october 27, 2017 pharmacotherapy of alcohol use disorders

PharmacotherapyofAlcoholUseDisordersin2017:WhatistheFirstLineMedication? /StevenBatki,MD

October27,2017CSAM– TreatingAddictioninthePreliminaryCareSafetyNet(TAPC)WebinarSeries

PharmacotherapyofAlcoholUseDisorders

in2017:WhatistheFirstLineMedication?

StevenL.Batki,M.D.UCSFDept.ofPsychiatry,SFVAMedicalCenter

AddictionResearchProgramandAddictionRecoveryTreatmentServices

October27,2017

Disclosures/Acknowledgments

• NIH/NIDA:researchgrants• DepartmentofDefense:researchgrants• DepartmentofVeteransAffairs:support

S.Batki,MD10/27/17 2



Objectives

• Followingthispresentation,participantsshouldbeableto:– Namethe4FDA-approvedmedicationsand1otherefficaciousmedicationforAUD

– Identifyadverseeffects,majorrisks,andcontraindicationsoftheseAUDmedications

– NamewhichAUDmedicationscanbeusedwithwhichspecificAUDpatientpopulations


CaseExample

• Your57yomalepatienttellsyouheisdrinkingheavilyandwantshelp

• Heisstilldrinking;hasnotyetstopped• Hewantstoreduce,notstop• Heisonopioidanalgesics• HisLFTsareelevatedto3xULN• HisEGFR/CrCl indicatesmoderatelysevererenalfn imapairment




UnderutilizationofAUDPharmacotherapy• Alcoholisoneofonly3substances(othersaretobaccoand

opioids)withFDA-approvedefficaciousmedicationsavailable

• Andtherearealsosomeefficaciousnon-FDA-approvedpharmacotherapies

• YetthereisverylittleuseofAUDmedications• Reasonsunclear,multiple,mayincludeperceptionof

ineffectiveness• only8%ofadultsintheUSwithAUDaretreatedwith

medications(SAMHSA.Resultsfromthe2012NationalSurveyonDrugUseandHealth:://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/Index.aspx.AccessedJuly15,2014.

• InseverallargeVAstudiesoverthepastdecade,veryfewveteranswithAUDwerereceivingAUDmedications– 4%ofVApatientswithAUDreceivedmedsinFY2009

(HarrisAHetal.PharmacotherapyofalcoholusedisordersbytheVeteransHealthAdministration:patternsofreceiptandpersistence.Psychiatr Serv.2012;63(7):679-685).


AUDPharmacotherapy:SomeKeyIssues

• AUDpatientsareheterogeneous– Somemedicationsarecontraindicated,absolutelyorrelatively

incertainpatientgroups(e.g.thosetakingopioidsorwithsevereliverdz),incertainstagesofAUD(e.g activedrinkingvsremission)

– ResponsetoanyoneAUDmedicationisdifficulttopredict• Geneticfactorsmayplayakeyroleinresponse

• DifferentAUDmedicationspresentdifferent– Effectssizedifferences– adverseeffectprofiles– risk/benefitratios– adherencechallenges– costs




Alcohol’sNeuropharmacologic EffectsAntonetal.2014Pharmacologictreatmentofalcoholism.Ch 30inHandbookofClinicalNeurology.125(3rd Ed)

AlcoholandtheNervousSystem,SullivanEV&Pfefferbaum AEds.

• ElevatesDAintheNAccàsalientattention,reinforcement,brainreward

• Opioid (Beta-endorphin)releaseà DAreleaseinNAcc

• GABAergic effectsduringintoxication;downregulation afterchronicuse

• Glutamateupregulation withchronicuse,increaseduringwithdrawal

• Otherneurochemicaleffectsinclude– nicotiniccholinergicreceptors– 5-HT– NA– Cannabinoid– Nociceptin-orphanin/ORL S.Batki,MD10/27/17 7

SomeNeurochemicalTargetsforAUDMedications

(adaptedfromAntonetal.2014Pharmacologictreatmentofalcoholism.Ch 30inHandbookofClinicalNeurology.125(3rd Ed)AlcoholandtheNervousSystem,SullivanEV&Pfefferbaum AEds..)

Phenomenon Neurochemistry Pharmacotherapy

Reward OpioidsGlutamate5-HT3Nicotinic cholinergic

Naltrexone*Acamprosate*,TopiramateOndansetronVarenicline

Protractedwithdrawal/dysphoria/anxiety

GlutamateGABA

Acamprosate*,TopiramateGabapentin, Baclofen

Impulsivity GlutamateOpioidsDA

?Topiramate?Naltrexone

*=FDA-approved;Boldface=moreevidenceexistsforefficacyS.Batki,MD10/27/178



EfficaciousAUDPharmacotherapies• FDA-approved

– Disulfiram (Antabuse)– Acamprosate (Campral)– Naltrexone

• Oral• Extended-releaseintramuscular(Vivitrol)

• Non-FDA-approved– Topiramate (Topamax,others)– Gabapentin(?)– Someothers:

• Nalmefene• Ondansetron (?)• Varenicline(?)• Baclofen(?)• Pregabalin• Zonisamide


SomePatientGroupswithClinicalRelevance

• Abstinentvsnonabstinent• Onopioidsvsnotonopioids• Severeliverdiseasevsnosevereliverdisease• Renalimpairmentvsnot• Goal– abstinencevsusereduction(“controlleduse”)

• Logistical:– Accesstofinancialmeansortoproviderswithspecializedtraining

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PossiblePredictors• Gender• Craving• Familyhistory• Sweet-liking• Typology:earlyvslateonset• Abstinencevsstillusingattxonset• Adherencecapacity

• Geneticvariationinvolvingallelesforgenescodingforopioid,glutamate,andotherreceptors

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Disulfiram,1• Oldest:FDAapprovedin1949• Mechanismofactionofdisulfiram(Antabuse)

– Chemical:inhibitsacetaldehydedehydrogenase– Behavioral:anticipationofaversiveconsequenceofdrinking

discouragesuse– altersdecisionalbalance• Pharmacology

– Irreversibleinhibitorofacetaldehydedehydrogenase– PreventsconversionofacetaldehydeàacetateàCO2+H2O– Inhibitioncanlastfordays– occasionallyupto14days– Disulfiram-alcoholreaction:headache,flushing,nausea,

vomiting,chestpain,vertigo,sweating,weakness,hypotension• Evidenceforefficacy

– Blindedstudiesshowno benefitoverplacebo(Jonas2014;Skinner2014)– Open-labelstudiesshowefficacyovercontrolgroups(Skinner2014)– Mosteffectiveinsupervisedadministration

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Disulfiram,2• Dose:

– 250– 500mgonceperday– Controversyaboutwhetherdoseshouldbeincreasedifpatientsdrinkanddo

nothaveDSF/Alcoholreaction;orwhetherDSFshouldbeDC’ed• Adverseeffects

– Drowsiness,headache,metallic/garlictaste,rash,veryrarelypsychosis– Occasional:transaminitis– Rare:fulminanthepatotoxicity

• Contraindications:– Alcoholuseinpast24hours– Severecardiovasculardisease– Pregnancy/nursing

• Predictorsofefficacy– Commitmenttoabstinence,observedadherence

• Clinicaluse– Can’tbeusedinpatientswhoarestilldrinking– Contraindicatedinpregnant/nursingwomen– LFTsbefore,every3monthsfor6months,thenevery6months– Warnptsabout“hidden”alcohol:food,mouthwash,etc.

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Acamprosate,1• FDA-approvedin2004• Mechanismofactionofacamprosate(Campral)

– Modulationofglutamatergic hyperactivityfollowingcessationofalcoholuse

– Thoughttoreducewithdrawal-associateddysphoria• Pharmacology

– ShorthalfliferequiresTIDdose• Dose:2tablets3x/day(total1998mg/day)• Evidenceforefficacy

– 3EuropeanstudiesledtoUSFDAapproval– Meta-analysisshowsefficacyinreducingreturntoanydrinking

(NNT12)(Jonas2014JAMA)

– However,notasingleUSstudyhasshownseparationfromplaceboinITTanalyses(e.g.ProjectCOMBINEfailedtoshowefficacy)

S.Batki,MD10/27/17 14



Acamprosate,2• Adverseeffects

– Diarrhea,fatigue,insomnia• Predictorsofefficacy

– Detoxificationandabstinenceinitiationpriortostart– Highmotivationforabstinence(asopposedtousereductionor“controlled”

drinking)– Abilitytoadheretocomplexregimen– Possibly:femalegender,highanxiety,negativefamilyhx,late ageofonset (Franck

&Jayaram-Lindsrom 2013)

• Contraindications– pregnant/nursingwomen– renalfailure

• Clinicaluse– Canbeusedinpatientswhoarestilldrinking– Reducedoseto50%inrenalimpairment(CrCl 30-50);contraindicatedCrCl

<30– Monitoradherence– verydifficult3x/dayregimen

S.Batki,MD10/27/17 15

Naltrexone,1• FDA-approvedforAUD:oralin1994,XR-NTXin2006• 2forms:oral andinjectableextended-releasenaltrexone(XR-NTX)

(Vivitrol)• Mechanismofaction

– Mu-opioidantagonist;thoughttoreduceeffectsofalcohol-mediatedincreaseinbetaendorphinandsubsequentincreaseinDAinNAc

– Reducescravingandreducespleasurableeffectsofalcohol– Mayimprovedecision-making,reducehypersalience ofalcoholcues,reduce

impulsivity• Pharmacology

– Oral:oncedaily– Extended-release- givenmonthly

• Dose– Oral:50mgonceperday– XR-NTX:monthlyIM380mg

• Evidenceforefficacy– Oralreducesreturntoanydrinkingandreturntoheavydrinking– Injectablereducesheavydrinkingdays(Jonas2014)

S.Batki,MD10/27/17 16



Naltrexone,2• Adverseeffects

– GIupset:nausea,cramping;dizziness,nervousness,fatigue,– Occasionaltransaminitis– XR-NTX:injectionsitereactions;rare– abscess,necrosis

• Contraindications– Opioidtreatment(withinpast7-10days)– pregnant/nursingwomen– Acutehepatitisorliverfailure

• Predictorsofeffectiveness– Positivefamilyhistory– HavingtheGallelefortheOPRM1gene(AtoG,orAsn40Asp

substitution)doesnot appeartopredictwhorespondsbetterbygreaterNTX-mediatedbluntingofalcoholreward(Oslin JAMAPsychiatry2015)

– EarlyonsetAUD(“TypeB”)– Highcraving– “sweet-liking”

S.Batki,MD10/27/17 17

Naltrexone,3

• Clinicaluse– NTXcanbeusedinpatientswhoarestilldrinking– Monitoring:LFTsbefore,q3monthsfor6months,thenq6months

– Paincontrolmayrequirenon-opioidapproaches• NSAIDS,local,regional,conscioussedation• NOTE:seeCSAMWebinaronperioperativepainandacutepainmanagementinpatientsreceivingopioidagonistsorantagonists

– XR-NTXformgreatlyimprovesadherence• Intragluteal IM

S.Batki,MD10/27/17 18



Topiramate,1• NotFDA-approvedforAUD,butapprovedasananticonvulsantandmigraine

prophylaxismedication• Mechanismofactionoftopiramate(Topamaxandothers)

– Chemical:• FacilitatesGABAneurotransmission;inhibitsAMPA-kainate glutamatetransmission

– Behavioral• Mayreducepost-withdrawaldysphoria;reducescraving;mayreduceimpulsivity

• Pharmacology– BIDdosing

• Dose– Precisedoseneededisunknown;moststudieshaveuseddosingupto300

mg/day,titratedupslowlyfrom25mg/dayto300mg/dayover6weeks–increaseby25-50mg/dayeachweek.

– Lowerdoses,eg.100-200mg/daymaybeeffective– moreresearchisneeded.– BIDdosing

• Adverseeffects– Memoryandconcentrationproblems;dizziness;somnolence– Paresthesias,alteredtaste– Appetite/weightloss– Rare:kidneystones,metabolicacidosis,narrow-angleglaucoma

S.Batki,MD10/27/17 19

Topiramate,2:EvidenceforEfficacy(Blodgettetal.2014AMeta-analysisoftopiramate’s effectsforindividualswithalcoholusedisorders.AlcoholismClin Exp Research.)

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Topiramate,3• Evidenceforefficacy:meta-analyses

– Blodgett(2014)foundefficacygreaterthanNTXoracamprosate,withlargesteffectforincreasingabstinence,andforreducingheavydrinking

– Jonas(2014)foundefficacyforreducingheavydrinkingdaysanddrinksperdrinkingday

• Predictorofeffectiveness– possiblegeneticpredictor– allelesforGRIK1gene

• Contraindications– Renalfailure– Historyofkidneystonesornarrow-angleglaucoma– pregnant/nursingwomen

• Clinicaluse– Canbeusedinpatientswhoarestilldrinking– IfCrCl <70ml/minàcut doseby50%– Checkbicarbonatelevelifmetabolicacidosisissuspected

(hyperventilation,etc)S.Batki,MD10/27/17 21

Gabapentin,1• NotFDA-approvedforAUD,butapprovedas

anticonvulsant;neuropathicpainmed• Mechanismofactionofgabapentin(Neurontinandothers)

– Chemical:facilitatesGABAtransmission– Behavioral:reduceswithdrawal-relatedanxiety,helpssleep,

• Pharmacology– Blocksalpha-2-deltasubunitofcalciumchannelàmodulates

GABAneurotransmission• Dose

– 1800mg/dayin3divideddoses• Evidenceforefficacy

– Mason(2014)JAMAInt Med:increasedabstinence,reducedcraving

• Adverseeffects– Sedation,dizziness,edema

S.Batki,MD10/27/17 22



Gabapentin,2

• Predictorsofeffectiveness– Notclearatthistime

• Clinicaluse– Canbeusedinindividualsstilldrinking– Canbeusedinpatientswithsevereliverdisease– EvidenceexistsforGBPaidingsleepinAUDpatients

– Careneedstobetakenincasesofrenalinsufficiency;doseshouldbereduced

S.Batki,MD10/27/17 23

Baclofen• NotFDA-approvedforAUD;approvedasmusclerelaxantfortreating

spasticity• Mechanismofaction

– Chemical:facilitatesGABAfunction– Behavioral:mayreduceanxiety/dysphoriaofpost-withdrawalstate

• Pharmacology– GABAb receptoragonist

• Dose– 10-20mgTID

• Evidenceforefficacy:mixed–mostlynegative– Jonas2014meta-analysisfailedtofindefficacy;severalEuropeancontrolled

trialssupportuse;2recentlargecontrolledUStrialsfailedtoshowbenefit• Adverseeffects

– Fatigue,sedation,dizziness,abdominalpain;overdosecanbedangerous• Predictorsofeffectiveness

– Noneestablished• Clinicaluse

– Canbeusedinpatientswhoarestilldrinking– Renalclearance,socanbeusedinpatientswithsevereliverdisease

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OtherPossibleAUDPharmacotherapies

• Ondansetron• Nalmefene• Varenicline

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CaseExample,1


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CaseExample,2


• Heisstilldrinking;hasnotyetstopped

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CaseExample,3


• Heisstilldrinking;hasnotyetstopped• Hisgoalistoreduce,notstop

S.Batki,MD10/27/17 28



CaseExample,4


• Heisstilldrinking;hasnotyetstopped• Hewantstoreduce,notstop• Heisprescribedopioidanalgesics

S.Batki,MD10/27/17 29

CaseExample,5

• Your57yo malepatienttellsyouheisdrinkingheavilyandwantshelp

• Heisstilldrinking;hasnotyetstopped• Hewantstoreduce,notstop• Heisonopioidanalgesics• HisLFTsareelevatedto3xULN

S.Batki,MD10/27/17 30



CaseExample,6


• Heisstilldrinking;hasnotyetstopped• Hewantstoreduce,notstop• Heisonopioidanalgesics• HisLFTsareelevatedto3xULN• HisEGFR/CrCl indicatesmoderatelysevererenalfn imapairment

S.Batki,MD10/27/17 31

IsThereaFirstLineMedicationforAUD?

Probably:…..oralNaltrexone

- startat25mg/day(1/2tablet)for2days,then50mg,withfood- checktransaminasesbeforeandafter3mos

S.Batki,MD10/27/17 32



ButIsThereReally aFirstLineMedicationforAUD?,1

• Itdepends…

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IsThereaFirstLineMedicationforAUD?,2

• Ifabstinent:canusedisulfiram– NaltrexoneoralorXR-NTX– Topiramate– Acamprosate– Disulfiram

S.Batki,MD10/27/17 34




• Ifstilldrinking:– Can’tusedisulfiram– Choices:• NaltrexoneoralorXR-NTX• Acamprosate• Topiramate

S.Batki,MD10/27/17 35


• Ifusingopioids:– Can’tuseNaltrexoneoralorXR-NTX– Choices:• Acamprosate• Disulfiram• Topiramate

S.Batki,MD10/27/17 36




• Ifsevereliverdisease:– Disulfiramisrisky:occasionaltransaminitis;rarefulminantliverfl

– NaltrexoneoralorXR-NTXmaycausetransaminitis

– Choices:• Acamprosate• Topiramate• Gabapentin

S.Batki,MD10/27/17 37


• Ifsevererenalimpairment:• Thesearerenally clearedà cutdoseinhalf– Topiramate– Acamprosate– Gabapentin– Baclofen

• Thesearehepatically metabolized– Naltrexone– Disulfiram

S.Batki,MD10/27/17 38




• Iffemalepatientofreproductiveageandnotreliablyusingbirthcontrol,checkforpregnancyandcheckifnursing.– Ifpregnantornursing:• NocurrentAUDpharmacotherapiesareconsideredsafe

S.Batki,MD10/27/17 39


Itdepends…perhapspharmacogenomic datawillultimatelyinformprescribing

(Batki&Pennington(2014)AmJPsychiatry)

*NOTE: OPRM1predictivevalueforNTXresponsehasbeendisproven(Oslin 2015JAMA)

*

S.Batki,MD10/27/17 40



SomeSalientQuestionsaboutAUDPharmacotherapy

• Whatisthebestmeasureofoutcome?– Abstinence?Usereduction?– Qualityoflife?– Cognitiveoutcomes?

• Predictors?• Bestdose?(e.g.topiramate,oralNTX)• Combinationsofmedications?• Bestrouteofadministration,forwhom?• Howlongshouldtreatmentbecontinued?• Howtoincreaseutilization?

S.Batki,MD10/27/17 41

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S.Batki,MD10/27/17 42



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october 27, 2017 pharmacotherapy of alcohol use disorders

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