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The eff ects of concurrent prescription of benzodiazepines for people undergoing opioid maintenance treatment
Systematic review
2016
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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
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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
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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
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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.
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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.
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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
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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
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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.
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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
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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
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13 Introduction
problems[14].However,thisevidenceismostlydescriptiveandderivedfromsurveysorobservationalstudies.Furthermore,thesefindingsdonotdistinguishbetweenpre‐scribedversusillicitlyprocuredbenzodiazepines,nordotheysufficientlyaccountforthepossibleunderlyingsymptomatologyofbenzodiazepinesusers.ConcurrentuseandmisuseofbenzodiazepinesamongpatientsintheLAR‐programhavebeenwidelydiscussed,butthereisnocomprehensiveevidenceevaluatingtheef‐fectsandconsequencesamongpeopleinopioidmaintenancetreatment.
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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)
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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
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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.
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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.
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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)
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19 Results
Excludedstudies
Weevaluatedthefull‐textoftheeightstudies,andfoundthatnoneofthemmetourin‐clusioncriteria.ThedetailedreasonsforexclusionareprovidedinAppendix2.Specifi‐cally,onestudyhadanobservationaldesignwithnointerventiongroup;onestudycomparedtheeffectoftwodrugswithnocontrolgroup;twostudiestargetedondiffer‐entpopulations;twostudiesfocusedonpharmacodynamicsofbenzodiazepinesandphysiologicalresponsesofsubjects;twostudieswerepublishedintheformoflongab‐stractbutnotfull‐textarticles.
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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
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21 Discussion
outcomes:drugretentionandabuse;patientsatisfaction;mentalhealth;sleepdisor‐ders;sideeffectsandcriminalbehaviours.
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22 Conclusion
Conclusion
Thereisalackofcontrolledstudiesontheeffectsandconsequencesofconcurrentben‐zodiazepinesprescriptionamongpeopleinopioidmaintenancetreatment.
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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.
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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.
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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