Research on placebo analgesia is relevant to clinical practice

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Research on placebo analgesia is relevant to clinical practice
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Chiropractic and Manual Therapies
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Charles W Gay
Mark D Bishop
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Chiropractic and Manual Therapies
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Placebo response
Placebo
Endogenous pain modulation

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Over the decades, research into placebo responses has shed light onto several endogenous (i.e. produced from within) mechanisms underlying modulation of pain perception initiated after the administration of inert substances (i.e. placebos). Chiropractors and manual therapists should embrace analgesic-placebo-research in an attempt to maximize clinical benefit. Historical views that placebo responses are fake, passive, undesirable, and require deception and therefore should be minimized and avoided in clinical practice are outdated. Further, statements that contend the placebo response represents a single mechanism are overly simplistic. This commentary will discuss research that shows that there are several active biological processes underlying modulation of pain perception involved in placebo analgesia and its counterpart nocebo hyperalgesia. We contend that it is highly likely that, to some extent, all of these biological processes are engaged, in varying degrees, following all interventions and represent endogenous pain modulating processes. Failure, of chiropractors and manual therapists, to embrace a more contemporary view of analgesic-placebo-research serves as a barrier to transferring knowledge into clinical practice and represents a missed opportunity to improve the delivery of current treatments.

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University of Florida
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COMMENTARYOpenAccessResearchonplaceboanalgesiaisrelevantto clinicalpracticeCharlesWGay1*andMarkDBishop2,3AbstractOverthedecades,researchintoplaceboresponseshasshedlightontoseveralendogenous(i.e.producedfrom within)mechanismsunderlyingmodulationofpainperceptioninitiatedaftertheadministrationofinertsubstances (i.e.placebos).Chiropractorsandmanualtherapistsshouldembraceanalgesic-placebo-researchinanattempt tomaximizeclinicalbenefit.Historicalviewsthatplaceboresponsesarefake,passive,undesirable,andrequire deceptionandthereforeshouldbeminimizedandavoidedinclinicalpracticeareoutdated.Further,statementsthat contendtheplaceboresponserepresentsasinglemechanismareoverlysimplistic.Thiscommentarywilldiscuss researchthatshowsthatthereareseveralactivebiologicalprocessesunderlyingmodulationofpainperception involvedinplaceboanalgesiaanditscounterpartnocebohyperalgesia.Wecontendthatitishighlylikelythat,to someextent,allofthesebiologicalprocessesareengaged,invaryingdegrees,followingallinterventionsand representendogenouspainmodulatingprocesses.Failure,ofchiropractorsandmanualtherapists,toembracea morecontemporaryviewofanalgesic-placebo-researchservesasabarriertotransferringknowledgeintoclinical practiceandrepresentsamissedopportunitytoimprovethedeliveryofcurrenttreatments. Keywords: Placebo,Endogenouspainmodulation,PlaceboresponseBackgroundEvidence-basedmedicinedealswiththeuseofcurrent bestevidenceinclinicaldecision-makingandotheraspectsofpatientcare.Theassumptionthatsimplyhaving theevidenceavailableorprovidingauthoritativeclinical practiceguidelineswillresultinpracticechangeandimprovedpatientoutcomesisincorrect[1,2].Anumberof physicianbehaviorshavebeenidentifiedthatactasbarrierstotranslatingevidenceintoclinicalpractice[3]. Twodomainsofthosebarriersarephysician ’ sknowledge andattitudes.Thiscommentaryaddressesknowledge awarenessandoutdatedattitudessurroundingtheclinical improvementseenfollowingtheadministrationofaplacebo.Byaddressingthesepotentialbarrierschiropractors andmanualtherapistsmaybemoreopentoanalgesicplacebo-researchanditscounterparthyperalgesia-noceboresearch.Inturn,clinicalpracticemaybeinfluencedby knowledgegainedfromthisfield,applyingevidenceto decision-makingandthecontextinwhichinterventions aredeliveredwithagoalofimprovingpatientoutcomes.MaintextMisconceptionsaboutplaceboresponsescontinueinthe generalpublicandamonghealthcareprofessionals[4,5]. Therehasbeenapushforhealthcareprofessionalsto re-thinkwhataplaceboresponserepresentsandtheapplicabilityofknowledgegainedfromplacebo-analgesiaresearchthatcanbeappliedethicallyinclinicalpractice [6-12].Rethinkingplaceboandnoceboresponsesasendogenousmodulatorymechanismsbroadensthefocusof carebeyondjusttheinterventiontoincludethecontext inwhichinterventionsaredelivered.Historicalviews thatplaceboresponsesrepresentfake,passive,andundesirableresults;requiredeception;andshouldbeminimizedandavoidedinclinicalpracticecontinuetoday amonghealthcareproviders.Further,theplaceboresponse hasbeendescribedasasinglemechanismthroughwhich aninterventionmayinduceapositivetherapeuticoutcome [9].Harboringsuchviewsmaybiasmanualtherapypractitionersawayfromvaluableclinicalevidencethatmay *Correspondence: chaz.gay@ufl.edu1RehabilitationScienceDoctoralStudent,UniversityofFlorida,Gainesville, Florida,USA Fulllistofauthorinformationisavailableattheendofthearticle CHIROPRACTIC & MANUAL THERAPIES 2014GayandBishop;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.GayandBishop Chiropractic&ManualTherapies 2014, 22 :6 http://www.chiromt.com/content/22/1/6

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influencetheirclinicaldeci sionmaking.Thiscommentary presentsresearchthatopposestheseviews. Changesintheperceivedintensityofpainareoftenattributedtoavarietyoffactorslumpedintothreeboard categories:(1)conditionrelatedfactors,(2)thespecific effectsoftreatment,and/or(3)treatmentcontextualeffects[13].Conditionrelatedfactorsincludethenatural courseoftheconditionandregressiontothemean.Specifictreatmenteffectsaretheuniqueeffectsassociated withthe ‘ active ’ ingredientofthetreatment.Treatment contextincludesahostofsigns,symbolsandphysician interactionsthatconveyinformationtotheindividual. Inrecentyears,researchershaveusedplacebo-analgesia anditsnegativeequivalent,nocebo-hyperalgesiatoinvestigatetheneuronalunderpinningsoftreatmentcontextual effects.Although,thesethreecategoriesarepracticaland useful,theycancreateamisconceptionthatthereare uniquebiologicalpathwaysthatdonotoverlaporinteractunderlyingthecategories.Thismisconceptionis highlightedbythenotionthatapredictableestimateof changeinpainperceptioncanbedeterminedsimplybya treatment ’ sactivebiologicalproperties. Forexample,findingsfromonestudysignificantlychallengetheconventionthatanactivebiologicalagentproducesaconsistenttherapeuticeffectwithinanindividual. Byconvention,researchersacknowledgethattheactive biologicalagentinadrugwillvaryacrosspeople,dependingonamultitudeofpersonalfactors.However,whatis notacknowledgedsofrequentlyisthatwithinoneindividual,thetherapeuticeffectcansignificantlyvary.Byexperimentallymanipulatinganindividual ’ sexpectationthrough instructionalsets,itwasshownthatthetherapeuticeffect oftheactiveingredientofremifentanil,apotentsynthetic -opioidagonist,canbesignificantlymodulated[14].The studymanipulatedsubjects ’ expectationsbyinstructing themthatremifentanilisawidelyusedopioidthatrelieves painwheninfusedintravenously,butcanworsenpain whentheinfusionceases[14].Hiddenadministrationof thedrugproducedlessperceivedpainthanbaseline,open administrationofthedrugproducedsignificantlymore hypoalgesiathanhiddenadministrationandwhenthe drugwascontinuouslyadministeredbutthesubjectswere toldithadstopped,theperceptionofpainretunedto baselinevalues[14].Theestimatedtherapeuticeffectsize oftheactiveingredientinremifentanilspannedfromno effecttoamoderateeffect,dependingontheexpectancy createdbytheinstructionalset. Embeddedineverypain-relievingtreatmentarecontextualeffects.Physicianinteractions,signsandsymbols conveyinformationtotheindividualwiththepotential forproducingtherapeuticandcounter-therapeuticresponses(ieplaceboandnoceboresponsesrespectively) [15].Theestimatedtherapeuticeffectoftreatmentcontextfollowingtheadministrationofaninertsubstance hasbeenshowntobesubstantial,albeitvariable[15-21]. Onefactorthatisnotcausingthetherapeuticeffectis theinertsubstance(ieplacebo).Therefore,placeboanalgesia-researchprovidesvaluableinformationabout thecontextinwhichinterventionsaredelivered.Research intoprinciplemediatorsofthecontextualeffectssuggest expectancy,desireforapositiveoutcomeandclassical conditioningaccountforasignificantportionofthevarianceincontextualeffects[22-24].Chiropractorsandmanualtherapistsshouldbeawarethatthecontextinwhich theydelivertheirinterventionsisasimportantasthe interventiontheyaregiving.Furtherevidencesuggestingtheeffectivenessofamanualtherapyinterventionis influencedbypatient ’ sexpectationcomesfromastudy publishedbyBialoskyetal.[25].Thestudyshowedthat byusingdifferentinstructionalsetstopositively,negativelyandneutrallyinfluencethesubjectsexpectation, theeffectofspinalmanipulationonadynamicpainsensitivitymeasure(temporalsummationofsecondpain) varied[25]. Placebo-analgesia-researchhasalsoshownthatdeceptionisnotintegraltoinducingaplaceboresponse.One studyadministeredopenlabeledplaceboswithpatient educationthatdescribedanactivebiologicalpathwayfor symptomimprovement[26].Inthisstudy,theinvestigatorstoldirritablebowelsyndrome(IBS)subjects,that theywouldberandomizedtoreceiveeitheraplacebo sugarpillornotreatment.Subjectsreceivingtheplacebo pillweretoldplaceboshavebeenfoundtoproduceclinicallyeffectiveresultsthoughamind-bodyconnection andthatbytakingthepill,thesubjectswouldbeharnessingtheirownrecuperativepowers.Greaterclinicalimprovementwasfoundintheplacebogroupcomparedto theno-treatmentgroup[26].Anotherstudyexamined therepeatabilityofcontextualeffectsaftersubjectswere toldtheyreceivedaninertsubstance.Inthisstudy,individuals,whoreceivedinertpain-relievingcreamandexperiencedpainreductions,werethentoldtheyhad receivedaplacebocream.Onasubsequentvisitthose sameindividualswereagainabletoexperiencepainreliefasecondtimeusinganinertcream[27].Bothof thesestudieschallengedeception ’ sroleasanecessary componentofthecontextinwhichaninerttreatmentis deliveredthatproducesapositivetherapeuticeffect. Finally,placebo-analgesia-researchhasshedlightonto neuralmechanismsunderlyingendogenouspainmodulation.Corticalnetworksinvolvedinprocessingand modulatingthepainexperiencehavebeenidentifiedand continuetobereinvestigated,redefinedandundergoreconceptualization.Activityinthesecorticalnetworksinfluencetheperceptionofpainandmodulationcanbe inhibitoryorfacilitatory.Researchhasidentifiedvarious neurotransmittersincludingopioids,cannabinoids,dopaminesandcholecystokinins,thatareusedwithintheseGayandBishop Chiropractic&ManualTherapies 2014, 22 :6Page2of4 http://www.chiromt.com/content/22/1/6

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corticalnetworks[28-31].Attributingclinicalbenefitfollowingtheadministrationofaninertsubstancetoasinglemechanism,ortermingitaplacebomechanismfails toaccountforthenumerousneuralandotherbiological pathwaysinvolvedinproducingandinfluencingtheperceptionofpain[32,33].ConclusionOverthedecades,researchintoplaceboresponseshas shedlightontoseveralendogenous(i.e.producedfrom within)mechanismsunderlyingmodulationofpainperceptioninitiatedbytheadministrationofinertsubstances (i.e.placebos/nocebos).Inaddition,thisgrowingbodyof workemphasizestheneedforchiropractors ’ andmanual therapists ’ tobemorealertto,andembrace, ‘ psychologicallyinformedpractice ’ ;thatis,practiceinwhichrecognitionofneuralmechanismsisequallyasimportantas identificationofstructuralpathology.Chiropractorsand manualtherapistsshouldembraceanalgesic-placeboresearchinanattempttomaximizeendogenouspainrelievingmechanismstoproducemaximumclinicalbenefit. Historicalviewsthatplaceboresponsesarefake,passive, undesirable,andrequiredeceptionandthereforeshould beminimizedandavoidedinclinicalpracticeareoutdated.Further,statementsthatcontendtheplaceboresponserepresentsasinglemechanismaretoosimplistic. Instead,inthiscommentarytheauthorsdiscussedhow severalactivebiologicalprocessesunderlieanalgesicplaceboresponses.Wecontendthatitishighlylikelythat tosomeextentallofthesebiologicalprocesses,whichrepresentendogenouspainrelievingprocesses,areengaged tovariousdegreesfollowingallinterventionsthatproduce apositiveclinicaloutcome. Failuretoembraceamorecontemporaryviewof analgesic-placebo-researchmaynegativelybiaschiropractors ’ andmanualtherapists ’ opinionsaboutthepotentialclinicalvalueofresul tsemergingfromthisfield. Thesebiasesserveasabarriertosuccessfullytranslatingpotentialbenefitsforpatientsintoclinicalpractice inanethicalmanner.Analgesic-placebo-researchprovidesinsightonhowtoimprovethedeliveryofcurrent treatmentsbyoptimizingc linicalbenefitandmatching therighttreatmenttotherightspinalpainpatientat therighttime.Competinginterests Theauthorsofthismanuscriptattesttherearenoconflictsofinteresttoreport. Authors ’ contributions CWGandMDBcontributedequallytotheconcept,thedrafting,andcritical revisionofthemanuscript.Allauthorsreadandapprovedthefinal manuscript. Acknowledgements ThismanuscriptwaswrittenwhileCWGreceivedsupportfromtheUniversity ofFloridaAlumniFellowship,NCMICFoundationandtheNationalCenterof ComplementaryandAlternativeMedicine(F32AT007729-01A1),MDB receivedsupportfromtheNationalCenterofComplementaryandAlternativeMedicine(R01AT006334). 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