The eff ects of concurrent prescription of benzodiazepines for people undergoing opioid maintenance treatment

Systematic review

2016

3 Table of contents

Title

Norwegiantitle

Publisher

Theeffectsofconcurrentprescriptionofbenzodiazepinesforpeopleundergoingopioidmaintenancetreatment:AsystematicreviewEffektenavsamtidigforskrivningavbenzodiazepinerforpersonerilegemiddelassistertrehabilitering:EnsystematiskoversiktNorwegianInstituteofPublicHealth(Folkehelseinstituttet)CamillaStoltenberg,Director‐General

Authors

KristofferYunpengDing,projectleader,researcher,NorwegianInstituteofPublicHealthAnnhildMosdøl,seniorresearcher,NorwegianInstituteofPublicHealthLailaHov,seniorresearcher,NorwegianInstituteofPublicHealthGyriHvalStaumann,researchLibrarian,NorwegianInstituteofPublicHealthGunnElisabethVist,Unitleader,NorwegianInstituteofPublicHealth

ISBN 978‐82‐8082‐798‐2 Typeofreport SystematicreviewNo.ofpages 24(31includingappendices)

Client NorwegianDirectorateofHealthSubjectheading(MeSH) Benzodiazepines,Opiatemaintenancetreatment,Methadone

Citation

DingKY,MosdølA,HovL,StaumannGH,VistGE.Theeffectsofconcurrentprescriptionofbenzodiazepinesforpeopleundergoingopioidmaintenancetreatment:Asystematicreview.Report2016.Oslo:NorwegianInstituteofPublicHealth,2016.

Forsidebilde Colourbox.com

4 Table of contents

Tableofcontents

TABLEOFCONTENTS 4

KEYMESSAGES 5

EXECUTIVESUMMARY 6

HOVEDBUDSKAP(NORSK) 8

SAMMENDRAG(NORSK) 9

PREFACE 11

INTRODUCTION 12

METHOD 14 Inclusioncriteria 14 Literaturesearch 15 Articleselectionandassessment 15 Assessmentofriskofbiasinincludedstudies 15 Dataextraction 16 Analyses 17 Assessmentofqualityofevidence 17

RESULTS 18 Descriptionofstudies 18

DISCUSSION 20 Keyfindingssummary 20 Strengthsandweaknesses 20 Consistencywithotherliterature 20 Identifiedresearchgaps 20

CONCLUSION 22

REFERENCES 23

APPENDICES 25 Appendix1.Searchstrategy 25 Appendix2.Excludedstudies 32

5 Key messages

Keymessages

Opioidmaintenancetreatmentuseslong‐actingopiatestoreduceanopioiddependentperson’surgetotakeillicitopioidsubstances.Opioid‐dependentpersonsarelikelytoexperienceelevatedlevelsofanxietyandsleepdisturbance.Therefore,patientsundergoingopioidmaintenancetreatmentoftenusemedicationscontainingbenzodiazepines,bothprescribedbyadoctorandfromtheillegalmarket,toalleviatetheseproblems.Concurrentuseofbenzodiazepinesduringopioidmaintenancetreatmentraiseaconcern.Thissystematicreviewaimedtosummarizetheeffectsofconcurrentprescriptionofbenzodiazepinesamongpeoplewhoreceiveopioidmaintenancetreatment.Afterasystematicliteraturesearchwedidnotfindanystudiesthatcouldanswerthisquestion.Experimentalstudieswithcontrolleduseofbenzodiazepinesareneededtoelucidatetheeffectsandconsequencesoftakingben‐zodiazepinesduringopioidmaintenancetreatment.

Title: The effects of concurrent prescription of benzodiazepines for people under-going opioid maintenance treatment: A systematic review ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Type of publication:

Systematic review A review of a clearly formulated ques-tion that uses systematic and explicit methods to identify, select, and criti-cally appraise relevant research, and to collect and analyse data from the studies that are included in the review. Statistical methods (meta-analysis) may or may not be used to analyse and summarise the results of the in-cluded studies. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Doesn’t answer everything: - Excluded studies are not evaluated - No recommendation - No cost-effectiveness evaluation ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Publisher:

Norwegian Institute of Public Health ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Updated: Last search for studies:

July, 2016. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Internal peer review: Rigmor C. Berg, Section leader, NIPH Atle Fretheim, Section leader, NIPH Liv M. Reinar, Section leader, NIPH ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

External peer review: Brittelise Bakstad, Helsedirektoratet Gabrielle Welle-Strand, Helsedirekto-ratet

6 Executive summary

Executivesummary

Background

In OpioidMaintenanceTreatmentpatientsreceivelong‐actingopioidsasasubstituteforheroinandothercommonillegallyusedopioids.Peoplewithopioiddependencearelikelytoexperienceelevatedlevelsofanxietyandsleepdisturbance.Therefore,benzo‐diazepinesareoftenprescribedforthesepatientstoalleviatesuchproblems.Mean‐while,benzodiazepinesarereadilyavailableontheillicitstreetmarketandareinhighrisktobemisused.Severalstudiesfindthatconcurrentprescriptionofbenzodiaze‐pinesduringopioidmaintenancetreatmentisassociatedwithmoredrugabuseandde‐pendence.Prolongeduseofbenzodiazepinesmayresultinanxietyandmentalhealthproblems,andincreasedriskofpersonalinjury.However,theevidenceismostlyde‐scriptiveanddoesnotdistinguishbetweenprescribedversusillicitlyprocuredbenzo‐diazepines.Objective

Thepurposeofthissystematicreviewistoassesstheeffectsofconcurrentbenzodiaze‐pinesprescriptionamongpeoplewhoreceiveopioidmaintenancetreatment(i.e.meth‐adone,buprenorphineorbuprenorphinecombinedwithnaloxone).Method

Wefirstsearchedforsystematicreviewsthatcouldanswerourresearchquestioninthefollowingdatabases:Epistemonikos,CochraneLibrary(CDSR,DARE,HTA),MED‐LINE(Ovid),PubMed[sb]andEmbase(Ovid).Thereafter,wesearchedforprimarystudiestoconductasystematicreviewtosummarizetheavailableevidence.Randomizedandnon‐randomizedcontrolledtrials,controlledbefore‐and‐afterstudiesandinterruptedtimeserieswereincludedasrelevantstudydesigns.Thetargetpopula‐tionwaspeople18yearsorolderwhoreceivedsubstitutiontreatmentwithmetha‐done,buprenorphineorbuprenorphinecombinedwithnaloxoneforopioiddepend‐ence.Relevantinterventionwasprescriptionofbenzodiazepinesascomparedwithnoprescriptionofbenzodiazepines.Theoutcomesofinterestwereretentionintreatment,patients’satisfaction,opioiduse(self‐reportorbiologicaltest),othersubstanceuse(self‐reportorbiologicaltest),extentofanxietyanddepression,sleepdisorders,mor‐tality,sideeffects(overdose,injuryanduseofhospitalemergency)andcriminalof‐fenses.

7 Executive summary

Wecarriedoutasystematicsearchforliterature,withnolimitofpublicationtimeorlanguage,inCochraneCentralRegisterofControlledTrials(CENTRAL),MEDLINE(Ovid),PubMed[sb],Embase(Ovid),CINAHL(EBSCO)andPsycINFO.Threeauthorsevaluatedthereferencesbasedonthetitleandabstract,inpairsindependentlyofeachother(KristofferYunpengDingevaluatedall,AnnhildMosdølandLailaHovhalfeach).Potentiallyrelevantreferenceswerereadinfull‐text(KristofferYunpengDingevalu‐atedall,AnnhildMosdølandLailaHovhalfeach).Weplannedtoassesstheriskofbias,synthesizethedataifpossibleandusetheGRADEmethod(GradingofRecommenda‐tionAssessment,DevelopmentandEvaluation)toassessourconfidenceintheesti‐matedeffects.Results

Theliteraturesearchforsystematicreviewsidentified998titlesandabstracts.Nosys‐tematicreviewswererelevantforthistopicafterscreening.Thesearchforprimarystudiesidentified3696references.Weconsideredeightrefer‐encesaspotentiallyrelevantandreadtheminfull‐text.However,noneoftheserefer‐encesmetourinclusioncriteria.Discussion

Wedidnotfindanyrelevantsystematicreviews,clinicaltrialsorcontrolledstudiesmeetingourinclusioncriteria.Experimentalstudieswithcontrolleduseofbenzodiazepinesareneededtoevaluatetheeffectsandconsequencesofbenzodiazepinesprescriptionduringopioidmainte‐nancetreatment.Wesuggestthefollowingoutcomes:drugretentionratesandabuse;patientsatisfaction;mentalhealth;sleepdisorders;sideeffectsandcriminalbehav‐iours.Conclusion

Wefoundnocontrolledstudiesfocusingontheeffectsandconsequencesofconcurrentbenzodiazepinesprescriptionduringopioidmaintenancetreatment.

8 Hovedbudskap (norsk)

Hovedbudskap(norsk)

Ilegemiddelassistertrehabiliteringfårpersonermedopioidavhengighetlangtidsvirkendeopiatersomkantasperoraltforatdeskalfåreduserttrangtilåtaillegaleopioider.Personermedopio‐idavhengighetharofteethøytnivåavangstogsøvnforstyrrelser.Endelpasienterilegemiddel‐assistertrehabiliteringbrukerlegemidlermedbenzodiazepinerforålettedisseplagene,bådeforskrevetfralegeogfradetulovligmarkedet.Slikbruk,ogmisbruk,avbenzodiazepinerregnessometproblem.Måletmeddennesystematiskeoversikteneråoppsummereeffektenavåforskrivebenzodiaze‐pinertilpasientersommottarlegemiddelassis‐tertrehabilitering.Etteråhagjennomførtetsystematisklitteratur‐søkfantviingenrelevantestudiersomkanbelysedettespørsmålet.Eksperimentellestudiermedkontrollertbrukavbenzodiazepinerernødvendigforåklargjøreef‐fekterogkonsekvenseravåforskrivebenzodia‐zepinertilpersonerilegemiddelassistertrehabi‐litering.

Tittel:

Effekten av samtidig foreskrivning av benzodiazepiner for personer i lege-middelassistert rehabilitering: En sys-tematisk oversikt ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Publikasjonstype:

Systematisk Oversikt En systematisk oversikt er resultatet av å – innhente, - kritisk vurdere og - sammenfatte relevante forsknings-resultater ved hjelp av forhåndsdefi-nerte og eksplisitte metoder. ------------------------------------------ Svarer ikke på alt:

- Ingen studier utenfor de eksplisitte inklusjonskriteriene

- Ingen helseøkonomisk evaluering

- Ingen anbefalinger ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Hvem står bak denne publikasjonen?

Kunnskapssenteret i Folehelseinstituttet har skrevet rapporten på oppdrag fra Helsedirektoratet. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Når ble litteratursøket utført?

Søk etter studier ble avsluttet Juli 2016. ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Eksterne fagfeller: Brittelise Bakstad, Helsedirektoratet Gabrielle Welle-Strand, Helsedirekto-ratet

9 Sammendrag (norsk)

Sammendrag(norsk)

Innledning

Ilegemiddelassistertrehabiliteringfårpersonermedopioidavhengighetlangtids‐virkendeopioidersomsubstitusjonforheroinogandreopioideroftestbruktillegalt.Personermedopioidavhengighetharofteethøytnivåavangstogsøvnforstyrrelserogpasienterilegemiddelassistertrehabiliteringfårofteforskrevetbenzodiazepinerfordisselidelsene.Benzodiazepinerkanogsåmisbrukesogerletttilgjengeligpådetille‐galemarkedet.Flerestudierviseratbrukavbenzodiazepinermensmanfårlegemid‐delassistertbehandlingerassosiertmedmerbrukavrusmidler,angst,psykiskehelse‐plagerogøktrisikoforpersonskade.Dissefunnenestammerimidlertidfraobserva‐sjonsstudierogskillerikkemellombenzodiazepinersomerforskrevetavlegeellerskaffetillegalt.Formål

Måletmeddennesystematiskeoversikteneråoppsummereeffektenavåforskrivebenzodiazepinerforpasientersommottarlegemiddelassistertrehabilitering(metadon,buprenorfinellerbuprenorfinkombinertmednalokson).Metode

Visøkteførstettersystematiskeoversiktersomkunnebesvareproblemstillingenvårifølgendedatabaser:Epistemonikos,CochraneLibrary(CDSR,DARE,HTA),MEDLINE(Ovid),PubMed[sb]ogEmbase(Ovid).Vifantingenrelevantesystematiskeoversikter.Derettersøktevietterprimærstudierforåfåoversiktovertilgjengeligkunnskap.Randomisertekontrollertestudierogikke‐randomisertekontrollertestudier,kontrol‐lertefør‐og‐etterstudierogavbruttetidsserierbleinkludertsomrelevantestudiede‐sign.Målgruppenvarpersoner18årellereldresomfikksubstitusjonsbehandlingforopioidavhengighetmedmetadon,buprenorfinellerbuprenorfinkombinertmednalok‐son.Relevantintervensjonvarforskrivningavbenzodiazepinersammenlignetmedingenforskrivingavbenzodiazepiner.Relevanteutfallergjennomførtbehandling,pasi‐enttilfredsstillelse,brukavopioider(selvrapportertellerbiologisketester),annenrus‐middelbruk(selvrapporteringellerbiologisktest),gradavangstogdepresjon,søvnfor‐styrrelser,dødelighet,bivirkninger(overdose,skade‐ogbrukavsykehusetsakuttmot‐tak)ogstraffbareforhold.VigjennomførteetsystematisklitteratursøkutenbegrensningeritidellerspråkiCochraneCentralRegisterofControlledTrials(CENTRAL),MEDLINE(Ovid),PubMed

10 Sammendrag (norsk)

[sb],Embase(Ovid),CINAHL(EBSCO)ogPsycINFO.Treforfatterevurdertereferansenebasertpåtittelogabstrakt,iparuavhengigavhverandre(KYDlestealle,AMogLHhalvpartenhver).Potensieltrelevantereferanserblelestifulltekst(KYDlestealle,AMogLHhalvpartenhver).Vihaddeplanlagtåvurdererisikoenforsystematiskeskjevhe‐ter,syntetiseredatahvismuligogbrukeGRADE(GradingofRecommendationAssess‐ment,Developmentandevaluation)metodenforåvurderevårtillittileffektestima‐tene.Resultat

Detsystematiskelitteratursøketettersystematiskeoversikteridentifiserte998titlerogabstrakter.Ingensystematiskeoversiktervarrelevantfortemaetetterscreening.Vårtsøketterprimærstudieridentifiserte3696referanser,ogvilesteåtteavdemifull‐tekst.Ingenavreferansenemøttevåreinklusjonskriterier.Diskusjon

Vifantingenrelevantekliniskestudierellerkontrollertestudiersomundersøkteproblemstillingenidenneoversikten.Eksperimentellestudiermedkontrollertbrukavbenzodiazepinerernødvendigforåskilleeffekterogkonsekvenseravåforeskrivebenzodiazepinertilpersonersommot‐tarlegemiddelassistertrehabiliteringfradetsomerknyttettilillegalbrukogkontrol‐lerefordenunderliggendesymptomprofilen.Detvilværerelevantåinkludereutfalls‐målene:narkotikaoppbevaringogmisbruk,pasienttilfredshet,mentalhelse,søvnfor‐styrrelser,bivirkningerogkriminellatferd.KonklusjonVifantingenkontrollertestudierommuligeeffekterogkonsekvenseravsamtidigfor‐skrivningavbenzodiazepinertilpasienterilegemiddelassistertrehabilitering.

11 Preface

Preface

TheNorwegianDirectorateofHealthisrevisingthenationalclinicalguidelineforthetreatmentofpeoplewithopioiddependence.TheyhavecommissionedthissystematicreviewtoTheKnowledgeCentrefortheHealthServicesintheNorwegianInstituteofPublicHealthfocusingontheeffectsandconsequencesofconcurrentprescriptionofbenzodiazepinesamongpeoplereceivingopioidmaintenancetreatment.Theprojectgroupconsistedof:

KristofferY.Ding(KYD),projectleader,NorwegianInstituteofPublicHealth AnnhildMosdøl(AM),NorwegianInstituteofPublicHealth LailaHov(LH),NorwegianInstituteofPublicHealth GyriH.Staumann(GHS),NorwegianInstituteofPublicHealth GunnE.Vist(GEV),NorwegianInstituteofPublicHealthWethankRigmorC.Berg,AtleFretheimandLivM.Reinarforbeingtheinternalre‐viewers,BritteliseBakstadandGabrielleWelle‐Strandastheexternalreviewersforourresearchprotocolandfinalreport.WealsowanttothankHildeStrømmeaspeerre‐viewerforourliteraturesearch.AllauthorshavecompletedtheConflictsofInterestform,andnoconflictsofinterestwasstated.

SigneFlottorpDepartmentDirector

GunnE.VistUnitleader

KristofferY.DingProjectleader

12 Introduction

Introduction

Opioiddependenceincludessignsandsymptomsthatreflectcompulsive,prolongedself‐administrationofopioidsubstancesthatareusedfornolegitimatemedicalpur‐poseor,ifanothermedicalconditionispresentthatrequiresopioidtreatment,thatareusedindosesgreatlyinexcessoftheamountneededforthatmedicalcondition(ICD‐10‐F11).Opioidmaintenancetreatment(Norwegian:Legemiddelassistertrehabiliter‐ing,LAR)isbasedontheadministrationofmedicationsthatworkthroughthesamere‐ceptorsastheaddictivesubstances,butarelongeracting,canadministeredorallyandarelesslikelytoproducetheharmfulbehaviorsthatcharacterizeaddiction[1].ThecurrentNorwegiannationalguidelineforLARrecommendsbuprenorphinecom‐binedwithnaloxoneasthefirstchoicefortheinitialsubstitutiontreatment.Othercom‐monlyusedmedicationsincludebuprenorphinemono‐formulationandmethadone.Ac‐cordingtoaNorwegiannationwidesurveyin2015,7498peoplewereenrolledinLAR.Ofthese,24%receivedthecombinedtreatmentofbuprenorphineandnaloxone,36%receivedbuprenorphinemono‐formulationand39%receivedmethadonetreatment[2].Peoplewithopioiddependencearemorelikelytoexperienceelevatedlevelsofanxiety[3].Benzodiazepinesareaclassofpsychoactivedrugsthatareusedtotreatanxietyandsleepdisorders.Althoughprescriptionofbenzodiazepinesforthesedisordersarequitecommon,theyshouldbeusedwithcautionasprolongedusemayresultinphysical[4]andpsychologicaldependence[5],andincreasedriskofpersonalinjury[6,7].Notably,althoughevidencesuggeststhatlong‐termbenzodiazepinestolerancedevelopsquicklyforthesedativeandanticonvulsantactions,itstolerancetoanxiolyticandamnesicef‐fectsmaynotdevelopatall[8].Findingsfrompopulation‐basedstudiesalsoshowedthatthereisnoincreaseinprescribeddoseofbenzodiazepinesamonglong‐termusers[9,10].Ontheotherhand,benzodiazepinescanbemisusedasadrugaloneinhighdosesorcombinedwithillicitsubstancesoralcohol.TheNorwegianPolicerecentlyreportedthatbenzodiazepinesarereadilyavailableontheillegalstreetmarket[11].AnannualreportoftheNorwegianLAR‐programshowedthatapproximately40%oftheLARpopulationreportedtakingbenzodiazepineswithinamonthbeforethesurvey.How‐ever,only25%reportedthattheirbenzodiazepineswereprescribedfromtheirdoctors[2].Severalstudiesdescribethatpatientswhousebenzodiazepinesduringopioidmaintenancetreatmenthavelowerretentionrateintreatmentandaremoreatriskofcontinueddrugabuse[12],higheranxietysensitivity[13]andmorementalhealth

13 Introduction

problems[14].However,thisevidenceismostlydescriptiveandderivedfromsurveysorobservationalstudies.Furthermore,thesefindingsdonotdistinguishbetweenpre‐scribedversusillicitlyprocuredbenzodiazepines,nordotheysufficientlyaccountforthepossibleunderlyingsymptomatologyofbenzodiazepinesusers.ConcurrentuseandmisuseofbenzodiazepinesamongpatientsintheLAR‐programhavebeenwidelydiscussed,butthereisnocomprehensiveevidenceevaluatingtheef‐fectsandconsequencesamongpeopleinopioidmaintenancetreatment.

14 Method

Method

First,wesearchedforsystematicreviewspublishedduringthelast5years(after1.1.2011)ontheeffectsofconcurrentbenzodiazepinesprescriptionforpeopleinopi‐oidmaintenancetreatmentinthefollowingdatabases:

Epistemonikos CochraneLibrary(CDSR,DARE,HTA) MEDLINE(Ovid)andPubMed[sb] Embase(Ovid)Sincewedidnotfindanysystematicreviewsrelevantforthetopic,weconductedasys‐tematicsearchforprimarystudiesontheeffectsofconcurrentbenzodiazepinespre‐scriptionforpeopleinopioidmaintenancetreatment.

Inclusioncriteria

Studydesign:Randomizedcontrolledtrials(RCT,includingclusterRCT) Non‐randomizedcontrolledtrials(NRCTs) Controlledbefore‐and‐afterstudies(CBA) Interruptedtimeseries(ITS)

Population: Peoplewhoare18yearsorolderwhoreceivebuprenorphine

withnaloxone,buprenorphineormethadonesubstitutiontreat‐mentforopioiddependence

Intervention: Prescriptionofbenzodiazepines

Comparison: Noprescriptionofbenzodiazepines

Outcome: Retentionintreatment

Patients’satisfactionOpioiduse(self‐reportorbiologicaltest)Othersubstanceuse(self‐reportorbiologicaltest)ExtentofanxietyExtentofdepressionSleepdisordersMortalitySideeffects(overdose,injuryanduseofhospitalemergency)

15 Method

CriminaloffensesLanguage: Nolanguagelimitsappliedtothesearches.Projectmembersonly

readEnglish,Norwegian,Danish,SwedishandChinese.Publica‐tionsinotherlanguageswouldnotbereadbutbelistedinata‐ble.

Literaturesearch

Wesearchedforprimarystudieswithnolimitofpublicationtimeorlanguageinthefollowingdatabases:

CochraneCentralRegisterofControlledTrials(CENTRAL) MEDLINE(Ovid)andPubMed[sb] Embase(Ovid) CINAHL(EBSCO) PsycINFOWealsosearchedforongoingtrialsinclinicaltrials.gov,WHOInternationalClinicalTri‐alsRegistryPlatform,CurrentControlledTrials,EUClinicalTrialsRegisterandTrials.Researchlibrarian,GyriHvalStraumann,conductedthesearch,whichwaspeer‐re‐viewedbylibrarianHildeStrømme.

Articleselectionandassessment

Threereviewauthorsindependentlyscreenedabstractsidentifiedbythesearchesinduplicates.KristofferYunpengDingscreenedallthereferenceswhileAnnhildMosdølandLailaHovscreenedhalfeach.Articleswereexcludedifthetitleand/orabstractdidnotmeettheinclusioncriteria.Forpotentiallyrelevantstudies,thefull‐textarticleswereobtainedandscreenedwithdiscrepanciesresolvedbyconsensusofreviewers.Studiesthatarerelevanttothere‐viewtopicbutdonotmeetalltheinclusioncriteriaforthereviewarelistedinthe‘Characteristicsofexcludedstudies’table,withthereasonfortheirexclusiondescribed.WerecordedtheselectionprocessinsufficientdetailtocompleteaPreferredReport‐ingItemsforSystematicReviewsandMeta‐Analyses(PRISMA)flowdiagram.

Assessmentofriskofbiasinincludedstudies

WehadplannedtoassesstheincludedstudiesforriskofbiasforRCTs,NRCTsandCBAsindependentlywiththeEPOCriskofbiastool[13].Potentialconflictswouldhave

16 Method

beensolvedbyconsensusorreferraltoathirdreviewauthorifdisagreementpersisted.Wewouldhaveassessedtheriskofbiasforeachofthefollowingdomains:

Adequatesequencegeneration Allocationconcealment Blindingofoutcomeassessors Incompleteoutcomedata Selectiveoutcomereporting Comparabilityofbaselineoutcomemeasurementsacrossgroups Comparabilityofbaselinecharacteristicsacrossgroups Freeofcontaminationbetweengroups FreeofotherbiasForclusterRCT,wewouldhaveconsideredparticularbiases[14]including:

Recruitmentbias Baselineimbalance Lossofclusters Incorrectanalysis ComparabilitywithindividuallyrandomizedtrialsAseparateriskofbiaschecklistwouldhavebeenusedforITSstudies,whichincludessevencriteria[13]asfollows:

Independentintervention Pre‐specifiedinterventioneffectshape Datacollectionbeingaffectedbyintervention Outcomesassessedblindly Missingdata Publicationbias Freeofotherbias

Dataextraction

KristofferYunpengDingwouldhavebeenresponsibleforextractingtherelevantdatafromtheincludedstudies,whileAnnhildMosdølvalidatedtheextraction.Thefollowinginformationwasplannedtobeextracted:authors,year,country,title,population,inter‐vention(drugtypeanddosage)aswellastheoutcomesasfollows:Retentionintreat‐ment;patients’satisfaction,opioiduse(self‐reportorbiologicaltest),othersubstanceuse(self‐reportorbiologicaltest),extentofanxiety,sleepdisorders,sideeffects(over‐dose,injury,hospitalemergencyuseormortality)andcriminaloffenses.

17 Method

Analyses

Weanticipatethatoutcomedatawouldbepresentedasdichotomous,continuousoror‐dinal.Incasesofdichotomousdata,riskratios(RR)wouldbecalculated.Incasesofcontinuousdata,wewouldusemeandifference(MD)orcalculatethestandardizedmeandifference(SMD)ifmorethanonestudymeasuredthesameoutcomeusingdif‐ferenttools.Theordinaldatawouldhavebeenanalyzedasacontinuousoutcome,orbeendichoto‐mizedbaseduponthescaleusedandexistenceofwell‐definedcut‐offvalues.Forallef‐fectmeasures,effectestimateswouldhavebeenpresentedwith95%confidenceinter‐vals(CIs).Wewouldhaveperformedmeta‐analysisusingRevMansoftware(RevMan5.3).Nota‐bly,meta‐analysiswouldonlyhavebeenperformedwhenthereweretwoormorestudieswithsufficientlysimilarinclusioncriteria.Iftheincludedstudiesreportedthesameorsimilaroutcome,andtherewerenoapparentunitofanalysiserrors(orICCdatawereavailableforclusterRCT),wewouldhavecalculatedsummarymeasuresofinterventioneffects.Inaddition,datasynthesiswouldhavebeenstratifiedandpre‐sentedseparatelyfordifferentstudydesigns.Wehadplannedtoconductmeta‐analysiswithrandomeffectsmodel,usingstandardmethodstoaccountforclusterRCTasrele‐vant.Ifsubstantialheterogeneity(I2>75%)wasfound,orwewereunabletoadjustforunitofanalysiserrorsintwoormorestudieswithsameorsimilaroutcomes,wewouldhavepresentedtheresultsdescriptivelyasthemedianeffectandinterquartilerange.

Assessmentofqualityofevidence

Thereviewteamplannedtoassessthecertaintyoftheevidencetogether(high,moder‐ate,loworverylow)foreachoutcomeusingtheGRADEapproach[15].Disagreementsoncertaintyratingswouldhavebeenresolvedbydiscussionandprovidingjustificationfordecisionstodown‐orup‐gradetheratingsusingfootnotesinthetable.

18 Results

Results

Weinitiallysearchedforsystematicreviewstoaddressthequestionoftheeffectsofconcurrentprescriptionofbenzodiazepinesamongpeopleinopioidmaintenancetreat‐ment.Aftertheliteraturesearch,wefound998systematicreviewsbutnoneofthemwererelevantforthetopic.

Descriptionofstudies

Resultsofliteraturesearch

Wesearchedforprimarystudiestoconductasystematicreviewandidentified3696references.Weconsideredeightreferencesaspotentiallyrelevantandreadtheminfull‐text.However,wefoundnoreferencethatmetourinclusioncriteria(Figure1).ThoseexcludedreferencesarepresentedinAppendix2withanexplanationforexclu‐sion.

Figure1 Flowchartofliteratureselection

References identified through  database searching (n=3096) 

References excluded on the basis of title and abstract (n=3088) 

Full‐text articles assessed  for eligibility (n=8) 

Full‐text articles excluded on the ba‐sis of full‐text assessment (n=8) 

Included studies (n=0) 

19 Results

Excludedstudies

Weevaluatedthefull‐textoftheeightstudies,andfoundthatnoneofthemmetourin‐clusioncriteria.ThedetailedreasonsforexclusionareprovidedinAppendix2.Specifi‐cally,onestudyhadanobservationaldesignwithnointerventiongroup;onestudycomparedtheeffectoftwodrugswithnocontrolgroup;twostudiestargetedondiffer‐entpopulations;twostudiesfocusedonpharmacodynamicsofbenzodiazepinesandphysiologicalresponsesofsubjects;twostudieswerepublishedintheformoflongab‐stractbutnotfull‐textarticles.

20 Discussion

Discussion

Keyfindingssummary

Wehaveconductedasystematicreviewontheeffectsandconsequencesofconcurrentprescriptionofbenzodiazepinesamongpeopleinopioidmaintenancetreatment.Afterconductingasystematicliteraturesearch,wedidnotfindanyrelevantsystematicre‐vieworprimarystudythatmeettheresearchquestion.

Strengthsandweaknesses

Astrengthofthissystematicreviewisthesystematicandexplicitmethodsused.Alt‐houghwedidnotfindanyrelevantstudyinoursystematicliteraturesearch,wehavetobearinmindthepossibilitythatrelevantstudiesmayhavebeenpublishedafterthesearchwasconducted,whichisalimitationofallsystematicreviews.Thissystematicreviewisconsideredup‐to‐dateasofJuly2016.

Consistencywithotherliterature

Thebackgroundforthisreviewistheconcernthatpatientswhoarereceivingthepre‐scriptionofbenzodiazepinesduringopioidmaintenancetreatmentmayhavelowerre‐tentionintreatmentorathigherriskofcontinueddrugabuse[12],elevatedanxietysensitivity[13]andmorementalhealthproblems[14].However,wefoundnocontrolledstudiesofbenzodiazepinesuse,asseparatedfromil‐licitsubstances,whichcantakeintoaccounttheunderlyingsymptomatologyofbenzo‐diazepinesusers.Oneoftheexcludedstudies,anobservationalstudyofpatientsinatrialwithdifferentopioidmaintenancetreatments[16],indicatesdifferentriskprofilesforpatientswithbaselinebenzodiazepinesuseandongoingbenzodiazepinesuse,butwithnoprescriptioninformation.

Identifiedresearchgaps

Experimentalstudiesareneededtoevaluatetheeffectsandconsequencesofcontrolleduseofbenzodiazepinesduringopioidmaintenancetreatment.Wesuggestthefollowing

21 Discussion

outcomes:drugretentionandabuse;patientsatisfaction;mentalhealth;sleepdisor‐ders;sideeffectsandcriminalbehaviours.

22 Conclusion

Conclusion

Thereisalackofcontrolledstudiesontheeffectsandconsequencesofconcurrentben‐zodiazepinesprescriptionamongpeopleinopioidmaintenancetreatment.

23

References

1. CenterforSubstanceAbuseTreatment,Medication‐AssistedTreatmentforOpioidAddictioninOpioidTreatmentPrograms.TreatmentImprovementProtocol(TIP)Series43.DHHSPublicationNo.(SMA)12‐4214.Rockville,MD:SubstanceAbuseandMentalHealthServicesAdministration,2005.

2. WaalH,BussesundK,ClausenT,SkeieI,HåsethA,andPH.L,Statusrapport2015.Motgrenseneforvekstognytte?Oslo:Senterforrus‐ogavhengighetsforskning.Nasjonaltkompetansesenterfortverrfaligspesialisertrubehandling,2016.

3. PosternakMAandMuellerTI,Assessingtherisksandbenefitsofbenzodiazepinesforanxietydisordersinpatientswithahistoryofsubstanceabuseordependence.TheAmericanjournalonaddictions/AmericanAcademyofPsychiatristsinAlcoholismandAddictions,2001.10(1):p.48‐68.

4. UzunS,KozumplikO,JakovljevicM,andSedicB,Sideeffectsoftreatmentwithbenzodiazepines.PsychiatriaDanubina,2010.22(1):p.90‐93.

5. KhongE,SimMG,andHulseG,Benzodiazepinedependence.Australianfamilyphysician,2004.33(11):p.923‐926.

6. EngelandA,SkurtveitS,andMørlandJ,RiskofRoadTrafficAccidentsAssociatedWiththePrescriptionofDrugs:ARegistry‐BasedCohortStudy.AnnalsofEpidemiology,2007.17(8):p.597‐602.

7. HemmelgarnB,SuissaS,HuangA,Jean‐FrancoisB,andPinardG,BEnzodiazepineuseandtheriskofmotorvehiclecrashintheelderly.JAMA,1997.278(1):p.27‐31.

8. VinkersCHandOlivierB,MechanismsUnderlyingToleranceafterLong‐TermBenzodiazepineUse:AFutureforSubtype‐SelectiveGABA(A)ReceptorModulators?AdvancesinPharmacologicalSciences,2012.2012:p.416864.

9. SoumeraiSB,Simoni‐WastilaL,SingerC,MahC,GaoX,SalzmanC,andRoss‐DegnanD,Lackofrelationshipbetweenlong‐termuseofbenzodiazepinesandescalationtohighdosages.Psychiatricservices(Washington,D.C.),2003.54(7):p.1006‐1011.

10. WillemsIA,GorgelsWJ,OudeVoshaarRC,MulderJ,andLucassenPL,Tolerancetobenzodiazepinesamonglong‐termusersinprimarycare.Familypractice,2013.30(4):p.404‐410.

11. Kripos.Narkotika‐ogdopingstatisitkk2015.2016[cited201610.08.2016];Availablefrom:https://www.politi.no/vedlegg/lokale_vedlegg/kripos/Vedlegg_3549.pdf.

12. PelesE,AdelsonM,andS.S,Benzodiazepineusageduring19.5YearsinmethadonemaintenanceTreatmentpatientsanditsRelationtoLong‐TermOutcome.israeljournalofpsychiatry,2014.51(4):p.285.

13. McHughRK,VotawVR,BogunovicO,KarakulaSL,GriffinML,andWeissRD,Anxietysensitivityandnonmedicalbenzodiazepineuseamongadultswithopioidusedisorder.AddictiveBehaviors.

14. SchmitzA,Benzodiazepineuse,misuse,andabuse:Areview.MentalHealthClinician,2016.6(3):p.120‐126.

24

15. GRADEworkinggroup,GRADEguidelines‐bestpracticesusingtheGRADEframework.Availablefrom:http://www.gradeworkinggroup.org/publications/JCE_series.htm.

16. Eiroa‐OrosaFJ,HaasenC,VertheinU,DilgC,SchaferI,andReimerJ,Benzodiazepineuseamongpatientsinheroin‐assistedvs.methadonemaintenancetreatment:findingsoftheGermanrandomizedcontrolledtrial.Drugandalcoholdependence,2010.112(3):p.226‐233.

25

Appendices

Appendix1.Searchstrategy

PartI.Searchstrategyforsystematicreviews.Database:CochraneDatabaseofSystematicReviews(Reviewsonly)Dateonsearch:01.07.16 Searches Results#1 MeSHdescriptor:[OpiateSubstitutionTreatment]explodealltrees 204#2 MeSHdescriptor:[Methadone]explodealltrees 997#3 MeSHdescriptor:[Buprenorphine]explodealltrees 733#4 MeSHdescriptor:[Naloxone]explodealltrees 1688#5 (((opiateoropioid)next(replacementorsubstitutionoragonistor

maintenance)next(therap*ortreatment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAlgoxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBunavail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLepetan*orMaloxon*orMa‐pin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMethex*orMiadon*orNalaxon*orNalone*orNa‐loxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPento‐rel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPre‐fin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)):ti,ab,kw

3878

#6 #1or#2or#3or#4or#5 4970#7 MeSHdescriptor:[Benzodiazepines]explodealltrees 8125#8 (benzodiazepine*oralprazolamorbromazepamorchlordiazepox‐

ideorclobazamorclonazepamorclorazepateordiazepamoresta‐zolamorflunitrazepamorflurazepamorhalazepamorketazolamorloprazolamorlorazepamorlormetazepamormedazepamornordazepamoroxazepamorprazepamorquazepamortemaze‐pamortriazolam):ti,ab,kw

11772

#9 #7or#8 17025#10 #6and#9PublicationYearfrom2011to2016,inCochraneRe‐

views(Reviewsonly)4

26

Database:DARE,HTA,CochraneDatabaseofSystematicReviews(Protocolsonly)Dateonsearch:01.07.16 Searches Results#1 MeSHdescriptor:[OpiateSubstitutionTreatment]explodeall

trees204

#2 MeSHdescriptor:[Methadone]explodealltrees 997#3 MeSHdescriptor:[Buprenorphine]explodealltrees 733#4 MeSHdescriptor:[Naloxone]explodealltrees 1688#5 (((opiateoropioid)next(replacementorsubstitutionoragonist

ormaintenance)next(therap*ortreatment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAlgoxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBunavail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLepetan*orMaloxon*orMa‐pin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMethex*orMiadon*orNalaxon*orNalone*orNa‐loxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPento‐rel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPre‐fin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)):ti,ab,kw

4130

#6 #1or#2or#3or#4or#5 5210#7 MeSHdescriptor:[Benzodiazepines]explodealltrees 8125#8 (benzodiazepine*oralprazolamorbromazepamorchlordiaze‐

poxideorclobazamorclonazepamorclorazepateordiazepamorestazolamorflunitrazepamorflurazepamorhalazepamorketa‐zolamorloprazolamorlorazepamorlormetazepamormedaze‐pamornordazepamoroxazepamorprazepamorquazepamorte‐mazepamortriazolam):ti,ab,kw

12526

#9 #7or#8 14514#10 #6and#9PublicationYearfrom2011to2016,inOtherReviews,

TechnologyAssesmments,CochraneReviews(Protocolsonly)7

Database:EpistemonikosDateonsearch:01.07.16benzodiazepines(last5years):1broadsynthesis,11structuredsummaries,37sys‐tematicreviewsDatabase:EpubAheadofPrint,In‐Process&OtherNon‐IndexedCitations,OvidMEDLINE(R)DailyandOvidMEDLINE(R)1946toPresentDateonsearch:01.07.16

27

Searches Results1 "Opiatesubstitutiontreatment"/orexp"Methadone"/orexp"Bu‐

prenorphine"/orexp"Naloxone"/or(((opiateoropioid)adj(re‐placementorsubstitutionoragonistormaintenance)adj(therap*ortreatment*orprogram*))or(Adadon*orAlgidon*orAlgoly‐sin*orAlgoxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBunavail*orBuprenex*orBuprenorpin*orBuprex*orBu‐prine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLepetan*orMaloxon*orMapin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMe‐thex*orMiadon*orNalaxon*orNalone*orNaloxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPentorel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPrefin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)).ab,ti,kw,kf.

47409

2 expBenzodiazepines/or(benzodiazepine*oralprazolamorbromazepamorchlordiazepoxideorclobazamorclonazepamorclorazepateordiazepamorestazolamorflunitrazepamorfluraze‐pamorhalazepamorketazolamorloprazolamorlorazepamorlormetazepamormedazepamornordazepamoroxazepamorprazepamorquazepamortemazepamortriazolam).ti,ab.

80651

3 1and2 21314 limit3to(yr="2011‐Current"and"reviews(maximizessensitiv‐

ity)")183

Database:Embase1974to2016June29Dateonsearch:01.07.16 Searches Results1 expbenzodiazepinederivative/ 1633142 (benzodiazepine*oradinazolamoralprazolamoranthramycinor

bentazepamorbromazepamorchlordiazepoxideorcinolazepamorclobazamorclonazepamor"clorazepamclorazepate"orcloti‐azepamorcloxazolamorcyprazepamordiazepamordoxefaze‐pamorestazolamoretizolamorflunitrazepamorflurazepamorflutazoramorfosazepamorgirisopamorhalazepamorhaloxaze‐pamorketazolamorloprazolamorlorazepamorlormetazepamormeclonazepamormedazepamormetaclazepamormexazolamormidazolamormidazepamornerisopamornitrazepamornordazepamoroxazepamoroxazolamorpinasepamorpinazepamorprazepamortemazepamortetrazepamortofiso‐pamortriazolamortriflubazam).ti,ab.

85631

3 1or2 189205

28

4 "Opiatesubstitutiontreatment"/or"Methadonetreatment"/or"Methadone"/or"Buprenorphine"/or"Burprenophineplusna‐loxone"/or"Naloxone"/or(((opiateoropioid)adj(replacementorsubstitutionoragonistormaintenance)adj(therap*ortreat‐ment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAl‐goxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBu‐navail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLep‐etan*orMaloxon*orMapin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMethex*orMiadon*orNalaxon*orNalone*orNaloxon*orNarcan*orNarcon*orNar‐vcam*orNorphin*orPentorel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPrefin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)).ab,ti,kw.

72658

5 3and4 93416 limit5to("reviews(maximizessensitivity)"andyr="2011‐Cur‐

rent")846

Database:PROSPERODateonsearch:01.07.16benzodiazepines:5PartII.Searchingstrategyforprimarystudies.Database:EpubAheadofPrint,In‐Process&OtherNon‐IndexedCitations,OvidMEDLINE(R)DailyandOvidMEDLINE(R)1946toPresentDateonsearch:01.07.16 Searches Results1 "Opiatesubstitutiontreatment"/orexp"Methadone"/orexp

"Buprenorphine"/orexp"Naloxone"/or(((opiateoropioid)adj(replacementorsubstitutionoragonistormaintenance)adj(therap*ortreatment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAlgoxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBunavail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLepetan*orMaloxon*orMapin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMe‐thex*orMiadon*orNalaxon*orNalone*orNaloxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPentorel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPrefin*orProbuphin*

47409

29

orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)).ab,ti,kw,kf.

2 expBenzodiazepines/or(benzodiazepine*oralprazolamorbromazepamorchlordiazepoxideorclobazamorclonazepamorclorazepateordiazepamorestazolamorflunitrazepamorflu‐razepamorhalazepamorketazolamorloprazolamorlorazepamorlormetazepamormedazepamornordazepamoroxazepamorprazepamorquazepamortemazepamortriazolam).ti,ab.

80651

3 dt.fs. 18777004 randomizedcontrolledtrial.pt. 4222325 controlledclinicaltrial.pt. 910946 multicenterstudy.pt. 2054827 (randomis*orrandomiz*orrandomlyorgroups).ti,ab. 20541108 (trialormulticenterormulticenterormulticentreormulticen‐

tre).ti.184649

9 (intervention*orcontrolledorcontrolgrouporcompareorcom‐paredorquasiexperiment*orquasiexperiment*orevaluat*oreffect*orimpact*).ti,ab.

9428146

10 or/3‐9 1091646011 1and2and10 157712 limit11toyr="1990‐Current" 1189Database:Embase1974to2016June29Dateonsearch:01.07.16 Searches Results1 expbenzodiazepinederivative/ 1633142 (benzodiazepine*oralprazolamorbromazepamorchlordiaze‐

poxideorclobazamorclonazepamorclorazepateordiazepamorestazolamorflunitrazepamorflurazepamorhalazepamorketa‐zolamorloprazolamorlorazepamorlormetazepamormedaze‐pamornordazepamoroxazepamorprazepamorquazepamortemazepamortriazolam).ti,ab.

72658

3 1or2 1774164 "Opiatesubstitutiontreatment"/or"Methadonetreatment"/or

"Methadone"/or"Buprenorphine"/or"Burprenophineplusna‐loxone"/or"Naloxone"/or(((opiateoropioid)adj(replacementorsubstitutionoragonistormaintenance)adj(therap*ortreat‐ment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAl‐goxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBu‐navail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLep‐etan*orMaloxon*orMapin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMethex*orMiadon*

76474

30

orNalaxon*orNalone*orNaloxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPentorel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPrefin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*)).ab,ti,kw.

5 expcrossoverprocedure/ 477296 expdoubleblindprocedure/ 1319757 expsingleblindprocedure/ 223808 expclinicaltrial/ 11000729 exprandomizedcontrolledtrial/ 41068510 (randomis*orrandomiz*orrandomlyortrialorintervention?or

effect?orimpact?ormulticenterormulticenterormulticentreormulticentreorcontrolledorcontrolgroup?orquasiexperiment*orquasiexperiment*ordoubleblind*orsingleblind*orassign*orallocat*orvolunteer*orcrossoverorcrossover).ti,ab.

7844788

11 or/5‐10 821539312 3and4and11 390113 limit12toyr="1990‐Current" 3132Database:CentralDateonsearch:01.07.16 Searches Results#1 MeSHdescriptor:[OpiateSubstitutionTreatment]explodeall

trees204

#2 MeSHdescriptor:[Methadone]explodealltrees 998#3 MeSHdescriptor:[Buprenorphine]explodealltrees 734#4 MeSHdescriptor:[Naloxone]explodealltrees 1690#5 (((opiateoropioid)next(replacementorsubstitutionoragonist

ormaintenance)next(therap*ortreatment*orprogram*))or(Adadon*orAlgidon*orAlgolysin*orAlgoxale*orAmidon*orAnorfin*orAntioplaz*orBiodon*orBunavail*orBuprenex*orBuprenorpin*orBuprex*orBuprine*orButalgin*orButrans*orDolophin*orEvzio*orFinibron*orLepetan*orMaloxon*orMa‐pin*orMetado*orMetasedin*orMethaddict*orMethado*orMethaforte*orMethex*orMiadon*orNalaxon*orNalone*orNaloxon*orNarcan*orNarcon*orNarvcam*orNorphin*orPentorel*orPhenadon*orPhymet*orPhysepton*orPinadon*orPrefin*orProbuphin*orSuboxon*orSubutex*orSymoron*orTemgesic*orTranstec*orZubsolv*orZynox*))

4140

#6 #1or#2or#3or#4or#5 5222#7 MeSHdescriptor:[Benzodiazepines]explodealltrees 8128#8 (benzodiazepine*oralprazolamorbromazepamorchlordiaze‐

poxideorclobazamorclonazepamorclorazepateordiazepamor12525

31

estazolamorflunitrazepamorflurazepamorhalazepamorketa‐zolamorloprazolamorlorazepamorlormetazepamormedaze‐pamornordazepamoroxazepamorprazepamorquazepamortemazepamortriazolam)

#9 #7or#8 14513#10 #6and#9PublicationYearfrom1990to2016,inTrials 154Database:ClinicalTrials.gov(www.clinicaltrials.gov)Dateonsearch:30.06.16benzodiazepineANDopioid:69Database:WorldHealthOrganization(WHO)InternationalClinicalTrialsRegis‐tryPlatform(ICTRP)Dateonsearch:30.06.16(apps.who.int/trialsearch/)benzodiazepineANDopioid:7benzodiazepinesANDopioids:14Database:CurrentControlledTrials(www.controlled‐trials.com/)Dateonsearch:30.06.16benzodiazepineANDopioid:3benzodiazepinesANDopioids:10Database:EUClinicalTrialsRegister(www.clinicaltrialsregister.eu)Dateonsearch:30.06.16benzodiazepineANDopioid:1benzodiazepinesANDopioids:5Database:Trials(www.trialsjournal.com)Dateonsearch:30.06.16benzodiazepineANDopioid:211benzodiazepinesANDopioids:313

32

Appendix2.Excludedstudies

Studiesevaluatedinfull‐text Reasonforexclusion

Eiroa‐Orosa,FranciscoJosé,etal.Benzodiazepineuseamongpatientsinheroin‐assistedvs.methadonemaintenancetreatment:findingsoftheGermanrandomizedcontrolledtrial.Drugandalcoholdependence112.3(2010):226‐233.

Thestudyhasnointerventiononbenzodiazepines(anobservationalstudyderivedfromaclinicaltrial).

Jariani,Mojhgan,etal.TheeffectofOlanzapineandSertralineonpersonalitydisorderinpatientswithmethadonemaintenancetherapy.PsychiatriaDanubina22.4.(2010):544‐547.

Thestudycomparedtheeffectofolanzapinewithanotherintervention(Sertraline)intreatingdepressionandanxietyamongpatientswithmethadonemaintenancetherapy.Thestudydesigndoesnotmeetourinclusioncriteria,becausetheycomparedtheeffectsoftwointerventionsandtherewasnocontrolgroup.

Lintzeris,Nicholas,etal.Interactionsonmixingdiazepamwithmethadoneorbuprenorphineinmaintenancepatients.Journalofclinicalpsychopharmacology26.3(2006):274‐283.

Theoutcomesofthisstudywerephysiologicalresponsesandsubjectivedrugeffects,whichwereonlymeasured6hoursafterdosing.Therewerenolong‐termoutcomesinthisstudy.

Lintzeris,Nicholas,etal.Pharmacodynamicsofdiazepamco‐administeredwithmethadoneorbuprenorphineunderhighdoseconditionsinopioiddependentpatients.Drugandalcoholdependence91.2(2007):187‐194.

Theoutcomesofthisstudywereaboutpharmacodynamicsofdiazepam,whichwasnotconsideredrelevantforthecurrentsystematicreview.

Lopatko,etal.Reducingbenzodiazepineconsumptioninopioidmaintenancetherapypatients:Acontrolledclinicaltrial.Proceedingsofthe68thAnnualScientificMeetingoftheCollegeonProblemsofDrugDependence;2006June17‐22;Scottsdale,Arizona,USA.

Thisisaconferencepaperwhichispublishedintheformoflongabstract,afull‐textarticleisnotavailable.

Mijatović,V.etal.PP042‐Safetyassessmentoflowdosesofmethadoneincombinationwithbenzodiazepinesinrealoccasionsduringmethadone

Thisisaconferencepaperwhichispublishedintheformoflongabstract,afull‐textarticleisnotavailable.

33

maintenancetreatment‐Apilotstudy.ClinicalTherapeutics,Volume35,Issue8,e30.

Stella,Luigi,etal.Naltrexoneplusbenzodiazepineaidsabstinenceinopioid‐dependentpatients.Lifesciences77.21(2005):2717‐2722.

Thepopulationinthisstudyusednaltrexonealonefortreatingopioiddependence,whichisnotthestandardtreatmentinNorway.Thepopulationisthereforeirrelevantforthecurrentstudy.

Zarghami,M.,etal.AcomparativestudyofbeneficialeffectsofOlanzapineandsodiumvalproateonaggressivebehaviorofpatientswhoareonmethadonemaintenancetherapy:arandomizedtripleblindclinicaltrial.EurRevMedPharmacolSci17.8(2013):1073‐1081.

Thestudycomparestheeffectofolazapineandsodiumvalporateonpatientsbehaviors.Thereisnocontrolgroupinthisstudy.

www.fhi.no

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