systematic review oud for peer review · 9 data sources: medline, cochrane library, google,...

UmbrellaSystematicReviewofSystematicReviewsofOpioidUseDisorderin1PrimaryCare:Setting,Diagnosis,Treatment,andManagementofComorbidities.2345Abstract6Objective:Tosummarizethebestavailableevidenceregardingavarietyoftopicsrelatedto7primarycaremanagementofopioidusedisorder(OUD).8DataSources:MEDLINE,CochraneLibrary,Google,referencesofincludedstudiesandrelevant9guidelines.10StudySelection:Systematicreviewsandnewerrandomizedcontrolledtrials(RCTs)fromthe11last5-10yearsthatinvestigatedpatient-orientedoutcomesacross23areasrelatedto:12managingOUDinprimarycare,diagnosis,pharmacotherapies(includingbuprenorphine,13methadone,andnaltrexone),taperingstrategies,psychosocialinterventions,prescribing14practices,andmanagementofco-morbidities.15Synthesis:From8626articles,39systematicreviewsandanadditional26RCTswereincluded.16Newmeta-analyseswereperformedwherepossible.RCTevidencewaseithernon-existentor17inadequatefor10areas.Onecohortstudysuggestsonecase-findingtoolmaybereasonableto18assistwithdiagnosis(positivelikelihoodratio(10.3).Meta-analysisdemonstratedthat19retentionintreatmentimproves:1)whenbuprenorphineormethadoneareused(65-70%20versus22-40%control),2)whenOUDistreatedinprimarycare[86%versus67%specialtycare,21RR1.25(95%CI1.07,1.47)],and3)whencounsellingisaddedtopharmacotherapy[75%versus2261%control,RR1.23(95%CI1.08,1.39)].Retentionwasalsoimprovedwithnaltrexone[33%23versus26%control,RR1.32(95%CI1.09,1.60)],andreducedwithmedication-related24contingencymanagement(example:lossoftake-homedosesasapunitivemeasure)[68%25versus77%nocontingency,RR0.86(95%CI0.76-0.98)].26Conclusion:ThereisreasonableevidencethatprimarycareshouldmanagepatientswithOUD.27DiagnosticcriteriaforOUDremainelusive,with1reasonablecase-findingtool.Methadoneand28buprenorphineimprovetreatmentretention,botharebetterthannaltrexone,andallshouldbe29continuedlong-term.Counsellingisbeneficialwhenaddedtopharmacotherapy.303132333435 36

Introduction37Opioidsandopioidusedisorder(OUD)areamajorpublichealthconcern.1While38

variousorganizationshaverespondedtothiscrisiswithavarietyofguidelinesand39educationalresources,nonehavedonesowithanexclusiveprimarycareaudienceinmind,40orwiththeinformationnecessarytoallowforshared,informed,decision-making.2,3With41theirbroadscopeofpractice,primarycarecliniciansrequireinformationonallaspectsof42OUDmanagement(examplescontractsandurinedrugscreens),andmanagementof43comorbidities(examplesanxietyandpain).Insomecases,theymighthavelimitedaccess44tomorespecialized,wrap-aroundservicesavailableinlargerandmorespecializedcentres,45furtheringtheneedforaccessibleevidence-basedinformation.46

Wecompleted16systematicreviewstoanswerkeyquestionsregarding47managementofOUDthatarerelevanttoprimarycareaccordingtoacommitteetasked48withwritingaOUDguidelineforprimarycare,4relatedto:49

1) TreatmentSetting50a. ThemanagementofOUDinprimarycare51b. Residentialtreatmentprograms52

2) DiagnosisofOUD533) Treatment54

a. PharmacotherapeuticmanagementofOUD,includingbuprenorphine,55methadone,naltrexoneandcannabinoids56

b. TaperingoffofdrugtherapyinOUD:57i. Taperingoffopioids,58ii. Taperingoffopioidagonisttherapy(OAT)comparedtolong-term59

maintenance,60iii. InpatientsdiscontinuingOAT,comparingfastandslowtapering61

regimens.62c. PsychosocialinterventionsforOUD63

i. Counselling64ii. Motivationalinterviewing65iii. CognitiveBehavioralTherapy(CBT)66iv. ContingencyManagement67v. Technology-basedpsychosocialinterventions68

d. Prescribingpractices,includinguseofdailywitnessedingestion,urine69drugscreeningandcontracts.70

4) ManagementofcomorbiditiesinpatientswithOUD(acutepain,chronicpain,71insomnia,anxietyandADHD).72

Twoadditionaltopics(theuseofsustainedreleaseoralmorphineandtheroleof73OATwithoutanyadditionalsupports)werealsoinvestigatedwithanabbreviated74systematicsearch.ResultsareavailableinAppendixYY.7576Methods77

Tocompletethisreview,wefollowedthePreferredReportingItemsforSystematic78ReviewsandMeta-Analyses(PRISMA)andthesystematicreviewofsystematicreviews79protocol.5,68081

82DataSources83

Theevidenceteamcreatedasearchstrategywithguidancefromanexperienced84librarianforeachoftheclinicalquestionscreated.Twoauthors(DP,JT)performedthesearch85ofsystematicreviewsandrandomized,controlledtrials(RCTs)foreachclinicalquestionwithno86languagerestrictions.Thesearchwasrestrictedtonon-animalstudies.Thedatabasesand87resourcesusedtosearchforrelevantsystematicreviewsincludedMEDLINE,CochraneLibrary,88Google,publishedguidelinesonopioidusedisorderandreferencelistsoftheincluded89systematicreviews.ThesearchincludedanyarticlesuptoJune2018,butwasgenerallylimited90tothelast5-10years.Keywordsof“opioidoropiate”wereusedforallsearches.Specificsfor91eachquestionandthecorrespondingkeywords,timelines,andsearchstrategiesusedcanbe92foundinAppendixYY(fullevidencereview).Afterthesearchforsystematicreviewswas93complete,anadditionalsearchofMedlinewasundertakentofindRCTspublishedsincethe94mostrecentsystematicreviewforeachclinicalquestion.Referencelistsofincludedarticles95werehandsearchedtoidentifypotentiallymissedarticles.9697StudySelection98

BeyondsystematicreviewsandnewerRCTs,inclusioncriteriawereadultpatientswith99opioidusedisorderreportingonatleastoneofthefollowingoutcomes:morbidityand100mortality,socialoutcomes,qualityoflifeandsymptoms,oropioiduseoutcomes(definitionsin101BoxXX).Systematicreviewsofobservationalstudieswereincluded,althoughobservational102datawasonlyutilizedwhenRCTsdidnotexist.Exclusioncriteriawerestudiesondetoxification103fromopioids,studiesinpediatric,pregnantorcancerpatients,andstudiescompletedwithina104prisonsetting.Anyexceptionsmadewererecorded(AppendixYY).105

Dualtitle,abstract,andfull-textreviewwerecompletedforallsystematicreviewand106RCTsearchestodeterminestudyeligibility.Asinglereviewerassessedtitlesandabstractsfrom107guidelinesandreferencelists,withdualassessmentiffull-textreviewwasrequired.108Disagreementsoverinclusionwereresolvedbyconsensus.109110Synthesis111DataExtraction112

Dualdataextractionwascompletedusingtemplatescreatedbytwoauthors(CF,JT),113onespecificallyforsystematicreviewsandoneforRCTs.Forsystematicreviews,dataextracted114includedauthor,year,title,studydesign,generalcharacteristics,setting,gender,meanage,115meanduration,durationrange,outcomesreported(alongwithnumberofstudies,RCTsand116patientsforeachoutcome),valuesassociatedwiththeoutcomes,interventionandcontrol.If117nousabledatawasfoundinagivensystematicreview,authorsattemptedtoobtainthatdata118fromtheincludedtrials.119

Followingextraction,datatablesofsystematicreviewsandRCTswerecreatedwith120headingsfor:totalstudies,age,population,relevantstudies,durationofstudies,intervention,121outcomesandriskofbiasqualityassessment.ThedatatablescreatedcanbefoundinAppendix122YY.123

124Risk-of-biasassessment125

Risk-of-biaswasassessedusingamodifiedAMSTARrubricforsystematicreviews,126focusingonthesixmostrelevantquestions:7,81)Wasstudyselectionanddataextraction127performedbydualreviewers?2)Wastheliteraturesearchcomprehensive?3)Werethe128includedstudycharacteristicsdescribed?4)Wasqualityoftheincludedstudiesassessedand129reported?5)Werethemethodsusedtocombineresultsappropriate?6)Wasconflictof130interestreported?Forsystematicreviews,eachquestionwasscoredas1(completed)or0(not131completed).Theseindividualscoreswerethensummatedwithahighertotalscoresuggestinga132lowerriskofbias.ForRCTs,theJADAD5-pointscoringrubricwasused.9Theriskofbias133assessmentforeacharticlewascompletedbyatleasttwoindependentauthorsand134disagreementwasresolvedbyconsensusorathirdauthor.Thescoresforeachrubricare135reportedinconjunctionwiththeirassociatedstudyinthedatatables(AppendixXX).136137Analysis138

Followingdataextraction,weusedstudyoutcomesandmeta-analysestoanswereach139clinicalquestion.Wereportedstudycharacteristicsandoutcomesdescriptivelyusingmeans140andotherstatisticalresultsaspertheoriginalpaper.WeprioritizedsystematicreviewsofRCTs141andindividualRCTresultsoverthoseofobservationaldata.Whereoutcomesweremeasuredin142avarietyofways,wepreferentiallyreportedonthemoreobjectiveoutcomes.Forexample,for143theoutcomeofcontinuedopioiduseinstudiesofpharmacotherapy,wereportontheresults144ofurinedrugtestsoverself-report.145146PerformingNewMeta-Analysis147

Ifnorelevantmeta-analysesexistedorifrelevantRCTshadbeenpublishedsincethe148mostrecentsystematicreview,anewmeta-analysiswascompletedusingtheRevMan5149software.WeusedaMantel-Haenszelstatisticalmethodandfocusedonreportingriskratios150whenappropriate.Notwantingtooverweighsmallerstudies,wechoseafixedeffectsanalysis151iftherewasnoreasontospeculatethattheeffectoftheinterventionwoulddeviate152meaningfullybetweenstudies.Additionally,weperformedanexploratorymeta-analysisofthe153effectsonbuprenorphine,methadoneandnaltrexoneonmortality.Duetotheloweventrate,154mortalityeventsfromthe3treatmentswerecombinedandmeta-analyzedusingtheexact155methodwithoddsratios.10156157Synthesis158

Detailsofstudyflow(PRIMSA)areprovidedinAppendixYY.Allsearchescombined159identifiedatotalof8626articles,with39systematicreviewsandanadditional26RCTsbeing160included.TableXXoutlinesthecharacteristicsoftheincludedsystematicreviews.Reasonsfor161exclusionofsystematicreviewsafterfull-textreviewareavailableinTableYY.Modified162AMSTARscoresandJADADscoresareoutlinedinTablesXXandXX,respectively.Detailson163GRADEevaluationandRisk-of-BiasassessmentareavailableinTableYY.164

Wepreferentiallyreportmeta-analysisfortreatmentretention,ongoingdrug-useand165selectkeyoutcomes.AllotheroutcomesareavailableinAppendixYY.Detailsofourmeta-166analyses,suchaswhichRCTscontributedtowhichmeta-analysis,areavailableinTableYY.167168NoRCTDataAvailable169

Overall,10topicshadeithernoRCTdataavailableforthespecifiedoutcomes,orthe170datawasconsideredinconclusive(TableXX).NotopichadRCTdatatosupportalloutcomes,171andnoindividualtopicprovidedadequatedataonmorbidityandmortality.172173TreatmentSetting174

Nosystematicreviewwasavailable,howeverfourRCTswereidentifiedthatcompared175themanagementofOUDinprimarycarecomparedtospecialtycare(n=46-221).Threeofthese176lookedatpatientsatisfactionratesandfoundstatisticallysignificantlyhigherrates(ie.more177satisfaction)withprimarycare(example:77%versus38%).Wemeta-analyzedtheeffectof178treatmentsettingonretentionandfoundprogramretentionwas86%inprimarycareversus17967%inaspecialtyclinic[RiskRatio(RR)1.25,p=0.005(95%CI1.07to1.47)I2=18%).Figure180XX.Streetopioidabstinencewasalsohigherinprimarycaresettings(53%versus35%,(RR1.50,181p=0.007,95%CI1.12to2.01,I2=74%),althoughthisincludedbothself-reportedaswellas182urinedrugscreendata.FigureXX.183184Diagnosis185

Fourteensystematicreviewswerefound.However,onlytwocase-findingtoolswere186comparedtotheDiagnosticandStatisticalManual(DSMIVor5):theCurrentOpioidMisuse187Measure(COMM),a17-questionscale,andthePrescriptionOpioidMisuseIndex(POMI),a6-188questionchecklist.Bothhavebeenassessedinonly1cohortstudy(238and74patients,189respectively),reportingpositivelikelihoodratiosof3.35and10.3,respectively.190191Treatment192

a. Pharmacotherapy193I. Buprenorphine194

Wefound2systematicreviewsandanadditional5RCTs(as8publications)of195buprenorphinealoneorcombinedwithnaloxone.Comparedto196placebo/detoxificationonly/psychotherapy,buprenorphinesignificantlyretained197morepatientsintreatment(65%versus40%control,numberneededtotreat198(NNT)=4at22weeks)(see,refYY).199200

II. Methadone201Onesystematicreviewand1RCTofmethadonewerefound.Retentionin202treatmentwashigherwithmethadonecomparedtonomethadone(73%versus20322%control,NNT=2at16weeks)(seerefYY).204205Ourmeta-analysisof24RCTsdirectlycomparingbuprenorphinetomethadone206revealedhigherretentionrateswithmethadone[45%versus60%methadone,207NNT=7,RR0.75(0.71,0.80)].FigureXX.However,substantialheterogeneitywas208present(I2=72%)duetotheinclusionof1open-labelRCTdesignedtocompare209theeffectsofbuprenorphineandmethadoneonliverindices.Thisalsodiffered210fromNeilsen’ssystematicreviewthatfoundnodifferenceinretentionrates211betweenbuprenorphineandmethadone.11Neilsen’ssystematicreviewmeta-212

analyzedsub-groupsofpatientsfrom3oftheabovestudieswhoused213prescriptionopioids,ratherthanheroin.11214

215Overall,opioidabstinenceappearshigherwithmethadonethanbuprenorphine216(FigureXX).However,therewasastatisticallysignificantdifferencebetween217subgroupsofstudiesthatmeasuredabstinenceobjectivelyandthosethatrelied218onself-report(P<0.00001).Ifonlystudiesthatusedobjectivemeasuresare219included,thereisnodifferenceinabstinencebetweenbuprenorphineand220methadone[RR0.99(0.78,1.24),I2=0].221

222Adverseeffectswerepoorlyreportedinboththebuprenorphineandmethadone223literature.TwoRCTsfoundnodifferencebetweendrugs,exceptformore224sedationwithmethadone(58%versus26%buprenorphine),in1RCT.TwoRCTs225foundfeweradverseeffectswithbuprenorphinethancontrols.226

227III. Naltrexone228

Twosystematicreviewsand6RCTswerefoundontheopioidantagonist229naltrexone.IndirectcomparisonrevealslowerratesofretentionthanOATs,but230naltrexoneisstillbetterthanplaceboorusualcare[33%versus26%control,RR2311.32(1.09,1.60)].Althoughsubgroupanalysisoforalnaltrexonewasnot232statisticallysignificant[RR1.28(0.97,1.68)],itwasnumericallysimilartothe233injectableresults,andthetestforsubgroupdifferencesbetweenoraland234injectableformswasnotsignificant(P=0.74).Naltrexonealsoincreased235abstinencefromopioids[39%versus27%control,RR1.48(95%CI1.11,1.98)]236(FigureXX).Basedon4smallRCTs,naltrexonedecreasesre-incarceration[24%237versus33%control,RR0.69(95%CI0.51,0.94)](figureXX).238

239Sincemortalityrateswereverylowacrossbuprenorphine,methadoneand240naltrexonestudies,weperformedanexploratorymeta-analysiscombiningevent241ratesforall3drugsandfoundastatisticallysignificantreductioninoverall242mortalitywiththeuseofpharmacotherapyinpatientswithOUD[Odds243Ratio=0.29(95%CI0.08,0.88),6RCTs]. 244

245b. Tapering246

TherewerenosystematicreviewsorRCTsoftaperingoffofopioidsversustheuseof247OATfortreatingOUD.TwoRCTscomparedtaperingoffofOATcomparedtolong-term248maintenance.Abstinencewasnotreported;however,thegroupthatwasmaintained249ontreatmenthadagreaternumberofopioid-negativeurinesin1RCT(53%versus35%250tapered,significancenotreported)(refYY).251

252c. PsychosocialSupports253

Eightsystematicreviewswereidentifiedonpsychosocialsupports.Therewas254substantialvariationwithregardstoinclusioncriteriaandanalysis,thusweprioritized5255keyinterventionsandassessedindividualRCTsidentifiedfromthesystematicreviews.256

TheadditionofstandardcounsellingtoOATismoreeffectiveinretainingpeople257intreatmentthannoorminimalcounselling[75%versus61%control,RR1.23(95%CI2581.23,1.39),NNT=8,3RCTs],althoughtheheterogeneitywashigh(I2=80%).No259differencewasnotedbetweenextendedcounselingsessions(45-60mins)comparedto260“standard”sessionsof15-20mins)[RR0.9395%CI0.68,1.26)].261

TheuseofcontingencyManagement,definedaseither“rewards”fordesired262behaviour,(example:vouchersorprizes)orlossprivilegesforundesiredbehavior263(example:lossofmedicationcarriesforpositiveurinedrugscreens),increasesretention264intreatment[RR1.11(95%CI1.06,1.17)](FigureXX).Subgroupanalysissuggeststhe265benefitsareprimarilyfrompositivecontingencies[RR1.15(95%CI1.09,1.21)],with266negativeormedicationrelatedcontingenciesworseningretention[RR0.86(95%CI0.76,2670.99)](testforsubgroupdifferenceP<0.0001).Methodsofreportingopioidusewere268tooheterogeneoustobemeta-analyzed.269

270d. PrescribingPractices271

I. Contracts272AllRCTsofcontractsinpatientswithOUDincorporatedcontingency273management.Therefore,itisnotpossibletodifferentiatetheeffectsof274contractsfromthecontingenciesonpatientoutcomes.275276

II. DailyWitnessedIngestion(“carries”)277Bothtreatmentretentionandcontinueddrugusearenodifferentbetweendaily278witnessedandunsupervisedingestion(FiguresXXandXX).However,noneof279theincludedRCTshadacompletelyunsupervisedarm;rather,theycompared280variouslevelsofsupervision(example2versus5timesperweek).281

282III. UrineDrugScreening283

NoRCTswerefound.Oneretrospectivecohortstudyfoundall-causemortality284waslowerinpatientswhounderwenturinetesting[HazardRatio0.33(95%CI2850.22,0.49)].However,thisfindinghassignificantpotentialforbias.286

287ManagementofComorbiditiesinPatientswithOUD288 TherewasinadequateRCTevidenceinallsearchedareas(AppendixYY).289290Resultsofothersystematicreviews,suchasresidentialtreatment,cannabinoids,fastversus291slowtapering,motivationalinterviewing,cognitivebehaviouraltherapyandtechnology-based292psychosocialinterventionsareavailableinAppendixYY.293294Discussion295

ThereisasurprisinglackofRCTdataforavarietyoftopicsimportanttothe296managementofOUDinprimarycare.Ofthe23areasinvestigated,10hadeithernoRCT297evidenceorRCTevidencethatwasimpossibletomakeconclusivestatementson.298

WhilesystematicreviewsofobservationaldatasuggestthatongoinguseofOATresults299inareductioninmortality,12,13wefoundnoRCTpoweredtoinvestigatethisoutcome.Our300

exploratorymeta-analysisofthecombinedeffectsofbuprenorphine,methadoneand301naltrexonesuggeststhatmedication-assistedtreatmentmayreducemortality.However,302adequatelypoweredRCTsareneededforconfirmation.Methadoneissuperiorto303buprenorphinefortreatmentretention,butopioidabstinenceratesdonotdifferbetween304methadoneandbuprenorphinewhenobjectivereportingmeasuresareused.Themajorityof305patientsinpharmacotherapystudieswereusingheroin,notprescriptionopioids.Thus,306outcomesinpatientsusingprescriptionopioidsmayvaryfromwhatwehavereported.One307smallmeta-analysisusingsubgroupsofpatientsonprescriptionopioidsfoundnodifferencein308retentionratesbetweenthe2drugs.Someprovincesmaintainprescribingrestrictionson309methadone,andmethadonetypicallyrequiresmoresupervisiontoachievetherapeuticdoses.310RCTsofnaltrexonetypicallyonlyincludedpatientswhohadundergonecompletedetoxification311offofopioidsbeforeenrollment.Thisdrasticallylimitsitsuseasafirst-lineagentinprimary312care.313

DespitefindingnumeroussystematicreviewsonthediagnosisofOUD,onlyone314questionnairewithstrongpredictiveabilityforOUDthatmaybeusefulinprimarycaresettings315(POMI)wasidentified.ThecurrentlyusedDiagnosticandScreeningManualforMental316Disorders(DSM5)criteriaforOUDisdifficulttoapplytopatientsonprescriptionopioidsforthe317managementofchronicpain.14DiagnosisofOUDinthesepatientsremainschallenging.318

PrimarycareisanappropriatesettingformanagementofOUD,withimprovedpatient319outcomescomparedtospecialtycare.WhilemostoftheincludedRCTsprovidedsometypeof320supportiveteamand/ortraining,otherRCTshaveshownthatOATalone,withoutany321additionalsupports,alsoimprovesoutcomes,particularlyretentionintreatment(refYY).322

Ourresultsforcounsellingandcontingencymanagementdiffersignificantlyfromother323systematicreviews.Themostfrequentlycitedsystematicreviewofcontingencymanagement324combinedRCTsofbothpositiveandnegativecontingencies,reportingnobenefitonretention325intreatment.15Sincenegativeormedication-relatedcontingenciesmaybeviewedas326disciplinarymeasure,itmaybemoreappropriatetometa-analyzepositiveandnegative327contingenciesseparately.Whenanalyzedseparately,positivecontingencies(examplebeing328giventheopportunitytoworkondayswhereurinedrugscreensarenegative)arenotedto329improvetreatmentretention,whereasnegativeormedicationrelatedcontingencies(example330lossofmedicationcarriesorloweringOATdoses)negativelyaffectretentionintreatment.This331isrelevantforoptimalOUDmanagement,asnegativecontingenciesareoftenusedwhen332patientsare“caught”usingopioids.Itisnotablethatcompleteabstinencewasrarelyachieved333evenincarefullymonitoredtrialsandpositiveurinesamplesmaybeasignofsuboptimal334treatment.Bestpracticesneedtobecarefullybalancedwiththesafetyofthepatientand335publicinanon-punitivemanner.336337Conclusion338

EvidencesupportsprimarycareasatreatmentsettingforOUD.WhilediagnosingOUD339remainsachallengeforpatientsonchronicprescriptionopioidsforpain,thePOMImaybea340usefultool.Buprenorphineandmethadonemayhelppatientsstayintreatment,particularlyif341usedlong-term,althoughtheoptimallengthoftreatmentisunknown.Theadditionof342counsellingtoOAT,evenbrief,helpspatientsstayintreatmentevenlonger.Punitivemeasures343

shouldbeavoidedforongoingdruguse.Rather,changestotreatmentmayberequiredtohelp344thepatientreachtheirtreatmentgoals,ortoensurethesafetyofthepatientandthepublic.345 346References:347

1. SpecialAdvisoryCommitteeontheEpidemicofOpioidOverdoses.Nationalreport:348Apparentopioid-relateddeathsinCanada(January2016toMarch2018)Web-based349Report.Ottawa:PublicHealthAgencyofCanada;September2018.350

2. GovernmentofCanada.StrengtheningCanada’sapproachtosubstancesuseissues.351https://www.canada.ca/en/health-canada/services/substance-use/canadian-drugs-352substances-strategy/strengthening-canada-approach-substance-use-issue.html,353GovernmentofCanada.354

3. BruneauJ,AhamadK,GoyerM,etal.Managementofopioidusedisorders:anational355clinicalpracticeguideline.CMAJ.2018;190:E247-57.356

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SystematicReviewsandMeta-analyses:thePRISMAstatement.BMJ.2009;339:b2535.3596. SmithV,DevaneD,BegleyCM,ClarkeM.Methodologyinconductingasystematic360

reviewofsystematicreviewsofhealthcareinterventions.BMCMedResMethodol.3612011;11:15.362

7. SheaBJ,GrimshawJM,WellsGA,BoersM,AnderssonN,HamelC,etal.Developmentof363AMSTAR:ameasurementtooltoassessthemethodologicalqualityofsystematic364reviews.BMCMedResMethodol.2007Feb15;7:10.365

8. AllanGM,FinleyCR,TonJ,PerryD,RamjiJ,CrawfordK,etal.Systematicreviewof366systematicreviewsformedicalcannabinoids:Pain,nauseaandvomiting,spasticity,and367harms.CanFamPhysician.2018Feb;64(2):e78-e94.368

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10. MehtaCR,PatelNR,GrayR.Computingandexactconfidenceintervalforthecommon372oddsratioinseveral2X2contingencytables.JASA.1985:80:969-73.373

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13. SordoL,BarrioG,BravoMJ,IndaveBI,DegenhardtL,WiessingL,etal.Mortalityrisk380duringandafteropioidsubstitutiontreatment:systematicreviewandmeta-analysisof381cohortstudies.BMJ.2017;357:i1550.382

14. TonJ,KorownykC,AllanGM.Doesthispatienttakingprescriptionopioidshaveopioid383usedisorder?ToolsforPractice#222onlinepublication.October22,2018.Available384at:https://gomainpro.ca/wp-content/uploads/tools-for-385practice/1539789463_tfp222opioidscreeningfv.pdfAccessed31-JAN-2019.386

15. AmatoL,MinozziS,DavoliM,VecchiS.Psychosocialcombinedwithagonist387maintenancetreatmentsversusagonistmaintenancetreatmentsalonefortreatmentof388opioiddependence.CochraneDatabaseSystRev.2011Oct5;(10):CD004147.389390

391

AppendixYY=fullevidencereview392393394TableXX.OutcomesConsideredRelevantforStudyInclusion(outcomehierarchy)395TheOutcome WhattheOutcomeIncludesMorbidityandMortality Mortality,fatalandnonfataloverdose,suicide,

hospitalization/ERvisits,andacquiringinfectionsuchasHepatitisBandC.

SocietalOutcomes Crime,incarceration,employment,housing,andtransmissionofinfectionsuchasHepatitisBandC.

QualityofLifeandSymptoms Incidenceofadverseevents,withdrawalsymptoms,patientsatisfaction,qualityoflifescales,andscalesrelatedtoguidelinequestion(eg.pain,anxiety).

OpioidUseandTreatmentRetention Ongoingopioiduse(fromurinetoxicologypreferentially),andabstinencefromopioids.

396397BoxXX.TopicsWithNoorInconclusiveRCTEvidenceforAnyOutcome398ResidentialTreatmentCannabinoidsforOUDImplementationofcontractversususualcareUrineDrugScreeningTaperingtodiscontinueprescriptionopioidswithoutOATManagementofacutepaininpatientswithOUDManagementofchronicpaininpatientswithOUDManagementofinsomniainpatientswithOUDManagementofADHDinpatientswithOUDManagementofanxietyinpatientswithOUD399400 401

TableXX.CharacteristicsofIncludedSystematicReviewsSystematicReview

CoreTopic Subgroup NumberofRCTs

NumberObservationalStudies

TotalPatients

TotalRCTPatients

Meta-analyses

ModifiedAMSTARScore

King2014 PrimaryCare NotApplicable 0 47 NR 0 N 2Lagisetty2017

PrimaryCare NotApplicable 10 25 7924 NR N 5

Maree2016

PrimaryCare NotApplicable 1 14 NR NR N 4

Simoens2005

PrimaryCare NotApplicable 45included(studydesignnotreported)

NR NR N 3

Argoff2013

Diagnosis NotApplicable 0 50 NR 0 N 1

Balbale2017

Diagnosis NotApplicable 0 12 1884 0 N 4

Becker2013


Blanchard2016


Canan2017

Diagnosis NotApplicable 0 15 190-2.3million

0 N 4

Chou2009 Diagnosis NotApplicable 0 16 2136 0 N 4Cochran2015


Dowell2016


Lawrence Diagnosis NotApplicable 0 34 5234 0 N 6

2017Shmulewitz2015

Diagnosis NotApplicable 0 NR 11458 0 N 2

Smith2013 Diagnosis NotApplicable 0 11 NR 0 N 2Smith2015 Diagnosis NotApplicable 0 6 1036 0 N 2Solanki2011

Diagnosis NotApplicable 0 5 ~5000 0 N 2

Turk2008 Diagnosis NotApplicable 0 9 16420 0 N 3Mattick2014

Pharmacotherapy Buprenorphine 31 0 5430 5430 Y 6

Neilsen2016

Pharmacotherapy Buprenorphine 6 0 607 607 Y 6

Mattick2009

Pharmacotherapy Methadone 11 0 1969 1969 Y 6

Jarvis2018 Pharmacotherapy Naltrexone(injectable)

12 6 NR NR Y 4

Minozzi2011

Pharmacotherapy Naltrexone(oral) 13 0 1358 1358 Y 6

Frank2017 Tapering(DurationofTherapy)

NotApplicable 11 56 12546 NR N 5

Gowing2017

Tapering(DurationofTherapy)

NotApplicable 27 0 3048 3048 Y 5

Amato2011

Psychosocial AllPsychosocialInterventions

35 0 4319 4319 Y 6

Chou2016 Psychosocial AllPsychosocialInterventions

28included(studydesignnotreported)

NR NR N 4

Gilchrist2017

Psychosocial AllPsychosocialInterventions

32 0 12840 12840 Y 6

Timko2016 Psychosocial AllPsychosocial 55included(studydesign NR NR N 4

Interventions notreported)DiClemente2017

Psychosocial MotivationalInterviewing


NR NR N 3

Ainscough Psychosocial ContingencyManagement

22 0 2333 2333 Y 4

Davis2016 Psychosocial ContingencyManagement


NR NR N 1

Dugosh2016

Psychosocial ContingencyManagement


NR NR N 2

Saulle2017 PrescribingPractices

WitnessedIngestion

4 2 7999 707 Y 6

Chou2014 PrescribingPractices

UrineDrugScreening

0 1 2378 0 N 5

Taveros2016

Comorbidities AcutePain 0 7 142 0 N 5

Morasco2011

Comorbidities ChronicPain 0 38 NR 0 N 5

Hassan2017

Comorbidities Anxiety 22 0 1416* 1416 Y 6

*From19/22studiesreportedinsystematicreview

TableXX.CharacteristicsofIncludedRandomized,Controlled,TrialsRCT Topic Intervention Comparator NumberofPatients

RandomizedJADADScore

Carrieri2014 PrimaryCare MethadonemaintenancetherapyinductioninPrimaryCare

MethadonemaintenancetherapyinductioninSpecialtyCare

221 2

Fiellin2001 PrimaryCare Methadonemaintenancetherapydeliveredbyprimarycarephysician

Methadonemaintenancetherapydeliveredbyanarcotictreatmentprogram

46 3

Gibson2003 PrimaryCare Buprenorphineinprimarycare

Buprenorphineinspecialtycare

115 2

O’Connor1998

PrimaryCare Buprenorphinedeliveredthroughprimarycare

Buprenorphinedeliveredintraditionaldrugtreatmentprogram

46 2

Dunlop2017 Pharmacotherapy Buprenorphine-naloxone Waitlist 50 3Sigmon2016 Pharmacotherapy Buprenorphine-naloxone Waitlist 50 1Wilson2010 Pharmacotherapy Methadone Waitlist 319 3Otiashvili2013

Pharmacotherapy Buprenorphine-naloxone Methadone 80 3

Neumann2013

Pharmacotherapy Buprenorphine-naloxone Methadone 54 2

Potter2013 Pharmacotherapy Buprenorphine-naloxone Methadone 1269 2Coviello2010 Pharmacotherapy Oralnaltrexone Treatmentasusual 111 1Krupitsky2012

Pharmacotherapy Oralnaltrexone+Placeboimplant

Placebooralnaltrexone+placeboimplant

306 4

Krupitsky2013

Pharmacotherapy Oralnaltrexone+Placeboguanfacine

Placebooralnaltrexone+placeboguanfacine

301 4

Mokri2016 Pharmacotherapy Oralnaltrexone Buprenorphine/naloxone 129 5Springer2018 Pharmacotherapy Injectablenaltrexone Placebo 93 4

Bisaga Pharmacotherapy(Cannabinoids)

Dronabinol Placebo 60 3

Blondell2010 Tapering(DurationofTherapy)

Buprenorphine-naloxonetaper

Buprenorphine-naloxonestable

12 3

Fiellin2014 Tapering(DurationofTherapy)

Buprenorphine-naloxonetaper

Buprenorphine-naloxonestable

113 3

Marsch2016 Tapering(DurationofTherapy)

Buprenorphine-naloxone28-daytaper


53 4

Ling2009 Tapering(DurationofTherapy)



516 2

Sigmon2013 Tapering(DurationofTherapy)

Buprenorphine-naloxone1-weektaperorBuprenorphine-naloxone2-weektaper

Buprenorphine-naloxone4-weektaper

70 4

Abbott1998 Psychosocial CommunityReinforcementApproach

StandardCare 180 2

Chawarski2011

Psychosocial Counseling+Methadonemaintenancetherapy

Methadonemaintenancetherapy

37 2

Fiellin2006 Psychosocial EnhancedMedicalManagement(45-minutecounselingsessions)

StandardManagement(20-minutesessions)

166 3

Gu2013 Psychosocial Counseling+Methadonemaintenancetherapy


288 2

Liu2018 Psychosocial Counseling+Methadonemaintenancetherapy


125 3

Tetrault2012 Psychosocial EnhancedMedical StandardManagement 47 2

Management(45-minutecounselingsessions)

(15-minutecounselingsessions)

Weiss2011 Psychosocial Counseling(45-60minutes)

StandardManagement(15-20minutes)

653 3

Bernstein2005


StandardCare 1175 5

Jaffray2014 Psychosocial MotivationalInterviewing

StandardCare 542 2

Saunders1995


Education 116 0

Stein2009 Psychosocial MotivationalInterviewing

Assessment 277 1

Abrahms1979

Psychosocial CognitiveBehavioralTherapy

GroupTherapy 14 1

Fiellin2013 Psychosocial PhysicianManagement+CognitiveBehavioralTherapy

PhysicianManagement 141 3

Ling2013 Psychosocial CognitiveBehavioralTherapy

NoBehavioralTherapy 104 3

Pan2015 Psychosocial CognitiveBehavioralTherapy+Methadonemaintenancetherapy


240 3

Scherbaum2005

Psychosocial MethadoneMaintenanceTherapy+GroupCognitiveBehavioralTherapy


73 3

Abbott1998 Psychosocial Methadone+ContingencyManagement

MethadonewithStandardCounseling

166 2

Bickel2008 Psychosocial ContingencyManagement

Standardcounseling 135 2

Brooner2004 Psychosocial MotivatedSteppedCare StandardSteppedCare 127 1Chen2013 Psychosocial Contingency

ManagementUsualCare 246 1

Chopra2009 Psychosocial Medicationcontingencywithcommunityreinforcementapproach

Standardcarewithcounseling

120 2

Chutuape1999


StandardCare 14 3

Chutuape2001


Weeklydrawsfortake-homedoses(notcontingent)

53 2

DeFulio2012 Psychosocial ContingencyManagementintherapeuticworkplace

Therapeuticworkplace 38 2

Dunn2013 Psychosocial Employment-basedcontingency

Prescriptionfornaltrexone

67 2

Epstein2009 Psychosocial High/LowDoseMethadonemaintenancetherapywithvouchers

High/LowDoseMethadonemaintenancetherapy

252 2

Everly2011 Psychosocial ContingencyManagementintherapeuticworkplace

Therapeuticworkplace 35 2

Ghitza2008 Psychosocial ContingencyManagement


116 1

Gross2006 Psychosocial ContingencyManagementforvouchersORmedication

BuprenorphineMaintenanceTherapywithcounseling

60 2

Hser2011 Psychosocial Incentives UsualCare 320 2Iguchi1997 Psychosocial Contingency

ManagementStandardTreatment 103 1

Jiang2012 Psychosocial ContingencyManagement

UsualCare 160 2

Katz2002 Psychosocial Vouchers NoVouchers 52 1Kidorf1996 Psychosocial Contingency

ManagementMethadonemaintenancetherapy

16 2

Kidorf2013 Psychosocial Reinforcedon-siteintegratedcare

Standardcare 125 2

Kosten2003 Psychosocial ContingencyManagement

Buprenorphine 160 2

Ling2013 Psychosocial ContingencyManagement+Buprenorphine-naloxone

Buprenorphine-naloxone 202 3

Milby1978 Psychosocial ContingencyManagement


75 2

Neufeld2008 Psychosocial ContingencyManagement


100 1

Oliveto2005 Psychosocial ContingencyManagement

StandardTreatment 140 2

Peirce2006 Psychosocial ContingencyManagement

StandardCare 388 2

Petry2002 Psychosocial ContingencyManagement

StandardTreatment 42 2



77 3



74 2

Preston2000 Psychosocial ContingencyManagement


120 3

Schottenfeld2005

Psychosocial ContingencyManagement(withbuprenorphineor

MethadonemaintenancetherapyORBuprenorphine

162 3

methadone) MaintenanceTherapySilverman2004



78 3

Stitzer1992 Psychosocial ContingencyManagement


53 1

Marsch2014 Psychosocial Web-basededucation StandardCounselling 160 1Bickel2008 Psychosocial Therapist-delivered

communityreinforcementapproachORComputer-deliveredcommunityreinforcementapproach

Standardtreatment 135 2

Bell2007 WitnessedIngestion

Supervisedbuprenorphine-naloxone(daily,second-dailyorthrice-weekly)

Weeklytake-homedosing 119 2

Fiellin2006 WitnessedIngestion

Enhancedmedicalmanagement+thriceweeklybuprenorphine-naloxonedispensing

Standardmedicalmanagement+onceweeklybuprenorphine-naloxonedispensing

166 3

Holland2012 WitnessedIngestion

Twiceweeklysupervisedmethadone

Daily,unsupervisedmethadone

60 3

Holland2014 WitnessedIngestion

Superviseddailybuprenorphine-naloxone

Unsuperviseddailybuprenorphine-naloxone

293 3

Rhoades1998 WitnessedIngestion

Supervisedmethadone(5daysperweek)

Supervisedmethadone(2daysaweek)

107 1

Solhi2016 Comorbidities(AcutePain)

MeperidineIV MorphineIV 122 1

Blondell2010 Comorbidities(ChronicPain)

Buprenorphine-NaloxoneSteadyDose

Buprenorphine-NaloxoneTaperingDose

12 3

Stein2012 Comorbidities(Insomnia)

Trazodone Placebo 137 4

McRae2004 Comorbidities(Anxiety)

Buspirone Placebo 36 5

Saedy2015 Comorbidities(Anxiety)

Acceptance-CommitmentTherapy(ACT)+Methadonemaintenancetherapy

Methadonemaintenancetherapyonline

28 0

Levin2006 Comorbidities(ADHD)

SustainedreleasemethylphenidateorSustainedreleasebupropion

Placebo 97 4

TableXX.RCTEvidencethatisAvailablebasedonOutcomes.

InterventionversusControlMorbidityandMortality1

SocietalOutcomes2

QualityofLifeandSymptoms3

OpioidUseandTreatmentRetention4

Diagnosis/ScreeningandManagementSettingPrimarycareversusSpecialty

care - - Primarycarebetter(PatientPreference)

Primarycarebetter

ResidentialTreatment - - - -Medications

BuprenorphineversusPlacebo,detoxificationorpsychotherapy

only• • -

Buprenorphinepossiblybetter(Inconsistent)

Buprenorphinebetter

BuprenorphineversusMethadone

• NoDifference Nodifference(QoLScales)

Inconclusive(AdverseEvents)5

Methadonebetter

BuprenorphineversusWaitlist • • Buprenorphinebetter(QoL)

Inconclusive(AdverseEvents)5

Buprenorphinebetter

Methadoneversusnomethadone

• NoDifference - Methadonebetter

OralNaltrexoneversusplaceboorusualcare - Naltrexonebetter

(Re-incarceration) - NoDifference NoDifference

OralNaltrexoneversusbuprenorphine - - - - Naltrexoneworse

InjectableNaltrexoneversusplaceboorusualcare

• NoDifference •Naltrexone

worse(AdverseEvents)6

Naltrexonebetter

InjectableNaltrexoneversusbuprenorphine

• - - • NoDifference

Dronabinolversusplacebo - - • •

ManagementToolsImplementationofContract

versusUsualcare - - - -Unsupervised(withuptoone

weekcarry)versusDailyorneardailysupervised

- Unsupervisedbetter

NoDifference NoDifference

UrineDrugScreening - - - -MedicationTaper(Discontinuation)

TaperingoffPrescriptionOpioidswithoutOAT7 - - - -OAT7-Taperingoff

versusOAT7-Maintenance - - - Taperingoffworse

FastversusSlowTaperofOAT7 - - NoDifference Slowtaperbetter

PsychosocialInterventionsinAdditiontoOATCounselingversus

minimaltonocounselling - - - Counsellingbetter

ExtendedCounselingversusBriefCounseling - - - Nodifference

InterventionversusControlMorbidityandMortality1

SocietalOutcomes2

QualityofLifeandSymptoms3

OpioidUseandTreatmentRetention4

MotivationalInterviewingversusUsualCare - - NoDifference

(QoL)Motivational

InterviewingbetterCognitiveBehavioralTherapy

versusUsualCare - - - Nodifference

ContingencyManagementversusUsualCare - - -

PositiveContingenciesbetter8

MedicationContingenciesworse9

Technology-Based10

PsychosocialInterventionsversusUsualCare

- - - NoDifference

ManagementofComorbiditiesinPatientsonOAT7AcutePain/Chronic

Pain/Insomnia/ADHD/Anxiety - - • •White-NoRCTEvidenceAvailableforthisOutcome.Grey-InconclusiveRCTEvidenceAvailableforthisOutcome.Green–RCTEvidenceSuggestsBenefitinthisOutcome.Yellow–RCTEvidenceSuggestsNoDifferenceinthisOutcome.Red-RCTEvidenceSuggestsHarminthisOutcome.1 MorbidityandMortalityincludesfatalandnonfataloverdose,suicide,hospitalization/ERvisits,andinfectionsuchasHepBandHepC.2 SocietalHarmsincludecrime,incarceration,employment,housing,andtransmissionofinfectionsuchasHepBandHepC.3 QualityofLifeandSymptomsincludeincidenceofadverseevents,withdrawalsymptoms,patientsatisfaction,qualityoflifescales,andscales

relatedtoguidelinequestion(eg.pain,anxiety).4 OpioidUseandTreatmentRetentionincludesdecreasedopioiduse(fromurinetoxicologyandself-report),abstinencefromopioids,andillicit

andothersubstanceabuse.5 AdverseEventsforbuprenorphineandmethadonewerepoorlyreportedandincludedsedationandchangesinliverindices.6 AdverseEventsfornaltrexoneincludesinjectionsitereactions,headache,GIupset,andinsomnia.7 OAT=OpioidAgonistTherapy8 Positivecontingencieswasdefinedasprizesorvouchersforongoingnonprescribeddrugabstinence.9 MedicationcontingencieswasdefinedasreductionofOATdosingand/orlossoftakehomepriveledgesforundesirablebehaviours.10 Technology-basedpsychosocialinterventionswasdefinedastheuseofestablishedtherapeuticstoolsonacomputerorweb-basedformat.

FigureXX,ModifiedAMSTARScoresofIncludedSystematicReviewsSystematicReview

DualSelectionandExtraction

ComprehensiveLiteratureSearch

CharacteristicsofIncludedStudies

QualityAssessmentofStudies

PooledEstimates

ConflictsofInterestStated

AMSTAR(0-6)

PrimaryCareKing2014 1 1 0 0 0 0 2Lagisetty2017

1 1 1 1 0 1 5

Maree2016 0 1 1 1 0 1 4Simoens2005

1 1 0 0 0 1 3

Diagnosis/ScreeningArgoff2013 0 0 0 0 0 1 1Balbale2017

1 1 1 0 0 1 4

Becker2013

1 1 1 1 0 1 5

Blanchard2016

0 1 1 0 0 0 2

Canan2017 0 1 1 0 1 1 4Chou2009 0 1 1 1 0 1 4Cochran2015

1 1 1 0 0 1 4

Dowell2016

1 1 1 0 1 1 5

Lawrence2017

1 1 1 1 1 1 6

Shmulewitz2015

0 1 0 0 0 1 2

Smith2013 0 1 0 0 0 1 2Smith2015 0 1 1 0 0 0 2Solanki2011

0 1 0 0 0 1 2

Turk2008 0 0 1 0 1 1 3Pharmacotherapy:BuprenorphineNaloxone

Mattick2014

1 1 1 1 1 1 6

Neilsen2016

0 1 1 1 1 1 5

Pharmacotherapy:MethadoneMattick2009

1 1 1 1 1 1 6

Pharmacotherapy:NaltrexoneMinozzi2011

1 1 1 1 1 1 6

Jarvis2018 0 0 1 1 1 1 4Pharmacotherapy:Cannabinoids

None WitnessedIngestion/DailyDispensing

Saulle2017 1 1 1 1 1 1 6

ContractsBosch-Capblanch2007

1 1 1 1 1 1 6

UrineDrugScreeningChou2014 1 1 1 1 0 1 5

DurationofTherapyFrank2017 1 1 1 1 0 1 5Gowing2017

0 1 1 1 1 1 5

PsychosocialandBehaviouralTherapyAinscough2017

0 1 0 1 1 1 4

Amato2011

1 1 1 1 1 1 6

Chou2016 1 1 1 0 0 1 4Davis2016 0 0 0 0 0 1 1DiClemente2017

0 1 1 1 0 0 3

Dugosh2016

0 1 0 0 0 1 2

Gilchrist2017

1 1 1 1 1 1 6

Timko2016 1 1 1 0 0 1 4Comorbidities:AcutePain

Taveros2016

1 1 1 1 0 1 5

Comorbidities:ChronicPainMorasco2011

1 1 1 1 0 1 5

Comorbidities:ADHDNone

Comorbidities:AnxietyHassan2017

1 1 1 1 1 1 6

Comorbidities:InsomniaNone

FigureXX.JADADScoresforIncludedRCTsRandomizedControlledTrial

Wasitrandomized?

Wasrandomizationprocessappropriate?

Wasitdouble-blind?

Wasblindingprocessappropriate?

Weredrop-outsdescribed?

Deductions(forinappropriaterandomizationorblinding)

JADAD(0-5)

PrimaryCareCarrieri2014 1 0 0 0 1 0 2Fiellin2001 1 1 0 0 1 0 3Gibson2003 1 1 0 0 0 0 2O’Connor1998

1 0 0 0 0 0 1

Diagnosis/ScreeningNone

Pharmacotherapy:BuprenorphineNaloxoneDunlop2017 1 1 0 0 1 0 3Potter2013 1 0 0 0 1 0 2Neumann2013

1 1 0 0 1 -1 2

Otiashvili2013

1 1 0 0 1 0 3

Sigmon2016 1 0 0 0 0 0 1Pharmacotherapy:Methadone

Wilson2010 1 1 0 0 1 0 3Pharmacotherapy:Naltrexone

Springer2018 1 1 1 0 1 0 4Coviello2010 1 0 0 0 0 0 1Krupitsky2012

1 1 1 1 0 0 4

Krupitsky2013

1 1 1 1 0 0 4

Mokri2016 1 1 1 1 1 0 5Pharmacotherapy:Cannabinoids

Bisaga2015 1 0 1 1 1 0 4WitnessedIngestion/DailyDispensing

Bell2007 1 1 0 0 0 0 2Fiellin2006 1 1 0 0 1 0 3Holland2012 1 1 0 0 1 0 3Holland2014 1 1 0 0 1 0 3Rhoades1998 1 0 0 0 0 0 1

ContractsNone

UrineDrugScreeningNone

DurationofTherapy

Blondell2010 1 1 0 0 1 0 3Fiellin2014 1 1 0 0 1 0 3Ling2009 1 1 0 0 0 0 2Marsch2014 1 1 1 1 0 0 4Sigmon2013 1 1 1 1 0 0 4

PsychosocialandBehaviouralTherapyAbbott1998 1 1 0 0 0 0 2Abrahms1979

1 0 0 0 0 0 1

Avants2004 1 1 0 0 1 0 3Bernstein2005

1 1 1 1 1 0 5

Bickel2008 1 1 0 0 0 0 2Brooner2004 1 0 0 0 0 0 1Chawarski2011

1 1 0 0 0 0 2

Chen2013 1 0 0 0 0 0 1Chopra2009 1 1 0 0 0 0 2Chutuape2001

1 1 0 0 0 0 2

Chutuape1999

1 1 0 0 1 0 3

DeFulio2012 1 1 0 0 0 0 2Dunn2012 1 1 0 0 0 0 2Epstein2009 1 1 0 0 0 0 2Everly2011 1 1 0 0 0 0 2Fiellin2006 1 1 0 0 1 0 3Fiellin2013 1 1 0 0 1 0 3Ghitza2008 1 0 0 0 0 0 1Gross2006 1 0 0 0 1 0 2Gu2013 1 1 0 0 0 0 2Holtyn2014 1 1 0 0 0 0 2Hser2011 1 1 0 0 0 0 2Iguchi1997 1 0 0 0 0 0 1Jaffray2014 1 0 0 0 1 0 2Jiang2012 1 1 0 0 0 0 2Katz2002 1 0 0 0 0 0 1

Kidorf1996 1 0 0 0 1 0 2Kidorf2013 1 1 0 0 0 0 2Kosten2003 1 0 0 0 1 0 2Ling2013 1 1 0 0 1 0 3Liu2018 1 1 0 0 1 0 3Marsch2014 1 0 0 0 0 0 1McLellan1993

1 0 0 0 1 0 2

Milby1978 1 1 0 0 0 0 2Neufeld2008 1 0 0 0 0 0 1Oliveto2005 1 0 0 0 1 0 2Pan2015 1 1 0 0 1 0 3Peirce2006 1 1 0 0 0 0 2Petry2002 1 1 0 0 0 0 2Petry2005 1 1 0 0 1 0 3Petry2007 1 1 0 0 0 0 2Petry2010 1 1 0 0 0 0 2Preston2000 1 1 0 0 1 0 3

Saunders1995

1 0 0 0 0 -1 0

Scherbaum2005

1 1 0 0 1 0 3

Schottenfeld2005

1 1 0 0 1 0 3

Silverman2004

1 1 0 0 1 0 3

Stein2009 1 0 0 0 0 0 1Stitzer1992 1 0 0 0 0 0 1Tetrault2012 1 0 0 0 1 0 2Wang2014 0 0 0 0 0 0 0Weiss2011 1 1 0 0 1 0 3

Comorbidities:AcutePainSolhi2016 1 0 0 0 0 0 1

Comorbidities:ChronicPainBlondell2010 1 1 0 0 1 0 3Neumann2013

1 1 0 0 1 0 3

Weist2015 1 1 0 0 0 0 2Comorbidities:ADHD

Levin2006 1 0 0 0 1 0 4Comorbidities:Anxiety

McRae2004 1 1 1 1 1 0 5Comorbidities:Insomnia

Stein2012 1 1 1 1 0 0 4

FigureXX.TreatmentRetentioninPrimaryCareversusSpecialtyCare

FigureXX.StreetOpioidAbstinenceinPrimaryCareversusSpecialtyCare

FigureXX.RetentioninTreatment.BuprenorphineversusMethadone.

FigureXX.Abstinence.BuprenorphineversusMethadone.

FigureXX.RetentioninTreatment.Naltrexoneversusplaceboorusualcare.

FigureXX.Abstinence.NaltrexoneversusPlacebo/UsualCare

FigureXX.Re-incarceration.NaltrexoneversusPlacebo/UsualCare

FigureXX.RetentioninTreatment.CounsellingversusMinimaltoNoCounselling

FigureXX.RetentioninTreatment.SupervisedversusUnsupervisedIngestion

FigureXX.Illicitdruguse.SupervisedversusUnsupervisedIngestion.

FigureXX.RetentioninTreatment.ContingencyManagementversusNoContingencyManagement

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