002 Hypnosedatives for Anxiety Insomnia Muscle Spasm

ReportNo:0610002R3

TransportAccidentCommission&WorkSafeVictoriaEvidenceService

Hypnosedativesforanxiety,insomniaandmusclespasmEvidenceMapMay2010EmmaDonoghue,DrissAitOuakrim

ReportNo:0610002R3 Hypnosedativesforanxiety,insomniaandmusclespasm2

EXECUTIVESUMMARYTheaimofthisworkistoprovideanevidencemapoftheexistinghighlevelstudies(systematicreviewsandevidencebasedguidelines)onthebenefitsandharmsofhypnosedativesforanxiety, insomniaandmusclespasm.Thedrugsincludedunderthetitleofhypnosedativeswere: benzodiazepines:alprazolam,bromazepam,clobazam,diazepam,flunitrazepam,lorazepam,midazolam,

nitrazepam,oxazepam,temazepam,triazolam nonbenzodiazpinehypnotics:zolpidem,zopiclone

Searches ofMedline and Embase, and the internet yielded 1,943 potentially relevant studies. Screeningagainstinclusionandexclusioncriteriaresultedinatotalof41relevantstudies(34systematicreviews[SRs]and7evidencebasedguidelines[EBGs]).Thenumbersofstudiesidentifiedforeachindicationwereasfollows:Anxiety: 18SRs,5EBGsInsomnia: 17SRs,2EBGsMuscleSpasm:1SR,0EBGsOneSRwasabouttheuseofhypnosedativesforallthreeindications.AllotherEBGsandSRswereaboutoneindicationonly.


BACKGROUNDSedativesareaclassofpsychoactivedrugscommonlyprescribedastreatmentforsleepdisorders,anxietyandavarietyof relatedconditions. Inorder todevelopandupdatepolicies for theiruse inpatientswiththeseconditions, theHealthServicesGroupof theTransportAccidentCommissionandWorkSafeVictoria(TAC/WSV)requestedamapoftheavailablehigh levelevidenceexamining thebenefitsandharmsoftheuseofsedativesinanxiety,insomniaandmusclespasm.The term hypnosedatives refers to benzodiazepines, benzodiazepine derivatives, and a group of nonbenzodiazepinehypnoticdrugs(referredtoasZdrugs),thatincludeszolpidemandzopiclone.Benzodiazepines have been widely used in clinical practice since their introduction in the 1950s andcontinue tobeoneof themost consumed andhighlyprescribed classofdrugs available. Their rangeofactionsedative/hypnotic,anxiolytic,anticonvulsantandmusclerelaxantcombinedwithlowtoxicityandcostgainedthempopularityamongphysiciansandpatients.(1)The Zdrugsarehypnoticswith similarpharmacology tobenzodiazepines.Theyhavebeenpromotedasbeing safer than benzodiazepines and inmany countries they are themostwidely prescribed drugs forinsomnia.(2)Sincetheearly1980sstudieshaveregularlypointedouttherisksandadverseeffectsrelatedto longtermuseofbenzodiazepinesandotherhypnotics.(3)Theaimofthiswork istoprovideanevidencemapoftheexistinghighlevelstudies(systematicreviewsandevidencebasedguidelines)onthebenefitsandharmsofhypnosedativesforanxiety,insomniaandmusclespasm.

THEQUESTIONTheresearchquestionsinitiallyposedwere: Inwhatconditionsaresedatives(benzodiazepineandnonbenzodiazepine)indicated? Whatistheeffectivenessofsedativesintheseconditions? Whatistheeffectofsedativesonfunction,qualityoflife,returntowork,othermedicationuse? Inwhatconditions/patienttypesshouldsedativesnotbeused,usedshorttermonlyorusedwith

caution? Whatrisksareassociatedwiththeuseofsedatives?

There isnowelldefined,universallyaccepteddefinitionofwhatasedative is,noradefinitive listofdrugsthatareconsideredsedatives.Drugsthatpeoplemightrefertoassedativescanfallundermanydifferentdrugclassessuchassedatives,hypnotics,antianxietyagents,orcomplementarymedicines,dependingontheorganizationclassifyingthedrugs.Suchabroadlistofdrugs,combinedwithopenscopeonconditionsforwhichtheyareindicatedmeantthattheresearchquestionsinitiallyposedwouldbeunfeasible.Afterfurtherdiscussion,thescopeofthequestionwasnarrowedfromsedativestohypnosedatives,whichcomprisesbenzodiazepinesandselectednonbenzodiazepinehypnoticagents.Thedrugschosenwere the


benzodiazepines listed in MIMS as either antianxiety agents or sedatives, hypnotics, and two nonbenzodiazepinehypnotics:zolpidemandzopiclone(seeTable1).Thequestionwasfurtherrefinedtoincludethreespecificindications: Whatistheeffectivenessofhypnosedativesinanxiety? Whatistheeffectivenessofhypnosedativesininsomnia? Whatistheeffectivenessofhypnosedativesinmusclespasm? Whataretherisksassociatedwithhypnosedativeuseintheseconditions?Table1.ListofincludedhypnosedativesBenzodiazepines NonbenzodiazepineHypnoticsAlprazolamBromazepamClobazamDiazepamFlunitrazepamLorazepamMidazolamNitrazepamOxazepamTemazepamTriazolam

ZolpidemZopiclone

METHODSTheSearchSearches of Medline and Embase, and the internet were conducted to identify systematic reviews andevidencebasedclinicalpracticeguidelines(seeAppendix1forfurtherdetail).InclusionandexclusioncriteriaSearchresultswerescreenedbytworeviewersaccordingtopredetermined inclusionandexclusioncriteria(seeAppendix1).Forastudytobe included,at leastoneofthehypnosedativeshadtobespecified inthesearchstrategytoensurethatallreferencesaboutthatdrugweresought.Wherean includeddrugwasnotthe focusofthestudy,butresultsofthedrugasacomparatorwerereported,thestudywasexcluded.DataextractionForincludedstudies,thefollowingdatawasextracted Studytype(systematicrevieworevidencebasedguideline) Hypnosedativesexamined Indication Whetherthestudywasaboutbenefits,harmsorboth


The extracted data was tabulated in evidence maps to allow determination of the volume of existingevidence,andidentifythegaps.

RESULTSThesearchreturned1,943results.Afterscreening,atotalof41relevantreferenceswereidentified,whichincluded34SystematicReviews(SRs)and7evidencebasedguidelines(EBGs)(seeFigure1).Figure1.screeningofsearchresultsforinclusion

Studiesidentified 1,943

Titlesand/orabstractsreviewed 1,670 Excluded

Fulltextretrieved 273 Fulltextreviewed 232 Excluded

TOTALINCLUDED 41 TOTALEXCLUDED 1,902

TotalSR 34 TotalEBG 7

Therewere18SRsand5EBGsonhypnosedativesforanxiety;17SRsand2EBGsforinsomnia;and1SRformusclespasm.TherewerenoEBGsonhypnosedativesformusclespasm(Table2).Oneofthestudieswasasystematic reviewofhypnosedatives forall three indications.Allotherguidelinesand systematic reviewswereaboutoneindicationonly.Table2.EvidencemapforeachindicationIndication SystematicReviews EvidenceBasedGuidelines

Anxiety 18 5Insomnia 17 2

Musclespasm 1 0


ThenumberofSRsandEBGsforeachdrugbyindicationarepresentedinTable3andmoredetailedinformationisincludedinTables48.AreferencelistofincludedstudiesispresentedinAppendix2.Table3.Evidencemapforeachdrugbyindication

ANXIETY INSOMNIA MUSCLESPASM TOTAL*DRUG SR EBG SR EBG SR EBG SR EBG

Benzodiazepines** 14 5 10 1 1 0 23 6

Alprazolam 16 2 2 0 1 0 17 2

Bromazepam 10 1 0 0 0 0 10 1

Clobazam 4 0 0 0 0 0 4 0

Diazepam 11 2 5 1 1 0 15 3

Flunitrazepam 2 0 5 0 0 0 7 0

Lorazepam 8 2 5 0 0 0 13 2

Midazolam 2 0 4 0 0 0 6 0

Nitrazepam 2 0 7 1 0 0 9 1

Oxazepam 4 0 2 0 0 0 6 0

Temazepam 2 0 11 2 0 0 13 2

Triazolam 4 0 10 1 1 0 13 1

Zolpidem 0 0 14 2 0 0 14 2

Zopiclone 1 0 8 1 0 0 9 1*totalreferstothetotalnumberofSRsorEBGsforeachdrug,thisfiguremaydifferfromthesumoftherow,asoneSRwasrelevanttoallthreeindications.**papersthatreportedresultsormaderecommendationsaboutbenzodiazepinesasagroup

Hypnosedativesforanxiety,insomniaandmusclespasm7

Table4.Includedsystematicreviewsofhypnosedativesforanxiety

STUDYBlanco2003p427

Blanco2003p29

Busto1998

Cox1992p175

Cox1992p300

Furukawa2001

Gould1997

Hidalgo2007

Inada2003

Ipser2006

Ipser2008

Kaplan2005

Mahe2000

Martin2007

Mitte2005

Robinson2007

Watanabe2009

Wetherell2005

INDICATIONS SAD SAD

anxiety,insomnia,'musclerelaxant' PDA

PDA,OCD,GAD

anxietyassociatedwithmajordepression GAD GAD anxiety

treatmentresistantanxietydisorders SAD

anxietydisorders GAD GAD GAD SAD

panicdisorder

geriatricanxietydisorders

OUTCOMES B&H B H B B B&H B B B B&HB&H B&H B B B B&H B&H B

BENZODIAZEPINESBenzodiazepines* X X X X X X X X X X X X X XAlprazolam X X X X X X X X X X X X X X X XBromazepam X X X X X X X X X XClobazam X X X XDiazepam X X X X X X X X X X XFlunitrazepam X XLorazepam X X X X X X X XMidazolam X XNitrazepam X XOxazepam X X X XTemazepam X XTriazolam X X X XOtherBenzos** X X X X X X X X X X X XNONBENZODIAZEPINEHYPNOTICSZolpidem Zopiclone X Other*** X X

*papersthatreferredtobenzodiazepinesasagroup**Otherbenzodiazepinesincludedinsomeofthesesystematicreviewswere:adinazolam,bentazepam,camazepam,chlordiazepoxide,clonazepam,clorazepate,clotiazepam,cloxazolam,estazolam,flurazepam,flutoprazepam,halazepam,ketazolam,loflazepate,lormetazepam,medazepam,metaclazepam,mexazolam,nordazepam,prazepam,propazepam,quazepam,tofisopam***Theothernonbenzodiazepinehypnoticsincludedinsomeofthesesystematicreviewswas:alpidem

KEY:INDICATIONSGAD:generalizedanxietydisorderOCD:obsessivecompulsivedisorderPDA:panicdisorderwithagoraphobiaSAD:socialanxietydisorder

OUTCOMESB:benefitsH:harmsB&H:bothbenefitsandharms


Table5.IncludedevidencebasedguidelinesofhypnosedativesforanxietySOURCE AACAP2007 Andrews2003

MotorAccidentAuthorityofNSW2003

NICE 2004Author:McIntosh2004

GACendorsedguidelinesAuthor:Swinson2006

TITLE

PracticeParameterfortheAssessmentandTreatmentofChildrenandAdolescentsWithAnxietyDisorders

AustralianandNewZealandclinicalpracticeguidelinesforthetreatmentofPanicdisorderandagoraphobia

Anxietyfollowingmotorvehicleaccidents.AGuidelines&technicalreport

ClinicalGuidelinesfortheManagementofanxiety(panicdisorder,withorwithoutagoraphobia,andgeneralisedanxietydisorder) ManagementofAnxietyDisorders

OUTCOMES Benefits&Harms Benefits&Harms Benefits&Harms Benefits&Harms Benefits&HarmsBENZODIAZEPINESBenzodiazepines* X X X X XAlprazolam X XBromazepam XClobazam Diazepam X XFlunitrazepam Lorazepam X XMidazolam Nitrazepam Oxazepam Temazepam Triazolam OtherBenzos** X XNONBENZODIAZEPINEHYPNOTICSZolpidemZopiclone

*papersthatreferredtobenzodiazepinesasagroup**Otherbenzodiazepinesincludedinsomeofthesesystematicreviewswere:adinazolam,andclonazepam


Table6.Includedsystematicreviewsofhypnosedativesforinsomnia

STUDYBain2006

Buscemi2007

Busto1998

Dundar2004

Glass2005

Grad1995

Hajak2003

Holbrook2000

Holm2000

Joya2009

Krystal2007

Nowell1997

Smith2002

Soldatos1999

SwainstonHarrison2005

VanLiempt2006

Verster2006

INDICATIONSchronicinsom

chronicinsom

anxiety,insom,musclespasm insom insom insom insom insom insom insom insom

chronic,primaryinsom insom insom insom

disordedsleepinPTSD insom

OUTCOMES B&H B&H H B&H B&H B&H H B&H B&H H B B B H B&H B HBENZODIAZEPINESBenzodiazepines* X X X X X X X X X XAlprazolam X XBromazepamClobazamDiazepam X X X X XFlunitrazepam X X X X XLorazepam X X X X XMidazolam X X X XNitrazepam X X X X X X XOxazepam X XTemazepam X X X X X X X X X X XTriazolam X X X X X X X X X XOtherBenzos** X X X X X X X X X X X X XNONBENZODIAZEPINEHYPNOTICSZolpidem X X X X X X X X X X X X X XZopiclone X X X X X X X XOther*** X X X X X X

*papersthatreferredtobenzodiazepinesasagroup**Otherbenzodiazepinesincludedinsomeofthesesystematicreviewswere:chlordiazepoxide,clonazepam,estazolam,flurazepam,loprazolam,lormetazepam,quazepam***Othernonbenzodiazepinehypnoticsincludedinsomeofthesesystematicreviewswere:Eszopiclone,zaleplon

KEY:INDICATIONSInsom:insomniaPTSD:posttraumaticstressdisorder



Table7.IncludedevidencebasedguidelinesofhypnosedativesforinsomniaSOURCE Bloom2009 NICE2004

TITLEEvidenceBasedRecommendationsfortheAssessmentandManagementofSleepdisordersinolderpersons

Guidanceontheuseofzaleplon,zolpidemandzopliconefortheshorttermmanagementofinsomnia.London:NationalInstituteforClinicalExcellence

OUTCOMES Benefits&Harms Benefits&HarmsBENZODIAZEPINESBenzodiazepines* XAlprazolam Bromazepam Clobazam Diazepam XFlunitrazepam Lorazepam Midazolam Nitrazepam XOxazepam Temazepam X XTriazolam X OtherBenzos** X XNONBENZODIAZEPINEHYPNOTICSZolpidem X XZopiclone XOther*** X X

*papersthatreferredtobenzodiazepinesasagroup**Otherbenzodiazepinesincludedinsomeofthesesystematicreviewswere:estazolam,flurazepam,lormetazepam,quazepam***Theothernonbenzodiazepinehypnoticincludedinoneguidelinewas:zaleplon

KEY:INDICATIONSInsom:insomniaPTSD:posttraumaticstressdisorder


ReportNo:0610002R3 Hypnosedativesforanxiety,insomniaandmusclespasm

11

Table8.IncludedsystematicreviewsofhypnosedativesformusclespasmSTUDY Busto1998

INDICATIONS anxiety,insomnia,musclespasmOUTCOMES HarmsBENZODIAZEPINESBenzodiazepines* XAlprazolam XBromazepamClobazamDiazepam XFlunitrazepamLorazepamMidazolamNitrazepamOxazepamTemazepamTriazolam XNONBENZODIAZEPINEHYPNOTICSZolpidemZopiclone

*papersthatreferredtobenzodiazepinesasagroup


DISCUSSIONThebenzodiazepineslistedintheresearchquestionarethoselicensedforuseinAustraliaandlistedinMIMsas either antianxiety agents or sedatives, hypnotics. Many studies identified included various otherbenzodiazepines.StudiesfromtheUKorUSoften includedonlythosebenzodiazepines licensedforuse inthat country. This should be kept in mind when looking at recommendations or reported results ofbenzodiazepines,asthelistofdrugsthatdifferentauthorsarereferringtoarenotlikelytobethesame.TheSRsidentifiedgenerallyfocusedonthedrug/sinquestionforaparticularindication,whereastheEBGsfocused on the indication as a whole, including other material such as diagnosis, prevention and nonpharmacologicalmanagement.Noqualityappraisalhasbeendoneonanyoftheincludedstudies.


DISCLAIMERThe information in this report is a summaryof that availableand isprimarilydesigned to give readers astartingpointtoconsidercurrentlyavailableresearchevidence.Whilstappreciablecarehasbeentaken inthepreparationofthematerialsincludedinthispublication,theauthorsandtheNationalTraumaResearchInstitutedonotwarranttheaccuracyofthisdocumentanddenyanyrepresentation,impliedorexpressed,concerningtheefficacy,appropriatenessorsuitabilityofanytreatmentorproduct.InviewofthepossibilityofhumanerrororadvancesofmedicalknowledgetheauthorsandtheNationalTraumaResearchInstitutecannot anddonotwarrant that the information contained in thesepages is in every aspect accurateorcomplete.Accordingly,theyarenotandwillnotbeheldresponsibleorliableforanyerrorsoromissionsthatmaybefoundinthispublication.Youarethereforeencouragedtoconsultothersourcesinordertoconfirmthe informationcontained inthispublicationand, intheeventthatmedicaltreatment isrequired,totakeprofessionalexpertadvicefromalegallyqualifiedandappropriatelyexperiencedmedicalpractitioner.

CONFLICTOFINTERESTTheTAC/WSVEvidenceService isprovidedby theNationalTraumaResearch Institute.TheNTRIdoesnotacceptfundingfrompharmaceuticalorbiotechnologycompaniesorothercommercialentitieswithpotentialvestedinterestintheoutcomesofsystematicreviews.The TAC/WSV Health Services Group has engaged the NTRI for their objectivity and independence andrecognise thatanymaterialsdevelopedmustbe freeof influence frompartieswithvested interests.TheEvidenceServicehasfulleditorialcontrol.

REFERENCES1. AshtonH.Thediagnosisandmanagementofbenzodiazepinedependence.CurrentOpinioninPsychiatry.2005May;18(3):24955.2. OlsonLG.Hypnotichazards:adverseeffectsofzolpidemandotherzdrugs.AustralianPrescriber.2008;31(6):1469.3. TyrerP,MurphyS.Theplaceofbenzodiazepinesinpsychiatricpractice.BrJPsychiatry.1987Dec;151:71923.4. LiberatiA,AltmanDG,TetzlaffJ,MulrowC,GtzscheP,IoannidisJPA.andthePRISMAGroup.ThePRISMAstatementforreportingsystematicreviewsandmetaanalysesofstudiesthatevaluatehealthcareinterventions:Explanationandelaboration.PLoSMed.2009;6:e1000100.


5. TheAGREECollaboration.TheAGREEInstrument.2010[updated2010;citedMarch2010];Availablefrom:www.agreecollaboration.org.

APPENDIX1:METHODSTAC/WSVstaffassistedinthedevelopmentofsearchtermsandinclusionexclusioncriteria.InclusionandexclusioncriteriaInclusionandexclusioncriteriawereestablishedapriori(TableA1.1)andwereappliedbytworeviewers.Anydiscrepancieswerediscussedandresolved.TableA1.1.InclusionandexclusioncriteriaPatient/population

Inclusion:patientswith: Anxiety(includinganxietydisorders) Insomnia,or MusclespasmAllagesExclusion:Conditionsoccurringinthecontextofcancer,StiffManSyndrome,Athetosis,Alcoholwithdrawal,Tetanus,Statusepilepticus,Allergytreatment(urticaria,pruritis),Spasticityduetouppermotorneuronlesion,Migraine,Dementia,Bipolardisorder,Schizophrenia,Psychosis,Neurodegenerativedisorders,Delirium,Borderlinepersonalitydisorder,Dyspnoea,Detoxificationorwithdrawalfrombenzodiazepineaddiction.Patientsreceivingsedativesforthefollowingpurposes:preoperativemedication,inductionofanaesthesia,sedationinintensivecareunit,asanantiemetic.

Intervention/indicator

Inclusion:Studieswherethefocusisatleastoneofthefollowinghypnosedatives:BenzodiazepinesAlprazolamBromazepamClobazamDiazepamFlunitrazepamLorazepamMidazolamNitrazepamOxazepamTemazepamTriazolamNonbenzodiazepineHypnoticsZolpidemZopicloneExclusion:Studieswheretheincludedhypnosedativeswereonlyreportedonasacomparator

Comparison/control

Inclusion:AnyExclusion:Nil

Outcomes Inclusion:Outcomesrelatedtoresolution orreductionofproblembeingtreated.Outcomes


relatedtotheeffectoftreatmentonfunction(abilitytoconductdailyactivities),QOL,othermedicationuse,returntowork.AdverseeffectsExclusion:studiesonpharmacokinetics

Setting Inclusion:Allhealthcaresettingsnotontheexclusionlist(e.g.acute,primarycare,rehabilitation)Exclusion: Intensivecareunit Nursinghomes Palliativecare

Studydesign Inclusion:EvidencebasedguidelinesorSystematicreviewsExclusion:NonEBGs,nonsystematicreviews,randomisedcontrolledtrials,controlledclinicaltrials,cohortstudies,casecontrolstudies,caseseries,editorials,letters,commentaries.

Publicationdetails Inclusion:StudiesinEnglishandconductedonhumansExclusion:StudiesinlanguagesotherthanEnglishand/orconductedonanimals

Timeperiod Inclusion:AnypublicationdateExclusion:Nil

Forastudytobe included,at leastoneofthehypnosedativeshadtobespecified inthesearchstrategytoensurethatallreferencesaboutthatdrugweresought.Wherean includeddrugwasnotthe focusofthestudy,butresultsofthedrugasacomparatorwerereported,thestudywasexcluded.Reviewswereconsideredsystematic reviews if theymet items4and8on thePRISMAchecklist(4),whichinvolves:astatementoftheobjectivesofthereviewandthetypesofstudiesthatwillbeincluded,andthesearchstrategyinsufficientdetailthatitcouldberepeated.GuidelineswereconsideredtobeEvidenceBasedGuidelinesiftheymetAGREE(5)criteria8and12,whichinvolves: the search strategy in sufficient detail that it could be repeated, and an explicit link betweenrecommendationsandthesupportingevidence.DataextractionDataoncharacteristicsofthestudieswereextractedandsummarisedforevidencemapping.SearchstrategyAhighlysensitivesearch inMedlineandEmbaseasdetailedbelowwasundertakenforallthegenericandAustralianproductdrugnamestobereviewed.Afurtherhighlysensitivefilterforsynthesizedevidencewasappliedandtheresults limitedtothose inEnglish.The largerEmbaseyieldwasfurtherreducedby limitingtheresultstothethreeconditionsunderreview;anxiety,insomniaandmusclespasm.TableA1.2.DatabasesaccessedDatabasename Datescovered Datesearched RefsEmbase 1980to2010Week04 05/02/2010 1,444


Medline 1950toJanuaryWeek32010 05/02/2010 595TOTAL 1,921

TableA1.3.SearchstrategiesusedDatabasename StrategyEmbase ES_Sedatives_Embase_withSRetcfilter

1.expAnxiety/2.(anxietyoranxious).ti,ab.3.or/124.exp"SleepInitiationandMaintenanceDisorders"/5.(insomniaorsleep*).ti,ab.6.or/457.expSpasm/8.((muscularormuscle*)adj5spasm*).ti,ab.9.or/7810.Alprazolam/11.(AlpraxorAlprazolamorKalmaorXanaxorXanaxorZamhexal).ti,ab.12.or/101113.Bromazepam/14.Lexotan.ti,ab.15.or/131416.(ClobazamorFrisium).ti,ab.17.Diazepam/18.(AntenexorDiazepamorDuceneorRanzepamorValiumorValpam).ti,ab.19.or/171820.Flunitrazepam/21.Hypnodorm.ti,ab.22.or/202123.Lorazepam/24.Ativan.ti,ab.25.or/232426.Midazolam/27.Hypnovel.ti,ab.28.or/262729.Nitrazepam/30.(AlodormorMogadon).ti,ab.31.or/293032.Oxazepam/33.(AlepamorMurelaxorSerepax).ti,ab.34.or/323335.Temazepam/36.(TemazepamorNormisonorTemazeorTemtabs).ti,ab.37.or/353638.Triazolam/39.Halcion.ti,ab.40.or/383941.(ZolpidemtartrateorDormizolorSomidemorStildemorStilnoxorZolpibellorZolpidem).ti,ab.42.(ZopicloneorImovaneorImrest).ti,ab.43.or/12,1516,19,22,25,28,31,34,37,404244.hypnosedative*.ti,ab.45.43or4446."review"/orreview.pt.orreview.ti.


47.(systematicorevidence$ormethodol$orquantitativ$oranalys$orassessment$).ti,sh,ab.48.46and4749.MetaAnalysis/50.metaanalysis.mp.51."systematicreview"/52.(metaanaly$ormetanaly$ormetaanaly$ormetaanaly$).mp.53.((systematic$orevidence$ormethodol$orquantitativ$)adj5(review$orsurvey$oroverview$)).ti,ab,sh.54.((pool$orcombinedorcombining)adj2(dataortrialsorstudiesorresults)).ti,ab.55.or/485456.exppracticeguideline/57.(clinicaladj3guideline*).ti,ab.58.or/555759.45and5860.3and5961.6and5962.9and5963.60or61or62Englisharticlesonly

Medline ES_Sedatives_Medline_withSRetcfilter1."review"/orreview.pt.orreview.ti.2.(systematicorevidence$ormethodol$orquantitativ$oranalys$orassessment$).ti,sh,ab.3.1and24.metaanalysis.pt.5.MetaAnalysis/6."systematicreview*".ti,ab.7.(metaanaly$ormetanaly$ormetaanaly$ormetaanaly$).mp.8.((systematic$orevidence$ormethodol$orquantitativ$)adj5(review$orsurvey$oroverview$)).ti,ab,sh.9.((pool$orcombinedorcombining)adj2(dataortrialsorstudiesorresults)).ti,ab.10.practiceguideline/11.(clinicaladj3guideline*).ti,ab.12.or/31113.Alprazolam/14.(AlpraxorAlprazolamorKalmaorXanaxorXanaxorZamhexal).ti,ab.15.or/131416.Bromazepam/17.Lexotan.ti,ab.18.or/161719.(ClobazamorFrisium).ti,ab.20.Diazepam/21.(AntenexorDiazepamorDuceneorRanzepamorValiumorValpam).ti,ab.22.or/202123.Flunitrazepam/24.Hypnodorm.ti,ab.25.or/232426.Lorazepam/27.Ativan.ti,ab.28.or/262729.Midazolam/30.Hypnovel.ti,ab.31.or/2930


32.Nitrazepam/33.(AlodormorMogadon).ti,ab.34.or/323335.Oxazepam/36.(AlepamorMurelaxorSerepax).ti,ab.37.or/353638.Temazepam/39.(TemazepamorNormisonorTemazeorTemtabs).ti,ab.40.or/383941.Triazolam/42.Halcion.ti,ab.43.or/414244.(ZolpidemtartrateorDormizolorSomidemorStildemorStilnoxorZolpibellorZolpidem).ti,ab.45.(ZopicloneorImovaneorImrest).ti,ab.46.or/15,1819,22,25,28,31,34,37,40,434547.hypnosedative*.ti,ab.48.46or4749.12and48Englisharticlesonly

GuidelinesearchesManyclinicalpracticeguidelinesarepublishedas standalonedocumentson the internet,rather thanasarticles inpeerreviewed journals.Additional searchmethodsareneeded to identifyguidelinespublishedoutside the health literature. Guidelines can be found by searching the internet as a whole, searchingrelevantwebsites,andsearchingelectronichealthdatabases.Anevidencebasedguidelineisdifferenttoasystematicreviewinthatasystematicreviewusuallyattemptsto answer one clinical question, whereas a guideline may encompass many clinical questions, and thecorrespondingsystematicreviews.WebsitesearchestoidentifyrelevantevidencebasedguidelinesThe reviewers were aware of websites of guideline clearinghouses, guideline developers, centres ofevidencebased practice, Australian government health services and websites of specific relevance (eg.accidentcompensationgroups)knowntocontainevidencebasedresources.The 17websitespreviously identified by the review team (9 guideline services, 2Australian governmentwebsitesand1centreofevidencebasedpractice,and5otheraccidentcommissionwebsites)weresearchedforrelevantEBGs.DetailsofwebsitessearchedcanbefoundinTableA1.4.Whereaninternalsearchenginewasavailable,websitesweresearchedusingthesearchstringsdetailedinthetablebelow. Ifnosearchenginewasavailable, listsofEBGs,publicationsorotherresources identifiedonthesitewerescannedforrelevantdocuments.InternetsearchestoidentifyrelevantevidencebasedguidelinesandsystematicreviewsThe systematic searchmethodologywouldnormally includea strategywith relevant terms in theGoogleAdvancedSearchfunction.However,theGoogleadvancedsearchscreendidnothavethecapacitytoallowasearchwhichencompassedallthepossiblenamesduetothesizeandcomplexityofthetopic(13drugsfor3 indications).Sample testswithabbreviatednameoptionsdidnot suggest thatanypossibleyieldwouldrepaythetimespentinattemptingthenumeroussearchesthatwouldberequired.


TableA1.4.WebsitessearchedtoidentifyrelevantguidelinesGuidelineServices NationalInstituteofClinicalStudies.ClinicalPracticeGuidelinesPortalhttp://www.clinicalguidelines.gov.au/

Therapeuticguidelinespsychotropicversion6(2008)http://www.clinicalguidelines.gov.au/browse.php?treePath=F.D001520.D004644.D001007&pageType=2&fldglrID=466&TherapeuticguidelinesRespiratoryversion4(2009)http://www.clinicalguidelines.gov.au/search.php?pageType=2&fldglrID=1600&Myhandsshake:Classificationandtreatmentoftremorhttp://www.racgp.org.au/afp/200909/200909sirisena.pdf

Webpagereviewed:GuidelinePortal,Browsebycondition

NationalHealthandMedicalResearchCouncil(NHMRC)www.nhmrc.gov.au AustralianGuidelinesfortheTreatmentofAdultswithAcuteStressDisorderandPosttraumaticStressDisorder

http://www.nhmrc.gov.au/publications/synopses/mh13syn.htm

Webpagereviewed:Guidelines,health

NationalInstituteforHealthandClinicalExcellenceUK(NICE)www.nice.org.uk

Anxiety:managementofanxiety(panicdisorder,withorwithoutagoraphobia,andgeneralisedanxietydisorder)inadultsinprimary,secondaryandcommunitycare.http://guidance.nice.org.uk/CG22

Insomnianewerhypnoticdrugs:Zaleplon,zolpidemand

Webpagereviewed:Ourguidance,healthtopic,MentalhealthandbehaviouralconditionsWebpagereviewed:Ourguidance,healthtopic,Musculoskeletal


zopicloneforthemanagementofinsomniahttp://guidance.nice.org.uk/TA77

NewZealandGuidelineGroup(NZGG)www.nzgg.org.nz

IdentificationofCommonMentalDisordersandManagementofDepressioninPrimaryCarehttp://www.nzgg.org.nz/guidelines/dsp_guideline_popup.cfm?guidelineCatID=8&guidelineID=152

Webpagereviewed:GuidelinesandReports

ScottishIntercollegiateGuidelinesNetwork(SIGN)www.sign.ac.uk

Earlymanagementofpatientswithaheadinjuryhttp://www.sign.ac.uk/guidelines/fulltext/110/index.html

Webpagereviewed:GuidelinesMentalHealthWebpagereviewed:GuidelinesOther

GuidelinesInternationalNetworkwww.gin.net

Australianguidelinesforthetreatmentofadultswithacutestressdisorderandposttraumaticstressdisorder(MH13)http://www.gin.net/membership/members/nhmrcaunationalhealthandmedicalresearch/guidelines/australianguidelinesforthetreatmentofadultsEffectivenessofnasalcontinuouspositiveairwaypressure(nCPAP)inobstructivesleepapnoeainadults(HPR21,HPR22)http://www.gin.net/membership/members/nhmrcaunationalhealthandmedicalresearch/guidelines/effectivenessofnasalcontinuouspositiveairway

Webpagereviewed::InternationalGuidelineLibrary(membersonly)Searchedbykeywords:sedative,sedatives*,anxiety,sleepORinsomnia,muscle,spasm,AlprazolamORbromazepamORclobazamORdiazepamORflunitrazepamORlorazepamORmidazolamORnitrazepamORoxazepamORtemazepamORtriazolamORzolpidemORzopiclone

GuidelinesAdvisoryCommitteewww.gacguidelines.ca

Anxietyhttp://www.gacguidelines.ca/index.cfm?ACT=topics&Summary_ID=233&Topic_ID=24

Webpagereviewed:Listalltopicsandsummaries


NationalGuidelineClearinghouseUS(NGC)(1) searchedon07/02/1013Resultstotal

www.guidelines.gov

Guidelinesforthemanagementofseveretraumaticbraininjury.Anesthetics,analgesics,andsedatives.http://www.guidelines.gov/summary/summary.aspx?doc_id=10999&nbr=005779&string=%28Alprazolam+OR+Bromazepam+OR+Clobazam+OR+Frisium+OR+Diazepam+OR+Flunitrazepam+OR++Lorazepam+OR+Midazolam+OR+Nitrazepam+OR+Oxazepam+OR+Temazepam+OR+Triazolam+OR+Zopiclone+or+Imovane+or+Imrest%29Guidanceontheuseofzaleplon,zolpidemandzopiclonefortheshorttermmanagementofinsomnia.http://www.guidelines.gov/summary/summary.aspx?doc_id=8641&nbr=004814&string=%28Alprazolam+OR+Bromazepam+OR+Clobazam+OR+Frisium+OR+Diazepam+OR+Flunitrazepam+OR++Lorazepam+OR+Midazolam+OR+Nitrazepam+OR+Oxazepam+OR+Temazepam+OR+Triazolam+OR+Zopiclone+or+Imovane+or+Imrest%29

Searchedby:Keyword:(AlprazolamORBromazepamORClobazamORFrisiumORDiazepamORFlunitrazepamORLorazepamORMidazolamORNitrazepamOROxazepamORTemazepamORTriazolamORZopicloneorImovaneorImrest)Disease/Condition:(traumaORspinalORspineORbrainORanxietyORsleepORinsomniaORmuscleORmuscular))

TRIPDatabase(1) searchedon07/02/101,780ResultstotalEvidenceBasedSynopses81SystematicReviews114Guidelines:Aus.&NZ12Canada5

AdultConditionedInsomnia:DiagnosistoManagement(CPDaccess)RecommendationsfortheSafeTransferofPatientswithBrainInjury2006http://www.aagbi.org/publications/guidelines/docs/brain_injury.pdfEvidencebasedtreatmentforthepharmacologicaltreatmentofanxietydisordersNationalLibraryofGuidelines(UK)2006(CPDaccess)

Searchedby:Drugnames


UK58USA8Other4

www.tripdatabase.com

ImplementingandensuringSafeSedationPracticeforhealthcareproceduresinadults.ReportofanIntercollegiateWorkingPartychairedbytheRoyalCollegeofAnaesthetistshttp://www.rcoa.ac.uk/docs/safesedationpractice.pdf

AustralianGovernmentWebsitescontainingGuidelinesAustralianGovernmentDepartmentofHealthandAgeingwww.health.gov.au

Webpagereviewed:HealthProfessionalsTreatments&TechniquesGuidelines

NSWHealthwww.health.nsw.gov.au Webpagereviewed:Publications&ResourcesPolicyDirectivesandGuidelines

CentresofEvidenceBasedPracticeWebsitesWACentreforEvidenceBasedNursingandMidwiferyhttp://wacebnm.curtin.edu.au

Webpagereviewed:ResourcesReports,GuidelinesandArticle

OtherAccidentCommissionsMotorAccidentsAuthorityNSWwww.maa.nsw.gov.au/

http://www.maa.nsw.gov.au/default.aspx?MenuID=170

MAASGuidelines

MASGuidelines

MedicalAssessmentGuidelines1October2008(2.1mb)

MedicalAssessmentGuidelinesMay2006 (77kb)(MSWordversion 929kb)

Webpagereviewed:Publications&ReportsMAAGuidelinesGuidesforProfessionals


CARSGuidelines

ClaimsAssessmentGuidelines1October2008(AmendedOctober12009) (260kb)

ClaimsAssessmentGuidelinesMay2006 (77kb)(MSWordversion 929kb)

InjuryManagementGuidelines

Guidesforprofessionals Guidesforinjuredpeople

AccidentCompensationCorporationwww.acc.co.nz/index.htm

Treatmentprofileshttp://www.acc.co.nz/forproviders/clinicalbestpractice/PRV00053

Webpagereviewed::ForProvidersClinicalBestPracticePublishedClinicalGuidelines

WorkSafeVICwww.workcover.vic.gov.au

Webpagereviewed:Safety&Prevention;HealthandSafetyTopics

WorkCoverNSWwww.workcover.nsw.gov.au

Webpagereviewed:Publications

WorkCoverWAwww.workcover.wa.gov.au

Webpagereviewed:PublicationsPublicationsforhealthproviders


APPENDIX2:INCLUDEDSTUDIESListofincludedsystematicreviews1. BainKT.Managementofchronicinsomniainelderlypersons.AmericanJournalGeriatric

Pharmacotherapy.2006Jun;4(2):16892.2. BlancoC,RazaMS,SchneierFR,LiebowitzMR.Theevidencebasedpharmacologicaltreatment

ofsocialanxietydisorder.InternationalJournalofNeuropsychopharmacology.2003Dec;6(4):42742.

3. BlancoC,SchneierFR,SchmidtA,BlancoJerezCR,MarshallRD,SanchezLacayA,etal.Pharmacologicaltreatmentofsocialanxietydisorder:Ametaanalysis.DepressionandAnxiety.2003;18(1):2940.

4. BuscemiN,VandermeerB,FriesenC,BialyL,TubmanM,OspinaM,etal.Theefficacyandsafetyofdrugtreatmentsforchronicinsomniainadults:AmetaanalysisofRCTs.JournalofGeneralInternalMedicine.2007Sep;22(9):133550.

5. BustoUE,PainT,LanctotKL,EinarsonTR,NaranjoCA.Assessmentoftheriskoftherapeuticdosebenzodiazepinewithdrawalreactionswithmetaanalysis.CanadianJournalofClinicalPharmacology.1998Sep;5(3):1618.

6. CoxBJ,EndlerNS,LeePS,SwinsonRP.Ametaanalysisoftreatmentsforpanicdisorderwithagoraphobia:Imipramine,alprazolam,andinvivoexposure.JournalofBehaviorTherapyandExperimentalPsychiatry.1992;23(3):17582.

7. CoxBJ,SwinsonRP,LeePS.Metaanalysisofanxietydisordertreatmentstudies[7].JournalofClinicalPsychopharmacology.1992;12(4):3001.

8. DundarY,BolandA,StroblJ,DoddS,HaycoxA,BagustA,etal.Newerhypnoticdrugsfortheshorttermmanagementofinsomnia:Asystematicreviewandeconomicevaluation.HealthTechnologyAssessment.2004Jun;8(24):iii68.

9. FurukawaTA,StreinerDL,YoungLT.Antidepressantplusbenzodiazepineformajordepression.CochraneDatabaseofSystematicReviews.2001(2):CD001026.

10. GlassJ,LanctotKL,HerrmannN,SprouleBA,BustoUE.Sedativehypnoticsinolderpeoplewithinsomnia:Metaanalysisofrisksandbenefits.BritishMedicalJournal.200519;331(7526):116973.

11. GouldRA,OttoMW,PollackMH,YapL.Cognitivebehavioralandpharmacologicaltreatmentofgeneralizedanxietydisorder:Apreliminarymetaanalysis.BehaviorTherapy.1997Mar;28(2):285305.


12. GradRM.Benzodiazepinesforinsomniaincommunitydwellingelderly:Areviewofbenefitandrisk.JournalofFamilyPractice.1995;41(5):47381.

13. HajakG,MullerWE,WittchenHU,PittrowD,KirchW.Abuseanddependencepotentialforthenonbenzodiazepinehypnoticszolpidemandzopiclone:Areviewofcasereportsandepidemiologicaldata.Addiction.2003Oct;98(10):13718.

14. HidalgoRB,TuplerLA,DavidsonJRT.Aneffectsizeanalysisofpharmacologictreatmentsforgeneralizedanxietydisorder.JournalofPsychopharmacology.2007Nov;21(8):86472.

15. HolbrookAM,CrowtherR,LotterA,ChengC,KingD.Metaanalysisofbenzodiazepineuseinthetreatmentofinsomnia.CanadianMedicalAssociationJournal.[Review].200025;162(2):22533.

16. HolmKJ,GoaKL.Zolpidem:Anupdateofitspharmacology,therapeuticefficacyandtolerabilityinthetreatmentofinsomia.Drugs.2000;59(4):86589.

17. InadaT,NozakiS,InagakiA,FurukawaTA.Efficacyofdiazepamasanantianxietyagent:Metaanalysisofdoubleblind,randomizedcontrolledtrialscarriedoutinJapan.HumanPsychopharmacology.2003Aug;18(6):4837.

18. IpserJC,CareyP,DhansayY,FakierN,SeedatS,SteinDJ.Pharmacotherapyaugmentationstrategiesintreatmentresistantanxietydisorders.CochraneDatabaseofSystematicReviews.2006;(4)(CD005473).

19. IpserJC,KariukiCM,SteinDJ.Pharmacotherapyforsocialanxietydisorder:Asystematicreview.ExpertReviewofNeurotherapeutics.2008Feb;8(2):23557.

20. JoyaFL,KripkeDF,LovingRT,DawsonA,KlineLE.Metaanalysesofhypnoticsandinfections:eszopiclone,ramelteon,zaleplon,andzolpidem.JournalofClinicalSleepMedicine.2009Aug15;5(4):37783.

21. KaplanEM,DuPontRL.Benzodiazepinesandanxietydisorders:Areviewforthepracticingphysician.CurrentMedicalResearchandOpinion.2005;21(6)(pp941950)(2947).

22. KrystalAD.Treatingthehealth,qualityoflife,andfunctionalimpairmentsininsomnia.JournalofClinicalSleepMedicine.200715;3(1):6372.

23. MaheV,BaloghA.Longtermpharmacologicaltreatmentofgeneralizedanxietydisorder.InternationalClinicalPsychopharmacology.2000;15(2):99105.

24. MartinJLR,SainzPardoM,FurukawaTA,MartinSanchezE,SeoaneT,GalanC.Review:Benzodiazepinesingeneralizedanxietydisorder:Heterogeneityofoutcomesbasedonasystematicreviewandmetaanalysisofclinicaltrials.JournalofPsychopharmacology.2007Sep;21(7):77482.

25. MitteK,NoackP,SteilR,HautzingerM.Ametaanalyticreviewoftheefficacyofdrugtreatmentingeneralizedanxietydisorder.JournalofClinicalPsychopharmacology.2005Apr;25(2):14150.


26. NowellPD,MazumdarS,BuysseDJ,DewMA,ReynoldsICF,KupferDJ.Benzodiazepinesandzolpidemforchronicinsomnia:Ametaanalysisoftreatmentefficacy.JournaloftheAmericanMedicalAssociation.199724;278(24):21707.

27. RobinsonHM,HoodSD.SocialanxietydisorderAreviewofpharmacologicaltreatments.CurrentPsychiatryReviews.2007May;3(2):95122.

28. SmithMT,PerlisML,ParkA,SmithMS,PenningtonJ,GilesDE,etal.Comparativemetaanalysisofpharmacotherapyandbehaviortherapyforpersistentinsomnia.AmericanJournalofPsychiatry.2002Jan;159(1):511.

29. SoldatosCR,DikeosDG,WhiteheadA.Toleranceandreboundinsomniawithrapidlyeliminatedhypnotics:Ametaanalysisofsleeplaboratorystudies.InternationalClinicalPsychopharmacology.1999;14(5):287303.

30. SwainstonHarrisonT,KeatingGM.Zolpidem:areviewofitsuseinthemanagementofinsomnia.CNSDrugs.2005;19(1):6589.

31. VanLiemptS,VermettenE,GeuzeE,WestenbergHGM.Pharmacotherapyfordisorderedsleepinposttraumaticstressdisorder:Asystematicreview.InternationalClinicalPsychopharmacology.2006Jul;21(4):193202.

32. VersterJC,VeldhuijzenDS,PatatA,OlivierB,VolkertsER.Hypnoticsanddrivingsafety:metaanalysesofrandomizedcontrolledtrialsapplyingtheontheroaddrivingtest.CurrDrugSaf.2006Jan;1(1):6371.

33. WatanabeN,ChurchillR,FurukawaTA.Combinedpsychotherapyplusbenzodiazepinesforpanicdisorder.CochraneDatabaseofSystematicReviews.2009;(1)(CD005335).

34. WetherellJL,LenzeEJ,StanleyMA.Evidencebasedtreatmentofgeriatricanxietydisorders.PsychiatricClinicsofNorthAmerica.2005Dec;28(4):87196.

Listofincludedevidencebasedguidelines1. AndrewsG.AustralianandNewZealandclinicalpracticeguidelinesforthetreatmentofpanic

disorderandagoraphobia.AustralianandNewZealandJournalofPsychiatry.2003Dec;37(6):64156.

2. AACAP.Practiceparameterfortheassessmentandtreatmentofchildrenandadolescentswithanxietydisorders.JournaloftheAmericanAcademyofChildandAdolescentPsychiatry.2007Feb;46(2):26783.

3. BloomHG,AhmedI,AlessiCA,AncoliIsraelS,BuysseDJ,KrygerMH,etal.Evidencebasedrecommendationsfortheassessmentandmanagementofsleepdisordersinolderpersons:Supplement.JournaloftheAmericanGeriatricsSociety.2009May;57(5):76189.


4. MAAMACoN.Guidelinesforthemanagementofanxietyfollowingmotorvehicleaccidents.2003.

5. McIntoshACA,TurnbullN,EsmondeL,DennisP,EatockJ,FeetamC,HagueJ,HughesI,KellyJ,KoskyN,LearG,OwensL,RatcliffeJ,SalkovskisPClinicalGuidelinesandEvidenceReviewforPanicDisorderandGeneralisedAnxietyDisorder''.2004.

6. NationalInstituteofHealthandClinicalExcellence.Guidanceontheuseofzaleplon,zolpidemandzopiclonefortheshorttermmanagementofinsomnia:TechnologyAppraisal77.NICE;April2004[updatedApril2004;citedMay2010];Availablefrom:www.nice.org.uk/TA077guidance.

7. SwinsonRP.Clinicalpracticeguidelines:managementofanxietydisorders.Citation:CanJPsychiatry.2006;51(2):1S92S.

Documents

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