MYOFASCIAL PAIN (RD GERWIN, SECTION EDITOR)Etiology of Myofascial Trigger PointsCarel Bron & Jan D. DommerholtPublished online: 27 July 2012#The Author(s) 2012. This article is published with open access at Springerlink.comAbstract Myofascial pain syndrome (MPS) is described asthesensory, motor, andautonomicsymptoms causedbymyofascial trigger points (TrPs). Knowingthe potentialcausesof TrPsisimportant toprevent their developmentand recurrence, but also to inactivate and eliminate existingTrPs. Thereis general agreement that muscleoveruseordirect trauma to the muscle can lead to the development ofTrPs. Muscleoverloadishypothesizedtobetheresult ofsustained or repetitive low-level muscle contractions, eccen-tricmusclecontractions, and maximalorsubmaximalcon-centric muscle contractions. TrPs maydevelopduringoccupational, recreational, or sports activities when muscleuse exceeds muscle capacity and normal recovery isdisturbed.KeywordsEtiology .Myofascial.Pain.Trigger points.Muscle damage . Calcium .Sustainedlow-level contractions .Eccentric .Cinderella hypothesisIntroductionMyofascial pain syndrome (MPS) is described as the senso-ry,motor, andautonomicsymptomscausedbymyofascialtrigger points (TrPs). TrPs are defined as exquisitely tenderspots in discrete taut bands of hardened muscle that producelocal andreferredpain, amongother symptoms. A TrPiscomposedofnumerousso-calledcontractionknots.An in-dividual contraction knot appears as a segment of a musclefiber with extremely contracted sarcomeres and an increaseddiameter. TheintegratedTrPhypothesispostulatesthat inmyofascial painmotor endplatesreleaseexcessiveacetyl-choline, which is evidenced histopathologically by the pres-enceof sarcomereshortening[1]. Theseareas of intensefocal sarcomere contraction have been described in animalsand humans.AnactiveTrPcauses aclinical paincomplaint. It isalways tender and refers a patient-recognized pain on com-pression. It prevents full lengthening of the muscle, weakensthe muscle, and mediates a local twitch response of musclefibers when adequately stimulated. When compressed with-inthepatientspaintolerance, it producesreferredmotorandoftenautonomicphenomena, generallyinitspainref-erencezone[2]. Alatent TrPisclinicallyquiescent withrespect to spontaneous pain; it is painful only when palpat-ed. Alatent TrPmayhaveall theotherclinicalcharacter-istics of anactiveTrPandalways has ataut bandthatincreases muscletensionandrestricts rangeof motion[2]. TrPsareverycommon, althoughliteratureabouttheirprevalence is sparse [37].Knowingthepotential causes of TrPs is important toprevent their development andrecurrence, but alsotoC. BronScientific Institute for Quality of Healthcare,Radboud University Nijmegen Medical Centre,Nijmegen, The NetherlandsC. Bron (*)Practice for Physical Therapy for Neck,Shoulder and Upper Extremity Disorders,Paulus Potterstraat 46,9718 TK, Groningen, The Netherlandse-mail: carelbron@mac.comJ. D. DommerholtBethesda Physiocare Inc. and Myopain Seminars LLC,7830 Old Georgetown Road, Suite C- 15,Bethesda, MD 20814-2440, USAJ. D. DommerholtUniversidad CEU Cardenal Herrera,Valencia, SpainJ. D. DommerholtShenandoah University,Winchester, VA, USACurr Pain Headache Rep (2012) 16:439444DOI 10.1007/s11916-012-0289-4inactivateandeliminate existingTrPs. There is generalagreement that any kind of muscle overuse or direct traumato the muscle can lead to the development of TrPs. Muscleoverload is thought to be the result of sustained or repetitivelow-level musclecontractions, eccentricmusclecontrac-tions,andmaximalorsubmaximalconcentricmusclecon-tractions[8]. Althoughmuscledamageisnot requiredforthe development of TrP, there may be a disruption of the cellmembrane, damagetothesarcoplasmicreticulumwithasubsequent releaseof highamounts of calcium-ions, anddisruption of cytoskeletal proteins, such as desmin, titin, anddystrophin. Ragged red (RR) fibers and increased numbersof cytochrome-c-oxidase(COX) negativefibers arecom-moninpatientswithmyalgia, whicharesuggestiveofanimpaired oxidative metabolism [9].Sustained Low-Level Contractions and IntramuscularPressureMechanicalmuscleoverusecanbe defined astheresultofmuscle contractions that exceed muscle capacity. Since thecapillary blood pressure ranges from approximately 35 mmHg at the beginning (arterial side) to 15 mm Hg at the end ofthe capillary beds (venous side), the capillary blood flow istemporarilyobstructedduringmuscle contractions. Thebloodflowrecoversimmediatelywithrelaxation,whichisconsistent with its normal physiological mechanism. In dy-namicrhythmiccontractions, intramuscular bloodflowisenhanced by this contraction-relaxation rhythm, also knownas themuscular pump. Duringsustainedmusclecontrac-tions, however, musclemetabolismis highlydependentupon oxygen and glucose, which are in short supply.Even contractions performedat only10 %and 25 %ofcapacityor maximumvoluntarycontraction(MVC) mayproduce intramuscular pressures high enough to significant-lyimpairtheintramuscularbloodcirculation.Theassocia-tionofthepercentageofMVCandintramuscularpressure(IMP) is highlydependent uponthe architecture of themuscle. It has been postulated that the percentage of MVCreportedas theupper limit for localizedmusclefatiguevariesbetweenmuscles, becauseof thevariationof IMPduringacontraction. For example, 10%of MVCof thesupraspinatus muscle produces approximately 50 mm Hg ofIMP, while 25 % of MVC of the trapezius muscle is good foronly 22 mm Hg of pressure. Even lower values of IMP mayaffect muscle metabolism [10]. The EMG signs of localizedmuscle fatigue did not recover until the muscle contractionpressurewasbelow20mmHginthebicepsmuscle[11].According to Otten, the increased pressure gradients duringlow-level exertionsmaycontributetothedevelopment ofpain [12] and eventually to the formation of TrPs (personalcommunication 2005).Since oxygen and glucose are required for the synthesis ofadenosinetriphosphate(ATP), whichprovidestheenergyneededformusclecontractions, sustainedcontractionsmaycausealocal energycrisisduetothelackof oxygen. Toguarantee an adequate supply of ATP, the muscle can switchwithinafewsecondstoanaerobicglycolysis. Duringtheinitial phase of glycolysis (sugar splitting) 1 glucose moleculeisbrokendowninto2pyruvicmoleculesreleasingenoughenergy to form 2 ATP molecules. Under aerobic circumstan-ces, oxygen reacts with pyruvic acid producing a high amountof ATP(16moleculesper pyruvicacidmolecule), carbondioxide and water. Under anaerobic circumstances, however,most of the pyruvic acid produced during glycolysis is con-vertedintolacticacid, therebyincreasingtheintramuscularacidity (pH). Most of the lactic acid diffuses out of the muscleinto the bloodstream; post-exercise lactic acid is washed outwithin30minutesafter exercise. Unfortunately, whenthecapillarycirculationisrestricted, asinsustainedlow-levelcontractions, this process comes to a standstill.Researchers at the US National Institutes of Health foundthat in the direct environment of active TrPs, the pH may bewell below 5, which is more than sufficient to excite musclenociceptors, including acid-sensing ion channels (eg, ASIC1and3), andthetransient receptorpotential vanilloidre-ceptorTRPV1[13, 14]. Small increases of the H+concen-tration, as seen with inflammation, heavy muscle work, andischemia,are sufficient to excite muscle groupIV endings,contributing to mechanical hyperalgesia and central sensiti-zation[15]. Furthermore, alowpHdownregulatesacetyl-chol i nest erase (AChE), i ncreases t he effi cacy ofacetylcholine(ACh),andmaintainsthesarcomere(super-)contraction. It also triggers the release of several nociceptivesubstances, such as calcitonin gene-related peptide (CGRP)[15], which can enhance the release of ACh from the motorendplateandsimultaneouslydecreasetheeffectivenessofAChEinthesynapticcleft. CGRPalsoupregulates theACh-receptors(AChR) at themuscleandtherebycreatesmore docking stations for ACh. Miniature endplate activitydepends on the state of the AChR and on the local concen-tration of ACh, which is the result of ACh-release, reuptake,and breakdown by AChE [12].Relaxation within the muscle cells occurs when myosin-actincross-bridges detach. After ATPis attachedtothemyosin molecule, the link between myosin and actin weak-ens, andthemyosinheaddetaches fromactin. Inotherwords, the cross-bridge between myosin and actin breaks.Simultaneously, theCa2+iondetaches fromthetroponinmolecule, which blocks tropomyosin. Under normal physi-ologicalcircumstances,largeamountsoffreecalcium-ionswill reenterthesarcoplasmicreticulumbytheCa2+pump(CalciumATPase), whichplaces ahighdemandonATPduringrelaxation. Incaseof severeenergydepletion, thesarcomeres maystay contracted, until enoughATPis440 Curr Pain Headache Rep (2012) 16:439444availabletoresolvetheintracellular Ca2+accumulation.High concentrations of intracellular Ca2+are associated withsustainedsarcomerecontractionandmuscledamage. Ca2+accumulation due to sustained motor unit activity has beensuggestedtoplayacausativeroleinthedevelopment ofmuscle disorders and TrPs [16].In a preliminary study using Doppler ultrasound, Sikdaretalhaveshownthatbloodflowwaveforms showsignifi-cant differences between active TrPs, latent TrPs and normalsites. Theflowwaveforms near activesites showedin-creasedsystolicvelocitiesandflowreversal withnegativediastolicvelocities [17]. Theyidentified2contributingfactors, namelyanincreaseinthevolumeofthevascularcompartment, andanincreasedoutflowresistance. In-creased outflow resistance could be due to muscle contrac-turesattheTrP thatcompressthecapillary or venousbed.Sustainedlow-levelcontractionsarecommoninthework-place where many occupations rely on prolonged postures,as seen in musicians, supermarket cashiers, computer oper-ators, hairdressers, and dentists, among others.Dynamic Concentric ContractionsCinderella HypothesisHenneman, workingwithanesthetizedcats, showedthat inresponsetoincreasingphysiological excitation, motorneu-rons are recruited in order of increasing size. This fundamen-tallyimportant findingwasverifiedinhumansbyMilner-Brown et al [18] and is nowgenerally accepted. Smaller motorunitshaveasmalleralpha-motorneuroncell body, smalleraxonsandfewer musclefiberstoactivatecomparedwithlarger ones. According to the size principle, small motor unitsinnervatingtypeI redcolored, slowoxidativefibers arerecruited first, followed by red to pink colored, fast oxidativefibers, andfinallybywhitecolored, fast glycolyticfibers.Furthermore, small type I muscle fibers are activated duringprolonged tasks [19], although a few studies have describedsome degree of motor unit substitution [20]. Hgg suggestedthat the continuous activity of these motor units in sustainedcontractions causes overuse muscle fiber damage, especiallytotheTypeI fibersduringlow-level activities, whichhesummarized in his Cinderella hypothesis [21]. It is conceiv-able that in sustained low-level contractions and in dynamicrepetitivecontractions, ischemia, hypoxiaandinsufficientATP synthesis in type I motor unit fibers are responsible forincreasing acidity, Ca2+accumulation, and subsequently sar-comere contracture. Furthermore, starting with the sarcomere(super-) contraction, the intramuscular perfusion slows downandischemiaandhypoxiawilloccur. Thismayleadtothereleaseofseveral sensitizingsubstancescausingperipheralsensitization [15, 22].Maximal or Submaximal Concentric ContractionsDuring (sub-) maximal concentric contractions high amountsof energy (ATP) are required. Initially, ATP is utilized fromstorage depots within the muscle fibers itself. Afterabout 46 seconds, the muscle shifts to direct phosphorylationof ADP by creatine phosphate (CP). Phosphorylation produ-ces ATP by coupling 1 phosphate group to an ADP moleculecatalyzed by the enzyme creatine kinase. Stored ATP and CPprovideenough energy for maximum muscle powerforap-proximately 1416 seconds. Hereafter, a short period of rest isneededtoreplenishtheexhaustedreservesof intracellularATPandCP. WhenongoingATPdemandsarewithinthecapacity of the aerobic pathway, muscular activity can contin-ue for hours in well-conditioned individuals. However, whenthedemandsofexercisebegintoexceedtheabilityofthemusclecellstocarryout thenecessaryreactionsquicklyenough,anaerobeglycolysiswillcontributemoreandmoreof the total generated ATP. Finally, the muscle will run out ofATP and sustained sarcomere contractions may occur, startingthe development of TrPs.Eccentric ContractionsDuring normal activity muscles are often active while beinglengthened. Thisisreferredtoasaneccentriccontraction[23]. Classicexamples of this arewalking, wherebythekneeextensorsareactive whilebeinglengthenedjustafterheel strikewhilethekneeflexes; placinganobject gentlydownwards, whereby the arm flexors are active while beinglengthened to control the rate of movement of the object. Inotherwords, eccentriccontractionsarecommonlyusedtocontrol the rate of movement. In another scenario, the loadon the muscle may increase to the point where the externalforce on the muscle is greater than the force that the musclecan generate. In that case, the muscle is forced to lengthendue to the high external load.ThereisnosolidevidencethateccentricloadingwouldleadtothedevelopmentofTrPs,butasGerwinetalsum-marized, there is much overlap between the mechanisms ofeccentriccontractionand thedevelopmentofTrPs[24].Inone study, Itoh et al found that healthy volunteers presentedwithtenderropytaut bands, whichwerepainful oncom-pression,immediatelyafter3setsofeccentricexercisesofthe middle finger extensor muscle [25]. One day and 2 daysafter the exercises the findings were similar. After 7 days themuscles wererecovered. Whilethis studysuggests thateccentricloadingdoes contributetothedevelopment ofTrPs, the study also employed isometric loading in additionto eccentric loading, which precludes definitive conclusions.There is evidence from biopsy studies that during eccen-triccontractions disruptionof thecytoskeletal structuresCurr Pain Headache Rep (2012) 16:439444 441occurs, especiallyoftheproteindesminthat interconnectstheadjacent myofibrils [26, 27] andof titin, thelargestprotein in the human body. Titin connects myosin filamentsto the Z-bands and is also linked to actin filaments [28, 29].Microscopic research revealed increased sections of abnor-mal fibers in eccentrically exercised muscles [30, 31], whichappeared to be approximately 4 times the normal size [32].This was onlyobservedwitheccentricexercise, andnotwith concentric exercise or passive stretching. Furthermore,all enlargedfiberswereexclusivelyof thefast glycolytictype or fast contracting type II fibers that are highly fatiga-ble. It is hypothesized that early in the exercise periodfastglycolyticfibers fatigueas theyareunabletoregenerateATP and as a result they enter into a rigor or high stiffnessstate. Subsequent stretching of the stiff fibers mechanicallydisrupts the fibers resulting in cytoskeletal and myofibrillardamage. Thereisalsoevidencethatineccentricexercisedmuscles theintracellular concentrationof calciumis in-creased, probably because of disruption of the sarcoplasmicreticulum. AswehaveseenbeforehighconcentrationsofCa2+keepmyosinandactinmolecules together. Further-more, increased Ca2+has the potential for activating severalmechanismsthatleadstofurtherdamageofthecellmem-brane and cytoskeletal disruption.In contrast, Hocking has postulated that eccentricloading does not provide a good model for the TrPpathogenesis. He suggested that sustained partial depo-larizationor plateaudepolarizationof an-motor neu-rondendrites leads tolastingalterations inthefunctionof the entire -motor neuron[33] due toanupregula-tionof L- or N- type voltage dependent calciumchan-nels and1-adrenergic receptors and a downregulationof calcium-activated potassiumchannels, which wouldlead to an increase in the motor terminal cytosoliccalciumion concentration (personal communication,2012). He suspects that the increased calciumconcen-trationtriggersthespontaneousreleaseofACh. Inotherwords, accordingtoHocking, theincreasedAChreleasewould be the cause and not the result of the energycrisis. Alpha-1-adrenergicreceptors arelinkedtoL-typevoltage dependent calciumchannels, whichwouldsug-gest that sympathetic activity would increase the cyto-solic calcium ion concentration and the excessiverelease of Ach [34]. Rather than looking at overusemechanisms, Hockingmaintains that persistent nocicep-tive input causes the formationof TrPs throughcentralsensitizationoftheC-fibernociceptivewithdrawal reflexandplateaudepolarizationof withdrawal agonist alpha-motor neurons and compensatory reticulospinal motorfacilitation of antigravity muscles and plateau depolar-ization of withdrawal antagonist alpha-motor neurons[33]. Future research in the underlying mechanisms ofTrPis muchneeded.Clinical ExampleEccentriccontractions occur duringall activities of dailylife, but have been researched especially in sports. Overheadthrowing, spiking in tennis and volleyball, javelin-throwing,downhill running, jumpingandrunning(landingphase)involveeccentricactivities. Duringthedecelerationphaseof throwing, theposterior shoulder muscles suchas theinfraspinatus,teresminorandmajor,posteriordeltoid,andlatissimusdorsimuscles, contracteccentricallynotonlytodeceleratehorizontaladductionandinternalrotationofthearm, but alsotoresist shoulder distractionandanteriorsubluxationforces. Ashoulder compressiveforceslightlygreater thanbodyweight is generatedtoresist shoulderdistraction, whileaposterior shear forceof 40%50%bodyweightisgenerated toresistshoulderanterior sublux-ation. Consequently,highactivityisgeneratedbythepos-terior shoulder musculature, inparticular therotator cuffmuscles. Thepercentageofmaximumvoluntaryisometriccontraction(MVIC) is calculatedinstudies usingneedleelectromyography. For example, theteres minor exhibitsitsmaximumactivity(84%of MVIC), theinfraspinatus37 %, supraspinatus 51 %, posterior deltoid 69 %, latissimus88%, subscapularis115%, andtriceps89%duringthedecelerationphase. Scapularmusclesalsoexhibithighac-tivity to control scapular elevation, protraction, and rotationduring this phase. The lower trapezius muscle, which exertsforce on the scapula in the direction of depression, retractionandupwardrotation, generateditshighest activityduringtheeccentricphase[35]. HighEMGactivityfromgleno-humeral and scapular musculature during eccentric contrac-tion illustrates the vulnerability of the posterior musculaturefor developing TrPs in the overhead-throwing athlete.Posterior shoulder pain is a common complaint of throw-ingathletesandismostlyexplainedbyposteriorimpinge-ment [36, 37]. Interestingly, stretching exercises have beenshown to assist in reducing the athletes pain and to normal-izeshouldermotion, particularlyshoulderinternal rotationandhorizontal adduction. It is commonfor theoverheadthrower to exhibit loss of internal rotation of 20 or more,referred to as glenohumeral internal rotation deficit(GIRD).Thisinternal rotationdeficit hasbeensuggestedtobeacauseofspecificshoulderinjuries.Wilkexpressedthat lossof internal rotationismost oftenduetoosseousadaptationsofthehumerusandposteriormuscletightness,andnot posterior capsular tightness. Stretchingexercises,including the sleepers stretch and supine horizontal adduc-tion with internal rotation, are advised to improve the flex-ibility of the posterior musculature, which may become tightbecauseofthemusclecontractionduringthedecelerationphase of throwing [38]. TrPs can be found in many sports-men, including elite volleyball players, swimmers, andrunners [3941].442 Curr Pain Headache Rep (2012) 16:439444ConclusionsIn spite of a lack of well-designed studies, the best availableevidencesupportsthat TrPsdevelopaftermuscleoveruse.Several potential mechanisms mayplayarole, suchaseccentricoverload,submaximalsustained,and(sub)-maxi-mal concentric contractions. A key factor is the local ische-mia, which leads to a lowered pH and a subsequent releaseofseveralinflammatorymediatorsinmuscletissue.Hock-ing proposed an interesting counterargument, whichdeserves further exploration. Whether overuse mechanismsarethecrucial initiatingfactor or persistent nociceptiveinput remains a point of debate and further study.Disclosures Nopotentialconflictsofinterestrelevanttothisarticlewere reported.Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use, distribution, andreproductioninanymedium, providedtheoriginal author(s) andthesource are credited.ReferencesPapers of particular interest, published recently, have beenhighlighted as: Of importance1. SimonsD. Reviewof enigmaticMTrPsasacommoncauseofenigmaticmusculoskeletal painanddysfunction. JElectromyogrKinesiol. 2004;14:95107.2. Simons D, Travell JG, Simons LS. Myofascial pain and dysfunction.Thetriggerpointmanual. Upperhalfofbody. 2nded.Baltimore:Lippincott, Williams and Wilkins; 1999.3. FrictonJ, KroeningR,HaleyD,SiegertR. Myofascialpainsyn-drome of the head and neck: a review of clinical characteristics of164patients. 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