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New Frontiers in the Matrix of Chronic Myofascial Pain: Integrating Pain Mechanisms with Objective Physical findings and Treatment Strategies Jay P. Shah, MD Massage and Myotherapy Australia 2017 Annual Conference Melbourne, Australia May 26 th , 2017
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Page 1: New Frontiers in the Matrix of Chronic Myofascial Pain€¦ · Myofascial trigger point diagnostic criteria Myofascial pain is identified by palpating skeletal muscle for myofascial

New Frontiers in the Matrix of

Chronic Myofascial Pain:

Integrating Pain Mechanisms with Objective

Physical findings and Treatment Strategies

Jay P. Shah, MD

Massage and Myotherapy Australia

2017 Annual Conference

Melbourne, Australia

May 26th, 2017

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Journal of Bodywork and Movement Therapies (2008) 12, 371–384

Bodywork and

Journal of

Movement Therapies

1360-8592/$ - sdoi:10.1016/j.j

�Correspondifax: +1 301 480

E-mail addr

www.elsevier.com/jbmt

MYOFASCIAL PAIN RESEARCH

Uncovering the biochemical milieu of myofascialtrigger points using in vivo microdialysis:An application of muscle pain concepts tomyofascial pain syndrome

Jay P. Shah, MD�, Elizabeth A. Gilliams, BA

Rehabilitation Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive,Room 1-1469, MSC 1604, Bethesda, MD 20892-1604 USA

Received 8 April 2008; received in revised form 27 May 2008; accepted 3 June 2008

KEYWORDSInflammation;Microdialysis;Myofascial pain;Rehabilitation;Myofascial triggerpoints

ee front matter & 2008bmt.2008.06.006

ng author. Tel.: +1 3010669.ess: [email protected].

Summary This article discusses muscle pain concepts in the context of myofascialpain syndrome (MPS) and summarizes microdialysis studies that have surveyed thebiochemical basis of this musculoskeletal pain condition. Though MPS is a commontype of non-articular pain, its pathophysiology is only beginning to be understooddue to its enormous complexity. MPS is characterized by the presence of myofascialtrigger points (MTrPs), which are defined as hyperirritable nodules located within ataut band of skeletal muscle. MTrPs may be active (spontaneously painful andsymptomatic) or latent (non-spontaneously painful). Painful MTrPs activate musclenociceptors that, upon sustained noxious stimulation, initiate motor and sensorychanges in the peripheral and central nervous systems. This process is calledsensitization. In order to investigate the peripheral factors that influence thesensitization process, a microdialysis technique was developed to quantitativelymeasure the biochemical milieu of skeletal muscle. Biochemical differences werefound between active and latent MTrPs, as well as in comparison with healthy muscletissue. In this paper we relate the findings of elevated levels of sensitizingsubstances within painful muscle to the current theoretical framework of musclepain and MTrP development.& 2008 Published by Elsevier Ltd.

Published by Elsevier Ltd.

496 4412;

gov (J.P. Shah).

Introduction

Myofascial pain syndrome (MPS) is a major progeni-tor of non-articular local musculoskeletal pain and

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J.P. Shah, E.A. Gilliams372

tenderness that affects every age group, and iscommonly recognized as ‘‘muscle knots’’ (Kaoet al., 2007). MPS has been associated withnumerous pain conditions including radiculopa-thies, joint dysfunction, disk pathology, tendonitis,craniomandibular dysfunction, migraines, tension-type headaches, carpal tunnel syndrome, compu-ter-related disorders, whiplash-associated disor-ders, spinal dysfunction, and pelvic pain andother urologic syndromes, post-herpetic neuralgia,and complex regional pain syndrome (Borg-Steinand Simons, 2002).

Characterized by a physical finding and symptomcluster, MPS lacked demonstrable pathology andattracted little research attention until recently.Although the specific pathophysiological basis ofMTrP development and symptomatology is un-known, several promising lines of scientific study(i.e. histological, neurophysiological, biochemical,and somatosensory) have revealed objective ab-normalities (Reitinger et al., 1996; Windisch et al.,1999; Mense, 2003; Shah et al., 2005, 2008; Kuan etal., 2007; Niddam et al., 2007). These findingssuggest that myofascial pain is a complex form ofneuromuscular dysfunction consisting of motor andsensory abnormalities involving both the peripheraland central nervous systems. MPS is not to beconfused with fibromyalgia syndrome, which isascribed to a collection of complaints includingchronic widespread pain, accompanied by tactileallodynia, fatigue, sleep disturbance, and psycho-logical distress (Wolfe et al., 1990).

Figure 1 Schematic of a trigger point complex. CTrPidentifies the central trigger point that is found in theendplate zone and contains numerous contraction knotsand electrically active loci among normal fibers. A tautband of muscle fibers extends from the trigger point tothe attachment (ATrP) at each end of the involved fiber.(Adapted from Simons, D.G., Travell, J.G. Myofascial Painand Dysfunction: The Trigger Point Manual, vol. 1; seconded., and Anvandare: Chrizz.)

Historical terminology

Since muscle pain and particularly MPS is describedas diffuse and can often refer to deep somatictissue, terminology regarding muscle pain has beencontroversial. The first descriptions of ‘‘muscularrheumatism’’ were made by a French physician, deBaillou, in the 16th century (Stockman, 1904).Later observations by the British physician Balfourin 1816 described nodular tumors and thickenings(Stockman, 1904). In the early 20th century,literature on muscle pain used several terms thatdescribed similar conditions: myalgic spots, fibro-sitis, and myogeloses—all used to identify painfulareas of hardened muscle. In 1940, Steindlerintroduced the term ‘‘trigger point’’ in a series ofpapers on gluteal myofascial pain (Steindler andLuck, 1938; Steindler, 1940). In the 1950s, Travelland Rinzler observed that fascia referred painpatterns appeared similar to underlying musclereferred pain patterns, leading them to alter theirterminology to ‘‘myofascial pain’’ to highlight the

interaction between these elements (Travell andRinzler, 1952; Travell, 1968).

Myofascial trigger point diagnosticcriteria

Myofascial pain is identified by palpating skeletalmuscle for myofascial trigger points (MTrPs). A MTrPis classically defined by Simons and Travell as ‘‘ahyperirritable spot in skeletal muscle that isassociated with a hypersensitive palpable nodulein a taut band’’ (Simons et al., 1999). Figure 1illustrates the trigger point complex. MTrPs aresensitive to pressure and are stiffer than surround-ing tissue. Palpation of a MTrP produces local painand sensitivity, as well as diffuse and referred painpatterns away from the affected area. Triggerpoints are classified in two ways. An ‘‘active’’ MTrPwill elicit pain locally and at some distance fromthe MTrP and generate seemingly spontaneous paincomplaints. ‘‘Latent’’ MTrPs show similar physicalcharacteristics as active MTrPs only when palpated,and can cause muscle dysfunction. Both active andlatent MTrPs are responsible for motor dysfunction,such as stiffness and restricted range of motion, aswell as autonomic dysfunction, though to a lesser

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Uncovering the biochemical milieu of MTrPs using in vivo microdialysis 373

degree for latent MTrPs (Travell and Simons, 1983;Mense and Simons, 2001). Healthy muscle tissuedoes not contain MTrPs. The cause of MPS and thedevelopment of active MTrPs are often linked topostural problems, muscle overload and overworkfatigue, as well as emotional stress (Mense andSimons, 2001). While the pain associated withMTrPs sometimes resolves without intervention,the mechanism(s) that underlies this change is notfully understood. Clinical observations support thatMPS may become chronic if perpetuating factorsare present (Edwards, 2005).

One of the most important characteristics foundin clinical examination that confirms the presenceof a MTrP is the local twitch response (LTR).Strumming or snapping the taut band in a directionperpendicular to muscle fibers produces a quickcontraction in the muscle fibers of the taut band.The origin of the LTR is not yet fully understood,though this response may be due to altered sensoryspinal processing resulting from sensitized periph-eral mechanical nociceptors (Mense and Simons,2001).

There are several widely accepted treatmentmethods for MPS and soft tissue pain, and althoughthere is no single accepted standard of care, dryneedling is an effective non-pharmacologic treat-ment that is thought to induce changes in theMTrP’s surrounding fascia (Hong, 1994; Langevin,2008). In this technique, a fine gauge acupunctureneedle is inserted into the MTrP and manipulateduntil several LTRs are elicited. Direct mechanicalstimulation through dry needling may induceconnective tissue remodeling and plasticity tointerrupt the pathogenic mechanism of MTrPs.Other needling therapies, such as superficial dryneedling, as well as manual therapies includingmassage and stretching, are targeted at releasingcontractured muscle fibers and surrounding con-nective tissue (Mense and Simons, 2001).

Figure 2 Comparisons of normal miniature endplatepotentials (MEPP, a result of random release of AChpackets) and endplate noise (EPN, thought to be a sign ofabnormal and increased motor endplate activity). (A)Normal human MEPPs. (B) Normal rat MEPPs. (C)Experimentally induced endplate noise. This methodproduced a thousand time increase of ACh release. (D)Textbook ‘‘normal’’ endplate potentials, with evidenceof EPN. (E) Endplate noise and spikes from a humantrigger point. (Reproduced by kind permission of ElsevierLtd., from Simons, 2004.)

Motor abnormalities of the myofascialtrigger point

Electrophysiology

The pathophysiology of MTrPs is incompletelyunderstood. MTrPs are hypothesized to be a resultof physiological dysfunction within the neuromus-cular junction and the surrounding connectivetissue. There is evidence that motor endplates ofneurons terminating at the muscle fibers of a MTrPhave abnormal activity. Electromyographic studieshave revealed spontaneous electrical activity (SEA)

generated at MTrP loci that was not seen insurrounding tissue (Hubbard and Berkoff, 1993).Originally attributed to dysfunctional muscle spin-dles, the excess electrical activity was lateridentified as an increase in miniature endplatepotentials and excessive acetylcholine (ACh) re-lease (Hubbard and Berkoff, 1993). Figure 2 dis-plays a comparison of endplate potentials andnoise. The dysfunctional motor endplates withinthe MTrP tissue is one piece of evidence that mayexplain the taut band phenomenon. Wang and Yu(2000) and others have hypothesized that theexcessive ACh release perpetuates a contractureof associated muscle fibers, resulting in increasedmetabolic demands in the muscle (Wang and Yu,2000; Mense and Simons, 2001). However, there isstill much controversy as to whether SEA representsnormal muscle endplate activity. There is disagree-ment in electromyography and physiology litera-ture on the significance of abnormal motorendplate potentials and ‘‘endplate noise.’’ Accord-ing to Simons, investigators who lack training inexamining muscles for MTrPs may misinterpret aMTrP’s abnormal ‘‘endplate noise’’ as a normalfinding (Wiederholt, 1970; Simons, 2004).

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The Integrated Trigger Point Hypothesis

Encompassing the pathophysiology of the motorendplate activity is the Integrated Trigger PointHypothesis introduced by Simons, which bringstogether several findings of MTrPs to describe apossible sequence of MTrP development (Simonset al., 1999). Included in this sequence is an‘‘energy crisis’’ that perpetuates an initial sus-tained contracture at the muscle fibers near anabnormal endplate. Due to excessive ACh releasefrom the motor endplate, it is hypothesized thatsustained sarcomere contracture leads to increasedlocal metabolic demands and compressed capillarycirculation. With reduced blood flow and dimin-ished sources of adenosine triphosphate (ATP),muscle fibers are locked in a contracture withoutsufficient energy to return Ca2+ to the sarcoplasmicreticulum and restore a polarized membranepotential. Additionally, the local hypoxic conditionsand energy crisis may elicit the release of neuror-eactive substances and metabolic by-products thatcould sensitize peripheral nociceptors (Huguenin,2004).

The Cinderella Hypothesis

The Cinderella Hypothesis (Hagg, 1988) provides apossible explanation of MTrP development thatcomplements the Integrated Trigger Point Hypoth-esis (Simons et al., 1999). The Cinderella Hypoth-esis describes how musculoskeletal disordersymptoms may arise from muscle recruitmentpatterns during sub-maximal level exertions witha moderate or low physical load. According toHenneman’s ‘‘size principle’’, smaller type 1muscle fibers will be recruited first and be de-recruited last during these static exertions, usingonly a fraction of motor units available. As a result,these ‘‘Cinderella’’ fibers are continuously acti-vated and metabolically overloaded, while largermotor units do not work as hard and spend less timecontinuously activated. Sub-maximal exertions,such as postural maintenance, can lead to possiblemuscle damage and disturbance of Ca2+ home-ostasis, suspected features that may contribute toMTrP pain. A study by Treaster et al. (2006)supports the Cinderella Hypothesis. The studydemonstrated that low-level, static, continuousmuscle contractions in office workers during 30minof typing induced the formation of MTrPs. Theirfindings suggest that ‘‘ya MTrP may provide auseful explanation for muscle pain and injury thatcan occur from low level static exertions’’ (Treasteret al., 2006).

Sensory abnormalities of the myofascialtrigger point

Nociceptor properties

Sensory processing and pain perception are keyaspects in the description of MPS, along with theabnormal motor findings mentioned above. Trans-duction of local pain sensation often begins withthe sensitization and activation of nociceptivesensory receptors. Nociceptors are located at freenerve endings in muscle, joint, skin, viscera, andblood vessels. Furthermore, muscle nociceptorsmay make up 50% of the composition of musclenerves (Willard, 2008). The abundance of thesenociceptors may explain the severity of pain andexquisite tenderness in the muscle upon palpation.Nociceptors also innervate the surrounding con-nective tissue of muscle fibers (Langevin, 2008;Willard, 2008). A preliminary study in mice indi-cates that sensory afferent and nociceptive term-inals are located in subcutaneous perimuscularfascia (Corey et al., 2007). Neurons involved inpain processing can be polymodal, meaning theycan be activated by several stimuli, depending onwhether they contain chemoreceptors, mechanor-eceptors, or thermoreceptors. Continuous activa-tion of muscle nociceptors is very effective atinducing neuroplastic changes and central sensiti-zation in dorsal horn neurons (Wall and Woolf,1984).

Chemical activation of afferent nerves

Muscle nociceptors monitor the sensitizing or pain-producing substances, as well as the strength of thestimuli present in the peripheral environment.Chemical activation of nociceptors by substancesreleased from surrounding damaged tissue orimmune cells is responsible for the muscle sorenessand pain associated with MPS (Gerwin et al., 2004).Chemical activation is specific at the nociceptor,where there are distinct receptors for substancesincluding bradykinin (BK), prostaglandins (PG), 5-hydroxytryptamin/serotonin (5-HT), protons (H+),adenosine triphosphate (ATP), and glutamate, aprimary excitatory neurotransmitter. There are alsopurinergic and vanilloid receptors. Purinergic re-ceptors bind ATP, which is released during muscletissue trauma (Cook and McCleskey, 2002). Vanilloidreceptors respond to low pH, and therefore areactivated under ischemic conditions where pH isacidic (Caterina and Julius, 1999). 5-HT is releasedfrom platelets and mast cells following tissueinjury. Nociceptor terminals also contain the

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Uncovering the biochemical milieu of MTrPs using in vivo microdialysis 375

neuropeptides substance P (SP) and calcitoningene-related peptide (CGRP), which cause vasodi-lation, plasma extravasation, and stimulation of aninflammatory cascade within the peripheral milieu.

The biochemicals that are released from injuredtissue stimulate a unique cascade of cytokines thatare integral to the inflammatory response. Forexample, BK and 5-HT are two agents that arereleased immediately at damaged tissue andstimulate cytokines that are involved in complexpain pathways. Pro-inflammatory cytokines in-volved in these pathways, such as tumor necrosisfactor alpha (TNF-a), Interleukin 1-beta (IL-1b),Interleukin 6 (IL-6), and Interleukin 8 (IL-8), havebeen shown to induce hypernociception whenadministered to peripheral tissue in animal models(Verri et al., 2006). Additionally, anti-inflammatorymediators are released in parallel to this pathway.

Endogenously released pain and inflammatorymediators not only carry nociceptive signals forcentral processing, but also alter the local condi-tions at the site of tissue damage. SP, in particular,alters the local microcirculation and vessel perme-ability, leading to local edema. Several biochem-icals, including BK, PG, 5-HT, CGRP, and SP, haveboth nociceptive and vasodilatory effects. There-fore, the release of these substances can increaselocal blood flow and pressure, activating mechan-oreceptors and nociceptors, leading to increasedlocal tenderness and pain. In addition, a persistentbarrage of algogenic substances leads to changes innociceptor responsiveness. For example, inflamma-tion in peripheral tissue changes the number andpopulation of BK receptors at the nociceptorterminal (Cunha et al., 2007). Thus, the biochem-ical cascade of inflammation makes primary affer-ent neurons susceptible to abnormal depolarizationactivity by various means, enhancing peripheraland central sensitization.

Peripheral and central sensitization

Sensitization of both peripheral and central affer-ents is responsible for the transition from normal toaberrant pain perception in the central nervoussystem that outlasts the noxious peripheral stimu-lus. In animal models of pain, nociceptive inputfrom skeletal muscle is much more effective atinducing neuroplastic changes in the spinal cordthan noxious input from the skin (Wall and Woolf,1984). Continuous input from peripheral musclenociceptors may lead to changes in function andconnectivity of sensory dorsal horn neurons viacentral sensitization. For example, sustained nox-ious input from an active MTrP may sensitize dorsal

horn neurons, leading to hyperalgesia and allody-nia, as well as generate expanded referred painregions. A possible explanation for this phenomen-on is increased synaptic efficiency through activa-tion of previously silent (ineffective) synapses atthe dorsal horn.

This concept was demonstrated in a rat myositismodel, in which experimentally induced inflamma-tion unmasked receptive fields remote from theoriginal receptive field, indicating that dorsal hornconnectivity expanded beyond the original neuronsinvolved in nociceptive transmission (Hoheiselet al., 1994). In this study, nociceptive inputresulted in central hyperexcitability, which helpsto explain referred pain patterns common to MPS.Central sensitization may also facilitate additionalresponses from other receptive fields due toconvergent somatic and visceral input at the dorsalhorn (Sato, 1995). Afferent fibers can also sproutnew spinal terminals that broaden synaptic con-tacts at the dorsal horn, and may contribute toexpanded pain receptive fields (Sperry and Gosh-garian, 1993). This change in functional connectiv-ity occurs within a few hours, before metabolic andgene induction changes in dorsal horn neurons(Mense and Hoheisel, 2004).

There is a biochemical basis to the developmentof peripheral and central sensitization in musclepain. Continuous activation of muscle nociceptorsleads to the co-release of glutamate and SP at thepre-synaptic terminals of the dorsal horn. Inaddition to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptorsby glutamate at the post-synaptic terminal, SPfacilitates activation of previously dormantN-methyl-D-aspartate (NMDA) receptors. This leadsto maximal opening of calcium-permeable ionchannels, which hyperexcites nociceptive neuronsand induces apoptosis of inhibitory interneurons(Mense, 2003), as seen in Figure 3. Consequently, apersistent noxious barrage from the periphery cancreate long-lasting alterations in the centralnervous system. Metabolic and gene inductionchanges, such as cyclo-oxygenase 2 (COX-2) induc-tion in dorsal horn neurons, are maximal at severalhours after an initial noxious stimulation andbolster functional changes after peripheral tissueinjury (Woolf, 2007).

In addition, glial cells that surround primaryafferent neurons can contribute to central sensiti-zation in the dorsal horn. In particular, astrocytesand microglia are activated by SP, and can producecytokines (such as TNF-a, IL-1, and IL-6) thatsensitize neurons and generate hyperalgesia(Watkins et al., 2007). Activated glial cells alsoinduce a rise in SP release from central terminals of

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Figure 3 Transition from normal to pathological pain perception, via central sensitization at the spinal cord dorsalhorn. Insets of central synaptic transmission. (A) Acute nociceptive transmission. Nociceptive signals may originatefrom muscle, cutaneous, or visceral afferent neurons. (B) Centrally sensitized nociceptive transmission. Convergence ofmuscle, cutaneous, and visceral afferents can be responsible for referred pain patterns. Activation of ineffectivesynapses in the dorsal horn may create additional receptive pain fields of pain. For example, input from the extensorcarpi radialis longus normally activates neuron I. With intense and/or continuous noxious input from the extensor carpiradialis longus, another previously ineffective (silent) synapse may be converted into an effective (active) synapse.Here, a synapse to neuron II, which normally receives input from the biceps brachii, becomes effective. The expansionof effective spinal connections at neuron II can create a new receptive field of pain at the biceps brachii, where nonociceptor is being activated and the tissue is normal. Increased neurotransmitter release at the dorsal horn altersreceptor ion channel activity. All of these factors contribute to central hyperexcitability via protein kinase activationand gene induction. Glu: glutamate, SP: substance P, CGRP: calcitonin gene-related peptide, GABA: gamma-aminobutyric acid, AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazole propionate, NMDA: N-methyl-D-aspartic acid, NK1:neurokinin 1. (Adapted from Mense, 2003; Vadivelu, N., Sinatra, R., 2005. Recent advances in elucidating painmechanisms. Current Opinion in Anaesthesiology 18, 540–547; Willard, 2008.)

J.P. Shah, E.A. Gilliams376

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Uncovering the biochemical milieu of MTrPs using in vivo microdialysis 377

primary afferent neurons, thus contributing to theexcessive calcium influx and the subsequent centralnervous system alterations described above (Inoueet al., 1999).

Though experimental mechanisms have impli-cated endogenously released substances in musclepain, the pathogenesis of MPS is still unclear (Mense,2003). As a result, standard treatments of MPS arelargely empirical and suboptimal. Treatments mayimprove symptoms, though may not resolve allsymptoms or eliminate the MTrP (Bennett, 2007).Eliciting an LTR through dry needling often has atherapeutic benefit (Hong, 1994). As mentionedabove, the initial peripheral conditions (inflamma-tion, ischemia, and hypoxia) within muscle seem tobe the source of feed-forward mechanisms thattransform and intensify central processing of musclepain. Therefore, assaying the peripheral milieu of aMTrP before, during, and after an LTR could disclosechanges in bioactive substances that may contributeto myofascial pain.

Figure 4 (A) Microdialysis schematic and (B) photo ofneedle. (Reproduced with kind permission by the Amer-ican Physiological Society and Elsevier, Ltd., from Shahet al., 2005, 2008.)

Uncovering the biochemical milieu ofmyofascial trigger points

We developed a microanalytical system to samplethe unique biochemical milieu of substances relatedto pain and inflammation in muscle tissue with andwithout MTrPs (Shah et al., 2005). This systememployed a minimally invasive 30-gauge needlecapable of in vivo collection of small volumes(�0.5ml) at sub nanogram levels (o75 kDa). Theneedle (Figure 4) has the same size and shape as anacupuncture needle and allows simultaneous sam-pling of skeletal muscle tissue when an LTR iselicited by advancement of the sampling needle.The complete sampling setup includes a microdia-lysis pump and Terasaki plate for fluid collection.

Clinicians use various dry needling techniques toinduce multiple LTRs in order to achieve therapeu-tic benefit (Chen et al., 2001; Dommerholt et al.,2006; Shah, 2008). The LTR is an involuntary spinalreflex contraction of muscle fibers within a tautband, and occurs during needling of a taut band. Asthis event is associated with pain relief andreduction of stiffness (Hsieh et al., 2007), samplingat the muscle during this event could reveal aspectsof the LTR’s biochemical basis.

Microdialysis sampling of the trapezius

In one study, the microanalytical system was usedto measure the local biochemical milieu ata standardized location, the acupuncture point

GB-21, at the upper trapezius muscle (Shah et al.,2005). Based on patient history and physicalexamination, nine subjects were classified intoone of three groups:

Group 1—Normal (no neck pain, no MTrP); � Group 2—Latent (no neck pain, MTrP present); � Group 3—Active (neck pain, MTrP present).

Samples were obtained at regular intervals

before needle movement, during needle advance-ment and LTR, and after the LTR, for a total of15min. After collection, dialysate samples wereanalyzed by immunoaffinity capillary electrophor-esis (ICE) and capillary electrochromatography(CEC). Outcome measures were levels of pH, andconcentrations of SP, CGRP, BK, 5-HT, norepinephr-ine (NE), TNF-a, and IL-1b.

The results showed that overall, the concentra-tions of SP, CGRP, BK, 5-HT, NE, TNF-a, and IL-1bwere higher in the Active group than in the Latentand Normal groups (po0.01). In addition, pH levelswere significantly lower in the Active group,indicating a greater concentration of protons thanin the Latent and Normal groups (po0.03). Therewere no overall differences between the Latentand Normal groups. At post-LTR for the Activegroup, concentrations of SP and CGRP weresignificantly lower than ‘‘pre’’ (2min following

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J.P. Shah, E.A. Gilliams378

needle insertion) or ‘‘peak’’ (about 5min followingneedle insertion) values (po0.02). These resultsshowed that the biochemical milieu of active MTrPsis different from latent MTrPs and normal tissue.Also, the milieu changes with the occurrence of aLTR, corresponding to clinically observed decreasein pain and tenderness after MTrP release by dryneedling. Changes in analyte levels after an LTRmight result from increasing local blood flow to theMTrP region, leading to a ‘‘wash out’’ of the painand inflammatory mediators.

Microdialysis sampling of the trapezius andgastrocnemius

In a second study, we sought to investigate whetherthe differences in levels of inflammatory media-

0

4

8

pH U

nits

Trapezius

Trapezius

0

100

200

300

0.00 5.00 10.00 15Time

pM/L

Figure 5 Analyte concentrations for the trapezius comparedwith kind permission by Elsevier Ltd., from Shah et al., 2008

tors, neuropeptides, catecholamines, and cyto-kines are present not only at the site of the MTrP,but also in an uninvolved site remote from the MTrP(Shah et al., 2008). Accordingly, samples werecollected from nine additional subjects using thesame procedure as the previous study at the uppertrapezius. Additionally, samples were also col-lected from a site in the upper medial gastro-cnemius at the acupuncture point LV-7. The sitewas examined before sampling to verify that noneof the subjects had active or latent MTrPs presentat this location in the muscle.

Results from the second study confirmed that inthe upper trapezius muscle, concentrations ofbiochemicals associated with pain and inflamma-tion agreed with levels found in the previousstudy. These findings verify that the selectedanalytes are elevated in soft tissue in the vicinity

Gastrocnemius

Gastrocnemius

.00 0.00 5.00 10.00 (min)

to the gastrocnemius for (A) pH and (B) BK. (Reproduced.)

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Uncovering the biochemical milieu of MTrPs using in vivo microdialysis 379

of active MTrPs. Two additional analytes known tobe associated with inflammation and intercellularsignaling, IL-6 and IL-8, were also measured. Theseanalytes were overall significantly elevated in theupper trapezius of the Active group compared tothe Latent and Normal groups (po0.002). As in theprevious study, each of the groups demonstrateddifferent responses to needle insertion in thetrapezius. The Active group exhibited the largestand most elevated response, the Latent group anintermediate response, and the Normal groupexhibited the smallest.

Comparisons between the trapezius and thegastrocnemius showed differences in levels ofanalytes, as seen in Figures 5–7. Within the Activegroup, almost all measurements of concentrationsfor the gastrocnemius were lower than concentra-tions for the trapezius muscle. In the Latent group,most gastrocnemius concentrations were signifi-

Figure 6 Analyte concentrations for the trapezius comparedwith kind permission by Elsevier Ltd., from Shah et al., 2008

cantly lower than trapezius peak values, though notfor other measurements in the trapezius. The onlyexception was pH, for which levels were similarwithin the trapezius and gastrocnemius muscles.This information showed that the biochemicalmilieu of active MTrPs in the upper trapezius differsquantitatively from a remote, uninvolved site inthe gastrocnemius muscle.

Analyte levels in the gastrocnemius were alsocompared among the Active, Latent, and Normalgroups. Although there were no MTrPs in any of thesubjects at the upper medial gastrocnemius, theanalyte concentrations of the Active group weresignificantly higher than in the Latent and Normalgroups (po0.05). In the Active group, the pH waslower (po0.01). This suggests that analyte ab-normalities may not be limited to local areas ofactive MTrPs in the upper trapezius, but may alsobe present in unaffected muscle remote from the

to the gastrocnemius for (A) SP and (B) NE. (Reproduced.)

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Figure 7 Analyte concentrations for the trapezius compared to the gastrocnemius for (A) TNF-a, and (B) IL-6.(Reproduced with kind permission by Elsevier Ltd., from Shah et al., 2008.)

J.P. Shah, E.A. Gilliams380

active MTrPs, albeit lower in concentration than inthe trapezius. The elevated levels of analytes inthe Active group at the gastrocnemius may berelated to central sensitization within these sub-jects. One explanation could be that widespreadelevation of substances associated with pain andinflammation follows initial development of MTrPs.Conversely, individuals who are susceptible todeveloping MTrPs may have preexisting elevatedlevels of these analytes. These findings presentquestions about what makes individuals susceptibleto possibly widespread elevations of biochemicals.An impaired ability to clear metabolites frominjured tissue could make some individuals proneto MTrP development, though the basis of such acondition is currently unknown.

Though both the trapezius and gastrocnemiusmuscles displayed elevated concentrations forsubjects in the Active group, these musclesexhibited different biochemical responses to nee-dle insertion. In the trapezius, analytes from allgroups reached a sharp peak value (in the case ofpH, a minimum value) at about 5min. In thegastrocnemius, no peak concentrations were notedfor any of the groups. As the trapezius (involved inposture maintenance) and gastrocnemius (involvedin locomotion) muscles have different functionsand fiber compositions, this may explain thedifference in responses to needle insertion.

The temporal changes in analyte concentrationscan also provide information about the specificbiochemical response of the trapezius muscle to

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needle insertion. As an analyte’s concentrationrises, its presence could influence the activity ofother biochemical mediators. Detailed analysis ofthe temporal sequence of analyte changes maycharacterize a possible inflammatory cascade.Further study is needed to understand the mechan-ism(s) underlying the myofascial tissue’s responseto needling procedures. In the following sections,we will discuss the properties of the biochemicalsmeasured in these studies and their involvement inmuscle pain and inflammation.

Roles of biochemical substancesassociated with pain and inflammation

pH

Acidic pH levels within muscle have been shown tobe associated with pain and lowered nociceptorthreshold sensitivity (Issberner et al., 1996). Thisassociation is supported by the microdialysis studiesabove, which found acidic pH levels in musclescontaining active (painful) MTrPs. In a study ofmouse model hyperalgesia, Sluka et al. (2001)showed that unilateral injections of acidic salineinto the gastrocnemius resulted in long-lastingbilateral mechanical hyperalgesia. Contralateralhyperalgesia was not affected by lidocaine injec-tions or dorsal horn rhizotomy on the contralateralside. This study demonstrated that contralateralpain perception could be maintained withoutconstant afferent input or muscle tissue injury,suggesting that neuroplastic changes may haveoccurred at the central nervous system, generatingsecondary hyperalgesia.

An acidic milieu is observed during ischemia andhypoxia, and after exercise. The release of protonsfrom physically stressed or injured muscle tissue islikely to activate acid sensing ion channels (ASICs) andvanilloid nociceptors that signal hyperalgesia. In lightof the capillary constriction and increased metabolicdemands of the muscle contracture proposed by theIntegrated Trigger Point Hypothesis, ischemia andhypoxia may result at the site of the MTrP, sensitizingperipheral and central nociceptors (Gerwin et al.,2004). Expanding on Simons’ Integrated Hypothesis,Gerwin et al. (2004) suggested that acetylcholineesterase (AChE) is inhibited by an acidic pH, leavingan excess of ACh in the synaptic cleft.

Neuropeptides

Stimulation of nociceptive neurons can also med-iate the orthodromic and antidromic release of

neuropeptides, such as SP and CGRP. Direct actionsof SP include sensitization of nociceptors, vasodila-tion, increased vascular permeability, and mast celldegranulation, leading to release of other inflam-matory mediators. While SP has known algesiceffects, it has been identified as a neuromodulatorthat brings about slow changes at the NK1 receptorand interacts with opioid transmission (Snijdelaaret al., 2000). CGRP appears to modulate nocicep-tive terminals. In an experimental rat model ofinflammation, noxious stimulation induced in-creased CGRP mRNA and numbers of primaryafferent neurons containing CGRP, which wasassociated with nociceptive behaviors (Ambalava-nar et al., 2006). Furthermore, Gerwin et al. (2004)hypothesized that CGRP intensifies the response toexcess ACh at the nerve terminal by enhancing AChreceptor activity and synthesis, supporting the roleof neuropeptides in the MTrP pathophysiology. Onthe other hand, a study by Ambalavanar et al.(2007) found that CGRP expression in the rat ismuscle-specific; e.g. craniofacial muscles reactdifferently to noxious stimuli than hindlimb mus-cles. Neuropeptide expression in muscle may alsodiffer from that in cutaneous or connective tissue.

Catecholamines

Significantly elevated levels of neurotransmitters NEand 5-HTwere found to be elevated in active MTrPs.5-HT is a pro-nociceptive substance with vasocon-strictive properties. In an area of tissue damage,5-HT is released from platelets, mast cells, andbasophils that infiltrate the damaged area. Activa-tion of the various 5-HT receptors has direct anddose-dependent nociceptive effects on the vascularbed (Giordano and Schultea, 2004). The increasedlevels of NE, the sympathetic neurotransmitter, maybe associated with increased sympathetic activity inthe motor endplate region of MTrPs. In one study,sympathetic activity was recorded from rabbitmyofascial trigger spots, which is a model of thehuman trigger point (Chen et al., 1998). Intra-arterialinjection of phentolamine, an a-adrenergic antago-nist, decreased the SEA from a locus of a myofascialtrigger spot in rabbit skeletal muscle (Chen et al.,1998). Effects of NE have also been linked withdepressed feedback control of muscle length andincreased SEA at motor endplates, pointing to thepossible role of NE in MTrP pathophysiology (Bukhar-aeva et al., 2002; Roatta et al., 2002).

Cytokines

Following injury and inflammation, a specificcascade of cytokines is initiated. Stimulation of

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J.P. Shah, E.A. Gilliams382

this cascade is suspected in the development ofmuscle pain associated with MPS, and elevation ofthe cytokines TNF-a, IL-1b, IL-6, and IL-8 wasobserved in the studies by Shah et al. Two majorcytokine pathways employ prostaglandins andsympathetic amines as final mediators that directlysensitize nociceptors. Studies of experimentallyinduced cutaneous and muscle hypernociception inrats have shown that TNF-a regulates both path-ways, including the intermediary pro-inflammatorycytokines IL-6, IL-8, and IL-1b (Sachs et al., 2002;Mense, 2003; Verri et al., 2006). IL-1b and IL-6stimulate cyclo-oxygenase (COX) mediated path-ways, which terminate with prostanoid activation(Verri et al., 2006). In an in vitro experiment withskeletal muscle, IL-1b was shown to stimulate therelease of IL-6, perhaps suggesting a synergisticeffect of IL-1b and IL-6 (Luo et al., 2003).

IL-8 and the rat homologue cytokine-inducedneutrophil chemoattractant 1 (CINC-1) mediate thesympathetic amine pathway. In a study by Loramet al. (2007) of experimentally induced rat musclehypernociception, CINC-1 demonstrated a uniqueability to induce primary hyperalgesia. While TNF-a, IL-1b, IL-6, and IL-8 have demonstrated time-and dose-dependent effects of injection in the skin,these cytokines had different effects in rat muscle(Verri et al., 2006; Loram et al., 2007). The studyshowed that primary hyperalgesia correspondedtemporally with high measurements of CINC-1.However, maintenance of secondary hyperalgesiamight be attributed to actions of IL-1b and IL-6,which were elevated at times later than initialinflammation (Loram et al., 2007). Additional studyis needed to clarify the cytokine cascade unique tomuscle pain and MPS, in order to investigatepossible pharmacologic targets.

Conclusion

Myofascial trigger points are a very common andcomplex component of non-articular musculoske-letal pain and dysfunction. However, they are alsoregularly found in asymptomatic individuals. There-fore, our studies sought to determine if there arebiochemical aspects that differentiate active MTrPsfrom latent MTrPs, and muscle without MTrPs. Ourmicroanalytical technique permits direct samplingof the biochemical milieu of MTrPs, includingbioactive substances (e.g., inflammatory media-tors, neuropeptides, catecholamines, and cyto-kines) that are released from and act on muscle,nerve, and connective tissue. We have confirmedthat biochemicals associated with pain, inflamma-tion, and intercellular signaling are elevated in the

vicinity of active MTrPs. Furthermore, subjects withactive MTrPs in the upper trapezius have elevatedlevels of these biochemicals in a remote, unaf-fected muscle, suggesting that these conditions arenot limited to localized areas of active MTrPs.A natural history study, following similar proce-dures to the biochemical studies discussed in thispaper, is underway to determine whether MTrPsresolve spontaneously or evolve into the activeforms from latent or normal conditions. Furtherresearch with these microanalytical techniquescould improve characterization and validation ofthe temporal cascade initiated during noxiousstimulation or dry needling treatment.

The recent lines of scientific investigation sug-gest that it may be useful for clinicians andscientists to develop a model of MTrP pathophysiol-ogy as a type of neuromuscular dysfunction. Fromthis perspective, future clinical research studiesshould focus on identifying the mechanisms respon-sible for the etiology, amplification, and perpetua-tion of MPS. The development of successfultreatment approaches depends upon identifyingand targeting these mechanisms and addressing theperpetuating factors that maintain this ubiquitouspain syndrome.

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