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FibromyalgiaPain:DoWeKnowthe
Source?
RolandStaud
CurrOpinRheumatol.200416(2)

AbstractandIntroduction
Abstract

Purposeofreview:FibromyalgiaSyndrome(FMS)isachronicpainconditionofunknownorigin.Multiple
abnormalitieshavebeendescribed,includingperipheraltissueandcentralnervoussystemchanges.Therelationof
thesemechanisms,however,islikelybidirectional.FMSpainclearlydependsonperipheralnociceptiveinputas
wellasabnormalcentralpainprocessing.Thisreviewwillfocusontheroleofperipheralnociceptiveinputforpain
inFMS.
Recentfindings:ThereisstrongevidenceforabnormalcentralpainprocessinginFMS.Sensitizedspinalcord
neuronsinthedorsalhornareresponsibleforaugmentedpainprocessingofnociceptivesignalsfromtheperiphery.
Inaddition,glialactivation,possiblybycytokinesandexcitatoryaminoacidsmayplayaroleintheinitiationand
perpetuationofthissensitizedstate.
Summary:NociceptiveinputclearlyplaysanimportantroleinFMS.Acuteorrepetitivetissueinjuryhasbeen
associatedwithFMSpain.Cytokinesrelatedtosuchinjuriesmayberesponsibleforlongtermactivationofspinal
cordgliaanddorsalhornneurons,thusresultingincentralsensitization.Abetterunderstandingoftheseimportant
neuroimmuneinteractionsmayproviderelevantinsightsintofutureeffectivetherapies.
Introduction

Chronicpainandtendernessexistasacontinuuminthegeneralpopulationandtheseverityofthesesymptoms
appearstobenormallydistributedwithmorewomenthanmenaffected.In1990theAmericanCollegeof
Rheumatologyconvenedagroupofexpertstobettercharacterizethelargenumberofchronicmusculoskeletalpain
patientsdiagnosedwithFibrositisthatcrowdedtheofficesofrheumatologists.Theexpertsagreedonseveral
criteriaforthenewsyndromeFibromyalgia,whichcapturesthischronicpainpopulationwithexcellentsensitivity
andspecificity. [1]Inaddition,thenewFMScriteriaofwidespreadchronicpain(>3months)andtenderpoints(11
of18)provideausefulcharacterizationofpatientswithchronicmusculoskeletalpainforresearchstudies.Theuse
ofthesameFMScriteriaforclinicalpractice,however,turnedouttobeproblematicbecausechronic
musculoskeletalpainpatientsfulfillingtheFMScriteriadiffermostlyinsymptomseverityfrompainpatientswhodo
notsatisfythesamecriteria.AlthoughthiscriticismhasledmanyphysicianstoquestiontheusefulnessoftheFMS
criteriaforclinicalpractice,theyneverthelessseemtocapturethemostafflictedpatients.SimilartoFMS,several
otherclinicallyimportantsyndromesalsorepresentextremesofacontinuumofsymptomsincludinghypertension
anddiabetes.Theparticularusefulnessofthelattersyndromes,however,reliesontheirabilitytopredictsignificant
morbidityandmortalityinlargenumbersofpatients.AlthoughinthepastthediagnosisofFMSappearedonly
predictiveforincreaseddysfunctionandemotionaldistress,recentepidemiologicalstudiesprovidedimportant
evidenceforexcessivemortalityinpatientswithwidespreadchronicpainsyndromeslikeFMS. [2,3**]Thesefindings
seemtosupporttherelevanceofFMSasadistinctclinicalsyndromeandprovideimpetusfortheidentificationof
relevantFMSpainmechanismsthatmayresultinbetterdiagnosisandtreatments.

FibromyalgiaSyndrome
Fibromyalgiaisachronicpainsyndromeofunknownetiologycharacterizedbydiffusepainandtenderpoints,which
mustbepresentformorethan3months.MostFMSpatients(80%)arefemaleandcomplainofpain,insomnia,
fatigue,andpsychologicaldistress.Inaddition,manysystemicillnessesalsocanpresentwithdiffusepainsimilarto
FMS,includingpolymyalgiarheumatica, [4]rheumatoidarthritis,inflammatorymyopathies, [5]systemiclupus
erythematosus, [6]andjointhypermobilitysyndrome. [7]Furthermore,severalinfectiousdiseasesincludinghepatitis
C,Lymedisease,coxsackieBinfection,HIV,andparvovirusinfection,havebeendescribedasatriggerfor
fibromyalgia. [8]AlthoughmostFMSpatientsreporttheinsidiousonsetofpainandfatigue,approximatelyhalfofall
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patientsdescribethestartofchronicpainafteratraumaticevent.
NociceptioninFibromyalgiaSyndrome

Thenumberofpatientswithchroniclocalandwidespreadpainincreaseswithage. [9]Muchofthispainincrease
seemstoberelatedtoprogressivestructuraltissueabnormalitiesincludingspinalandperipheraljointdegenerative
changes.ThereforeincreasednociceptionmayplayanimportantroleforagerelatedpainaswellasFMSpain.
ThereisconvincingevidenceforthepresenceofwidespreadhyperalgesiainFMSpatients. [10]FMSpatientsshow
increasedsensitivitytomechanical,thermal,andelectricalstimuli,whichseemstosuggestthatabnormalcentral
painmechanismsmaybeinstrumentalfortheaugmentedpainexperienceofFMSpatients. [1115*]
ImportantcentralnervoussystemmechanismsrelevantforFMSpainincludetemporalsummationofpain(windup)
andcentralsensitization. [1618]ThesepainmechanismsdependonNmethylDaspartate(NMDA)andsubstanceP
receptorsofwidedynamicrange(WDR)andnociceptionspecific(NS)neuronsinthedorsalhornofthespinalcord.
[19]Windup(WU)representsanimportantpainmechanismthatcanresultinshortandlongtermchangesof
neuronalresponsiveness,includingcentralsensitization.WUoccursduringrepetitivenociceptivestimuliofsufficient
intensityorfrequencytoremovethemagnesiumblockoftheNMDAreceptor.Thiseventisfollowedbycalcium
influxintothecellandsubsequenttriggeringofsignalingcascadesthatcanresultinamplificationofnociceptive
inputandlongtermcentralsensitization.Themechanismsresponsibleforcentralsensitizationseemtostrongly
dependonstimulusintensityanddescendingpaininhibition. [17]Importantly,oncecentralsensitizationhasoccurred
onlyminimalnociceptiveinputisrequiredtomaintainthesensitizedstateandclinicalpain.Severalstudieshave
providedconvincingevidenceforabnormalWUandcentralsensitizationinpatientswithFMS. [15,16,20]Itis
thereforeconceivablethatacuteorchronictriggers,liketraumaorinfectionscanresultinthechronicwidespread
painofFMS.

GeneticorFamilialPredisposition
ThereissomeevidenceofafamilialaggregationforFMS,althoughthesedataoftenareinferentialratherthan
definitive.SeveralprospectivestudieshavesuggestedthatrelativesofFMSpatientsdisplayhigherthanexpected
ratesofFMS. [2124]FamilymembersofpatientswithFMSalsodisplayahighfrequencyofanumberofconditions
relatedtoFMS,includingirritablebowelsyndrome,migraineheadaches,andmooddisorders. [25]Manyofthese
alliedconditions,suchasmigraineheadaches,havealsobeennotedindependentlytohaveafamilialpredilection.
[26]

TriggeringEventsforFibromyalgiaSyndrome

TheonsetofFMShasfrequentlybeenassociatedwithcertaintriggers. [27]Likemanyillnesses,thestartofFMS
symptomsmayoccurwhenageneticallypredisposedindividualsbecomesexposedtocertainenvironmentaltriggers
thatcaninitiatethedevelopmentofsymptoms.Mostenvironmentalexposuresthathavebeendescribedastriggers
forFMScanbecategorizedasstressorsincludingphysicaltrauma,infections,emotionaldistress,endocrine
disorders,andimmuneactivation,whichsometimesresultinautoimmunedisorders. [2830]

ResponsetoStressors
Thebiologicresponsetostressorsappearspredictableinanimalsandhumans.Particularly,eventsthatare
perceivedasinescapableorunavoidable,orthatappearunpredictable,evokethestrongestadversebiologic
responses. [3135]ThismayexplainwhytraumavictimsappeartodevelopmuchhigherratesofFMSthanthose
whoareresponsiblefortheaccident. [29]Inaddition,earlylifestressorscanhaveapermanentandprofoundimpact
onsubsequentbiologicresponsestostressinanimalsandhumans.Studiesinrodentshavedemonstratedthat
exposuretomultiplestressorsincluding,traumaorseparationintheneonatalperiodcanleadtopermanent
changesinthebiologicresponsetostress. [36,37]Thispermanenteffectofearlystressorscouldexplainthehigher
thanexpectedincidenceoftraumaticchildhoodeventsinindividualswholaterdevelopchronicpain. [38,39]
PosttraumaticStressDisorder

Morethan50%ofpatientswithFMShavebeenfoundtosufferfromposttraumaticstressdisorder(PTSD)inthe
[40,41]

USandIsrael.
ComparedwiththeprevalenceofPTSDinthegeneralpopulation(6%),FMSpatientsshowa2/12
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USandIsrael. [40,41]ComparedwiththeprevalenceofPTSDinthegeneralpopulation(6%),FMSpatientsshowa
greatlyincreasedratesimilartoVietnamveteransandvictimsofnaturaldisastersormotorvehicleaccidents. [42,43]
Thesyndromeoccursafterasignificanttraumaticeventandischaracterizedbybehavioral,emotional,functional,
andphysiologicsymptoms.RelevanttraumaticeventsrelatedtoPTSDareusuallyperceivedasthreateningone's
lifeorphysicalintegrityandcanleadtoemotionalresponsesincludinghorror,helplessness,orintensefear.The
psychologicalsymptomsofPTSDincludereexperienceofthetraumaticevent,avoidance,andincreasedarousal.It
hasbeenshownthattheexperienceoftraumaisassociatedwithincreasedsomaticandphysicalcomplaints,
includingpain. [44,45]Notsurprisingly,theincidenceofFMSisincreasedinpatientswithPTSD(21%)andoften
associatedwithincreasedpainratings,moredistress,andhigherfunctionalimpairment. [46]Aswithseveralother
disorders,however,itisunclearwhetherPTSDisthecauseorconsequenceforFMS.

TraumaasPrecipitatingEventforFibromyalgiaSyndrome
ManypatientswithFMSreportpainprecipitatingevents,particularlyphysicaloremotionaltraumas,infections,or
surgeries. [47]Thesestressorsseemtoresultinhighdegreesofpain,disability,lifeinterference,andaffective
distress,aswellaslowlevelsofphysicalactivity. [48]Someofthestrongestevidencesupportingtheassociationof
traumaandFMSsymptomswasobtainedduringprospectivestudiesofadultswithneckinjuries. [27]Comparedwith
adultswithlowerextremityfracturesorankleinjury,necktraumacarriedamorethantenfoldincreasedriskof
developingFMSwithin1yearoftheirinjury. [49,50]Additionalevidencesupportingsuchanassociationincludepost
injuryreportedsleepabnormalities, [51]localinjurysitesasasourceofchronicdistantregionalpain, [52]andrecent
evidenceofextensiveCNSneuroplasticityinFMS. [53]Chronicpainafterneckinjuryraisesseveralimportant
questionsincludingtherolethatthelocationofinjuryplaysforlongtermoutcome.Obviously,thereissomething
differentbetweenneckandlegtrauma.Oneimportantfactmayberelatedtothedifferenceinlocalpainsensitivity
withneckandupperchestareashowingdecreasedmechanicalpainthresholdscomparedwiththelower
extremities.Furtherprospectivestudies,however,areneededtoconfirmthisassociationandtoidentifywhether
traumaplaysacausalroleforFMSpain. [54]
WhiplashassociatedInjuries

Althoughmostwhiplashinjuries(WI)resultincervicalstrainonly,asubstantialnumberofpatients(22%)will
developwidespreadpainandFMS. [5557]WIisextremelycommonandresultsfromaccelerationofthecervical
spine,mostfrequentlyduringrearendmotorvehiclecollisions.Thismotioncausesabrupthyperextensionofthe
cervicalspinefollowedbyflexion.ApproximatelyhalfofallWIrelatedneckpainisdelayedinonsetwith65%of
accidentvictimsreportingneckpainwithinsixhoursaftertheinjuryand28%between24and72hours. [58,59]
SimilartoFMS,mostWIpatientsarefemale[60]andalsoreportheadacheasafrequentsymptom. [61]Duringan
accelerationinjury,excessiveshearandtensileforcesareexertedonthecervicalspine[62]andstructuraldamage
fromWIhasbeendemonstratedinanimals,comprisingoftears,avulsions,hemorrhages,rupturesofspinal
ligaments,diskherniations,retropharyngealhematomas,cervicalsympatheticnerveandnerverootinjuries. [63,64]
Insomnia,fatigue,anddepressionaretwotothreetimesmorecommonafterwhiplashinjurythanlowerextremity
injuriesandcorrelatewellwithpainintensity. [50]

Hypermobility
Hypermobilityofjointsandspineisaconsequenceofabnormallaxityofligaments,jointcapsules,and
intervertebraldiscs.Hypermobilityperseisastate,notadisease.However,itmayleadtogeneralizedarthralgiaor
localizedsymptoms(frequentanklesprains,kneeeffusions,dislocationsoftheshoulders,orrecurrentepisodesof
backpain).Theseeventsmayoccurevenafterminorstrains.Youngwomenarepreferentiallyaffected. [7]
Hypermobilityisconsideredariskfactorformusculoskeletalpain.Itismorecommoninwomenandhasshowna
strongassociationwithFMS. [65]Inaddition,hypermobilityisfrequentlydetectableinadolescentswithchronicpain
andFMS. [66]
Paindominatesthelivesofmanypatientswithhyperlaxitysyndromes,mostcommonlythosewiththebenignjoint
hypermobilitysyndrome(BJHS).AsaresultofchronicpainBJHSpatientsmayexperiencepsychosocialproblems,
whichinmanycasesseverelyaffecttheirhealthyfunctioning.Mostchronicpainislocatedinjoints,muscles,and
ligaments,andmayresultfromaninherentpredispositiontotheeffectsofeverydaytrauma,butotherfactorssuch
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asassociatedosteoarthritisarealsoimportant.Abdominalpainanddistresscanresultfromlaxityofconnective
tissuethatprovidessupportfortheabdominal,thoracic,orpelvicorgans.Theseconnectivetissueabnormalities
oftenresultinhernia,uterine,and/orrectalprolapse,mitralvalveprolapse,orspontaneouspneumothorax.In
childrenjointhyperlaxityisanimportantandoftenunderrecognizedsourceofrheumaticsymptoms,whichis
sometimeserroneouslyattributedtojuvenileidiopathicarthritis.Effectivetherapiesincludephysiotherapeuticand
orthoticstabilizationofhyperlaxjoints,proprioceptiveenhancement,analgesics,andnonpharmacologicaltherapies
includingcognitivebehavioraltherapy. [67]StudiesofFMSpatientsshowahigherprevalenceofBJHS(28%)
comparedwithnormalcontrols[68]buttheincidenceofFMShasnotyetbeendeterminedinpatientswithjoint
hyperlaxity.Apossibleroleofrepetitivemicrotraumamustbeconsideredasacauseforchronicpaininpatients
withBJHS.

RegionalMusculoskeletalPain
Myofascialpain(MP)orregionalmusculoskeletalpainisoneofthemostcommonpainsyndromesencounteredin
clinicalpractice.MPrepresentsthemostcommoncauseofchronicpain,includingneckandshoulderpain,tension
headaches,andlowerbackpain.SimilartoFMS,MPismorefrequentlyfoundinfemalepatientsandhasbeen
definedaspainsyndromeassociatedwithmyofascialTriggerPoints(MTP).MTPrepresentareasoflocal
mechanicalhyperalgesiaandcanalsobefoundinseveralotherchronicpainconditions,includingosteoarthritisand
rheumatoidarthritis.MTParelocatedintautbandsandwhenpalpatedcauselocalandreferredpain.Inaddition,a
muscletwitchresponsecanfrequentlybeelicitedbypalpationorneedlingofMTP.MPisstronglycorrelatedwith
FMSandMTParefoundwithgreatfrequencyinFMSpatients(68%). [69]ThepresenceofMTPinmostifnotall
FMSpatientsrepresentsastrongevidenceforlocalmuscleabnormalitiesinchronicmusculoskeletalpain.Although
itisunclearwhetherMTParethecauseoreffectofmuscleinjury,theyrepresentabnormallycontractedmuscle
fibers.Thismusclecontractioncanleadtoaccumulationofhistamine,serotonin,tachykinins,andprostaglandins,
whichmayresultintheactivationoflocalnociceptors.Prolongedmusclecontractionsmayalsoresultinlocal
hypoxemiaandenergydepletion. [70]

RoleofCytokinesforFibromyalgiaSyndromePain
CytokinessuchasIL1beta,IL6,andtumornecrosisfactoralpha(TNFalpha)havebeenshowntocontribute
directlytocentralandperipheralneuropathicpain. [71]Immunecellsactivatedinresponsetoinfection,
inflammation,ortrauma,releaseproteinscalledproinflammatorycytokines.Theseproinflammatorycytokines
providesignalstothecentralnervoussystemtherebycreatingexaggeratedpainaswellasanumberofphysiologic,
behavioral,andhormonalchanges.Thesechangesarefrequentlyreferredtoasthesicknessresponse,which
seemsrepresentativeofFMSpatients'symptoms. [72*]Releaseofproinflammatorycytokinesbyimmunecellsinthe
bodyleads,inturn,toreleaseofproinflammatorycytokinesbygliawithinthebrainandspinalcord. [73]
Proinflammatorycytokinescanexertpowerfulpainfacilitatoryeffectsfollowingtheirreleaseinthebody,inthe
brain,andinthespinalcord.Suchexaggeratedpainstatesnaturallyoccurinsituationsinvolvinginfection,
inflammation,ortraumaoftheskin,ofperipheralnervesandmuscles,andofthecentralnervoussystemitself. [74]
Thecellsmostimportantforcytokine/chemokinesignalingaremacrophages/monocytes.Thishasbeenshownin
animalexperimentsofmicelackingthechemokinereceptorchemotacticcytokinereceptor2(CCR2).These
knockoutmicedemonstratedamarkedattenuationofmonocyterecruitmentinresponsetovariousinflammatory
stimuliandareductionofinflammatorylesions. [71]AfterCCR2receptorswereremovedfromthecellsthrough
geneticmanipulationstheanimalsunderwenttestingofpainresponsetoinflammationandnerveinjury.As
expectedtherewasnodifferenceinpainrespondingoftheseanimalstoacutepainstimuli.Inmodelsof
inflammatorypain,however,CCR2knockoutmiceshoweda70%reductionofthepainresponseandmore
importantly,inamodelofneuropathicpain,thedevelopmentofmechanicalallodyniawascompletelyabrogated.In
responsetonerveligation,persistentandmarkedupregulationofCCR2mRNAwasevidentinthenerveandDRG.
ChronicpainalsoresultedintheappearanceofactivatedCCR2positivemicrogliainthespinalcord.Thesedata
suggestthattherecruitmentandactivationofmacrophagesandmicrogliaperipherallyandinneuraltissuemay
contributetobothinflammatoryandneuropathicpainstates.Accordingly,blockadeoftheCCR2receptormay
provideanoveltherapeuticmodalityforthetreatmentofchronicpain. [71]

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Cytokineshavebeenamultidisciplinaryresearchfocusforovertwodecades.Todate,severaltopicshaveemerged
ascriticalissues,including:(1)howdocytokinesmodulatethefunctionsoftheCNSand(2)whatistheroleof
cytokinesinthepathogenesisofFMS?Thusfar,ithasbeenclearlyestablishedthatcytokinescanalterthe
functionsoftheCNSthroughautonomic,neuroendocrine,andbehavioralmechanisms. [75]Furthermore,increasing
evidencepointstothepotentialinvolvementofcytokinesintheinductionandmodulationofanarrayofneurologic
diseasesrangingfromAlzheimer'sdiseasetochronicpain. [76*]Thereforecytokinesignalingmayrepresentan
importantmechanismthatlinksrelevantstressorsliketraumaandinfection,tothechronicpainofFMS.

PolymyalgiaRheumatica
Polymyalgiarheumatica(PMR)isasystemicinflammatorysyndromethatcancloselymimicFMS. [77]Itis
characterizedbyproximalshoulderandhipgirdlepainaccompaniedbylonglastingmorningstiffnessandgelling
phenomenon.SimilartoFMSmalaiseandfatiguearecommon.Activerangeofmotionmaybeseverelylimited
secondarytopain.Importantly,PMRisexceedinglyrareinpatientsyoungerthan50years.Womenaretwiceas
likelyaffectedasmenandmostpatientsshowhighlevelsofacutephasereactantslikeerythrocytesedimentation
rate(ESR)orCreactiveprotein(CRP).Peripheralbloodmonocytesdemonstratesignsofactivationwithincreased
productionofIL1andIL6. [78,79]ThesymptomsofPMRthatcloselyresemblethoseofFMSincludewidespread
pain,stiffness,andfatigue.Inaddition,PMRdemonstratessignsofsystemicinflammationrelatedtoanunknown
antigen. [80]IncontrasttoFMS,PMRisexquisitelysensitivetocorticosteroidtherapy.Thestrongsimilaritybetween
thetwosyndromesseemstosuggestacommonnociceptivepathway,possiblycytokinesthatresultsinwidespread
painandcentralsensitization.

NeuroendocrineAbnormalitiesinFibromyalgiaSyndrome
Patientswithendocrinedeficienciesincludingcortisol,growthhormone,andthyroidhormonedeficiencies,
experiencesymptomssimilartothoseobservedinFMS.Thisobservationhaspromptedstudiesthatexaminethe
functioningofvarioushypothalamicperipheralglandaxesinFMS. [81,82]Hypothalamichormonesregulatethe
pulsatilesecretionofspecificpituitaryhormones,whicharereleasedintotheperipheralcirculationandactonthe
targetperipheralglandtostimulatehormonesecretion.Theamplitudeorfrequencyofpituitarysecretorypulsesare
influencedbymanydifferentfactors,includingnutrition,sleep,stressors,likeemotionalstress,exercise,
hypoglycemia,infection,andpain. [83]
PatientsundergoingawithdrawalfromsteroidtherapyhavelowlevelsofCRH,ACTH,andcortisol.They
experienceavarietyofsymptomssimilartothoseseeninFMS,includingmyalgias,fatigue,GIcomplaints,
disruptedsleep,andimpairedcognitivefunction. [84]
MoststudiesofneuroendocrinefunctioninFMSshowednoincreasedHPAaxisactivityasseenunderacutestress
conditions. [85,86]Onthecontrary,stressdoesnotseemtosufficientlyactivatethehypothalamicCRHpituitary
ACTHaxisofFMSpatients. [87]StimulationofthehypothalamuswiththecytokineIL6showeddelayedACTH
responsivenessinFMS. [88]Importantly,thesestudieshavedemonstratedthattheneuroendocrineresponsesof
FMSpatientsappearadequateunderbaselineconditionsbutarenotsufficientinresponsetonormalactivitiesof
dailylivingorstress.Thesefindings,however,arenotuniquetoFMSbuthavealsobeendemonstratedinpatients
withchronicfatiguesyndromeandPTSD.Althoughitstillunclearwhethertheabnormalitiesoftheneuroendocrine
axisareintegralorsecondaryforthepathogenesisofFMS,severalneurohormones,includingCRH,playimportant
rolesinpainperceptionandmaythereforeberelevantforFMSpain. [89]

InfectionsAssociatedWithFibromyalgiaSyndrome
Fibromyalgiasyndromeisadisorderofdiffusepaininthemusclesorjointsaccompaniedbytendernessatspecific
tenderpointsandaconstellationofrelatedsymptoms.Thesesymptomsarereminiscentofthoserelatedtomany
acuteorchronicinfections.
HepatitisCVirusInfection

ManypatientsinfectedwithhepatitisCvirus(HCV)infectioncomplainofmyalgias,arthritis,andwidespreadpain.
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MusculoskeletalpainismorefrequentamongpatientswithisolatedhepatitisCinfectionthanamongpatientswith
isolatedhepatitisBoralcoholicliverdisease(91,59,and48%,respectively).Similarly,morepatientswithisolated
hepatitisCthanwithisolatedalcoholicliverdiseaseorhepatitisBcomplainoffatigue(66,30,and29%,
respectively). [90]However,whenthediagnosticFMScriteriawereusedfortheevaluationofHCVpatientswith
chronicpain,alargerpercentagethanexpectedinthegeneralpopulation(16%),fulfilledthesecriteria. [91]
HumanImmunodeficiencyVirusInfection

SeveralstudiesindicatethatHIVpatientscommonlycomplainofchronicmusculoskeletalpain.Upto26%of
patientswithHIVinfectionpresentwithmusculoskeletalsymptomsand41%ofthesepatientsqualifyforthe
diagnosisofFMS. [92]Thus,largenumbersofpatientswithchronicviralinfectionshavechronicpainconsistentwith
FMSandmayrepresentnaturalmodelsforthestudyofFMSpainmechanisms.

ExposureSyndromes
Anumberofconditionsfallwithinthisspectrum,includingmultiplechemicalsensitivities,sickbuildingsyndrome,
andGulfWarsyndrome.
TheGulfWarsyndromerelatestotheexperienceofcoalitiontroopsdeployedtoliberateKuwaitfromtheIraqi
occupation.Upto45%ofdeployedveterans(incontrastto15%ofnondeployedveterans)developedaseriesof
symptomsincludingmusclepain,fatigue,memoryproblems,headaches,andgastrointestinalcomplaints. [93]This
experiencewasnotuniquetoUStroopsbecauseBritishveteransofthisconflictexperiencedacomparableincrease
insimilarsymptoms. [29]OverhalfoftheveteranswithunexplainedmusculoskeletalpainmetthecriteriaforFMS,
andasignificantportionoftheveteranswithunexplainedfatiguemetthecriteriaforchronicfatiguesyndrome.
Unexplainedsymptomsinmilitarypersonnel,however,arisingafterawarhavebeendescribedbefore. [94]For
futureresearchofGulfWarsyndromeandpossiblyFMS,aprospectivemultidisciplinarystudyshouldbeconducted
todistinguishthecauseandeffectofwarrelatedeventsonmultiplepossiblepainmechanisms. [95]

Conclusion
Convincingevidencesuggeststhatmultiplestressorshaveasignificantroleinthepathogenesisofchronicpain
syndromesandfibromyalgia.Thesestressorsmayaffectperipheraltissues(traumaandinfection)aswellasthe
centralnervoussystem(exposuresyndromes)andresultinhyperalgesia/allodyniaand/orcentralsensitization.Such
alterationsofrelevantpainmechanismsmayleadtolongtermneuroplasticchangesthatexceedtheanti
nociceptivecapabilitiesofaffectedindividualsresultingineverincreasingpainsensitivityanddysfunction.There
are,however,severalpromisingwaystocontainorevenimproveFMSpainincludingbehavioralmodificationsand
reductionofnociceptionaswellascentralsensitization.Thelatterinterventionsmaybemostdifficulttoachieve
aftercentralsensitizationhasoccurred,becauseonlyminimalperipheralnociceptiveinputmayberequiredto
maintainthechronicpainstateoftheseindividuals.Futureresearchneedstoaddresstheimportantroleof
abnormalnociceptionand/orantinociceptionforchronicpaininFMS.
References

1. WolfeF,SmytheHA,YunusMB,etal.:TheAmericanCollegeofRheumatology1990Criteriaforthe
ClassificationofFibromyalgia.ReportoftheMulticenterCriteriaCommittee.ArthritisRheum1990,33:160
172.
2. MacfarlaneGJ,McBethJ,SilmanAJ:Widespreadbodypainandmortality:prospectivepopulationbased
study.BMJ2001,323:662664B.
3. McBethJ,SilmanAJ,MacfarlaneGJ:Associationofwidespreadbodypainwithanincreasedriskofcancer
andreducedcancersurvival:Aprospective,populationbasedstudy.ArthritisRheum2003,48:16861692.
**Thisprospectivestudyshowedthatwidespreadpainreportedinpopulationsurveysisassociatedwitha
substantialsubsequentincreasedincidenceofcancerandreducedcancersurvival.
4. GowinKM:Diffusepainsyndromesintheelderly.RheumDisClinNorthAm2000,26:673682.
http://www.medscape.com/viewarticle/470556_print

6/12

10/20/2015

www.medscape.com/viewarticle/470556_print

5. SultanSM,IoannouY,MossK,etal.:Outcomeinpatientswithidiopathicinflammatorymyositis:morbidity
andmortality.Rheumatology(Oxford)2002,41:2226.
6. TenchC,BentleyD,VleckV,etal.:Aerobicfitness,fatigue,andphysicaldisabilityinsystemiclupus
erythematosus.JRheumatol2002,29:474481.
7. NefW,GerberNJ:Hypermobilitysyndrome.Whentoomuchactivitycausespain.SchweizMedWochenschr
1998,128:302310.
8. BarkhuizenA:Rationalandtargetedpharmacologictreatmentoffibromyalgia.RheumDisClinNorthAm
2002,28:261290.
9. BrattbergG,ParkerMG,ThorslundM:Alongitudinalstudyofpain:reportedpainfrommiddleagetoold
age.ClinJPain1997,13:144149.
10. GravenNielsenT,SorensenJ,HenrikssonKG,etal.:Centralhyperexcitabilityinfibromyalgia.J
MusculoskelPain1999,7:261271.
11. GrangesG,LittlejohnG:Pressurepainthresholdinpainfreesubjects,inpatientswithchronicregionalpain
syndromes,andinpatientswithfibromyalgiasyndrome.ArthritisRheum1993,36:642646.
12. ArroyoJF,CohenML:Abnormalresponsestoelectrocutaneousstimulationinfibromyalgia.JRheumatol
1993,20:19251931.
13. SorensenJ,GravenNielsenT,HenrikssonKG,etal.:Hyperexcitabilityinfibromyalgia.JRheumatol1998,
25:152155.
14. GracelyRH,PetzkeF,WolfJM,etal.:Functionalmagneticresonanceimagingevidenceofaugmentedpain
processinginfibromyalgia.ArthritisRheum2002,46:13331343.
*Thisstudyshowedthatcomparablesubjectivelypainfulconditionsresultedinactivationpatternsthatwere
similarinFMSpatientsandcontrols,whereassimilarpressuresresultedingreaterbrainactivationofFMS
patients.ThesefindingssupportthehypothesisthatFMSischaracterizedbycorticalorsubcortical
augmentationofpainprocessing.
15. StaudR,CannonRC,MauderliAP,etal.:Temporalsummationofpainfrommechanicalstimulationof
muscletissueinnormalcontrolsandsubjectswithfibromyalgiasyndrome.Pain2003,102:8795.
16. StaudR,VierckCJ,CannonRL,etal.:Abnormalsensitizationandtemporalsummationofsecondpain
(windup)inpatientswithfibromyalgiasyndrome.Pain2001,91:165175.
17. WoolfCJ:Windupandcentralsensitizationarenotequivalent.Pain1996,66:105108.
18. LiJ,SimoneDA,LarsonAA:Windupleadstocharacteristicsofcentralsensitization.Pain1999,79:7582.
19. DaviesSN,LodgeD:EvidenceforinvolvementofNmethylaspartatereceptorsin`windup'ofclass2
neuronesinthedorsalhornoftherat.BrainRes1987,424:402406.
20. PriceDD,StaudR,RobinsonME,etal.:Enhancedtemporalsummationofsecondpainanditscentral
modulationinfibromyalgiapatients.Pain2002,99:4959.
21. BuskilaD,NeumannL:Fibromyalgiasyndrome(FM)andnonarticulartendernessinrelativesofpatientswith
FM.JRheumatol1997,24:941944.
22. YunusMB:Geneticfactorsinfibromyalgiasyndrome.ZRheumatol1998,57(Suppl2):6162.
23. StormorkenH,BrosstadF:Fibromyalgia:familyclusteringandsensoryurgencywithearlyonsetindicate
geneticpredispositionandthusatruedisease.ScandJRheumatol1992,21:207.
http://www.medscape.com/viewarticle/470556_print

7/12

10/20/2015

www.medscape.com/viewarticle/470556_print

24. PellegrinoMJ,WaylonisGW,SommerA:Familialoccurrenceofprimaryfibromyalgia.ArchPhysMed
Rehabil1989,70:6163.
25. HudsonJI,GoldenbergDL,PopeJr,HGetal.:Comorbidityoffibromyalgiawithmedicalandpsychiatric
disorders.AmJMed1992,92:363367.
26. MessingerHB,SpieringsEL,VincentAJ,etal.:Headacheandfamilyhistory.Cephalalgia1991,11:1318.
27. BuskilaD,NeumannL:Thedevelopmentofwidespreadpainafterinjuries.JMusculoskelPain2002,
10:261267.
28. WaylonisGW,PerkinsRH:Posttraumaticfibromyalgia.Alongtermfollowup.AmJPhysMedRehabil
1994,73:403412.
29. GreenfieldS,FitzcharlesMA,EsdaileJM:Reactivefibromyalgiasyndrome.ArthritisRheum1992,35:678
681.
30. MiddletonGD,McFarlinJE,LipskyPE:Theprevalenceandclinicalimpactoffibromyalgiainsystemiclupus
erythematosus.ArthritisRheum1994,37:11811188.
31. SapolskyRM,RomeroLM,MunckAU:Howdoglucocorticoidsinfluencestressresponses?Integrating
permissive,suppressive,stimulatory,andpreparativeactions.EndocrRev2000,21:5589.
32. ViauV,SharmaS,PlotskyPM,etal.:IncreasedplasmaACTHresponsestostressinnonhandled
comparedwithhandledratsrequirebasallevelsofcorticosteroneandareassociatedwithincreasedlevelsof
ACTHsecretagoguesinthemedianeminence.JNeurosci1993,13:10971105.
33. ChrousosGP,GoldPW:Theconceptsofstressandstresssystemdisorders.Overviewofphysicaland
behavioralhomeostasis.JAMA1992,267:12441252.
34. GoldPW,GoodwinFK,ChrousosGP:Clinicalandbiochemicalmanifestationsofdepression.Relationto
theneurobiologyofstress(1).NEnglJMed1988,319:348353.
35. GoldPW,GoodwinFK,ChrousosGP:Clinicalandbiochemicalmanifestationsofdepression.Relationto
theneurobiologyofstress(2).NEnglJMed1988,319:413420.
36. McNamaraRK,HuotRL,LenoxRH,etal.:PostnatalMaternalSeparationElevatestheExpressionofthe
PostsynapticProteinKinaseCSubstrateRC3,butNotPresynapticGAP43,intheDevelopingRat
Hippocampus.DevNeurosci2002,24:485494.
37. SapolskyRM:Whystressisbadforyourbrain.Science1996,273:749750.
38. AnderbergUM,MarteinsdottirI,TheorellT,etal.:Theimpactoflifeeventsinfemalepatientswith
fibromyalgiaandinfemalehealthycontrols.EuropeanPsychiatry2000,15:295301.
39. BaileyBE,FreedenfeldRN,KiserRS,etal.:Lifetimephysicalandsexualabuseinchronicpainpatients:
psychosocialcorrelatesandtreatmentoutcomes.DisabilRehabil2003,25:331342.
40. ShermanJJ,TurkDC,OkifujiA:Prevalenceandimpactofposttraumaticstressdisorderlikesymptomson
patientswithfibromyalgiasyndrome.ClinJPain2000,16:127134.
41. CohenH,NeumannL,HaimanY,etal.:Prevalenceofposttraumaticstressdisorderinfibromyalgia
patients:Overlappingsyndromesorposttraumaticfibromyalgiasyndrome?SeminArthritisRheum2002,
32:3850.
42. GreenMM,McFarlaneAC,HunterCE,etal.:Undiagnosedposttraumaticstressdisorderfollowingmotor
vehicleaccidents.MedJAust1993,159:529534.
http://www.medscape.com/viewarticle/470556_print

8/12

10/20/2015

www.medscape.com/viewarticle/470556_print

43. ShoreJH,TatumEL,VollmerWM:Psychiatricreactionstodisaster:theMountSt.Helensexperience.AmJ
Psychiatry1986,143:590595.
44. BeckhamJC,CrawfordAL,FeldmanME,etal.:Chronicposttraumaticstressdisorderandchronicpainin
Vietnamcombatveterans.JPsychosomRes1997,43:379389.
45. BeckhamJC,MooreSD,FeldmanME,etal.:Healthstatus,somatization,andseverityofposttraumatic
stressdisorderinVietnamcombatveteranswithposttraumaticstressdisorder.AmJPsychiatry1998,
155:15651569.
46. AmirM,KaplanZ,NeumannL,etal.:Posttraumaticstressdisorder,tendernessandfibromyalgia.J
PsychosomRes1997,42:607613.
47. AaronLA,BradleyLA,AlarconGS,etal.:Perceivedphysicalandemotionaltraumaasprecipitatingevents
infibromyalgia.Associationswithhealthcareseekinganddisabilitystatusbutnotpainseverity.Arthritis
Rheum1997,40:453460.
48. TurkDC,OkifujiA,StarzTW,etal.:Effectsoftypeofsymptomonsetonpsychologicaldistressand
disabilityinfibromyalgiasyndromepatients.Pain1996,68:423430.
49. BuskilaD,NeumannL,VaisbergG,etal.:Increasedratesoffibromyalgiafollowingcervicalspineinjury.A
controlledstudyof161casesoftraumaticinjury.ArthritisRheum1997,40:446452.
50. KaschH,BachFW,StengaardPedersenK,etal.:Developmentinpainandneurologiccomplaintsafter
whiplashA1yearprospectivestudy.Neurology2003,60:743749.
51. BerglundA,AlfredssonL,JensenI,etal.:Theassociationbetweenexposuretoarearendcollisionand
futurehealthcomplaints.JClinEpidemiol2001,54:851856.
52. ArendtNielsenL,SvenssonP:Referredmusclepain:Basicandclinicalfindings.ClinJPain2001,17:11
19.
53. CarliG:Neuroplasticityandclinicalpain.ProgBrainRes2000,129:325330.
54. WhiteKP,HarthM,SpeechleyM,etal.:Ageneralpopulationstudyoffibromyalgiatenderpointsin
noninstitutionalizedadultswithchronicwidespreadpain.JRheumatol2000,27:26772682.
55. KoelbaekJohansenM,GravenNielsenT,SchouOA,etal.:Generalisedmuscularhyperalgesiainchronic
whiplashsyndrome.Pain1999,83:229234.
56. ElertJ,KendallSA,LarssonB,etal.:Chronicpainanddifficultyinrelaxingposturalmusclesinpatients
withfibromyalgiaandchronicwhiplashassociateddisorders.JRheumatol2001,28:13611368.
57. BuskilaD,NeumannL:Musculoskeletalinjuryasatriggerforfibromyalgia/posttraumaticfibromyalgia.Curr
RheumatolRep2000,2:104108.
58. DeansGT,McGalliardJN,RutherfordWH:Incidenceanddurationofneckpainamongpatientsinjuredin
caraccidents.BrMedJ(ClinResEd)1986,292:9495.
59. DeansGT,MagalliardJN,KerrM,etal.:Necksprainamajorcauseofdisabilityfollowingcaraccidents.
Injury1987,18:1012.
60. CroftPR,LewisM,PapageorgiouAC,etal.:Riskfactorsforneckpain:alongitudinalstudyinthegeneral
population.Pain2001,93:317325.
61. YoungWB,PackardRC:Headachesassociatedwithheadtrauma.InWolff'sHeadacheandOtherHead
Pain.EditedbySilbersteinSD,LiptonRB,DalessioDJ.NewYork:OxfordUniversityPress2001:325348.
http://www.medscape.com/viewarticle/470556_print

9/12

10/20/2015

www.medscape.com/viewarticle/470556_print

62. StemperBD,YoganandanN,PintarFA:Kineticsoftheheadneckcomplexinlowspeedrearimpact.
BiomedSciInstrum2003,39:245250.
63. HohlM:Softtissueneckinjuriesareview.RevChirOrthopReparatriceApparMot1990,76(suppl1):1525.
64. GebhardJS,DonaldsonDH,BrownCW:Softtissueinjuriesofthecervicalspine.OrthopRev1994,
(suppl):917.
65. HudsonN,FitzcharlesMA,CohenM,etal.:Theassociationofsofttissuerheumatismandhypermobility.Br
JRheumatol1998,37:382386.
66. GedaliaA,PressJ,KleinM,etal.:Jointhypermobilityandfibromyalgiainschoolchildren.AnnRheumDis
1993,52:494496.
67. GrahameR:Pain,distressandjointhyperlaxity.JointBoneSpine2000,67:157163.
68. AcasusoDM,CollantesEstevezE:Jointhypermobilityinpatientswithfibromyalgiasyndrome.ArthritisCare
Res1998,11:3942.
69. GrangesG,LittlejohnG:Prevalenceofmyofascialpainsyndromeinfibromyalgiasyndromeandregional
painsyndrome:acomparativestudy.JMusculoskelPain1993,1:1935.
70. TravellJG,SimonsLS,SimonsDG:MyofascialPainandDysfunction:TheTriggerPointManual,edn2.
NewYork:Lippincott,Williams&Wilkins1999.
71. AbbadieC,LindiaJA,CumiskeyAM,etal.:Impairedneuropathicpainresponsesinmicelackingthe
chemokinereceptorCCR2.PNAS2003,100:79477952.
72. KelleyKW,BlutheRM,DantzerR,etal.:Cytokineinducedsicknessbehavior.BrainBehavImmun2003,
17:S112S118.
*SimilartoFMSpatients,sickindividualsarelistless,complainoffatigueandmalaise,loseinterestin
socialactivities,andhavesignificantchangesinsleeppatterns.Theydisplayaninabilitytoexperience
pleasure,haveexaggeratedresponsestopain,andfailtoconcentrate.Proinflammatorycytokinesactingin
thebraincausesicknessbehaviors.Thesenearlyuniversalbehavioralchangesareamanifestationofa
centralmotivationalstate.
73. HayleyS,MeraliZ,AnismanH:Stressandcytokineelicitedneuroendocrineandneurotransmitter
sensitization:implicationsfordepressiveillness.Stress2003,6:1932.
74. WatkinsLR,MaierSF:Thepainofbeingsick:implicationsofimmunetobraincommunicationfor
understandingpain.AnnuRevPsychol2000,51:2957.
75. QuanN,HerkenhamM:Connectingcytokinesandbrain:areviewofcurrentissues.HistolHistopathol2002,
17:273288.
76. MaierSF:Bidirectionalimmunebraincommunication:Implicationsforunderstandingstress,pain,and
cognition.BrainBehavImmun2003,17:6985.
*Proinflammatorycytokineplayacriticalroleforpaininboththeperipheryandthenervoussystem.Inthe
periphery,thesecytokinesinitiatetheprocessesthatsignalthebrainthatimmuneactivationhasoccurred
andcommunicatethisinformationoverbothneuralandbloodborneroutes.Thearrivalofthesesignalsin
thecentralnervoussysteminducesaneuralcascadethatincludesthedenovoinductionofproinflammatory
cytokines.Thesecytokinesinthenervoussystemplayakeyroleinregulatingtheneuralcontrolofimmune
processesintheperiphery.
77. DaoudKF,BarkhuizenA:Rheumaticmimicsandselectedtriggersoffibromyalgia.CurrPainHeadacheRep
2002,6:284288.
http://www.medscape.com/viewarticle/470556_print

10/12

10/20/2015

www.medscape.com/viewarticle/470556_print

78. WeyandCM,HicokKC,HunderGG,etal.:Tissuecytokinepatternsinpatientswithpolymyalgiarheumatica
andgiantcellarteritis.AnnInternMed1994,121:484491.
79. PountainG,HazlemanB,CawstonTE:CirculatinglevelsofIL1beta,IL6andsolubleIL2receptorin
polymyalgiarheumaticaandgiantcellarteritisandrheumatoidarthritis.BrJRheumatol1998,37:797798.
80. CohenMD,GinsburgWW:Polymyalgiarheumatica.RheumDisClinNorthAm1990,16:325339.
81. VaeroyH:ImpairedneuroendocrineaxisandFMS.JRheumatol1989,16:14601465.
82. HaddadJJ,SaadeNE,SafiehGarabedianB:Cytokinesandneuroimmuneendocrineinteractions:arolefor
thehypothalamicpituitaryadrenalrevolvingaxis.JNeuroimmunol2002,133:119.
83. ReichlinS:Neuroendocrinology.InWilliamsTextbookofEndocrinology.EditedbyWilsonJD,FosterDW,
KronenbergHM,LarsenPR.Philadelphia:W.B.SaundersCo.1998:165248.
84. MagiakouMA,ChrousosGP:Corticosteroidtherapy,nonendocrinedisease,andcorticosteroidwithdrawal.
CurrTherEndocrinolMetab1994,5:120124.
85. MaesM,LinA,BonaccorsoS,etal.:Increased24hoururinarycortisolexcretioninpatientswithpost
traumaticstressdisorderandpatientswithmajordepression,butnotinpatientswithfibromyalgia.Acta
PsychiatrScand1998,98:328335.
86. CroffordLJ:Thehypothalamicpituitaryadrenalstressaxisinfibromyalgiaandchronicfatiguesyndrome.Z
Rheumatol1998,57:6771.
87. AdlerGK,KinsleyBT,HurwitzS,etal.:Reducedhypothalamicpituitaryandsympathoadrenalresponsesto
hypoglycemiainwomenwithfibromyalgiasyndrome.AmJMed1999,106:534543.
88. TorpyDJ,PapanicolaouDA,LotsikasAJ,etal.:Responsesofthesympatheticnervoussystemandthe
hypothalamicpituitaryadrenalaxistointerleukin6Apilotstudyinfibromyalgia.ArthritisRheum2000,
43:872880.
89. LariviereWR,MelzackR:Theroleofcorticotropinreleasingfactorinpainandanalgesia.Pain2000,84:1
12.
90. BarkhuizenA,RosenHR,WolfS,etal.:Musculoskeletalpainandfatigueareassociatedwithchronic
hepatitisCAreportof239hepatologyclinicpatients.AmJGastroenterol1999,94:13551360.
91. BuskilaD,ShnaiderA,NeumannL,etal.:FibromyalgiainhepatitisCvirusinfection.Anotherinfectious
diseaserelationship.ArchInternMed1997,157:24972500.
92. SimmsRW,ZerbiniCA,FerranteN,etal.:Fibromyalgiasyndromeinpatientsinfectedwithhuman
immunodeficiencyvirus.TheBostonCityHospitalClinicalAIDSTeam.AmJMed1992,92:368374.
93. FukudaK,NisenbaumR,StewartG,etal.:ChronicmultisymptomillnessaffectingAirForceveteransofthe
GulfWar.JAMA1998,280:981988.
94. BeckhamJC,CrawfordAL,FeldmanME,etal.:Chronicposttraumaticstressdisorderandchronicpainin
Vietnamcombatveterans.JPsychosomRes1997,43:379389.
95. SoetekouwPMMB,deVriesM,PreijersFWMB,etal.:PersistentsymptomsinformerUNTACsoldiersare
notassociatedwithshiftedcytokinebalance.EurJClinInvest1999,29:960963.
ReprintAddress
CorrespondencetoRolandStaud,AssociateProfessorofMedicine,DivisionofRheumatologyandClinical
Immunology,UniversityofFlorida,POBox100221,Gainesville,FL326100221USA.Tel:3528462639fax:352
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3928483email:staudr@ufl.edu
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