RichardE.Liebanoa,⇑,BarbaraRakelb,CarolG.T.Vancec,DeirdreM.Walshd,KathleenA.SlukacaUniversityoftheCityofSaoPaulo,PhysicalTherapyDepartment,SaoPaulo,BrazilUniversityofIowa,CollegeofNursing,IowaCity,IA52242-1121,USAcUniversityofIowa,CollegeofMedicine,GraduatePrograminPhysicalTherapyandRehabilitationScience,IowaCity,IA52242-1121,USAdUniversityofUlster,HealthandRehabilitationSciencesResearchInstitute,Newtownabbey,NorthernIreland,UKbarticleinfoabstract
Transcutaneouselectricalnervestimulation(TENS)isanoninvasivemodalityusedtocontrolpain.Ani-malmodelsshowthatrepeatedTENSapplicationproducesanalgesictoleranceandcross-toleranceatspinalopioidreceptors.Theaimofthepresentinvestigationwastoexaminewhetherrepeatedapplica-tionofTENSproducesanalgesictoleranceinhumans.Onehundredhealthysubjectswererandomlyassignedto1of4groups:control,placebo,low-frequency(4Hz)orhigh-frequency(100Hz)TENS.TENSwasapplieddailyfor5daystothenondominantupperlimb;pressure-painthreshold(PPT)measure-mentswererecordedbeforeandafterTENS.Temporalsummationtomechanicalstimulationwasrecordedondays1and5,beforeandafterTENS.Diffusenoxiousinhibitorycontrol(DNIC)wastestedonday5usingthecoldpressortestandPPTmeasurements.TherewasaninitialincreaseinPPTsinbothlow-andhigh-frequencyTENSgroupswhencomparedwithplaceboorcontrolgroups.However,byday5thisTENS-inducedincreaseinPPTdidnotoccur,andtherewasnodifferencebetweenactiveTENSandplaceboorcontrolgroups.High-frequencyTENSdecreasedtemporalsummationonday1whencom-paredwithday5.DNICincreasedthePPTsimilarlyinallgroups.ThesedatasuggestthatrepeateddailyapplicationofTENSresultsinadecreaseinitshypoalgesiceffectbythefifthdayandthatthetolerance-likeeffecttorepeatedTENSresultsfromtoleranceatcentrallylocatedopioidreceptors.ThelackofchangeinDNICresponsesuggeststhatTENSandDNICutilizeseparatepathwaystoproduceanalgesia.Ó2010InternationalAssociationfortheStudyofPain.PublishedbyElsevierB.V.Allrightsreserved.Articlehistory:Received19April2010Receivedinrevisedform9September2010Accepted27October2010Keywords:TranscutaneouselectricalnervestimulationPainmeasurementPainthreshold1.IntroductionTranscutaneouselectricalnervestimulation(TENS)involvestheapplicationofelectricalcurrentstotheskinforpaincontrol;itisanoninvasivemodalitythatiscommonlyusedbyhealthcareprofes-sionalstocontrolbothacuteandchronicpainarisingfromseveralconditions[3,18,20,24,49,52,53].TENSemergedandbecamewidelyacceptedafterthepublicationofthegatecontroltheoryofpain[44].Bothhigh-andlow-frequencyTENScausehypoalgesiathroughthereleaseofendogenousopioidsinthecentralnervoussystem[9,34,58].Atthespinallevelandtherostralventralmedul-la,therearedifferentopioidsreleasedwithdifferentstimulationfrequenciesandthusdifferentopioidreceptorsactivatedtopro-duceanalgesiawithhigh-orlow-frequencyTENS[62].Lowfrequencies,usuallybelow10Hz,activatel-opioidreceptors,andhighfrequencies,above50Hz,activated-opioidreceptors[9,34,58].⇑Correspondingauthor.Address:UniversityoftheCityofSaoPaulo(UNICID),PhysicalTherapyDepartment,RuaCesarioGaleno448/475,Tatuape,SaoPaulo,SP–CEP03071-000,Brazil.Tel.:+551121781479;fax:+551121781380.E-mailaddress:liebano@gmail.com(R.E.Liebano).Repeatedstimulationofopioidreceptorsbyrepeatedadminis-trationofmorphineoropioidanalgesicscanleadtoananalgesictolerance,definedasadecreaseinanalgesiceffectivenesswithre-peateduse[43].Inasimilarway,repeatedutilizationoftherapeu-ticelectrophysicalagentsthatreducepainthroughreleaseofendogenousopioidscouldhaveagradualdiminutionoftheiranal-gesiceffect.ChandranandSluka[9]demonstratedinratsthatre-peatedadministrationoflow-andhigh-frequencyTENSleadstoadevelopmentofopioidtolerancewithacorrespondingcross-tol-erancetointrathecallyadministeredl-andd-opioidagonists,respectively.Inclinicalpractice,TENSisusuallyapplieddailyovermanyweeks.Approximately30%ofpatientsfailtorespondtoTENSand,ofthepatientswhorespondinitially,onlyonethirdcontinuetoobtainpainreliefafter2years[4].Solomonetal.[63]showedthatpeoplewhohadbeentakingopioidslongenoughtodeveloptolerancebeforesurgerydidnotrespondtoTENSwhenusedpostoperatively.AlthoughcommonlyacceptedthatTENSre-ducesitsefficacywithrepeatedapplication,thedevelopmentoftolerancetoTENShasnotbeeninvestigatedandconfirmedinhu-mansubjects.Withtheseconcernsinmind,theaimofthepresentinvestigationwastoexaminetheanalgesictolerancetoTENSinhumansubjects.0304-3959/$36.00Ó2010InternationalAssociationfortheStudyofPain.PublishedbyElsevierB.V.Allrightsreserved.doi:10.1016/j.pain.2010.10.040336R.E.Liebanoetal./PAIN152(2011)335–342Ò2.Methods2.1.SubjectsAtotalof100healthy,TENS-naïve,pain-freesubjects(48men,52women;meanage31.75±12.05years;agerange18to60years)wererecruitedfromthestaffandstudentsoftheUniversityofIowaafterapprovalwasobtainedfromthelocalinstitutionalreviewboard.Thesamplesizewascalculatedusingdatafrompreviousstudiesonpressure-painthreshold(PPT)andTENS[51].Consideringasignificancelevelof5%,powerof80%,4treatmentgroups,andaneffectsizeof0.4,itwascalculatedthat25partici-pantswererequiredineachgroup.Subjectswerescreenedandex-cludediftheyhadalteredskinsensationorhistoryofrecenttraumainupperlimbs,cardiacpacemaker,pregnancy,oriftheywerereceivinganytypeofpainmedication.Aftertheparticipantsprovidedwritteninformedconsent,theywerestratifiedbygenderandrandomlyassignedto1of4groups:control(n=25),placeboTENS(n=25),low-frequencyTENS(n=25),orhigh-frequencyTENS(n=25).Randomizationwasperformedusingthesequen-tiallynumbered,opaquesealedenvelopesallocationconcealmentmethod[22,55].Theenvelopeswerestoredinasecurecabinetthatonlytheallocationinvestigatorhadaccessto,andwereopenedimmediatelybeforeinterventionallocation.Demographicinformation,includingage,race,gender,height,andweight,wererecorded.Therewerenosignificantdifferencesbetweengroupsbasedonage,race,gender,orbodymassindex(Table1).2.2.PPTThePPThasbeenreportedtoreflectmainlypressure-painsen-sitivityofdeepertissues[36–38].PPTmeasurementswerere-cordedbyanassessorwhowasblindtogroupallocationusingaSomedicTypeIIdigitalpressurealgometer(SomedicInc.,Hörby,Sweden)from3markedspotsalongtheextensormassofthenon-dominantforearm(2,3,and4cmbelowtheelbowcrease)(Fig.1).Thepressurewasappliedperpendicularlytotheskinatarateof50kPa/sthroughaflatcircularprobemeasuring1cm2andcoveredwith1mmofrubbertoavoidpainfulskinstimuliduetosharpme-taledges[37,38].Subjectswereinstructedtopressthealgometerbuttonwhenpressurewasfirstperceivedaspain,andthealgom-eterwasretractedatthispoint.TheaverageofthePPTscoresre-cordedatthe3pointswasusedasthefinalvalueateachmeasurementtime.Eachsubjecthad2practicetrialsonthenon-testingforearmfollowedbythedatacollectionround.2.3.TonicexperimentalpressurepainstimulusPainintensitiestotonicpressurewereusedtodeterminepres-suretemporalsummation.Atemporalsummation(TS)areawasTable1
Characteristicsofthestudyparticipants.
Control(n=25)GenderMaleFemaleAge(mean±SD)BMI(mean±SD)RaceCaucasianAfricanAmericanAsianOther12(48%)13(52%)30.48±2.0425.21±0.9221(84%)1(4%)1(4%)2(8%)PlaceboTENS(n=25)12(48%)13(52%)30.4±2.5326.16±0.6224(96%)0(0%)1(4%)0(0%)Low-frequencyTENS(n=25)12(48%)13(52%)38.2±2.8525.46±1.0921(84%)0(0%)3(12%)1(4%)High-frequencyTENS(n=25)12(48%)13(52%)27.92±1.6725.59±1.0922(88%)1(4%)1(4%)1(4%)Fig.1.Theplacementoftranscutaneouselectricalnervestimulationelectrodesandrecordingsitesforpressure-painthreshold(PPT)andtemporalsummation(TS).markedontheposterioraspectofthenondominantforearm,overtheextensormass,6cmbelowthecreaseoftheelbow(Fig.1).Temporalsummationwasmeasuredwithacustom-builtdeviceincorporatingapressuretransducerandaleverwithamovableweighttogradethepressureapplied(kPa).Theforearmwasse-curedinplacewithavacuumpillow(VersaForm,SammonsPres-ton,Bolingbrook,IL),andthepressurestimuluswasdeliveredthrougha1-cm2probe.Temporalsummationwastestedatan8/20painratingfor2minwithsubjectsratingtheirpainevery10sona0to20numericratingscale(0=nopainand20=theworstpainimaginable)startingattime0.Theareaunderthecurvewascalculatedfordataanalysisusingthefollowingformula:A¼12Xi¼1ðPiÀP0ÞÃDtwhereA,areaunderthecurve;Pi,painintensityatmomenti;P0,painintensityatmoment0;Dt,timeframebetweenthemeasure-mentsofpainintensity(10s).The0-to-20numericratingscalewasusedbecauseitwasfoundtobeeasiertouseandassociatedwithhighercomplianceandlow-erfailurerateswhencomparedwiththeVisualAnalogueScale[28].Ithasestablishedvalidityandreliabilityforassessingacutepain[23,30,46].2.4.TENSprocedureThesubject’sskinwascleansedwithmildsoapandwater,and2squareself-adhesiveelectrodes(5Â5cm)(StimCarePremiumElectrodes,EmpiInc.,St.Paul,MN)wereplaced1cmproximaltotheelbowcreaseand1cmproximaltothewristcreaseonthedor-sumofthenondominantupperlimb.Thecornersoftheelectrodesweremarkedontheskinusingapermanentmarkertoallowexactlythesameelectrodespositioningduringthe5consecutiveBMI,bodymassindex;TENS,transcutaneouselectricalnervestimulation.R.E.Liebanoetal./PAIN152(2011)335–342Ò337daysofthestudy(Fig.1).Subjectswereinstructednottowashoffthesemarkingsduringtheweekoftesting.Twoactiveunitswereused:onewassetatlowfrequency(4Hz)andanotherwassetathighfrequency(100Hz).TheseactiveunitsappliedTENS(100-lspulseduration)atmaximaltolerableinten-sityfor20mintothenondominantforearm,dailyfor5days.ThisdurationofTENSapplicationwasbasedonotherstudiesshowingtheeffectofTENSinexperimentalpainmodels[10–12,51,72].Maximaltolerableintensitywasthegreatestintensitythesubjectcouldtoleratethatwasnotpainful.Insomecasesthisintensityproducedamotorcontraction.Theaverageamplitudeusedinthelow-frequencyTENSgroupwas30.64±1.59mAandinthehigh-frequencyTENSgroupwas25.79±1.29mA.PreviousworkfromourlaboratoryinanimalsshowsthatTENSactivateslarge-diameterafferentsatjustbeloworjustabovemotorthreshold.Nociceptorswerenotactivateduntilwegotto2timesmotorthreshold,aclearlypainfulstimulusinhumans[50].Inhumans,asimilarpatternofactivationisobservedintherangesthatweused.LevinandHui-Chan[41]performedrecordingsfromthemediannerveinhumansubjectsandshowedthathigh-frequencyTENS(100Hz)appliedat3timesthesensorythresholdactivatesonlylarge-diameterAbfibers.Similarly,low-frequencyTENS(4Hz),atmaximaltolerableintensity,activatesonlyAbafferentfibers,whereasAdactivationonlyoccursatintensitiesabovemaximaltolerableintensity.Thus,webelievethattheintensitiesweusedinthepresentstudyonlyactivatedAbafferentfibers.Thepulseamplitudeappliedonday1wasnoted,andonallsubse-quentdaysthesamedoseofTENSwasapplied,i.e.,allTENSparameterswerekeptconstantfortherestoftheweek.TheplaceboTENSwasappliedusingashamunitthatlookedsimilartotheactiveunit.ThisunitactivelyappliedTENS(continuousmode,100Hz,100ls)atmaximaltolerableintensityfor30s,andthenthecurrentrampedoffoverthenext15s.Thesameparametersusedonday1wereusedfortherestoftheweek.AlldeviceswereRehabilicareMaximaTENSunits,andtheywereidenticalinappearance(EmpiInc.,St.Paul,MN).Theydeliveredarectangular,balanced,asymmetrical,biphasicpulsedcurrent.TheTENSunitswerecalibratedusingadigitaloscilloscope(TDS430A,TektronixInc.,Beaverton,OR)beforestartingthestudy.Foreachpulseamplitudesettingonthedevices,peak-to-peakvoltagewasmeasuredacrossa1-kOresistortocalculatethecorrespondingcurrentinmA.TENSapplicationswereperformedbyaninvestigatorwhodidnotparticipateinoutcomeassessments.Duringthepainmeasure-ments,theintensityofTENSwasdecreasedandkeptatasensoryintensityleveltoensurethepainassessorwaskeptblindtothesubject’sgroupallocation.2.5.ActivationofdiffusenoxiousinhibitorycontrolThecoldpressortestwasusedonday5toinducepainandtotriggerthediffusenoxiousinhibitorycontrol(DNIC)response[35,65].Theconditioningstimulusconsistedoftheimmersionofthesubjects’testingsidelowerextremityinabucketoficewater(4°C)tojustabovetheankle.Painintensityratingwasmeasured20safterimmersionona0-to-20scale.PPTwasrecorded30safterimmersionfromthe3locationsoverthenondominantfore-armasdescribedbefore.Beforetheyremovedthefootfromthewater,subjectswereaskedtoratetheirpainagainona0-to-20scale.ThepercentageofPPTchangewascalculatedconsideringthePPTvaluesrecordedonday5(baseline).2.6.GeneraloverviewofprotocolOneday1afterobtainingconsentanddemographicinforma-tion,thesubjectswererandomizedinto1of4groups.Theywereaskedtoremainseatedinacomfortableuprightpositionduringallprocedures.Thenondominantforearmwascleansed,thePPTandTSareasweremarkedasdescribedbefore,andtheTENSelec-trodeswereappliedtosubjectsallocatedinactiveorplaceboTENSgroups.PPTswereassessed,followedbyTSmeasurement,andthepainassessorlefttheroom.IntheplaceboTENS,low-frequencyTENS,andhigh-frequencyTENSgroups,theleadswereconnectedtotheelectrodesandthetreatmentwasappliedfor20min.Subjectsinthecontrolgroupwereinformedthattheyshouldrestfor20min.Aftera20-mintreatmentinterval,thepainassessorre-turned,TSandPPTswerereassessed,andthesubject’sweightandheightweremeasured.Ondays2to4,PPTswererecordedbeforeandaftera20-mintreatment(orrestincontrolgroup)interval.Onday5,thePPTsandTSwererecordedbeforeandafterthe20-minTENSapplication(orrestincontrolgroup).AfterTENS,theDNICresponsewasassessed.2.7.BlindingassessmentAttheconclusionoftesting,theTENSinvestigatoraskedthesubject,‘‘DoyouthinkyoureceivedactiveTENS,placeboTENS,ordon’tknow?’’Thepainassessorwasasked‘‘DoyouthinkthesubjectreceivedactiveTENS,placeboTENS,ordon’tknow?’’Theirresponsestothesequestionswererecordedandusedtogaugetheadequacyofsubjectandinvestigatorblinding[51].2.8.StatisticalanalysesChangesinPPTwerecalculatedeachdayaspercentageofbase-line(pre-TENS),wherenochangewasequivalentto0%.Positivepercentagevaluesrepresenthypoalgesia,andnegativevaluesrep-resenthyperalgesia.Changesintemporalsummationforpressurestimuliwerecalculatedasadifferenceintheareaunderthecurveforthedurationoftesting(i.e.,120s)post-TENStopre-TENS.Descriptivestatisticswerecalculatedforallvariables,andtestsfornormaldistribution(Shapiro–Wilk)werecarriedout.ThePPTpercentagechangedatawerenormallydistributed,andwerethereforeanalyzedusingarepeated-measuresANOVAwithbe-tween-subjectsfactors.Aone-wayANOVAforindependentsam-plescompareddifferencesbetweengroupsateachtimeperiod.Post-hoctestingwasperformedwithaTukeytestfordifferencesbetweengroups.Av2testwasusedtocomparethepercentageofsummatorsandnonsummatorsondays1and5.Repeated-measuresANOVAwasalsousedtocomparedifferencesacrosstimeduringTS,betweensummatorsandnonsummators,andbetweendays1and5forgroups.ApairedStudentttestcomparedthedif-ferenceinTSbetweendays1and5foreachgroupandthepainintensityduringDNICtestat20sandattheendoftest.ThePPTpercentageofchangedatarecordedduringDNICtestswerenotnormallydistributedandwerethereforeanalyzedusingaKruskal–Wallistest.AssociationsamongthepainintensityandpercentageofPPTchangeduringDNICtestswereassessedusingPearson’sproduct–momentcorrelationcoefficients.Statisticalsig-nificancewassetatP<.05.AllanalyseswereperformedusingSPSS(version17.0;SPSSInc.,Chicago,IL).Dataarepresentedasmean±SEM.3.Results3.1.PPTdataMeanPPTpercentagesofchange(±SEM)forallexperimentalgroupsoneachdayareshowninFig.2.Therepeated-measuresANOVAwithbetween-subjectsfactorsrevealeddifferencesoverdays(P=.006)andbetweengroups(P>.001).Therewasnosignif-icantinteractiveeffectbetweendaysandgroups(P=.091).338R.E.Liebanoetal./PAIN152(2011)335–342ÒFig.3.Painintensityduringtemporalsummationtotonicpressureinallsubjects,summators,andnonsummators.Fig.2.Percentageofchangeinpressure-painthreshold(PPT)foreachexperimentalgroupduringthe5consecutivedays.TENS,transcutaneouselectricalnervestimulation.Post-hocTukeytestsindicatedasignificanthypoalgesiceffectinthelow-frequencyTENSgroupwhencomparedwiththecontrolgroup(P=.024)andtheplaceboTENSgroup(P=.004).Similarlythehigh-frequencyTENSgroupshowedasignificantdifferencewhencomparedwithcontrolandplaceboTENSgroups(P=.012,P=.002).NosignificantdifferenceswerefoundbetweencontrolandplaceboTENSgroups(P=.945)orbetweenlow-andhigh-frequencyTENSgroups(P=.995).Forcomparisonsbetweengroupsoneachday,controlandpla-ceboTENSgroupswerecombinedbecausetherewerenosignifi-cantdifferencesbetweenthem.One-wayANOVAforindependentsamplesidentifiedthatsignificantdifferencesoccurredbetweenthecombinedcontrolandplaceboTENSgroupsandtheotherexperimentalgroupsfromday1today4withvaluesrangingfromP<.0001toP=.0443.Onday5,nodifferenceswereobservedbe-tweengroups(P=.8766),representingadecreaseinhypoalgesiceffectpresentedbyactiveTENSgroups.Post-hocTukeytestsaresummarizedinTable2.3.2.MechanicaltemporalsummationdataOnesubjectwasexcludedfromanalysisduetoalargevariationinpressurereadingsformechanicaltemporalsummationtesting.Fig.3showsthepainintensityduringtemporalsummationtoto-nicpressureinallsubjects.Therewasasignificantincreaseinpainovertime(P<.0001).Further,thesubjectsweredividedinsumma-tors(n=53)andnonsummators(n=46)(summatorsweredefinedashavinganareaunderthecurveabove100painintensityÁsec).Therewasasignificanthigherincreaseinpainintensityovertimeinsummatorswhencomparedwithnonsummators(P=.001).Av2testrevealednosignificantdifferenceinpercentageofsummatorsonday1comparedwithday5(P=.1070).Whenconsideringallsubjects(summatorsandnonsummators),therewerenosignificantchangesinareaunderthecurvebeforeandafterTENSondays1and5(P>.05).However,consideringonlythesummators,boththeplaceboTENSandthehigh-frequencyTENSgroupspresentedadecreaseinmechanicaltemporalsumma-tiononday1aftertreatment(P=.0325,P=.0120)(Fig.4).Repeated-measuresANOVAdidnotshowsignificantdifferencesinthedifferencescoresintheareaunderthecurve(areaunderthecurveafterTENSminusareaunderthecurvebeforeTENS)betweengroups(P=.072)andacrosstime(P=.132)insummators.Never-theless,whencomparingthedifferenceintheareaunderthecurveonday1today5,thehigh-frequencyTENSgroupshowedasignif-icantdecreaseindifferencescores(P=.036)onday5(Fig.5),sug-gestingreducedeffectivenessofhigh-frequencyTENSontemporalsummation.3.3.DNICdataAsdescribedbefore,painintensitywasmeasuredduringthecoldpressortest,20safterimmersionandattheendoftest,ona0-to-20scale.Themeanpainratingforallsubjectsat20swas8.95±0.48,andattheendwas12.19±0.50.Therewasasignifi-cantdifferenceinpainintensitybetweenthe2times(P<.0001).TherewasalsoapositivecorrelationbetweenthepainintensityduringthecoldpressortestandthepercentageofchangeinPPT(r=.289,P=.004)(Fig.6).TherewasnosignificantdifferenceinTable2
SummaryofTukeypost-hoctestsforstatisticalcomparisonbetweenlow-andhigh-frequencyTENSgroupswiththecombinedcontrol+placeboTENSgroupsateachday.Day1GroupControl+placeboLowfrequencyControl+placeboLowfrequencyControl+placeboLowfrequencyControl+placeboLowfrequencyControl+placeboComparisongroupLowfrequencyHighFrequencyHighfrequencyLowfrequencyHighFrequencyHighfrequencyLowfrequencyHighFrequencyHighfrequencyLowfrequencyHighFrequencyHighfrequencyNosignificantdifferencesMeandifferencebetweengroupsÀ6.39À20.11À13.72À15.60À10.734.86À19.13À20.10À0.96À11.65À4.976.68Pvalue>.05<.001>.05<.05>.05>.05<.01<.001>.05<.05>.05>.052345TENS,transcutaneouselectricalnervestimulation.BoldnumbersrepresentsignificantPvalue.R.E.Liebanoetal./PAIN152(2011)335–342Ò339Fig.4.Areaunderthecurveaftertemporalsummationtotonicpressureinsummatorssubjectsonday1.*Significantdifferencewiththepre-TENSarea.TENS,transcutaneouselectricalnervestimulation.thepercentageofchangeinPPTbetweenthestudygroups(P=.6858)(Fig.7).3.4.AssessmentofblindingThepainassessorcorrectlyidentifiedthatsubjectsreceivedanactiveTENSunitin4%(1of25)ofcasesinboththehigh-andlow-frequencyTENSgroups.ThesameratewasobservedintheplaceboTENSgroup,inwhichtheassessorcorrectlyidentifiedtheplacebounitin4%(1of25)ofthetime.Inotherwords,theassessorwasblinded96%ofthetimewhenrecordingpainmea-suresinplacebo,low-frequency,andhigh-frequencyTENSgroups,indicatingsuccessfulblinding(P<.0001).Subjectswereblindedtothetreatment20%(5of25)ofthetimeinthehigh-frequencyTENSgroup,36%(9of25)inthelow-fre-quencyTENSgroup,and48%(12of25)intheplaceboTENSgroup.TherateofblindingintheplaceboTENSgroupwasnodifferentthanchance(random50:50probability)(P=.8415).4.DiscussionPatientswithchronicpainwhoinitiallyrespondtoTENSmaybecomelong-termusers[8,26,32,33].BecauseanimalstudiesshowthatTENSactivatesopioidsreceptorstoproduceanalgesia,re-peatedTENSapplicationscouldcauseanalgesictolerancesimilartolong-termuseofopioids[43].AlthoughanalgesictolerancetoTENShasbeendemonstratedinrats[9,17,19],thisisthefirststudydesignedtoaddressspecificallytheanalgesictolerancetoTENSinFig.5.Differencescores(post-TENSarea–pre-TENSarea)inareaunderthecurveafter*temporalsummationtotonicpressureinsummatorssubjectsondays1and5.Significantdifferencewithday1.TENS,transcutaneouselectricalnervestimulation.Fig.6.Scatterplotandcorrelationbetweenpainintensityandpercentchangeinpressure-painthreshold(PPT)duringdiffusenoxiousinhibitorycontroltest.TENS,transcutaneouselectricalnervestimulation.humans.Theresultsshowthatrepeateddailyapplicationofeitherhigh-orlow-frequencyTENSwiththesamedailydose(intensity,frequency,pulseduration,andtreatmentduration)andelectrodepositionresultsinadecreaseinitshypoalgesiceffectbythefourthandfifthconsecutivedays,respectively.Thesedataparallelfind-ingsinanimalstudiesshowingthatthetolerance-likeeffecttore-peatedTENSresultsfromtoleranceatcentrallylocatedopioidreceptors[9].Clinicalstudiesinhumansubjectsconfirmthatopi-oidreceptorsplayaroleinTENSanalgesia.Thesestudiesshowre-leaseofendogenousopioidsinhumansubjectsduringTENS,thatlow-andhigh-frequencyTENSanalgesiaisblockedbysystemicnaloxone,andthatTENSislesseffectiveinpatientswhoareopioidtolerant[27,39,40,54,56,63].Clinically,32%oflong-termusersofTENSwithavarietyofchronicpainconditionsreportadeclineinTENSefficacyfromthetimetheunitwasissued[32].However,thelengthofTENSutilizationnecessarytocauseanalgesictoler-anceintheseuserswasnotreported.Itispossiblethatinaclinicalsetting,thedevelopmentofanalgesictolerancecanbedelayedifTENSparametersortreatmentschedulearechanged.Weprevi-ously[19]showedinratsthatmixed-frequency(lowandhighfre-quencysimultaneously)ordaily-alternating-frequency(4/100Hz)TENSdelaystheoccurrenceofanalgesictolerance.Alternatively,increasingthepulseamplitude,andtherebyincreasingthedose,couldalsoalleviateanalgesictolerancetoTENS.Futureexperi-mentsneedtoconfirmwhetherchangingstimulationparametersinhumansubjectscanpreventanalgesictolerance.PriorstudiescomparedtheefficacyofdifferentfrequenciesofTENSandmixedTENSfrequenciesonavarietyofoutcomes.Alter-natingTENSfrequency(2Hz,100ls,3.5sÂ100Hz,700ls,2.5s)resultsinagreaterincreaseinheatpainthresholdsinhealthysub-jectswhencomparedwith2Hz,100Hz,orcontrol(noTENS)[64].Fig.7.Percentageofchangeinpressure-painthreshold(PPT)duringcoldpressortestinallgroups.TENS,transcutaneouselectricalnervestimulation.340R.E.Liebanoetal./PAIN152(2011)335–342ÒHowever,100-HzTENSwasmoreeffectiveforincreasingthemechanicalpainthreshold[64].WhencomparingdifferentpulsepatternsofTENSonice-painthresholdsinhealthysubjects,contin-uoushigh-frequencyTENS(80Hz)producedthegreatestmeanelevationwhencomparedwithburst,modulation(burstwithamplitudemodulation),andrandomfrequencies(14to188Hz),althoughallpulsepatternsincreasedice-painthresholdswhencomparedwithcontrols[31].Indirectcontrast,ChenandJohnson[10]foundnodifferencesinhypoalgesiceffectbetweenconstant-frequencyTENS(80Hz)andfrequency-modulatedTENS,inwhichthefrequencyvariedfrom20to100Hz.Itispossiblethatbothapplications(constant-frequencyandfrequency-modulatedTENS)activatedonlyhigh-frequencymechanisms,whereaspriorstudiesactivatedlow-frequencymechanisms[17,19,57–59,61,62].Unfor-tunately,fewstudieshaveutilizedplacebocontrolsforcompari-son.AlthoughJohnsonetal.[31]compareddifferentfrequenciesagainstno-treatmentcontrols,ChenandJohnson[10]didnotuseacontrolgroup.Thecurrentstudyshowedanalgesiawithbothlow-frequency(4Hz)andhigh-frequency(100Hz)TENSwhencomparedwithplaceboorano-treatmentcontrolgroup,butnodifferencebetweenthe2activeTENSgroups.However,onday1,4HzhadnoeffectonPPTs,whereas100HzincreasedthePPTs.Thisfindingsuggeststhatlow-frequencyTENShasadelayedhypoalgesiceffectwhencomparedwithhigh-frequencyTENS.Low-frequencyTENSincreasedthePPTondays2,3,and4,whereashigh-frequencyTENSincreasedPPTondays1,2,and3.Theseresultsareinaccordancewiththoseofotherinvestigators,whocompareddifferentTENSfrequenciesonPPT,performingonly1treatmentsession.Inthesestudies,high-frequencyTENSwasmoreeffectivethanlow-frequencyTENSforPPTincrease[12,14,64,69,70].Animalstudiesshowthathigh-andlow-frequencyTENSactivatedifferentneuropharmacologicalmechanismsinthecentralnervoussystem[59–61].Therefore,itispossiblethatmechanismsactivatedbyhigh-frequencyTENSpromoteafasterhypoalgesicresponsethanlow-frequencyTENSinanexperimentalmodel.Increasingintensityofstimulationisanotherpotentialmechanismbywhichwecouldalleviatetolerance.Priorstudiesshowthatlow-intensityTENSdoesnotproduceanalgesia[1,6,13,14,45,52,71],andtheintensityofstimulationiscorrelatedwiththedegreeofanalgesia[51].Weproposethatcontinuouslyincreasingintensityofstimulationwithinasinglesessionordailycouldincreasedoseandpreventthedevelopmentofanalgesictolerance.ThecurrentstudyusedanoveltypeofshamTENSunittodeli-verplaceboTENSthathasbeenvalidatedrecently[51].ThisshamunitappliedTENS(100Hz,100ls)atmaximaltolerableintensityfor30s,andthenthecurrentrampedoffoverthenext15s.Thefactthattheshamunitdeliverselectricalcurrentforashortperiodoftimeincreasestherateofsubjectblinding[15,51].Thistimeisconsideredtoobrieftohaveanydefinitephysiologicaleffect[15].Oursuccessinblindingthepainassessor(96%)wassimilartopre-viousstudiesthatusedthisnoveltypeofTENSplacebo[15,51].Thepainassessorcorrectlyidentifiedthatsubjectswerereceivingac-tiveTENStreatmentonlyonceinbothhigh-andlow-frequencyTENSgroups;thiswasbecauseitwaspossibletonoticemildmus-clecontractionsduringPPTrecordingsinthesesubjects.Thesuc-cessofsubjectblindingintheplaceboTENSgroup(48%)isinaccordancewithresultsfromapreviousstudy(40%)[51].How-ever,thislevelofblindingwaslowerthanthatobservedbyCowanetal.[15](71%)whenusingthecurrentintensityatsensorythreshold.Itispossiblethattheuseofamaximaltolerableinten-sityinthepresentstudywasresponsibleforthisdifference,mak-ingiteasierforthesubjectstonoticewhenthecurrentrampedoff.Themechanismofanalgesictoleranceisnotcompletelyunder-stood,andanumberofneurotransmittersandreceptorshavebeendescribed.Theneuropeptidecholecystokinin(CCK)hasbeenimpli-catedinthedevelopmentoftolerancetoTENS[17].CCKisanendogenousopioidantagonistthatactivatesCCK-AandCCK-Breceptors[17,74].Priorworkshowsthatbothhigh-andlow-frequencyTENStolerancecanbepreventedbyblockadeofCCK-AandCCK-Breceptors,respectively[17].TheN-methyl-D-aspartate(NMDA)receptorsinthecentralnervoussystemhavealsobeenimplicatedinopioidanalgesia,andblockadeofNMDAreceptorsduringTENSpreventsthedevelopmentofanalgesiatolerance[29].IthasalsobeensuggestedthattoleranceisaconsequenceofanadaptivechangebythenervoussystemtoregularrepetitivestimuliproducedbyTENS[32].Thishypothesisledtoanincorpo-rationofparametermodulation(suchasfrequencyandamplitude)inmostTENSdevices;asdescribedbefore,theusefulnessofthesemodulationsstilllacksstrongscientificevidence.Analgesictoler-ancetoTENS,however,seemstoresultfromtoleranceatopioidreceptorsinthecentralnervoussystem,andusesknownopioid-tolerancemechanisms.Thetemporalsummationprotocolusedinthisstudyreflectsthecentralexcitabilityfromdeeptissuepressurepain.Itisbelievedthattemporalsummationisaconsequenceofwind-upofdorsalhornneurons[73].High-frequencyTENSdecreasedtemporalsum-mationonday1whencomparedwithpre-TENStemporalsumma-tion;however,thisdecreasewasnotdifferentfromplaceboTENS.Interestingly,thereductionintemporalsummationinbothgroupswasnotpresentonday5,likelyaresultofopioidtolerance.BecauseTENSandplaceboeffectsareopioidmediated[2,5,16,42,68,75],wesuggestthatrepetitiveactivationofopioidreceptorsleadstoanalgesictolerancebyreducingtheeffectivenessontemporalsummation.Itisnotclear,however,whysubjectsreceivinglow-frequencyTENSdidnotshowadifferenceintempo-ralsummationbecausel-opioidagonists,thereceptorinvolvedinlow-frequencyTENSanalgesia,reducetemporalsummationinhu-mansubjects[25]andwind-upinanimals[21].Itispossiblethatstrongmusclecontractionsobservedinthisgroupcouldhavesen-sitizedtheextensormassofforearm,impairingtheTENS-inducedhypoalgesiceffect.AnimportantbutnotsurprisingfindingisthattolerancetoTENSdidnotaffecttheDNICresponse,leadingustoconcludethatdescendingsystemswerenotinvolvedinanalgesictolerance.However,itshouldbepointedoutthatalthoughbothDNICandTENSuseendogenousopioidmechanismstoproduceanalgesia,theydothisthroughactivationofdifferentpathways.Specifically,DNICactivatesneuronsinthesubnucleusreticularisdorsalisinthecaudal–dorsalmedulla[7,66,67],whicharerichinl-opioidrecep-tors[47,48].Ontheotherhand,TENSutilizestheperiaqueductalgrayandrostralventralmedullatoproduceanopioid-mediatedanalgesia[16,34,62].Insummary,thefindingspresentedinthisnovelstudysupportthatbothhigh-andlow-frequencyTENSproduceanalgesictoler-ancebythefourthandfifthdayoftreatment,respectively.Thesedataextendandvalidatepriorstudiesinanimalsshowingtoler-ancetoTENS[9,17,29].FuturestudiesshouldbeperformedtofindwaystodelayandpreventtheoccurrenceoftolerancetorepeatedTENSinhumans.ConflictofintereststatementTheauthorshavenoconflictofinteresttodisclose.AcknowledgementsSupportedbytheNationalInstitutesofHealthR03NR010405,theMarshaandRalphCongdonFacultyDevelopmentFellowshipinAcuteCarefortheChronicallyIll,CoordinationfortheImprove-mentofHigherLevelPersonnel(CAPES),theInstituteforClinicalR.E.Liebanoetal./PAIN152(2011)335–342Ò341andTranslationalScience,andtheUniversityofIowa–NationalCenterforResearchResources(NCRR)5UL1RR024979-3.SpecialthankstoShannonLehmannforassistancewithrecruitmentandscheduling.References[1]AarskogR,JohnsonMI,DemminkJH,LofthusA,IversenV,Lopes-MartinsR,JoensenJ,BjordalJM.Ismechanicalpainthresholdaftertranscutaneouselectricalnervestimulation(TENS)increasedlocallyandunilaterally?Arandomizedplacebo-controlledtrialinhealthysubjects.PhysiotherResInt2007;12:251–63.[2]AmanzioM,BenedettiF.Neuropharmacologicaldissectionofplaceboanalgesia:expectation-activatedopioidsystemsversusconditioning-activatedspecificsubsystems.JNeurosci1999;19:484–94.[3]AubinM,MarksR.Theefficacyofshort-termtreatmentwithtranscutaneouselectricalnervestimulationforosteo-arthritickneepain.Physiotherapy1995;81:669–75.[4]BatesJA,NathanPW.Transcutaneouselectricalnervestimulationforchronicpain.Anaesthesia1980;35:817–22.[5]BenedettiF,MaybergHS,WagerTD,StohlerCS,ZubietaJK.Neurobiologicalmechanismsoftheplaceboeffect.JNeurosci2005;25:10390–402.[6]BjordalJM,JohnsonMI,LjunggreenAE.Transcutaneouselectricalnervestimulation(TENS)canreducepostoperativeanalgesicconsumption.Ameta-analysiswithassessmentofoptimaltreatmentparametersforpostoperativepain.EurJPain2003;7:181–8.[7]BouhassiraD,VillanuevaL,BingZ,leBarsD.Involvementofthesubnucleusreticularisdorsalisindiffusenoxiousinhibitorycontrolsintherat.BrainRes1992;595:353–7.[8]ChabalC,FishbainDA,WeaverM,HeineLW.Long-termtranscutaneouselectricalnervestimulation(TENS)use:impactonmedicationutilizationandphysicaltherapycosts.ClinJPain1998;14:66–73.[9]ChandranP,SlukaKA.Developmentofopioidtolerancewithrepeatedtranscutaneouselectricalnervestimulationadministration.Pain2003;102:195–201.[10]ChenCC,JohnsonMI.Aninvestigationintotheeffectsoffrequency-modulatedtranscutaneouselectricalnervestimulation(TENS)onexperimentally-inducedpressurepaininhealthyhumanparticipants.JPain2009;10:1029–37.[11]ChenCC,JohnsonMI.Acomparisonoftranscutaneouselectricalnervestimulation(TENS)at3and80pulsespersecondoncold-pressorpaininhealthyhumanparticipants.ClinPhysiolFunctImaging2010;30:260–8.[12]ChenCC,JohnsonMI.Aninvestigationintothehypoalgesiceffectsofhigh-andlow-frequencytranscutaneouselectricalnervestimulation(TENS)onexperimentally-inducedbluntpressurepaininhealthyhumanparticipants.JPain2010;11:53–61.[13]ChestertonLS,BarlasP,FosterNE,LundebergT,WrightCC,BaxterGD.Sensorystimulation(TENS):effectsofparametermanipulationonmechanicalpainthresholdsinhealthyhumansubjects.Pain2002;99:253–62.[14]ChestertonLS,FosterNE,WrightCC,BaxterGD,BarlasP.EffectsofTENSfrequency,intensityandstimulationsiteparametermanipulationonpressurepainthresholdsinhealthyhumansubjects.Pain2003;106:73–80.[15]CowanS,McKennaJ,McCrum-GardnerE,JohnsonMI,SlukaKA,WalshDM.AninvestigationofthehypoalgesiceffectsofTENSdeliveredbyagloveelectrode.JPain2009;10:694–701.[16]DesantanaJM,daSilvaLF,deResendeMA,SlukaKA.Transcutaneouselectricalnervestimulationatbothhighandlowfrequenciesactivatesventrolateralperiaqueductalgreytodecreasemechanicalhyperalgesiainarthriticrats.Neuroscience2009;63:1233–41.[17]DeSantanaJM,daSilvaLF,SlukaKA.CholecystokininreceptorsmediatetolerancetotheanalgesiceffectofTENSinarthriticrats.Pain2010;148:84–93.[18]DeSantanaJM,Santana-FilhoVJ,GuerraDR,SlukaKA,GurgelRQ,daSilvaJrWM.Hypoalgesiceffectofthetranscutaneouselectricalnervestimulationfollowinginguinalherniorrhaphy:arandomized,controlledtrial.JPain2008;9:623–9.[19]DeSantanaJM,Santana-FilhoVJ,SlukaKA.Modulationbetweenhigh-andlow-frequencytranscutaneouselectricnervestimulationdelaysthedevelopmentofanalgesictoleranceinarthriticrats.ArchPhysMedRehabil2008;89:754–60.[20]DesantanaJM,SlukaKA,LaurettiGR.Highandlow-frequencyTENSreducepostoperativepainintensityafterlaparoscopictuballigation:arandomizedcontrolledtrial.ClinJPain2009;25:12–9.[21]DickensonAH,SullivanAF.Electrophysiologicalstudiesontheeffectsofintrathecalmorphineonnociceptiveneuronesintheratdorsalhorn.Pain1986;24:211–22.[22]DoigGS,SimpsonF.Randomizatio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