Stability of Conditioned Pain Modulation in two musculoskeletal pain models: investigating the influence of shoulder pai...

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Stability of Conditioned Pain Modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender
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Valencia C, Kindler LL, Fillingim RB, George SZ. Stability of conditioned pain modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender. BMC Musculoskelet Disord. 2013;14(1):182. Epub 2013/06/14. doi: 10.1186/1471-2474-14-182. PubMed PMID: 23758907; PubMed Central PMCID: PMCPmc3682910.
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Valencia, Carolina
Kindler, Lindsay L
Fillingim, Roger B
George, Steven Z
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BioMed Central (BMC Musculoskeletal Disorders)
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Background: Several chronic pain populations have demonstrated decreased conditioned pain modulation (CPM). However there is still a need to investigate the stability of CPM paradigms before the measure can be recommended for implementation. The purpose of the present study was to assess whether shoulder pain intensity and gender influence CPM stability within and between sessions. Methods: This study examined two different musculoskeletal pain models, clinical shoulder pain and an experimental model of shoulder pain induced with eccentric exercise in healthy participants. Patients in the clinical cohort (N = 134) were tested before surgery and reassessed 3 months post-surgery. The healthy cohort (N = 190) was examined before inducing pain at the shoulder, and 48 and 96 hours later. Results: Our results provide evidence that 1) stability of inhibition is not related to changes in pain intensity, and 2) there are sex differences for CPM stability within and between days. Conclusions: Fluctuation of pain intensity did not significantly influence CPM stability. Overall, the more stable situations for CPM were females from the clinical cohort and males from the healthy cohort. Keywords: Conditioned pain modulation, Stability, Shoulder pain
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Haeden Roberson.
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RESEARCHARTICLEOpenAccessStabilityofconditionedpainmodulationintwo musculoskeletalpainmodels:investigatingthe influenceofshoulderpainintensityandgenderCarolinaValencia1,LindsayLKindler2,RogerBFillingim3andStevenZGeorge4,5*AbstractBackground: Severalchronicpainpopulationshavedemonstrateddecreasedconditionedpainmodulation(CPM). HoweverthereisstillaneedtoinvestigatethestabilityofCPMparadigmsbeforethemeasurecanbe recommendedforimplementation.Thepurposeofthepresentstudywastoassesswhethershoulderpainintensity andgenderinfluenceCPMstabilitywithinandbetweensessions. Methods: Thisstudyexaminedtwodifferentmusculoskeletalpainmodels,clinicalshoulderpainandan experimentalmodelofshoulderpaininducedwitheccentricexerciseinhealthyparticipants.Patientsintheclinical cohort(N=134)weretestedbeforesurgeryandreassessed3monthspost-surgery.Thehealthycohort(N=190) wasexaminedbeforeinducingpainattheshoulder,and48and96hourslater. Results: Ourresultsprovideevidencethat1)stabilityofinhibitionisnotrelatedtochangesinpainintensity,and2) therearesexdifferencesforCPMstabilitywithinandbetweendays. Conclusions: FluctuationofpainintensitydidnotsignificantlyinfluenceCPMstability.Overall,themorestable situationsforCPMwerefemalesfromtheclinicalcohortandmalesfromthehealthycohort. Keywords: Conditionedpainmodulation,Stability,ShoulderpainBackgroundVariousquantitativesensorytesting(QST)modalities havebeenusedtoassessparticularmechanismsofpain perceptioninhealthyindividualsandthosewithchronic pain.Conditionedpainmodulation(CPM)isoneQST methodologywithpurportedclinicalrelevance[1,2]and potentialtopredictthedevelopmentofchronicpain[3]. Thistestparadigmhasbeenpreviouslydescribedasdiffusenoxiousinhibitorycontrolsbutarecentconsensus [4]concludedthatthetermCPMmoreaccurately describesthetestingphenomenonbeingobserved.In short,CPMusesa “ paininhibitspain ” testparadigmto activatethedescendingendogenousanalgesiasystem[5]. Itisbelievedthatonenoxiousconditioningstimulus inhibitspainfromanothernoxiousteststimulusby activatingaspinal-supraspinal-spinalloop,resultingin functionalinhibitorypainmodulation[1].Theinability ofthenoxiousconditioningstimulustodecreasethe painintensityofthenoxioustestingstimulusindicatesa potentialdeficiencyinthebody ’ sendogenouspainmodulatoryability.Severalchronicpainpopulations,includingfibromyalgia[6],tempromandibularjointdisorder [7],andirritablebowelsyndrome[8],havedemonstrated decreasedCPMefficiency.Theseresults,alongwith othersshowingtheassociationofCPMwiththedevelopmentofchronicpain[3],resolutionofpainfollowing treatment[9],andabilitytopredictclinicalpain[1],has ledresearcherstoadvocateforCPMasaclinicallyrelevantQSTmodality[10]. Recently,effortshavegoneintostandardizingproceduresusedtoassessCPM[4,5,11];howeverthereisstill aneedtoinvestigatefactorsthatinfluenceCPMstability. Oneinvestigationthatexaminedthetestretestreliability ofCPMinasmallsampleofhealthysubjectsfoundhigh reliabilityamongrepeatedtestingwithinasinglesession *Correspondence: szgeorge@phhp.ufl.edu4DepartmentofPhysicalTherapy,UniversityofFlorida,UFHSC,Box100154, Gainesville,FL32610-0154,USA5CenterforPainResearchandBehavioralHealth,UniversityofFlorida, Gainesville,FL,USA Fulllistofauthorinformationisavailableattheendofthearticle 2013Valenciaetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182 http://www.biomedcentral.com/1471-2474/14/182

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[11],howevertheexplorationofCPMreliabilityindifferentmusculoskeletalpainmodelshasnotyetbeen described.Thisisanimportantissuewhichwouldhave implicationsforuseofthismeasureinclinicalpopulations.Sincetheevidenceshowsadysfunctionofendogenousanalgesiasystemamongchronicpaingroups [12],itisreasonabletothinkthatCPMreliabilitycould beaffectedbyhavingthesystemalreadyengagedwiththe presenceofshoulderpain.Furthermore,sincesexdifferencesinpainrelatedresponsestoexperimentalpainmeasureshavealsobeenreported[13,14],theeffectofsexon reliabilityofCPMalsohasclinicalimplications. Therefore,thepresentstudyusedtwodifferentmusculoskeletalpainmodelstoassesswhetherpresenceof shoulderpainandgenderinfluenceCPMstabilitywithin andbetweensessions.Toservethispurpose,thisstudy examinedpatientswithacuteandsub-acuteshoulder painpreparingtoundergoshouldersurgery,andhealthy subjectswithexerciseinducedmusclepain(EIMP)at theshoulder[15,16].Understandinghowshoulderpain andgenderaffectpaininhibitoryresponses,andestimatingtheerrorassociatedwiththiscommonlyused measure,willaddtoourunderstandingofCPMprovidingclinicalrelevanceforthisparticularexperimental painmeasure.MethodsSubjectsTheUniversityofFlorida ’ sinstitutionalreviewboardfor humanparticipantsapprovedthisstudy.Thisprospectivedesignwaspartofalargerstudyandincludestwo groupsofparticipants,aclinicalcohortofpatientshavingshouldersurgery,andahealthycohort.Allparticipantsprovidedinformedconsentbeforeparticipatingin thisstudy.Clinicalcohort(clinicalpainmodel)Thisstudyincludesdatafromconsecutivepatientsseekingtreatmentofshoulderdisorder,whichwererecruited fromUniversityofFlorida ’ sOrthopedicsSportsMedicineInstitute(OSMI).Theinclusioncriteriaforbeinga participantintheclinicalcohortwere:patientbetween 18and85yearsofage,complaintsofpainlimitedto anterior,lateral,orposteriorshoulder,rotatorcufftendinopathy,adhesivecapsulitis,SLAP(SuperiorLabrum fromAnteriortoPosterior)lesion,andscheduledfor arthroscopicsurgery.Exclusioncriteriafortheprospective clinicalcohortwere:currentcomplaintsofpaingreater thanthepast3monthsinvolvingneck,elbow,hand,low back,hip,knee,orankle,massiveorcompleterotatorcuff tear,shoulderOAorRA,priorshouldersurgerywithin thepastyear,currentshoulderfracture,tumor,orinfection,previouslydiagnosedchronicpaindisorder,current psychiatricmanagement,andgastrointestinalorrenal illness[17].Healthycohort(acutepainmodel)Healthyvolunteerswererecruitedviaadvertisements fromtheUniversityandlocalcommunity.Theinclusion criteriaforthehealthycohortwere:healthysubjects(withoutanypainorpsychologicalcondition)between18and 85yearsofage,andEnglishspeaking.Theexclusioncriteriawere:historyofneckorshoulderinjury,sensoryor motorimpairmentoftheshoulder,regularorrecentparticipationinhighorlowintensityupper-extremityweight training,orcurrentlytakingpainmedication.Theseeligibilitycriteriahavebeenusedinourpreviousstudiesof exercise-inducedshoulderpain[15,16].Measuresandprocedure DemographicinformationStudyparticipantscompletedastandardintakeinformationform.Demographicdatacollectedatinitialevaluationincludedgender,age,race,ethnicity,employment status,maritalstatus,andeducationallevel.Conditionedpainmodulation(CPM)Teststimulus Suprathresholdheatpainresponse (SHPR)wasusedastheteststimulus.PathwayPain& SensoryEvaluationSystem(Medoc,RamatYishai,Israel), withathermodeof2.5cm2surfaceareawasused.Sequencesof5consecutiveheatpulsesof<1-seconddurationatinterpulseintervalsof0.33Hzweredeliveredto thethenareminenceofthenon-surgicalsidefortheclinicalcohort,andnon-dominantsideforthehealthycohort, aspreviouslydescribed[18-20].Thetemperatureusedfor theteststimuluswasdeterminedfromapreviousSHPR assessment(fiveminutesbeforeCPMassessment).One seriesoffivestimuliwasappliedateachofthreedifferent targettemperatures(46C,48Cand50C),andthe temperaturethatproducedanaveragepainintensityscore closestto50ona0-100visualanaloguescale(VAS)was usedfortheteststimulusintheCPMprotocolcompleted onthatday.ThisprocesswasrepeatedeachdaythatCPM wasassessedtodeterminethetemperaturenecessaryto evokemoderatepainduringtheteststimuli.Subjects verballyratedtheintensityofeachthermalpulseonanumericalratingscalefrom0= “ nopain ” to100= “ theworst painimaginable ” [19].WeselectedSHPRasthetest stimulusbecauseevidencesuggeststhatCPMeffectsare largestforC-fibermediatedpain[21,22].Foranalysespurposes,thisstudyusedthe “ 5thpainrating ” whichwasthe fifthpainratingfromthefifthpulseofeachtrial[23-26], whichisconsideredtorepresentasimplemeasureof SHPRassessment[27].Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page2of10 http://www.biomedcentral.com/1471-2474/14/182

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Conditioningstimulus(cold-pressorpain) Subjects wereinstructedtoimmersetheirsurgicalsidehand(for theclinicalcohort),anddominanthand(inhealthycohort)uptothewristintoacoldwaterbathforupto oneminute.Thewaterwasmaintainedataconstant temperatureof8Cbyarefrigeratedwatercirculator, andwasconstantlycirculatedtopreventwarming aroundthehand. CPMprocedure ParticipantsfrombothcohortsunderwenttheCPMassessmentwiththeapplicationofthe teststimulus(describedabove)onthenon-surgicalside fortheclinicalcohort,andnon-dominantsideforthe healthycohort.After30sfromthelastheatstimulus, subjectswereinstructedtoimmersetheircontralateral handuptothewristintothecoldwaterbath(conditioningstimulus).Thirtysecondsafterhandimmersion,subjectswereaskedtoratethepainintensity(0-100)from theimmersedhand,andwereinstructedtomaintain theirhandinthewaterbathforaslongastheycould tolerateforamaximumofoneminute.Oneminuteafter theimmersionofthehand,anewteststimuluswas deliveredonthenon-surgicalsidefortheclinicalcohort, andnon-dominantsideforthehealthycohort.Theprotocolwascreatedwithconsecutivestimuli(teststimulus, thenconditioningstimulus,handremovedfromwater, andthenteststimulus).Thissequenceofdeliveringthe teststimuli,followedbytheconditioningstimulus,and endingwithre-deliveringtheteststimuliconstitutedthe firstCPMtrial(CPM1).Afteratwo-minuterestperiod, theCPMprotocolwasrepeatedinexactlythesamemannerforasecondtrial(CPM2).Exerciseinducedmusclepain(EIMP)Painwasinducedinsubjectsfromthehealthycohort withashoulderfatigueprocedureusingaKin-Com (Chattanooga,TN)isokineticdynamometer.UpperextremityEIMPisconsideredaclinicallyrelevantpain modelsinceparticipantsexperienceincreasedpainintensity,decreasedrangeofmotion,aninflammatoryresponse,alteredproprioception,andtheuseofself-care behaviors[28-32].Musclesorenessoccurswithin24hours followingtheshoulderfatigueprocedurewithmaximal sorenesstypicallylasting48hoursfromthetimeofthe procedure[28].Subjectstypicallyexperiencedecreasing levelsofmusclesorenessthreetofivedayspost-shoulder fatigueprotocol. Maximumvoluntaryisometriccontraction(MVIC) wasdeterminedbyhavingtheparticipantsperformexternalrotationcontractionswithmaximaleffortwhile receivingverbalencouragementduringthecontractions. TheMVICwascalculatedbyaveragingthepeakforce fromthemiddle3repetitions,amethodwithdocumentedreliabilityfrompreviousstudies[33,34].After MVICwascalculated,participantscompletedeccentric/ concentricexternalrotationrepetitionstoinducemuscle fatigue.Previouslyestablishedprocedureswereutilized toinducepaininthiscohort,whichisdescribedinmore detailinourpreviousstudies[15,16].PainintensityThesedatawereincludedtodescribetheeffectsof clinicalpain(surgicalcohort)andexercise-induced shoulderpain(healthycohort)onCPMstability.Pain intensityinbothcohortswasassessedwiththeBrief PainInventory(BPI)questionnaire[35],whichincludes anumericalratingscale(NRS)forpainintensity.Subjectsfromtheclinicalcohort(beforeand3months aftersurgery)andfromthehealthycohort(afterEIMP protocol)ratedtheirpainintensityoverthreeconditions,thepresentpainintensity,theworstpainintensityoverthepast24h,andthebestpainintensityover thepast24h.These3ratingswereaveragedforusein dataanalyses[36,37].TestingsequencePatientsfromtheclinicalcohorthadabaselineexamination(baseline)tocollectdemographicdata,shoulder painintensity,andquantitativesensorytesting72to 24hoursbeforethesurgery.Theywerereassessed 3monthsafterthesurgery(3months).Subjectsfrom thehealthycohortwerescheduledtocometothetesting facilityonday1,day3,andday5.OnDay1,subjects hadabaselineexaminationtocollectdemographicdata, shoulderpainintensity,andquantitativesensorytesting (CPMandpainthreshold)inapainfreestate.Subjects completedstrengthtesting,followedbyeccentric/concentricexternalrotationrepetitionstoinducemuscle fatigue.Collectionofquantitativesensorytestingand shoulderpainintensitywasrepeatedondays3and5followingEIMPinduction.DataanalysisDataanalysiswasperformedinSPSS,Version19.0at alphalevelof0.05.Descriptivestatistics(mean,standarddeviation)werecalculatedforallvariables.The distributionsofvariablesweretestedbyvisualexaminationandwithKolmogorov-Smirnovtestbeforeusein analysis.CalculationsforCPMForanalysispurposesonCPM,wefollowedrecentrecommendations[4]onpresentingresultsandcalculation ofCPMusingtheabsolutedifferenceforCPMandthe percentchange.The “ absolutedifference ” forCPM,was calculatedbythedifferencebetweenteststimulusbefore theapplicationofconditioningstimulus(preCPM),minus theteststimulusaftertheapplicationofconditioningValencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page3of10 http://www.biomedcentral.com/1471-2474/14/182

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stimulus(postCPM).The “ percentchange ” forCPMwas calculatedasfollows: postCPM preCPM = preCPM 100 Foreachsessionthereweretwoabsolutedifference andtwopercentchangescoresforCPMvariables;one fromthefirstCPMtrial(CPMtrial1)andonefromthe secondCPMtrial(CPMtrial2).CPMtrialswererepeatedbeforeand3monthafterthesurgeryfortheclinicalcohort,andonthreedifferentdays(Days1,3,and 5)forthehealthycohort.ClinicalcohortStabilityanalysesforCPMmeasuresincludedintraclass correlations(ICC ’ s)fortheabsolutedifferenceofCPM andthepercentchangeofCPMonlywithinsession(trial 1andtrial2).Theseresultswerereportedwiththeappropriatecoefficientand95%confidenceinterval(CI). Fromthesedatathestandarderrorofmeasurement (SEM)wascalculatedforeachmeasureusingapreviouslydescribedmethod[standarddeviation* (1 – test restreliabilitycoefficient)][38-40].Theminimaldetectablechange(MDC95)wascalculatedusingapreviously describedmethod(1.96*SEM* 2)[41].Thestabilityestimates(SEMandMDC95)provideanideaofhowmuch individualchangeisnecessarybeforemeasurementerror islikelytohavebeenexceeded.Todeterminewhether sexinfluencesCPMstability,ICC ’ sstratifiedbysexwere alsoreported. RepeatedmeasuresANOVAswereusedtoassessthe effectoftrial(trial1andtrial2)onwithinsessionfor theabsolutedifferenceofCPM.Next,shoulderpainintensitywasincludedasacovariatetoinvestigatethe impactthatpainintensityhadonCPMstability.The analysiswasperformedseparatelyforeachsessionofthe clinicalcohort(session1and3months).HealthycohortStabilityanalysesforCPMmeasuresincludedintraclass correlations(ICC ’ s)fortheabsolutedifferenceofCPM andthepercentchangeofCPMwithinsession(trial1 andtrial2)andbetweensessions(day1,day3,andday 5).Asintheclinicalcohort,theseresultswerereported withtheappropriate95%CI,SEM,andtheMDC95.ICC ’ sstratifiedbysexwerealsoreported. RepeatedmeasuresANOVAswereusedtoassessthe effectoftrial(trial1andtrial2)onwithinsessionfor theabsolutedifferenceofCPM.Theanalysiswasperformedseparatelyforeachsessionofthehealthycohort (day1,day3,andday5).Inaddition,repeatedmeasures ANOVAwereusedtoassesstheeffectoftime(day1, day3,andday5)ontheabsolutedifferenceofCPM withandwithouttheinclusionofshoulderpainintensity asacovariatetoinvestigatetheimpactthatpainintensityhadonCPMstabilityonbetweensessions.ResultsSubjectsAtotalof134subjectsfromtheclinicalcohort,and190 subjectsfromthehealthycohortrecruitedfromMarch 2009toMay2012wereincludedinthisanalysis.Descriptivestatisticsforthemeasuresaresummarizedin Table1fortheclinicalandhealthycohorts.Absolute changeandpercentchangeofCPMstratifiedbysexare summarizedinTable2forbothcohorts.Allvariables werefoundtoapproximateanormaldistributionby visualexaminationandKolmogorov-Smirnovtest( p > 0.05),andwerethereforedeemedappropriateforour plannedparametricanalyses.ClinicalcohortTable3showsstabilityresultsfromtheclinicalcohort withinsession(trial1vstrial2).EstimatedICC ’ sforthe absolutedifferenceandpercentchangeofCPMstratified bysexarereportedinTable4.Intheclinicalcohortonly femaleshadICCvaluesapproachingthecommonlyused pointestimateintheliteratureof0.70[42].Itshouldbe notedthatformalesthewithinsessionstabilityatbaselinedidnotexceedtherecommendedICC ’ sthreshold scoreof0.50(fortheabsolutedifference)[42]. Inaddition,analysisrevealedthattheshoulderpain intensitydecreasedsignificantly[F(1,101)=65.83;p< 0.001]fromthepresurgicaltimepoint(mean=3.26; SD=2.31)to3monthspost-surgery(mean=1.52;SD= 1.56).RepeatedmeasuresANOVAshowedasignificant differenceontrial1andtrial2fortheabsolutedifference ofCPMwithinsession1(beforesurgery)[F(1,122)= 10.55,p<0.01].Asexpected,thefirstCPMtrial(mean= 9.05,SD=11.79)producedsignificantlygreaterinhibition ascomparedtothesecondCPMtrial(mean=4.69,SD= 8.29)(Figure1).Afterincludingpainintensityasacovariatenodifferenceswerefoundfrompreviousresults,indicatingthatthedifferencebetweenbothtrialsofCPM withinthesamesessionwasnotaffectedbyamountof shoulderpain.HealthycohortTable3showsstabilityresultsfromthehealthycohort forwithinsession(trial1vstrial2),andbetweensession (day1,day3,day5).EstimatedICC ’ sfortheabsolute differenceandpercentchangeofCPMstratifiedbysex arereportedinTable4.Malesfromthehealthycohort hadICC ’ svaluesconsideredashighscores(forthe absolutedifference)[42],whereasfemaleshadmoderate ICC ’ s[42]. Consistentwithourpreviousstudies[15,16],induced shoulderpainintensitychangedbetweenday1,day3,Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page4of10 http://www.biomedcentral.com/1471-2474/14/182

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andday5[F(2,374)=178.19;p<0.001]increasingsignificantlyfromday1(mean=0.45;SD=0.77)today3 (mean=2.45;SD=1.72),anddecreasingsignificantly fromday3today5(mean=1.23;SD=1.21).Repeated measuresANOVAshowedasignificantdifferencebetweentrial1andtrial2fortheabsolutedifferenceof CPMwithinday1[F(1,189)=6.16,p=0.01].Asexpected, thefirstCPMtrial(mean=9.06,SD=11.51)produced significantlygreaterinhibitionascomparedtothesecond CPMtrial(mean=7.10,SD=10.34)(Figure2).These significantdifferencesweremaintainedwithinday3and day5(Figure3).Therewasnosignificantinteractionterm betweenCPMtrialandpainintensitylevel(onlyday3 andday5)(p>0.05),indicatingthatthedifferencebetweenbothtrialsofCPMwithinthesamesessionwasnot affectedbypainintensity. Thebetweensessionstability(day1,day3,andday5) ofCPMtrial1[F(2,364)=0.18,p=0.84],didnotchange significantlyovertime(Figure3).Inexploringwhether shoulderpainintensityinfluencedCPMbetweensession Table1Demographiccharacteristics,CPMratings,absolutechangeandpercentchangeofCPMforclinicalandhealthy cohortsClinicalcohortMean(SD)Painratingfor teststimulus Painratingfor conditioningstimulus AbsolutechangeofCPMPercentchangeofCPM Age43.83(17.80) Sex(Female)47(35.1%) (Male)87(64.9%) BPIsess1(presurgery)3.28(2.31) BPIsess2(3months)1.56(1.55) PreCPMtrial1(presurgery)28.75(23.39)64.30(27.39)8.11(11.78)23.9% PostCPMtrial1(presurgery)20.38(20.99) PreCPMtrial2(presurgery)23.69(19.99)62.81(27.71)4.66(8.23)22.9% PostCPMtrial2(presurgery)18.96(19.69) PreCPMtrial1(3months)23.86(17.35)62.69(27.56)6.51(9.33)36.8% PostCPMtrial1(3months)17.45(17.81) PreCPMtrial2(3months)19.51(16.60)62.13(27.73)4.18(10.02)9.6% PostCPMtrial2(3months)15.33(16.00) Healthycohort Age23.02(6.04) Sex(Female)116(61.1%) (Male)74(38.9%) BPIday10.45(0.77) BPIday22.05(1.04) BPIday32.44(1.71) BPIday51.23(1.21) PreCPMtrial1(day1)20.81(20.45)50.19(27.77)9.06(11.51)48.4% PostCPMtrial1(day1)11.75(14.91) PreCPMtrial2(day1)18.09(18.87)50.88(27.29)7.08(10.35)46.4% PostCPMtrial2(day1)11.01(15.14) PreCPMtrial1(day3)20.30(19.43)53.97(27.66)9.08(12.74)46.6% PostCPMtrial1(day3)11.21(14.54) PreCPMtrial2(day3)17.66(18.46)52.70(27.11)6.99(11.09)41.0% PostCPMtrial2(day3)10.67(13.52) PreCPMtrial1(day5)19.97(20.61)54.37(28.05)8.60(13.38)41.7% PostCPMtrial1(day5)11.37(14.24) PreCPMtrial2(day5)16.95(18.04)51.96(27.98)6.27(9.99)39.6% PostCPMtrial2(day5)10.69(14.39) Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page5of10 http://www.biomedcentral.com/1471-2474/14/182

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stability,resultsshowthattherewasnointeractionterm betweentime(day1,day3,day5)andpainintensity[F (2,362)=1.89,p=0.15],indicatingthatthebetweensessionstabilityofCPMwasnotaffectedbysubject ’ spain intensity.Theseresultsdidnotdifferwhenexploring CPMtrial2.DiscussionThepresentstudyinvestigatedwhethergenderandpain intensityinfluenceCPMstabilityintwodifferentmusculoskeletalpainmodels.OurfindingssuggestthatthestabilityofCPMdidnotappeartoberelatedtoshoulder painintensityinsurgicalorexerciseinducedpaincohorts,howeverthestabilityofCPMwithinandbetween daysdifferedbysex.Reliabilityisanessentialpropertyof anymeasurementthatneedstobeestablishedbeforethe measurementcanbeusedwidelyinclinicalsettings. However,psychometricstudiesofCPMhavenotbeen widelyreported[11,43].Thedatareportedinthispaper arenovelbecausetoourknowledge,thisisthefirst studytoinvestigatestabilityofCPMusingthesame protocolinsubjectswith2differentformsofmusculoskeletalpain. Wewereinterestedindeterminingiftheinhibition producedbytheconditioningstimuluswasreliable withinthesamesession(trial1andtrial2)inacohort ofpatientsbeforeandaftershouldersurgery(clinical painmodel),andinahealthycohortbeforeandafter paininduction(acutepainmodel).Thisisanimportant issuebecauseameasurewithpoorreliabilityisunlikely tobevalid[44].Usingthemostcommonparadigmto evokeendogenouspaininhibition[4,5,45],CPMproved tosuppressSHPRasateststimulus,suchthattherewas asignificantinhibitionintrial1andintrial2(within session)inbothcohorts.Asexpectedtherewaslessinhibitionintrial2comparedwithtrial1inbothcohorts andacrossbothsessions.Thestartingpointsintrial2 (PreCPM)werelowerthantrial1(Table1),producing potentiallylessroomforaninhibitoryeffect(floor effect).Thiscouldbeexplainedbylingeringinhibition fromthefirsttrial,suggestinganinadequateresting periodbetweentrials,andcorroboratingthattheCPM Table2AbsolutechangeandpercentchangeofCPMstratifiedbysexforclinicalandhealthycohortsFemalesMales ClinicalcohortAbsolutechangePercentchangeAbsolutechangePercentchange CPMtrial1(presurgery)8.56(11.39)34.1%8.86(12.04)18.9% CPMtrial2(presurgery)3.94(7.80)21.1%5.06(8.47)23.8% CPMtrial1(3months)4.97(9.22)40.3%7.04(9.37)35.6% CPMtrial2(3months)2.72(7.77)1.2%4.69(10.70)12.3% Healthycohort CPMtrial1(day1)9.11(11.56)44.7%8.96(11.50)54.0% CPMtrial2(day1)7.42(11.98)41.5%6.55(7.10)54.0% CPMtrial1(day3)10.05(13.87)50.9%7.62(10.67)39.6% CPMtrial2(day3)8.11(13.13)41.9%5.27(6.61)39.7% CPMtrial1(day5)9.87(14.81)37.8%6.66(10.67)47.8% CPMtrial1(day5)6.57(10.17)38.6%5.81(9.77)41.2% Table3StabilityestimatesforCPMwithinandbetweensessionsfortheoverallsampleClinicalcohortICC ’ sfortheabsolute difference(95%CI) ICC ’ sforthepercent change(95%CI) SEM*MDC* WithinsessionCPMtrial1-CPMtrial2(baseline)0.54(0.34-0.68)0.42(0.16-0.59)6.7918.82 CPMtrial1-CPMtrial2(3months)0.62(0.43-0.74)0.07(-0.51-0.36)5.9616.52 Healthycohort WithinsessionCPMtrial1-CPMtrial2(day1)0.66(0.55-0.75)0.60(0.46-0.70)6.3717.66 CPMtrial1-CPMtrial2(day3)0.72(0.62-0.79)0.55(0.39-0.67)6.3017.46 CPMtrial1-CPMtrial2(day5)0.70(0.60-0.78)0.64(0.51-0.73)6.4017.74 BetweensessionCPMtrial1(day1)-CPMtrial1(day3)-CPM trial1(day5) 0.71(0.62-0.77)0.61(0.49-0.70)6.7518.71 CPMtrial2(day1)-CPMtrial2(day3)-CPM trial2(day5) 0.68(0.60-0.76)0.59(0.46-0.69)5.9316.44*SEMandMDCwerecalculatedusingICC ’ sfortheabsolutedifferenceofCPM.Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page6of10 http://www.biomedcentral.com/1471-2474/14/182

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inhibitoryeffectmaylastlongerthan2minutes,asother authorshavepreviouslysuggested[5,7,10].Therefore, futurestudiesshouldconsideralongerrestperiodifthe goalistohaverepeatedassessmentofCPMwithinthe samesession. StabilityofCPMwasalsoassessedbetweensessions. Thisenabledustodetermineifpreandpost-surgery changesonpainintensity(fortheclinicalcohort),and changesonpainintensityduringoneweek(inthe healthycohort),impactedthestabilityoftheCPMparadigminacontrolledsituation.Whiletheshoulderpain intensitychangedovertime(surgicalproceduresignificantlydecreasedtheamountofpain3monthsafterthe surgery,andEIMPprocedureinthehealthycohortinducedasignificantamountofpainover5days),the amountofinhibitionremainrelativelyconstantover time,showingthatstabilityofCPMseemsnottobeaffectedmuchbyashortperiodoftimeandnottobe affectedbyacuteorsub-acutechangesonpainintensity. ThemoderatestabilityofCPMintwomusculoskeletal painmodelsunderdifferentconditionsofpainintensity, corroboratetheassumptionthatCPMrepresentsamoderatelystableresponsethatislargelyindependentof changesinpainintensity.Eventhoughthepurposeof ourstudywasnotdirectlytocomparebothcohorts (clinicalvshealthy),itisinterestingtomentionthatthe conditioningstimulus(coldwaterbath)producedasignificantandcomparablepaininhibitioninbothcohorts. Theseresultscouldsuggestthattheongoingpaininthe clinicalcohortandtheinducedpaininthehealthycohortdidnotaffectthemechanismsofCPM,reinforcing theideaofthemoderatelystablenatureofthismeasure, andconfirmingusingcoldwaterbathasaconditioning stimulusaswaspreviouslyrecommended[4,5].Interms ofCPMcalculations,ourresultsfurtherconfirmthe Table4StabilityestimatesforCPMwithinandbetweensessionsstratifiedbysexforclinicalandhealthycohortsFemalesMales ClinicalcohortICC ’ sforthe absolute difference (95%CI) ICC ’ sforthe percentchange (95%CI) SEM*MDC*ICC ’ sforthe absolute difference (95%CI) ICC ’ sforthe percentchange (95%CI) SEM*MDC* WithinsessionCPMtrial1-CPMtrial 2(baseline) 0.63(0.33-0.80)0.57(0.19-0.78)5.8316.160.49(0.21-0.67)0.39(0.05-0.61)7.3320.32 CPMtrial1-CPMtrial 2(3months) 0.75(0.43-0.89)0.73(0.36-0.89)4.2511.780.58(0.32-0.73)0.41(-0.03-0.66)6.5018.02 Healthycohort WithinsessionCPMtrial1-CPMtrial 2(day1) 0.60(0.42-0.72)0.55(0.34-0.69)7.4520.650.79(0.67-0.87)0.66(0.45-0.79)4.2611.81 CPMtrial1-CPMtrial 2(day3) 0.71(0.57-0.80)0.61(0.42-0.74)7.2820.180.74(0.58-0.84)0.52(0.22-0.71)4.4012.20 CPMtrial1-CPMtrial 2(day5) 0.64(0.47-0.75)0.74(0.61-0.82)7.4920.760.83(0.73-0.89)0.48(0.13-0.68)4.2111.66 BetweensessionCPMtrial1(day1)-CPMtrial 1(day3)-CPMtrial1(day5) 0.65(0.51-0.75)0.62(0.47-0.73)7.9321.980.82(0.73-0.88)0.60(0.40-0.75)4.6412.86 CPMtrial2(day1)-CPMtrial 2(day3)-CPMtrial2(day5) 0.63(0.49-0.74)0.61(0.46-0.73)7.1519.820.82(0.74-0.88)0.58(0.35-0.74)3.329.20*SEMandMDCwerecalculatedusingICC ’ sfortheabsolutedifferenceofCPM. Figure1 Significantdifferencebetweentheabsolutedifference ofwithinsession(trial1vstrial2)beforethesurgery(session 1)and3monthsafterthesurgeryfortheclinicalcohort. Figure2 Significantdifferencebetweentheabsolutedifference ofwithinsession(trial1vstrial2)onday1,day3,andday5 forthehealthycohort. Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page7of10 http://www.biomedcentral.com/1471-2474/14/182

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importanceofreportingtheabsoluteandpercentchange whenreportingCMP[4].Notsurprisingly,theICC ’ scalculatedwiththepercentchangehadlowerreliability values.Thiscouldbeexplainedbythedifferentinformationthateachcalculationprovides,wheretheabsolute differencerepresentstheabsolutemagnitudeofchange, andthepercentchangeaccountsforthesubject ’ sbaselinelevelofsensitization. RegardingtheinfluenceofsexonCPMstabilitywithin andbetweensessions,thepresentstudyrevealedthat thestabilityofCPMwithinandbetweendaysdifferedby sex(Tables2and4).Anumberofstudiesusingwidely differentmethodologieshaveinvestigatedsexdifferences inexperimentalpainsensitivity[12]usingCPM,orother paradigms.SomeresearcherssuggestlessefficientCPM inwomenthanmen[14,26,46]whileotherstudiesdid notdetectsexdifferencesinCPM[47,48].Severalfactorshavebeenproposedtoexplainsexdifferences;howeverthestabilityofthisexperimentalpainmeasure acrosssexeshadnotbeenexploredbefore.Inthisstudy, ICC ’ sstratifiedbysexshowedthatmalesfromthe clinicalcohortshowedlowerscoresthanfemales(within session),andthefemalesfromthehealthycohortshowed lowerscoresthanmales(withinandbetweensessionfor theabsolutedifference).Furthermore,thestandarderror ofmeasurement(SEM)isdirectlyrelatedtothereliability ofatest;thatis,thelargertheSEM,thelowerthereliabilityofthetestandthelessprecisioninthemeasurestaken andscoresobtained.Consequently,ourresultsshoweda largedifferenceonSEMbetweenmalesandfemales, wheremalesfromthehealthycohortandfemalesfrom theclinicalcohorthadlowerlevelsofstandarderrorof measurementindicatinghigherlevelsofscoreconsistency. Theresultsofthepresentstudyintwomusculoskeletalpainmodelssuggestthatthemoststablesituation touseaCPMparadigmisinfemalesfromtheclinical cohort(wherechangesneedtoexceedaMDCof16to exceedmeasurementerror)andmalesfromthehealthy cohort(wherechangesneedtoexceedaMDCof12to exceedmeasurementerror).Thishasadirectclinical implicationbecausewhethersexaffectsreliabilityof CPM,orwhethertheamountofmeasurementvariation differsacrosssexmayleadtobiasedclinicalresultsand biasedclinicalimplications.ThisdifferencesonCPM stabilitybetweensexcouldpotentiallyexplainthecontradictoryresultsintheliteratureusingCPMasameasureof centralpainprocessing[3,9,12,49,50],becausealackof reliabilitydoespotentiallylimittheoverallvalidityofa measure.Aspeculativeexplanationforourresultscould befoundondifferencesonpsychologicalfactorsassociatedwiththisexperimentalpainmeasure[1,51,52],differencesinexpectationbetweensex[53],effectofdistraction betweensex[26],menstrualcycleeffect[54],howeverfutureclinicalstudiesneedtoexplorewhetherthesefactors directlyaffectCPMstability. Previousstudiesinvestigatingendogenouspainmodulationinchronicpainpopulationshaveshownapotential deficiencyofpaininhibitorysystem[3,6,7,10,12,26,50,55]. IthasalsobeenshownthatCPMcouldbeapredictorfor postoperativepainandpotentiallysensitivetochangesin thecentralnervoussystem[3,50].However,sinceCPMis aproxymeasureofcentralpaininhibitoryprocess,t,itis particularlyimportanttoestimatetheerrorassociated withthiscommonlyusedmeasureinordertobeusefulin researchandclinicaldecisionmaking.Afterperforminga reliabilityanalysisinthesetwocohortsandestablishing thatCPMisameasuremoderatelystableindependentof changesinpainintensity,weareinabetterstagetouse thismeasureinclinicalsettings(fromareliabilitystand point).IfwethinkthatCPMisaproxymeasureofcentral paininhibitorysystem,withamoderatereliabilitywemay speculatethathigherstabilitymaybeexpectedwhen assessingapopulationwithchronicpain(whichmayhave lessvariabilityincentralsensitization),howeverfuture studiesneedtobeperformedtotestthishypothesis. Someimportantlimitationsofthisstudywillneedto beaddressedbyfutureresearch.First,thisinvestigation waspartofalargerstudy;thereforetheprocedureswere notdesignedsolelyforthepurposeofestablishingCPM stability.Second,thisinvestigationwouldhavebeenenhancedbyaddingacontrolconditionwhereCPMtestingwasrepeatedonasecondpain-freeday.Inaddition, eventhoughthepurposeofthestudywasnottoassess thereliabilityofCPMintheclinicalcohortbeforeand afterthesurgery,ourwithinsessionanalysiscouldbeaffectedbytheeffectofdrugs.Futurestudiesshouldconsiderthepotentialeffectofdrugsbeforeandafterthe surgery.Lastly,someauthorshavereportedsignificantsex differencesinpainreportassociatedwithexperimenter sex.Thepresentstudyexaminedtheeffectofsexon CPM,howeverwedidnotcontrolforexperimentersexeffect,menstrualcyclephasesorcontraceptiveuse.Future Figure3 Significantdifferencebetweentheabsolutedifference ofbetweensessions(day1,day3,andday5)forthe healthycohort. Valencia etal.BMCMusculoskeletalDisorders 2013, 14 :182Page8of10 http://www.biomedcentral.com/1471-2474/14/182

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studiesshouldcontrolforthesefactors,andshouldinvestigatetheinfluenceofotherrelevantdemographiccharacteristic(suchasraceorethnicity)onCPMstability. Despitetheselimitations,thecurrentstudyrepresents anovelcontributiontotheliteraturebyidentifyingfactorsthatinfluenceCPMstabilityintwodifferentmusculoskeletalshoulderpainmodels.Evidencesuggeststhat alteredcentralprocessingofnoxiousstimulimightbe relevantinthepathogenesisofpaindisorders[55-58]. However,establishingthestabilityofameasurementis essentialbeforeconsiderCPMaclinicallyusefulmeasure.Ourresultssuggestthat1)CPMstabilityisnotrelatedtochangesinpainintensity,and2)therearesex differencesforCPMstabilitywithinandbetweendays. Applyingtheseresultstoclinicalpsychophysics,our studysuggestthatthefluctuationofshoulderpainintensitydidnotsignificantlyaffectCPMstability,thiscould reiteratethemoderatelystablenatureofthisconstruct andtherelativeconsistencyofthiscommonlyusedexperimentalpainmeasure.ConclusionsThisstudyassessedwhethershoulderpainintensityand genderinfluenceCPMstabilityintwomusculoskeletal painmodels.Ourresultsprovideevidencethatthefluctuationofpainintensitydidnotsignificantlyinfluence CPMstability.Inaddition,therearesexdifferencesfor CPMstabilitywithinandbetweendays,wherethemore stablesituationsforCPMwerefemalesfromtheclinical cohortandmalesfromthehealthycohort.Abbreviations (QST): Quantitativesensorytesting;(CPM):Conditionedpainmodulation; (EIMP):Exerciseinducedmusclepain;(MVIC):Maximumvoluntaryisometric contraction;(SLAP):Superiorlabrumfromanteriortoposterior;(VAS):Visual analoguescale;(NRS):Numericalratingscale;(BPI):Briefpaininventory; (ICC):Intraclasscorrelations. Competinginterest Theauthorsdeclarethattheyhavenocompetinginterest. Authors ’ contribution CV,contributedtoconception,design,dataanalyses,datainterpretation,and draftingthearticle.LK,contributedtoconception,design,anddraftingthe article.RF,contributedtodatainterpretationandcriticallyrevisingitfor intellectualcontent.SGprocuredthefunding,contributedtoconception, design,analysesandinterpretationofdata.Allauthorscriticallyrevisedthe manuscriptanddiscussedtheresultsandcommentedonit.Allauthorsread andapprovedthefinalmanuscript. Acknowledgements TheauthorswishtothankWarrenGreenfieldIIIforhisassistancewithclinical participantscreeningandrecruitment,Dr.TomasWright,Dr.MichaelMoser, andDr.KevinFarmerforallowingustorecruitfromtheirsurgicalclinic,and RoyCoronadoandCoreySimonforassistancewithtesting.Theauthorsalso wishtothankDr.JeffreyParrandDr.KellyLarkinfortheirassistancewith recruitmentandtestingsubjectsfromthehealthycohortandDr.PaulBorsa forprovidingthephysicalspacefortestingsubjectsfromthehealthycohort. Thisstudywassupportedbygrant#AR055899fromNIAMS/NIH. Authordetails1DepartmentofAppliedMedicineandRehabilitation,IndianaState University,TerreHaute,IN,USA.2SchoolofNursing,UniversityofPortland, Portland,OR,USA.3DepartmentofCommunityDentistryandBehavioral Science,UniversityofFlorida,Gainesville,FL,USA.4DepartmentofPhysical Therapy,UniversityofFlorida,UFHSC,Box100154,Gainesville,FL326100154,USA.5CenterforPainResearchandBehavioralHealth,Universityof Florida,Gainesville,FL,USA. 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