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  • 8/3/2009

    1

    l iPaulG.Kreis,MDMedicalDirector:Div.ofPainMedicineDept.ofAnesthesia&PainMedicineUCDavisMedicalCenter

    ProfessorofAnesthesiologyandPainMedicineUniv.ofCalifornia,DavisSchoolofMedicine

    1. Introduction

    2. OpioidReceptorPhysiology

    3. Tolerance

    4. EvidenceforOpioidInducedHyperalgesiap yp g

    5. TheroleofNMDAreceptorsinOIH

    6. NovelMechanismsforOIHTRPV1SpinalNK1ReceptorsLCalciumChannelsGlutamateTransportersAdaptiveHomeostasis

    Opioidscontinuetobeamongthemainstaysofpharmacologicaltreatmentofmoderatetoseverepain.

    Manypatients,especiallyadvancedcancerpatients,requirehigh doseopioidtherapyhighdoseopioidtherapy.

    Clinicalefficacyandtolerabilityishinderedbytwophenomena

    Tolerance

    OpioidInducedHyperalgesia

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    Four(sofar)classesofopioidreceptors1. Mu

    EndogenousLigand BetaEndorphinLocation Highlyconcentratedinouterlaminaofdorsalhornofthespinalcord

    2. DeltaEndogenousLigand EnkephalinLocationDiffuselydistributedthroughoutthedorsalhorn

    3. KappaEndogenousLigand DynorphinLocationOuterlaminaofthedorsalhornofthelumbosacralcordandarecloselyassociatedwithinputfromvisceralstructures

    4. ORL1(Orphanreceptor)(18)EndogenousLigand Nociceptin=,activationblocksopioidinducedantinociceptionActivatedbybuprenorphineLocation cortex,amygdala,hippocampus,septalnuclei,habenula(nearpinealbody),hypothalamus,spinalcord

    Lutfy et al, Buprenorphine-induced antinociception is mediated by mu-opioid receptors

    and compromised by concomitant activation of opioid receptor-like receptors, J Neurosci. 2003 Nov 12;23(32):10331-7

    KappaSpinalAnalgesiaSedationDyspneaDependenceDysphoria

    DeltaPsychomimeticEffectsDysphoria

    Mu1AnalgesiaEuphoriaSerenity

    Mu2 DysphoriaResp.Depression

    Mu2Resp.DepressionPruritusProlactinReleaseVomitingSedationDependenceAnorexiaUrinaryretention

    ORL1Anxiety Depression Appetite suppression Tolerance mitigationCough suppression

    Brain:LimbicSystem(thalamus,amygdala,hippocampus)

    Brainstem:RostralVentromedialMedulla(RVM)

    PeriaquaductalGray(PAG)

    MuandsomeDeltareceptorswithintheRVMandPAGinhibitpaintransmissionbysecondorderneurons.

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    Differingpotencyandefficacyatvariousreceptors.

    Actionisthesumofalltherelevantreceptors,activatedorinhibited.

    S b f h i h i ffi i f Sevensubtypesofmureceptors,eachwithvaryingaffinityformuagonists.(1)

    500genesinfluencepain,with100variationsinthehumanmuopioidreceptorgenealone.(2)

    Ross,etal.in2005

    Influenceofvariationsingenesthatencodeformureceptorsandmorphineresponseincancerpatients.FINDINGS:

    N i ifi tdiff i t b t th Nosignificantdifferencesinmureceptorsgenesbetweenthoseresponsiveandthoseintoleranttomorphine.

    *Significantdifferencesintworegulatoryproteins

    stat6 muopioidgenetranscriptionalfactor

    arrestin intracellularregulatoryprotein

    Geneticvariationinfluencesresponsestomorphine.

    Seventransmembranesegments.

    Gproteinsareintracellularsignalingproteins.

    Fourfamilies(Gs,Gi,Gq,G12).

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    InhibitsreleaseofsubstancePreleasefromthepresynapticneuron.

    Postsynapticmembrane,opioidreceptorsmediatehyperpolarizationbyopeningK+channels.

    PhosphokinaseCandGPCRkinasesphosphorylateopioidreceptors,increasingaffinityforintracellulararrestinmolecules.

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    Repeatedexposuretoanopioidthatresultsindecreasedtherapeuticeffectorhigherdosestomaintainthesameeffect.

    InnatetoleranceGeneticallydeterminedsensitivityorinsensitivity.

    A i dT l AcquiredTolerancePharmacodynamicPharmacokineticLearned

    PharmacodynamicTolerance

    Adaptationtothechangesthatoccurwithinasystemaffectedbyanopioid,includingchangesinreceptordensityordesensitization,suchthataresponsetoagivenconcentrationofthedrugisreduced concentrationofthedrugisreduced.

    EvidenceshowsthatmanyofthemechanismsrelatedtothistypeoftoleranceinvolvetheNMDAreceptor.

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    PharmacokineticTolerance

    Changesinthedistributionormetabolismoftheopioidafterrepeateddrugadministrationresultinginreducedconcentrationoftheopioidinthebloodoratthesitesofdrugaction drugaction.

    Themostcommonmechanismofthisphenomenonisanincreaseintherateofmetabolismoftheopioid.

    LearnedTolerance

    Reductionintheeffectsofanopioidasresultofmechanismsthatarelearned.

    Onetypeoflearnedtoleranceisconditionedorassociativetolerance.L d h i h d l h i l Learnedmechanismthatdevelopswhenenvironmentalcuesareconsistentlypairedwiththeadministrationofadrug.(1)

    Tolerancemayormaynotjustifyanopioiddoseescalation.

    Maybethefirstsignofopioidinducedhyperalgesia,suggestingareductionoftheopioiddose.

    Theissueishowtodistinguishthetwoelements:

    OpioidTolerance

    OpioidInducedHyperalgesia

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    ThreeproposedmechanismsareassociatedwithdesensitizationofGproteincoupledreceptors(GPCR)

    Receptorphosphorylation

    Receptorinternalization/sequestration

    Receptordecoupling

    Internalizationofthereceptorwasoriginallythoughttocontributetotolerancebydecreasingthenumbersofreceptors.

    However,increasedinternalization(endocytosis)ofreceptorsshowntodramaticallydecreaseopioidtolerance (7)dramaticallydecreaseopioidtolerance.(7)

    Morphinefailstopromoteendocytosisofreceptors.(36)

    Currentconcept:desensitizationandreceptorinternalizationreducetolerancedevelopment.(7)

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    Desensitizationoccurswhentheintracellularregulatoryproteinsorenzymesareactivated.

    ActivationdecouplestheopioidreceptorfromtheGprotein.

    ThisswitchchangesthereceptortoanonanalgesicGprotein,decreasinganalgesiaactivity.(8)

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    Multiplestudieswhichhaveconcludedthatopioidadministrationcanunexpectedlycause:

    Hyperalgesia(enhancedpainresponsetonoxiousstimuli)

    Allodynia(painelicitedbyinnocuousstimuli)

    Witnessedinbothacuteandchronicopioidsuseandobservedinbothanimalmodelsandhumans.

    Thecontributionofopioidtoleranceversusopioidinducedhyperalgesiaisnotknown.

    AcuteadministrationofOpioidsresultsindosedependentincreasesinreceptorlatency:

    1.Thermal2.Chemical3.Mechanical3

    Withrepeatedexposuretheeffectofgivendoseofopioidwilldecreaseinmagnitudeordurationofaction.

    Toleranceisshownbyarightwarddisplacementofthedoseresponsecurve.

    Animalstudiesdemonstrateopioidinducedhyperalgesia,withsystemicorintrathecalopioids.

    Rivatelalin2005,ratsgivenchronicintrathecalbolusinjectionsf hi h d ifi i l db h i ofmorphineshowednonspecificpainrelatedbehaviors

    Fighting

    Scratching

    Aggression

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    Repeatedopioiddosingcanleadtoaprogressive,lastingincreaseinpainsensitivity.Increasedcoldhyperalgesiaseeninmethadonemaintenancepatients.

    S i di f b f lb l i SeeninratstudiesaftersubcutaneousfentanylbolusesusingtheRandallSellittotest.

    Decreasednociceptivethresholdslastingaslongasfivedaysafterfentanylboluses.(Rivatet.al.2009)

    Decreasednociceptivethresholdswithbolusdosemaybewithdrawal.

    Progressivereductionofnociceptivethresholdsseenalsowithcontinuousintrathecalinfusions.

    Thermalhyperalgesiaandtactileallodyniawasobservedinanimals i h i i idi f ievenwithcontinuousopioidinfusion.

    Activecellularmechanism.

    NMDAreceptorandOIH.

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    RecentStudiesandProposedNovelMechanisms

    Transientreceptorpotentialvanilloid1(TRPV1),ligandgated,nonselectivecationchannels.(7,8)

    Moleculartransducerofnoxiousthermalandchemicalstimuli.

    Importantroleinthedevelopmentofinflammationinducedhyperalgesia.(710)

    InflammationincreasestheexpressionofTRPV1.

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    13

    Vardanyanetal.TheJournalofPain,2008

    TRPV1wildtypeandTRPV1knockoutmicetoexploreTRPV1sroleinhyperalgesiaformation.

    Conclusions:

    1.MorphinesubQelicitedboththermalandtactilehypersensitivityinTRPV1WTmice,butnotintheKOmice.

    2.OralTRPV1antagonistreversedboththermalandtactilehypersensitivityinducedinWTmice.

    3.TRPV1isessentialinmorphineinducedhyperalgesia.

    Changesinducedbymorphineexposurearesimilartothoseininflammatoryinjurysuggestingcommonmechanisms.

    Bothshowupregulationinthespinalcord:

    SpinalDynorphin

    CGRP

    SubstanceP

    TRPV1KOmicelackabilitytodevelopopioidinducedhyperalgesia

    InflammationinducedhyperalgesiaandOIHisduetoupregulationofperipheralTRPV1channels.

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    Rivatetal.EuropeanJournalofNeuroscience2009(11)

    RoleofspinalNK1receptorexpressingneuronssupportingfentanylinducedhypersensitivity.

    C l iConclusions:AcuteFentanylenhancesmechanicalhypersensitivityinsurgicalpaininducedbyplantarincisioninrats.

    Neurokinin1(NK1)andspinaldynorphinarenecessaryforthedevelopmentandmaintenanceofopioidinducedhyperalgesia.

    NK1hypersensitivityproducedbyacutefentanyladministration.

    Innonoperatedrats,fentanylinducedanalgesiawasfollowedbyprolongedhypersensitivity.

    Fentanylalsoenhancedpaininducedbyplantarincision.

    AblationofNK1neuronswithSaporinreducedsensoryhypersensitivityinfentanyltreatedratsthatunderwentincisioncomparedwiththosethatdidnot.

    Spinaldynorphinincreasedby30%and66%infentanylandfentanyl/incisiontreatedrats.

    Antiserumtodynorphinattenuatedhypersensitivityinfentanyltreatedrats.

    NK h i l i h i fOIHi NK1receptorshaveimportantrolesinthepromotionofOIHinascendinganddescendingpainpathways.

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    Dogrul,A.,Bilsky,E,Ossipov,M,Lai,JandPorreca,F,etal.AnesthAnalg,101,17301735(2005)

    Severaltypesofcalciumchannelsidentified:Ntype,Ltype,P/Qtype,Rtype,Ttype

    BlockadeofLtypecalciumchannels(usingcalciumblockerantiarrhythmicsandant

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