muscle pain is common in Normal Motor Endplates? Am J Phys Med Rehabil 80:134–140 dermatomyositis and overlap syndromes, but is less 10. Simons DG (2002) Understanding Effective Treatments of My- prominent or even missing in chronic polymyositis ofascial Trigger Points. J Bodywork and Movement Therapy 6:81–88 and especially inclusion body myositis. From a clinical 11. Simons DG, Hong C-Z, Simons LS (2002) Endplate Potentials point of view, there is a predominant involvement of are Common to Midfiber Myofascial Trigger Points. Am J Phys the proximal muscles of the limbs and the arms. Only Med Rehabil 81:212–222 in inclusion body myositis is the presence of distal 12. Simons DG, Travell JG, Simons LS (1999) Travell & Simons’ Myofascial Pain and Dysfunction: The Trigger Point Manual, muscle weakness, especially of the foot extensors and vol 1, edn 2. Williams & Wilkins, Baltimore finger flexors, a diagnostic clue from the beginning. Myositis 1255

The pharyngeal and neck flexor muscles are often af- seen by electron microscopy. Perifascicular atrophy fected in all forms of myositis causing dysphagia and, and fiber damage is diagnostic of dermatomyositis even at times, difficulties in holding up the head. Muscular in the absence of infiltration. wasting develops during the course of the illness, and Immunohistological methods show that the cellular in- is pronounced in chronic polymyositis and inclusion filtrates in this disease consist of B lymphocytes, CD4+ body myositis. lymphocytes and macrophages. C5b9 complement de- posits within small blood vessels are very characteris- Special Signs of Dermatomyositis tic, causing destruction of the capillaries and muscle is- Dermatomyositis is characterized by skin lesions ac- chemia. companying or preceding muscle symptoms. There is In polymyositis, infiltrates are predominantly en- the typical heliotrope erythema (lilac disease), involv- domysial, producing the picture of a diffuse myositis. ing especially the eyelids, face, and upper trunk. More There is no evidence of microangiopathy. Immunohis- chronic skin lesions show depigmentation and hyper- tologically, cytotoxic CD8+ lymphocytes are the pre- pigmentations. As the disease progresses, subcutaneous dominant cells that invade nonnecrotic muscle fibers. calcifications occur. The muscle fibers themselves aberrantly express major histocompatibility complex class I (MHC I) antigen, Laboratory Diagnosis and Differential Diagnoses which is absent in normal muscle. Laboratory diagnosis is based on: Inclusion body myositis is characterized by endomysial inflammation with CD8+ lymphocytes in particular, 1. Measurement of muscle enzymes similar to those seen in polymyositis. In addition, 2. Electromyography rimmed vacuoles with eosinophilic cytoplasmatic in- 3. Muscle biopsy clusions can be found, as a rule, within many muscle 4. In some cases, clinical or laboratory signs of an asso- fibers. On electronmicroscopy,the vacuoles correspond ciated connective tissue disease may be an additional to the so-called autophagic vacuoles. In addition, fil- M aid ( overlap syndromes) amentous inclusions in the cytoplasm and nuclei are Muscle MRI with STIR sequence is helpful in chronic prominent. formstoestablishthebestpositionforperformingamus- High levels of myositis-associated autoantibodies are cle biopsy (muscle edema). found in overlap syndromes. The level of muscle enzymes, especially creatine kinase (CK), usually parallels disease activity, and can be ele- Natural Course vated in acute stagesby asmuch as50× above normal. In The incidence of polymyositis, dermatomyositis and rare cases of active polymyositis and dermatomyositis, inclusion body myositis is approximately 1/100.000. however, CK can also be within normal range. In inclu- The natural course of polymyositis and deratomyositis sion body myositis, the level of CK is not usually ele- is relatively unknown because patients are almost al- vated more than 10-fold, and in some cases it may be ways treated with steroids. Inclusion body myositis is normal. relatively resistant to all therapies and, as a rule, slowly Needle electromyography shows myopathic poten- progressive. tials characterized by short duration, low amplitude Principles of Therapy and polyphasic configuration on voluntary activation in combination with increased spontaneous activity As corticosteroids and immunosuppressive drugs seem (fibrillations, positive sharp waves, complex repeti- to be of benefit, polymyositis and dermatomyositis be- tive discharges). This pattern also occurs in a variety long to the treatable group of myopathies. In contrast, of active myopathic processes of other origins, and inclusion body myositis is resistant to most therapies, should therefore not be considered diagnostic for the although treatment with intravenous immunoglobulins inflammatory myopathies. Mixed myopathic and neu- maybeofsomebenefit. rogenic potentials may be present in some cases as a Muscle Pain in Systemic Inflammation (Polymyalgia consequence of inclusion body myositis. Rheumatica, Giant Cell Arteritis, Rheumatoid Arthri- Muscle biopsy is the definitive test, not only for estab- tis) lishing the diagnosis of dermatomyositis, polymyositis Muscle Pain Model, Inflammatory Agents-Induced or inclusion body myositis, but also for excluding other Nocifensive Behaviors (Muscle and Joint) neuromuscular disorders. Opioids and Muscle Pain In dermatomyositis inflammatory infiltrates are found predominantly in perivascular and perifascicular re- References gions, producing the characteristic picture of a myositis 1. Dalakas MC, Illa I, Dambrosia JM (1993) A Controlled Trial of of the perifascicular type. There are striking lesions of High-Dose Intravenous Immune Globulin Infusions as Treatment for Dermatomyositis. N Eng J Med 329:1993–2000 the small intramuscular blood vessels, with endothelial 2. Dalakas MC (1991) Polymyositis, Dermatoyositis, and Inclusion proliferation and so-called tubulovesicular inclusions Body Myositis. N Eng J Med 325:1487–1498 1256 Myotomal Pain

3. Dalakas MC, Pongratz D (2003) Inﬂammatory Myopathies Neu- rological Disorders – Course and Treatment: Muscle and Periph- Myotomal Pain eral Nervous System, chapter 95, 2nd edn. Elsevier Science, USA 4. Pongratz DE (1992) Myositiden. In: Therapiehandbuch. Urban Myofascial Pain an Schwarezenberg, Munich, Vienna, and Baltimore, MD 5. Walter MC, Lochmüller H, Toepfer M (2000). High Dose Im- munoglobulin Therapy in Sporadic Inclusion Body Myositis: A Double-Blind, Placebo-Controlled Study. J Neurol 247:22–28