new frontiers in the pathophysiology of myofascial pain

Myofascial pain arises from muscle and itsconnective tissue. This noninflammatorycondition is distinguished from other softtissue disorders such as fibromyalgia,

tendonitis, and bursitis. It presents with regional pain,often present in select quadrants of the body, and isaccompanied by increased tension and decreasedflexibility in the related muscle and fascia. Myofascialpain may present independently but is often acomponent of many acute and chronic pain conditions.Critical in its diagnosis is the presence of one or moremyofascial trigger points (MTrPs)—discrete,hyperirritable nodules located in a taut band of skeletalmuscle that are palpable during physical examination(Figure 1). Active MTrPs cause spontaneous pain insurrounding tissue and/or distant sites in particularreferral patterns. Latent MTrPs have a similar physicalfinding, but are only painful upon deep palpation.Both active and latent MTrPs may cause muscledysfunction, weakness, and a limited range of motion.

Unique Neurobiology of Muscle PainMuscle pain has a unique neurobiology with distinctivecharacteristics that are critical in explaining the clinicalpresentation of myofascial pain. Muscle pain can often bedescribed as aching, cramping, deep, and difficult tolocalize. It is distinguished from cutaneous pain in thatmuscle pain involves nociceptive-specific neurons in thebrainstem and spinal cord (1,2) and activates uniquecortical areas that are associated with affective or emotionalcomponents of pain (3). Although muscle nociception isinhibited more intensely than cutaneous nociception bydescending pain-modulating pathways (4,5), persistentmuscle nociception is more effective at inducingmaladaptive neuroplastic changes within the dorsal horn (6). Such neuroplastic changes support the clinicalobservation that muscle pain is often difficult to resolve.

Characteristics, Evaluation, and Diagnostic CriteriaAn MTrP has been defined as a “hyperirritable spot,usually within a taut band of skeletal muscle or in themuscle’s fascia, that is painful on compression and thatcan give rise to characteristic referred pain, tenderness,and autonomic phenomena (7).” Accordingly, activeMTrPs have a significantly lower pain pressure thresholdthan latent MTrPs and normal, uninvolved muscle tissue (8). Diagnosis depends exclusively upon history and physical examination, including specialized manualpalpation techniques (7).

Whereas MTrPs are associated with local pain uponpalpation, it is also common for myofascial pain to beexperienced in seemingly unrelated areas. Continuedpressure over an active MTrP should cause increased localpain and mimic the patient’s reported referral painpatterns. A latent MTrP, though not spontaneouslypainful, is usually tender and may also be associated withreferred pain upon palpation.

26 | THE PA IN PRACT I T IONER | S U M M E R 2 0 1 2

FEATURE | NEW FRONTIERS IN THE PATHOPHYSIOLOGY OF MYOFASCIAL PAIN

Schematic of a trigger point complex. A trigger point complex in a taut band of muscle is composedof multiple contraction knots (Adapted from Simons DG, Travell JG. Myofascial Pain and Dysfunction:The Trigger Point Manual. vol. 1; 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; 1998 [7].)

Figure 1.

New Frontiers in thePathophysiology of Myofascial PainBy JAY P. SHAH, MD, and JULIANA HEIMUR, BA

A characteristic physical finding of the MTrP is thepresence of a local twitch response (LTR), an involuntary,localized contraction of muscle fibers that is both transientand rapid and can be elicited by manual palpation. Whilecontroversy still exists over diagnostic criteria of an MTrP,Gerwin described the following features: 1) an exquisitelytender spot found in a taut band of muscle; 2) an LTRand/or referred pain to distant sites upon manual palpationor needling of the tender spot; 3) restricted range ofmotion; 4) reproduction of the patient’s pain complaintthrough pressure on an active MTrP; 5) regional muscleweakness; and 6) autonomic symptoms (9).

MTrPs are the most common, yet misdiagnosed and inadequately treated component of nonarticularmusculoskeletal pain disorders. Clinicians tend to treatthe symptoms of muscle pain (e.g., with medications)rather than the cause, which are usually MTrPs. Musclepain is often given little consideration because there isneither consensus on the diagnosis nor any standardizedobjective measures to verify the presence of MTrPs. Todate, accurate diagnosis of myofascial pain dependsexclusively upon the palpation skills, clinical acumen, andexperience of the examiner.

Peripheral to Central SensitizationActive MTrPs are a source of ongoing peripheralnociception that may induce central sensitization. Musclenociception is especially effective at inducing centralsensitization (6). Continuous input from peripheralmuscle nociceptors may lead to changes in function andconnectivity of sensory dorsal horn neurons throughcentral sensitization. Such activity increases the “afferentdrive” (i.e., impulses per second bombarding dorsal hornneurons in the spinal cord).

MTrPs are Associated with Peripheral AbnormalitiesWhile the pathophysiology of myofascial pain remainsenigmatic, various studies have begun to elucidate itsunderlying properties. Our research team has sought todetermine if there are objective biochemical differencesamong active MTrPs, latent MTrPs, and normal muscletissue. To accomplish this, we developed a novelmicrodialysis needle (Figures 2A and 2B) with the samesize, shape, and characteristics of an acupuncture needle.Use of this needle allows us to safely and quantitativelymeasure the local biochemical environment of muscle invivo using continuous, real-time sampling (10-12).

We chose to investigate the levels of biochemicalsubstances known to be associated with sensitization, pain,intercellular signaling, and inflammation (e.g., inflammatorymediators, neuropeptides, catecholamines, cytokines, etc.)that are released from and act on muscle, nerve, andconnective tissue. Results from studies on the uppertrapezius muscle indicate that active MTrPs have a uniquebiochemical milieu compared to latent MTrPs and musclewithout palpable MTrPs. Subjects with neck painsecondary to an active MTrP had significantly elevatedlocal levels of endogenous substance P (SP), calcitoningene-related peptide (CGRP), bradykinin (BK),serotonin/5-hydroxytryptamin (5-HT), norepinephrine(NE), tumor necrosis factor-alpha (TNF-α), andinterleukin-1β (IL-1β) compared to carefully matchedcontrols (10-12). Interestingly, compared to controls,subjects with active MTrPs in the upper trapezius also had elevated levels of these biochemicals in a remote,unaffected muscle (the gastrocnemius) (11,12).

Together, these studies demonstrated and confirmedthat the clinical distinction between active and latentMTrPs is associated with a highly significant objectivedifference in the local biochemical milieu. These findings

THE PA IN PRACT I T IONER | VO LU M E 2 2 , N U M B E R 2 | 27

(A) Microdialysis schematic. (B) Photo of needle. (Reproduced with kind permission by theAmerican Physiological Society and Elsevier, Ltd., from Shah et al., 2005, 2008 [10,11]).

Figures 2A and 2B.

may help to explain why active MTrPs, which areassociated with high concentrations of the biochemicalsknown to cause both peripheral and central sensitization,are acutely painful, tender, and a source of referred pain.Our biochemical studies have helped to establish theclinical importance of palpating and identifying activeMTrPs. They also suggest that myofascial pain is anobjective entity in the spectrum of clinical pain states andmay also explain why specific treatments are effective. For example, studies have found that an injection of theserotonin antagonist tropisetron was found to be more effective than lidocaine in relieving pain fromMTrPs (13,14). Fittingly, our research indicates elevatedlocal levels of 5-HT in individuals suffering from activeMTrPs. CGRP, which was also found to be elevated inthese individuals (10-12), has implications for activitywithin the neuromuscular junction. CGRP enhances therelease of acetylcholine (ACh) from the motor endplate,decreases the effectiveness of acetylcholinesterase (15,16),and upregulates the ACh-receptors in the muscle. As AChactivity becomes more pronounced, the frequency ofminiature endplate potentials increases as does thedevelopment of persistent focal muscle fiber contraction,a defining characteristic of the MTrP (17).

Various electromyography studies suggest thatspontaneous electrical activity (SEA) has an importantrole within MTrPs in muscle pain and centralsensitization. SEA is dysfunctional endplate potential ofthe extrafusal muscle fiber (18) that is characteristic ofMTrPs (18,19). Damage to the cell membrane, as a resultof mechanical trauma, may cause muscle damage (20) thatbegins a series of events to cause SEA. Ca2+ overload (21)and an increase in Na+ permeability, accompanied by aNa+ influx (22), induces depolarization at the motorendplate (23-25). While other ion channels may also beresponsible, this process also results in ACh release at theMTrP (26). SEA is a combination of endplate noise andendplate spikes generated by increased spontaneousrelease of ACh (27,28). As such, SEA may play asignificant role in pain. A study in humans showed thatlower pain pressure thresholds at MTrPs were associatedwith higher amplitudes of the SEA; thus, the irritabilityof an MTrP was highly correlated with the prevalence oflocal SEA (29).Furthermore, the SEA represents a focalmuscle fiber contraction, contributing to the formation of muscle tension (30) and the taut band associated with MTrPs (26,31).

MTrPs and Abnormalities in the Dorsal HornA barrage of nociceptive activity in the periphery (i.e., afferent drive) has the ability to induce maladaptiveneuroplastic alterations in the dorsal horn of the spinalcord. Mechanisms involved in central sensitizationinclude a lowered activation threshold for excitatoryneurons, reorganization of spinal cord neurons, and newsynaptic connections. Further, sustained input from anactive MTrP may induce apoptosis of inhibitory neuronsat the segmental levels affected by the peripheral noxiousinput, and such an action can sensitize dorsal hornneurons leading to allodynia, hyperalgesia, temporalsummation of pain (32), and expanded pain patterns. A possible explanation for this phenomenon is increasedsynaptic efficiency through activation of previously silent (ineffective) synapses in the dorsal horn. Thesefindings are hallmarks of central sensitization and, as onecan imagine, their clinical consequences may be verydistressing to patients suffering from chronic myofascialpain. Furthermore, fear of movement may followresulting in muscle disuse, weakness, and dysfunction.Evidence suggests that patients with MPS have anabnormal stress response, as indicated by highly activated sympathetic and hypothalamus-pituitary adrenal (HPA) systems (33).

The concept of opening previously ineffectiveconnections was demonstrated in a rat myositis model.Experimentally-induced inflammation unmaskedreceptive fields remote from the original receptive field,indicating that dorsal horn connectivity expanded beyond the original neurons involved in nociceptivetransmission (34). In this study, nociceptive inputresulting in central hyperexcitability helps to explainreferred pain patterns common to myofascial pain.Central sensitization may facilitate additional responsesfrom other receptive fields as a result of convergentsomatic and visceral input at the dorsal horn (35) viawide dynamic range (WDR) neurons located in LaminaIV and Lamina V. These neurons are called “widedynamic range” because they receive afferent input frommultiple sources including skin, muscle, viscera,periosteum, and bone. In addition to Lamina I, muscleafferents preferentially activate Lamina V. Thisneuroanatomical fact explains how muscle nociceptionand pain can spread to alternate structures (e.g., viscera)and, vice versa, how nociceptive input from these alternatestructures (e.g., viscera) can manifest as muscle pain.



Furthermore, afferent fibers have the ability to sproutnew spinal terminals that broaden synaptic contacts at thedorsal horn and may also contribute to expanded painreceptive fields (36). This change in functionalconnectivity may occur within a few hours of the initialperipheral nociception, even before metabolic and geneticalterations occur in dorsal horn neurons (37). Althoughlatent MTrPs are not associated with spontaneous pain,palpation may cause referred pain. According to Mense,“pain referral from a latent TrP is probably due to the fact that the latent TrP has only ineffectiveconnections with the central nervous system and thatthese synapses are located on neurons that supply regionsremote from the TrP (38).”

There is a biochemical basis to explain the developmentof peripheral and central sensitization in muscle pain.Continuous activation of muscle nociceptors leads to theco-release of L-glutamate and SP at the pre-synapticterminals of the dorsal horn. In addition to activation ofalpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid (AMPA) receptors by L-glutamate at the post-synapticterminal, SP facilitates activation of previously dormantN-methyl-D-aspartate (NMDA) receptors. This leads tomaximal opening of calcium-permeable ion channels,which hyperexcites nociceptive neurons and causesapoptosis of inhibitory interneurons (39). Consequently, apersistent noxious bombardment from the periphery cancreate long-lasting alterations in the central nervoussystem. Metabolic and gene induction changes, such ascyclooxygenase-2 (COX-2) induction in dorsal hornneurons, are maximal several hours after an initial noxiousstimulation and bolster functional changes afterperipheral tissue injury (40). In turn, central sensitizationmay enhance MTrP sensitivity, resulting in decreasedmechanical pain threshold (41) and increased amplitudeof SEA (42).

Higher Brain Centers Dynamically Modulate Muscle PainAs aforementioned, persistent afferent input from activeMTrPs preferentially activates and sensitizes WDRneurons in the dorsal horn. The stimuli then ascend thespinothalamic tract to reach higher brain centers. Inaddition to activating the thalamus, muscle afferent inputpreferentially activates the limbic system (i.e., the anteriorcingulate gyrus, insula, and amygdala), which plays acritical role in modulating muscle pain and the emotionalor affective component to persistent pain (3). Increasedactivity in the limbic system leads to greater fear, anxiety,

and stress. Niddam and colleagues demonstratedincreased limbic system activity in patients with uppertrapezius myofascial pain syndrome (43).

There is a dynamic balance between supraspinaldescending facilitation and inhibition. For example, therostral ventral medulla (RVM) is a relay area between theperiaqueductal gray (a structure located in the midbrain)and the spinal cord. The RVM contains a population of“on” cells and “off ” cells which can either increase ordecrease the level of pain, respectively, throughprojections that modulate activity in the dorsal horn.Following initial tissue injury, the “on” cells serve a usefuland protective purpose designed to prevent furtherdamage. Under ordinary circumstances, tissue healingwould lead to a decrease in “on” cell activity and anincrease in “off ” cell activity. However, in chronicmusculoskeletal pain conditions, there appears to be anoverall shift to a decrease in inhibition, presumably due toan imbalance of “on” cell and “off ” cell activity (44).

Muscle pain also impairs diffuse noxious inhibitorycontrol (DNIC) (45). Disrupted descending inhibition inchronic musculoskeletal pain may lead to an increase inpain sensitivity of muscle tissue (46). Current data suggest


that MTrPs are not merely a peripheral phenomenon butrather, they activate and sensitize WDR neurons in thedorsal horn and higher brain centers and may, in turn, be

dynamically modulated by these structures (38,43).

Dry Needling and the Local Twitch ResponseDry needling is an effective, non-pharmacologicaltreatment of MTrPs that has approached acceptance asthe “standard of practice” for deactivating active MTrPs. It may be performed using either a superficial or deep dryneedling technique. Elicitation of one or more localtwitch responses (LTRs) is a goal of dry needling andoften benefits those with pain secondary to MTrPs.Though the mechanism of an LTR is unknown, studiessuggest a biochemical component. Following theinduction of a single LTR, our group found a dramaticchange in the biochemical milieu of the upper trapeziusmuscle. Within minutes of the LTR, the initially elevatedlevels of SP and CGRP within the active MTrP drasticallydecreased to levels approaching that of normal uninvolvedmuscle tissue. The reduction of these biochemicals in the local muscle area may be due to a small, localizedincrease in blood flow and/or nociceptor and mechanistic changes associated with an augmented inflammatoryresponse (10,12). Though not designed as a treatmentintervention, dry needling may, in fact, activate the

descending inhibitory pain system and cause localdeactivation of the MTrP (47).

Limitations of Digital PalpationCurrent diagnostic standards formyofascial pain rely on palpationfor the presence of MTrPs in a tautband of skeletal muscle (7).However, proper diagnosis requiresa highly skilled clinician, and somestudies have found low inter-raterreliability among examiners in theirattempts to identify MTrPs (48,49).Furthermore, digital palpation doesnot 1) provide an objective, reliable,and sensitive method of diagnosisand measurement of treatmentefficacy; 2) provide quantitativecomparisons of the tissue propertiesbefore and after treatment; 3) objectively differentiate amongactive MTrPs, latent MTrPs, and palpably normal tissue;



Vibration sonoelastography can be used to visualize MTrPs in muscle.

Figure 3.

Figures 4A and 4B.

(A) Upper trapezius muscle with a palpable MTrP. A hypoechoic region and a well-defined focaldecrease of color variance indicating a localized stiffer region are visible.

(B) Normal upper trapezius muscle. A myofascial trigger point is not palpable and the normalmuscle appears isoechoic and has uniform color variance.

Hypoechoeic trigger pointFocal decrease of colorvariance indicates a localizedstiffer region

upper trapezius

+2.3

+2.3

4) objectively discriminate between superficial and deepMTrPs; and 5) permit objective study of the naturalhistory of MTrPs.

Visualization and Characterization of MTrPsThere is a need to develop objective, repeatable, andreliable diagnostic tests for evaluating MTrPs anddetermining treatment outcome measures. Such measurescan be used to properly diagnose MTrPs, understand theirnatural progression, and overcome the subjectivity andlimitations of digital palpation. Accordingly, our grouphas applied three types of ultrasound diagnostic imagingtechniques—grayscale (2D ultrasound), vibrationsonoelastography (Figure 3), and Doppler—todifferentiate tissue characteristics of MTrPs in the uppertrapezius muscle compared to surrounding soft tissue.

These office-based measures are readily available,portable, and inexpensive imaging modalities, suitable foruse in a clinician’s office. We have demonstrated thatultrasound elastography can serve as an objective image-based measure of MTrPs. Using ultrasound, MTrPs can beimaged, appearing as focal hypoechoic (darker) areas witha heterogeneous echotexture. MTrPs also show reducedvibration amplitude on elastography, indicating alocalized area of stiffer tissue compared to surroundingsoft tissue (Figure 4) (8,50).

Our studies have also revealed that MTrPs have aunique vascular environment. Doppler ultrasound wasable to show differences in the microcirculation in andaround active MTrPs compared to latent MTrPs andnormal tissue. For example, blood flow waveformcharacteristics can be used to differentiate active andlatent MTrPs. Blood flow reversal in diastole wasassociated with active MTrPs, indicating a highly resistantvascular bed. This may be due to a blood vessel compressionby a local muscle contracture (e.g., an MTrP) and/orbiochemically-mediated vasoconstriction of the localblood vessels (50,51). Further analysis has alsodemonstrated that active MTrPs have a significantly largersurface area than latent MTrPs and normal sites (8).

SummaryMyofascial trigger points are a very common yet enigmaticcomponent of non-articular musculoskeletal pain anddysfunction that have been long recognized in clinicalpractice. However, these hyperirritable nodules are alsopresent in many asymptomatic individuals. This dichotomyrequires that clinicians learn to distinguish active from

latent MTrPs in order to accurately identify and treat amyofascial component of pain. There is a lack of concretescientific knowledge concerning the pathophysiology andpathogenesis of myofascial pain. However, recent lines ofscientific investigation (e.g. histological, neurophysiological,biochemical, and imaging studies) have demonstratedobjective abnormalities that support the assertion thatMTrPs are a complex form of neuromuscular dysfunction,involving skeletal muscle as well as peripheral and centralsensitization. Without proper medical treatment, latentMTrPs may become active, and pain from active MTrPsmay persist indefinitely as dorsal horn neurons and higherbrain centers undergo neuroplastic changes as a result ofchronic nociception. Development of proper treatmentdepends upon identifying and targeting the mechanismsof myofascial pathology by addressing the contributing andperpetuating factors that maintain this pain syndrome.

Future DirectionsOur group is currently developing a model for theperipheral and central mechanisms involved in myofascialpain. Now that we have identified objective differences thatdistinguish active MTrPs from latent MTrPs and normaltissue, we plan to further study the nature of MTrPs andsurrounding soft tissue over time. Although painful MTrPsactivate muscle nociceptors that, upon sustained noxiousstimulation, initiate peripheral and central sensitization,what is their etiology and pathophysiology? What is themechanism by which the pain state begins, evolves, andpersists? What are the levels of antiinflammatorysubstances, analgesic substances, and muscle metabolites inthe local biochemical milieu of muscle with and withoutMTrPs? How does a tender nodule progress to a myofascialpain syndrome? Which soft tissues are involved? Are thereobjective measures for assessing therapeutic outcomes?Future clinical research studies should focus on identifyingthe mechanisms responsible for the pathogenesis andpathophysiology of myofascial pain and linking thesymptoms and physical findings to the physical propertiesand biochemical changes in the muscle tissue. �

JAY P. SHAH, MD, is a senior staffphysiatrist in the Rehabilitation Medicine

Department at the NIH Clinical Center in

Bethesda, Maryland, and a diplomate of

the American Board of Physical Medicine

and Rehabilitation. He lectures

internationally on the mechanisms of


chronic pain and myofascial pain and teaches workshops on

examination and treatment techniques including acupuncture and

dry needling. His research has been published in the Journal of

Applied Physiology, Archives of Physical Medicine and Rehabilitation,

the Journal of Ultrasound in Medicine, and the Journal of Bodywork

and Movement Therapies. Dr. Shah completed a Bravewell fellowship

at the Arizona Center for Integrative Medicine and was selected

by the American Academy of Pain Management as the 2010

recipient of the Janet Travell Clinical Pain Management Award.

Contributions to the article also made by Juliana Heimur, BA.

JULIANA HEIMUR received a B.A. from The George Washington

University. She is a research assistant within the Rehabilitation

Medicine Department at the National Institutes of Health in

Bethesda, MD.

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new frontiers in the pathophysiology of myofascial pain

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