TransportAccidentCommission&WorkSafeVictoria

EvidenceService

Hypnosedativesforanxiety,insomniaand
musclespasm
EvidenceMap
May2010
EmmaDonoghue,DrissAitOuakrim

Report No: 0610002R3

EXECUTIVESUMMARY

Theaimofthisworkistoprovideanevidencemapoftheexistinghighlevelstudies(systematicreviewsand
evidencebasedguidelines)onthebenefitsandharmsofhypnosedativesforanxiety,insomniaandmuscle
spasm.
Thedrugsincludedunderthetitleofhypnosedativeswere:
benzodiazepines:alprazolam,bromazepam,clobazam,diazepam,flunitrazepam,lorazepam,midazolam,
nitrazepam,oxazepam,temazepam,triazolam
nonbenzodiazpinehypnotics:zolpidem,zopiclone

Searches of Medline and Embase, and the internet yielded 1,943 potentially relevant studies. Screening
againstinclusionandexclusioncriteriaresultedinatotalof41relevantstudies(34systematicreviews[SRs]
and7evidencebasedguidelines[EBGs]).
Thenumbersofstudiesidentifiedforeachindicationwereasfollows:
Anxiety:
18SRs,5EBGs
Insomnia:
17SRs,2EBGs
MuscleSpasm:1SR,0EBGs
OneSRwasabouttheuseofhypnosedativesforallthreeindications.AllotherEBGsandSRswereaboutone
indicationonly.

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Hypnosedatives for anxiety, insomnia and muscle spasm 2

BACKGROUND

Sedativesareaclassofpsychoactivedrugscommonlyprescribedastreatmentforsleepdisorders,anxiety
and a variety of related conditions. In order to develop and update policies for their use in patients with
these conditions, the Health Services Group of the Transport Accident Commission and WorkSafe Victoria
(TAC/WSV)requesteda mapoftheavailablehigh levelevidenceexamining the benefits andharmsofthe
useofsedativesinanxiety,insomniaandmusclespasm.
The term hypnosedatives refers to benzodiazepines, benzodiazepine derivatives, and a group of non
benzodiazepinehypnoticdrugs(referredtoasZdrugs),thatincludeszolpidemandzopiclone.
Benzodiazepines have been widely used in clinical practice since their introduction in the 1950s and
continue to be one of the most consumed and highly prescribed class of drugs available. Their range of
actionsedative/hypnotic,anxiolytic,anticonvulsantandmusclerelaxantcombinedwithlowtoxicityand
costgainedthempopularityamongphysiciansandpatients.(1)
The Zdrugs are hypnotics with similar pharmacology to benzodiazepines. They have been promoted as
being safer than benzodiazepines and in many countries they are the most widely prescribed drugs for
insomnia.(2)
Sincetheearly1980sstudieshaveregularlypointedouttherisksandadverseeffectsrelatedtolongterm
useofbenzodiazepinesandotherhypnotics.(3)Theaimofthisworkistoprovideanevidencemapofthe
existinghighlevelstudies(systematicreviewsandevidencebasedguidelines)onthebenefitsandharmsof
hypnosedativesforanxiety,insomniaandmusclespasm.

THEQUESTION

Theresearchquestionsinitiallyposedwere:

Inwhatconditionsaresedatives(benzodiazepineandnonbenzodiazepine)indicated?

Whatistheeffectivenessofsedativesintheseconditions?

Whatistheeffectofsedativesonfunction,qualityoflife,returntowork,othermedicationuse?

Inwhatconditions/patienttypesshouldsedativesnotbeused,usedshorttermonlyorusedwith
caution?

Whatrisksareassociatedwiththeuseofsedatives?

Thereisnowelldefined,universallyaccepteddefinitionofwhatasedativeis,noradefinitivelistofdrugs
thatareconsideredsedatives.Drugsthatpeoplemightrefertoassedativescanfallundermanydifferent
drugclassessuchassedatives,hypnotics,antianxietyagents,orcomplementarymedicines,depending
ontheorganizationclassifyingthedrugs.Suchabroadlistofdrugs,combinedwithopenscopeonconditions
forwhichtheyareindicatedmeantthattheresearchquestionsinitiallyposedwouldbeunfeasible.
Afterfurtherdiscussion,thescopeofthequestionwasnarrowedfromsedativestohypnosedatives,which
comprises benzodiazepines and selected nonbenzodiazepine hypnotic agents. The drugs chosen were the
Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 3


benzodiazepines listed in MIMS as either antianxiety agents or sedatives, hypnotics, and two non
benzodiazepinehypnotics:zolpidemandzopiclone(seeTable1).
Thequestionwasfurtherrefinedtoincludethreespecificindications:

Whatistheeffectivenessofhypnosedativesinanxiety?

Whatistheeffectivenessofhypnosedativesininsomnia?

Whatistheeffectivenessofhypnosedativesinmusclespasm?

Whataretherisksassociatedwithhypnosedativeuseintheseconditions?

Table1.Listofincludedhypnosedatives

Benzodiazepines

NonbenzodiazepineHypnotics

Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam

Zolpidem
Zopiclone

METHODS
TheSearch
Searches of Medline and Embase, and the internet were conducted to identify systematic reviews and
evidencebasedclinicalpracticeguidelines(seeAppendix1forfurtherdetail).

Inclusionandexclusioncriteria
Searchresultswerescreenedbytworeviewersaccordingtopredeterminedinclusionandexclusioncriteria
(seeAppendix1).
Forastudytobeincluded,atleastoneofthehypnosedativeshadtobespecifiedinthesearchstrategyto
ensurethatallreferences aboutthatdrugweresought.Whereanincludeddrugwasnotthefocusofthe
study,butresultsofthedrugasacomparatorwerereported,thestudywasexcluded.

Dataextraction
Forincludedstudies,thefollowingdatawasextracted

Studytype(systematicrevieworevidencebasedguideline)
Hypnosedativesexamined
Indication
Whetherthestudywasaboutbenefits,harmsorboth

Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 4

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

RESULTS

Thesearchreturned1,943results.Afterscreening,atotalof41relevantreferenceswereidentified,which
included34SystematicReviews(SRs)and7evidencebasedguidelines(EBGs)(seeFigure1).
Figure1.screeningofsearchresultsforinclusion

Studiesidentified
1,943

Fulltextretrieved

TOTALINCLUDED
TotalSR
TotalEBG

Titlesand/orabstractsreviewed

273

1,670

Excluded

232

Excluded

Fulltextreviewed

41
34
7

1,902

TOTALEXCLUDED

Therewere18SRsand5EBGsonhypnosedativesforanxiety;17SRsand2EBGsforinsomnia;and1SRfor
musclespasm.TherewerenoEBGsonhypnosedativesformusclespasm(Table2).Oneofthestudieswasa
systematic review of hypnosedatives for all three indications. All other guidelines and systematic reviews
wereaboutoneindicationonly.

Table2.Evidencemapforeachindication

Indication
Anxiety

SystematicReviews
18

EvidenceBasedGuidelines
5

Insomnia

17

Musclespasm

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Hypnosedatives for anxiety, insomnia and muscle spasm 5


ThenumberofSRsandEBGsforeachdrugbyindicationarepresentedinTable3andmoredetailed
informationisincludedinTables48.AreferencelistofincludedstudiesispresentedinAppendix2.

Table3.Evidencemapforeachdrugbyindication

DRUG

SR

Benzodiazepines**
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
Zolpidem
Zopiclone

ANXIETY
EBG

INSOMNIA
SR
EBG

MUSCLESPASM
SR
EBG

SR

TOTAL*
EBG

14

10

23

16

17

10

10

11

15

13

11

13

10

13

14

14

*totalreferstothetotalnumberofSRsorEBGsforeachdrug,thisfiguremaydifferfromthesumoftherow,asoneSRwas
relevanttoallthreeindications.
**papersthatreportedresultsormaderecommendationsaboutbenzodiazepinesasagroup

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Hypnosedatives for anxiety, insomnia and muscle spasm 6


Table4.Includedsystematicreviewsofhypnosedativesforanxiety
STUDY

INDICATIONS

Blanco
2003
p427

SAD

OUTCOMES

Blanco
2003
p29

SAD

B&H

Busto
1998
anxiety,
insomnia,
'muscle
relaxant'

Cox
1992
p175

Cox
1992
p300

PDA

PDA,OCD,
GAD

Furukawa
2001
anxiety
associated
withmajor
depression

B&H

Gould
1997

GAD

Hidalgo
2007

GAD

Inada
2003

anxiety

Ipser
2006
treatment
resistant
anxiety
disorders

B&H

Ipser
2008

Kaplan
2005

SAD

anxiety
disorders

GAD

B&H

B&
H

Mahe
2000

Martin
2007

GAD

Mitte
2005

GAD

Robinson
2007

Watanabe
2009

Wetherell
2005

SAD

panic
disorder

geriatric
anxiety
disorders

B&H

B&H

BENZODIAZEPINES
Benzodiazepines*

Alprazolam

Bromazepam

Diazepam

Flunitrazepam

Lorazepam

Midazolam

Nitrazepam

Oxazepam

X
X
X
X
X
X

Temazepam

Triazolam
OtherBenzos**

Clobazam

NONBENZODIAZEPINEHYPNOTICS
Zolpidem

Zopiclone

Other***

*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:
INDICATIONS
OUTCOMES
GAD:generalizedanxietydisorder
B:benefits
OCD:obsessivecompulsivedisorder
H:harms
PDA:panicdisorderwithagoraphobia
B&H:bothbenefitsandharms
SAD:socialanxietydisorder

Hypnosedatives for anxiety, insomnia and muscle spasm 7


Table5.Includedevidencebasedguidelinesofhypnosedativesforanxiety
SOURCE

AACAP2007

Andrews2003

MotorAccidentAuthorityofNSW
2003

TITLE
OUTCOMES

PracticeParameterforthe
AssessmentandTreatmentof
ChildrenandAdolescentsWith
AnxietyDisorders
Benefits&Harms

AustralianandNewZealandclinical
practiceguidelinesforthetreatment
ofPanicdisorder
andagoraphobia
Benefits&Harms

Anxietyfollowingmotorvehicle
accidents.AGuidelines&technical
report
Benefits&Harms

NICE 2004
Author:McIntosh2004
ClinicalGuidelinesforthe
Management
ofanxiety(panicdisorder,withor
withoutagoraphobia,
andgeneralisedanxietydisorder)
Benefits&Harms

GACendorsedguidelines
Author:Swinson2006

ManagementofAnxietyDisorders
Benefits&Harms

BENZODIAZEPINES
Benzodiazepines*

Alprazolam

Bromazepam

Clobazam

Diazepam

Flunitrazepam

Lorazepam

Midazolam

Nitrazepam

Oxazepam

Temazepam

Triazolam

OtherBenzos**

NONBENZODIAZEPINEHYPNOTICS
Zolpidem
Zopiclone
*papersthatreferredtobenzodiazepinesasagroup
**Otherbenzodiazepinesincludedinsomeofthesesystematicreviewswere:adinazolam,andclonazepam

Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 8

Table6.Includedsystematicreviewsofhypnosedativesforinsomnia
STUDY

INDICATIONS
OUTCOMES

Bain
2006

Buscemi
2007

chronic
insom

chronic
insom

Busto
1998
anxiety,
insom,
muscle
spasm

Dundar
2004

insom

Glass
2005

Grad
1995

insom

insom

B&H

B&H

B&H

B&H

B&H

Hajak
2003

insom

Holbrook
2000

insom

B&H

Holm
2000

insom

B&H

Joya
2009

insom

Krystal
2007

Nowell
1997

insom

chronic,
primary
insom

Smith
2002

insom

Soldatos
1999

insom

Swainston
Harrison
2005

Van
Liempt
2006

Verster
2006

insom

disorded
sleepin
PTSD

insom

B&H

BENZODIAZEPINES
Benzodiazepines*

Alprazolam

Bromazepam
Clobazam

Diazepam

Flunitrazepam

Lorazepam

Temazepam

Triazolam

OtherBenzos**

Nitrazepam

X
X

Midazolam

X
X
X

X
X

X
X

Oxazepam

X
X

NONBENZODIAZEPINEHYPNOTICS
Zolpidem

Zopiclone

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

KEY:
INDICATIONS
Insom:insomnia
PTSD:posttraumaticstressdisorder

OUTCOMES
B:benefits
H:harms
B&H:bothbenefitsandharms

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Hypnosedatives for anxiety, insomnia and muscle spasm 9

Table7.Includedevidencebasedguidelinesofhypnosedativesforinsomnia
SOURCE

Bloom2009

TITLE
OUTCOMES

EvidenceBasedRecommendationsforthe
AssessmentandManagementofSleepdisorders
inolderpersons
Benefits&Harms

NICE2004
Guidanceontheuseofzaleplon,zolpidemand
zopliconefortheshorttermmanagementof
insomnia.London:NationalInstituteforClinical
Excellence
Benefits&Harms

BENZODIAZEPINES
Benzodiazepines*

Alprazolam

Bromazepam

Clobazam

Diazepam

Flunitrazepam

Lorazepam

Midazolam

Nitrazepam

Oxazepam

Temazepam

Triazolam

OtherBenzos**

NONBENZODIAZEPINEHYPNOTICS
Zolpidem
Zopiclone

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

KEY:
INDICATIONS
Insom:insomnia
PTSD:posttraumaticstressdisorder

OUTCOMES
B:benefits
H:harms
B&H:bothbenefitsandharms

Hypnosedatives for anxiety, insomnia and muscle spasm 10


Table8.Includedsystematicreviewsofhypnosedativesformusclespasm
STUDY

Busto1998

INDICATIONS
OUTCOMES

anxiety,insomnia,musclespasm
Harms

BENZODIAZEPINES
Benzodiazepines*

Alprazolam

Bromazepam
Clobazam
Diazepam

Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam

NONBENZODIAZEPINEHYPNOTICS
Zolpidem
Zopiclone
*papersthatreferredtobenzodiazepinesasagroup

Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm

11

DISCUSSION

ThebenzodiazepineslistedintheresearchquestionarethoselicensedforuseinAustraliaandlistedinMIMs
as either antianxiety agents or sedatives, hypnotics. Many studies identified included various other
benzodiazepines.StudiesfromtheUKorUSoftenincludedonlythosebenzodiazepineslicensedforusein
that country. This should be kept in mind when looking at recommendations or reported results of
benzodiazepines,asthelistofdrugsthatdifferentauthorsarereferringtoarenotlikelytobethesame.
TheSRsidentifiedgenerallyfocusedonthedrug/sinquestionforaparticularindication,whereastheEBGs
focused on the indication as a whole, including other material such as diagnosis, prevention and non
pharmacologicalmanagement.
Noqualityappraisalhasbeendoneonanyoftheincludedstudies.

Hypnosedatives for anxiety, insomnia and muscle spasm 12

DISCLAIMER

The information in this report is a summary of that available and is primarily designed to give readers a
startingpointtoconsidercurrentlyavailableresearchevidence.Whilstappreciablecarehasbeentakenin
thepreparationofthematerialsincludedinthispublication,theauthorsandtheNationalTraumaResearch
Institutedonotwarranttheaccuracyofthisdocumentanddenyanyrepresentation,impliedorexpressed,
concerningtheefficacy,appropriatenessorsuitabilityofanytreatmentorproduct.Inviewofthepossibility
ofhumanerrororadvancesofmedicalknowledgetheauthorsandtheNationalTraumaResearchInstitute
cannot and do not warrant that the information contained in these pages is in every aspect accurate or
complete.Accordingly,theyarenotandwillnotbeheldresponsibleorliableforanyerrorsoromissionsthat
maybefoundinthispublication.Youarethereforeencouragedtoconsultothersourcesinordertoconfirm
theinformationcontainedinthispublicationand,intheeventthatmedicaltreatmentisrequired,totake
professionalexpertadvicefromalegallyqualifiedandappropriatelyexperiencedmedicalpractitioner.

CONFLICTOFINTEREST

The TAC/WSV Evidence Service is provided by the National Trauma Research Institute. The NTRI does not
acceptfundingfrompharmaceuticalorbiotechnologycompaniesorothercommercialentitieswithpotential
vestedinterestintheoutcomesofsystematicreviews.
The TAC/WSV Health Services Group has engaged the NTRI for their objectivity and independence and
recognise that any materials developed must be free of influence from parties with vested interests. The
EvidenceServicehasfulleditorialcontrol.

REFERENCES

1.
AshtonH.Thediagnosisandmanagementofbenzodiazepinedependence.CurrentOpinionin
Psychiatry.2005May;18(3):24955.
2.
OlsonLG.Hypnotichazards:adverseeffectsofzolpidemandotherzdrugs.AustralianPrescriber.
2008;31(6):1469.
3.
TyrerP,MurphyS.Theplaceofbenzodiazepinesinpsychiatricpractice.BrJPsychiatry.1987
Dec;151:71923.
4.
LiberatiA,AltmanDG,TetzlaffJ,MulrowC,GtzscheP,IoannidisJPA.andthePRISMAGroup.The
PRISMAstatementforreportingsystematicreviewsandmetaanalysesofstudiesthatevaluatehealthcare
interventions:Explanationandelaboration.PLoSMed.2009;6:e1000100.

Hypnosedatives for anxiety, insomnia and muscle spasm 13

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

APPENDIX1:METHODS
TAC/WSVstaffassistedinthedevelopmentofsearchtermsandinclusionexclusioncriteria.

Inclusionandexclusioncriteria
Inclusionandexclusioncriteriawereestablishedapriori(TableA1.1)andwereappliedbytworeviewers.
Anydiscrepancieswerediscussedandresolved.

TableA1.1.Inclusionandexclusioncriteria
Inclusion:patientswith:
Patient/
population
Anxiety(includinganxietydisorders)
Insomnia,or
Musclespasm
Allages
Exclusion:Conditionsoccurringinthecontextofcancer,StiffManSyndrome,Athetosis,Alcohol
withdrawal,Tetanus,Statusepilepticus,Allergytreatment(urticaria,pruritis),Spasticitydueto
uppermotorneuronlesion,Migraine,Dementia,Bipolardisorder,Schizophrenia,Psychosis,
Neurodegenerativedisorders,Delirium,Borderlinepersonalitydisorder,Dyspnoea,Detoxification
orwithdrawalfrombenzodiazepineaddiction.Patientsreceivingsedativesforthefollowing
purposes:preoperativemedication,inductionofanaesthesia,sedationinintensivecareunit,as
anantiemetic.
Intervention/
indicator

Inclusion:Studieswherethefocusisatleastoneofthefollowinghypnosedatives:
Benzodiazepines
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
NonbenzodiazepineHypnotics
Zolpidem
Zopiclone
Exclusion:Studieswheretheincludedhypnosedativeswereonlyreportedonasacomparator

Comparison/
control

Inclusion:Any
Exclusion:Nil

Outcomes

Inclusion:Outcomesrelatedtoresolution orreductionofproblembeingtreated.Outcomes

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Hypnosedatives for anxiety, insomnia and muscle spasm 14


relatedtotheeffectoftreatmentonfunction(abilitytoconductdailyactivities),QOL,other
medicationuse,returntowork.Adverseeffects
Exclusion:studiesonpharmacokinetics
Setting

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

Studydesign

Inclusion:EvidencebasedguidelinesorSystematicreviews
Exclusion:NonEBGs,nonsystematicreviews,randomisedcontrolledtrials,controlledclinical
trials,cohortstudies,casecontrolstudies,caseseries,editorials,letters,commentaries.

Publicationdetails

Inclusion:StudiesinEnglishandconductedonhumans
Exclusion:StudiesinlanguagesotherthanEnglishand/orconductedonanimals

Timeperiod

Inclusion:Anypublicationdate
Exclusion:Nil

Forastudytobeincluded,atleastoneofthehypnosedativeshadtobespecifiedinthesearchstrategyto
ensurethatallreferences aboutthatdrugweresought.Whereanincludeddrugwasnotthefocusofthe
study,butresultsofthedrugasacomparatorwerereported,thestudywasexcluded.
Reviews were considered systematic reviews if they met items 4 and 8 on the PRISMA checklist(4), which
involves:astatementoftheobjectivesofthereviewandthetypesofstudiesthatwillbeincluded,andthe
searchstrategyinsufficientdetailthatitcouldberepeated.
GuidelineswereconsideredtobeEvidenceBasedGuidelinesiftheymetAGREE(5)criteria8and12,which
involves: the search strategy in sufficient detail that it could be repeated, and an explicit link between
recommendationsandthesupportingevidence.

Dataextraction
Dataoncharacteristicsofthestudieswereextractedandsummarisedforevidencemapping.

Searchstrategy
AhighlysensitivesearchinMedlineandEmbaseasdetailedbelowwasundertakenforallthegenericand
Australianproductdrugnamestobereviewed.Afurtherhighlysensitivefilterforsynthesizedevidencewas
appliedandtheresultslimitedtothoseinEnglish.ThelargerEmbaseyieldwasfurtherreducedbylimiting
theresultstothethreeconditionsunderreview;anxiety,insomniaandmusclespasm.
TableA1.2.Databasesaccessed
Databasename
Datescovered

Datesearched

Refs

Embase

05/02/2010

1,444

1980to2010Week04

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Hypnosedatives for anxiety, insomnia and muscle spasm 15


Medline

1950toJanuaryWeek32010

TOTAL

05/02/2010

595
1,921

TableA1.3.Searchstrategiesused
Databasename
Strategy
Embase

ES_Sedatives_Embase_withSRetcfilter

1.expAnxiety/
2.(anxietyoranxious).ti,ab.
3.or/12
4.exp"SleepInitiationandMaintenanceDisorders"/
5.(insomniaorsleep*).ti,ab.
6.or/45
7.expSpasm/
8.((muscularormuscle*)adj5spasm*).ti,ab.
9.or/78
10.Alprazolam/
11.(AlpraxorAlprazolamorKalmaorXanaxorXanaxorZamhexal).ti,ab.
12.or/1011
13.Bromazepam/
14.Lexotan.ti,ab.
15.or/1314
16.(ClobazamorFrisium).ti,ab.
17.Diazepam/
18.(AntenexorDiazepamorDuceneorRanzepamorValiumorValpam).ti,ab.
19.or/1718
20.Flunitrazepam/
21.Hypnodorm.ti,ab.
22.or/2021
23.Lorazepam/
24.Ativan.ti,ab.
25.or/2324
26.Midazolam/
27.Hypnovel.ti,ab.
28.or/2627
29.Nitrazepam/
30.(AlodormorMogadon).ti,ab.
31.or/2930
32.Oxazepam/
33.(AlepamorMurelaxorSerepax).ti,ab.
34.or/3233
35.Temazepam/
36.(TemazepamorNormisonorTemazeorTemtabs).ti,ab.
37.or/3536
38.Triazolam/
39.Halcion.ti,ab.
40.or/3839
41.(ZolpidemtartrateorDormizolorSomidemorStildemorStilnoxorZolpibell
orZolpidem).ti,ab.
42.(ZopicloneorImovaneorImrest).ti,ab.
43.or/12,1516,19,22,25,28,31,34,37,4042
44.hypnosedative*.ti,ab.
45.43or44
46."review"/orreview.pt.orreview.ti.
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Hypnosedatives for anxiety, insomnia and muscle spasm 16


47.(systematicorevidence$ormethodol$orquantitativ$oranalys$or
assessment$).ti,sh,ab.
48.46and47
49.MetaAnalysis/
50.metaanalysis.mp.
51."systematicreview"/
52.(metaanaly$ormetanaly$ormetaanaly$ormetaanaly$).mp.
53.((systematic$orevidence$ormethodol$orquantitativ$)adj5(review$or
survey$oroverview$)).ti,ab,sh.
54.((pool$orcombinedorcombining)adj2(dataortrialsorstudiesor
results)).ti,ab.
55.or/4854
56.exppracticeguideline/
57.(clinicaladj3guideline*).ti,ab.
58.or/5557
59.45and58
60.3and59
61.6and59
62.9and59
63.60or61or62
Englisharticlesonly
Medline

ES_Sedatives_Medline_withSRetcfilter

1."review"/orreview.pt.orreview.ti.
2.(systematicorevidence$ormethodol$orquantitativ$oranalys$or
assessment$).ti,sh,ab.
3.1and2
4.metaanalysis.pt.
5.MetaAnalysis/
6."systematicreview*".ti,ab.
7.(metaanaly$ormetanaly$ormetaanaly$ormetaanaly$).mp.
8.((systematic$orevidence$ormethodol$orquantitativ$)adj5(review$or
survey$oroverview$)).ti,ab,sh.
9.((pool$orcombinedorcombining)adj2(dataortrialsorstudiesor
results)).ti,ab.
10.practiceguideline/
11.(clinicaladj3guideline*).ti,ab.
12.or/311
13.Alprazolam/
14.(AlpraxorAlprazolamorKalmaorXanaxorXanaxorZamhexal).ti,ab.
15.or/1314
16.Bromazepam/
17.Lexotan.ti,ab.
18.or/1617
19.(ClobazamorFrisium).ti,ab.
20.Diazepam/
21.(AntenexorDiazepamorDuceneorRanzepamorValiumorValpam).ti,ab.
22.or/2021
23.Flunitrazepam/
24.Hypnodorm.ti,ab.
25.or/2324
26.Lorazepam/
27.Ativan.ti,ab.
28.or/2627
29.Midazolam/
30.Hypnovel.ti,ab.
31.or/2930

Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 17


32.Nitrazepam/
33.(AlodormorMogadon).ti,ab.
34.or/3233
35.Oxazepam/
36.(AlepamorMurelaxorSerepax).ti,ab.
37.or/3536
38.Temazepam/
39.(TemazepamorNormisonorTemazeorTemtabs).ti,ab.
40.or/3839
41.Triazolam/
42.Halcion.ti,ab.
43.or/4142
44.(ZolpidemtartrateorDormizolorSomidemorStildemorStilnoxorZolpibell
orZolpidem).ti,ab.
45.(ZopicloneorImovaneorImrest).ti,ab.
46.or/15,1819,22,25,28,31,34,37,40,4345
47.hypnosedative*.ti,ab.
48.46or47
49.12and48
Englisharticlesonly

Guidelinesearches
Many clinical practice guidelines are published as stand alone documents on the internet, rather than as
articles in peerreviewed journals. Additional search methods are needed to identify guidelines published
outside the health literature. Guidelines can be found by searching the internet as a whole, searching
relevantwebsites,andsearchingelectronichealthdatabases.
Anevidencebasedguidelineisdifferenttoasystematicreviewinthatasystematicreviewusuallyattempts
to answer one clinical question, whereas a guideline may encompass many clinical questions, and the
correspondingsystematicreviews.

Websitesearchestoidentifyrelevantevidencebasedguidelines
The reviewers were aware of websites of guideline clearinghouses, guideline developers, centres of
evidencebased practice, Australian government health services and websites of specific relevance (eg.
accidentcompensationgroups)knowntocontainevidencebasedresources.
The 17 websites previously identified by the review team (9 guideline services, 2 Australian government
websitesand1centreofevidencebasedpractice,and5otheraccidentcommissionwebsites)weresearched
forrelevantEBGs.DetailsofwebsitessearchedcanbefoundinTableA1.4.
Whereaninternalsearchenginewasavailable,websitesweresearchedusingthesearchstringsdetailedin
thetablebelow.Ifnosearchenginewasavailable,listsofEBGs,publicationsorotherresourcesidentified
onthesitewerescannedforrelevantdocuments.

Internetsearchestoidentifyrelevantevidencebasedguidelinesandsystematicreviews
The systematic search methodology would normally include a strategy with relevant terms in the Google
AdvancedSearchfunction.However,theGoogleadvancedsearchscreendidnothavethecapacitytoallow
asearchwhichencompassedallthepossiblenamesduetothesizeandcomplexityofthetopic(13drugsfor
3 indications). Sample tests with abbreviated name options did not suggest that any possible yield would
repaythetimespentinattemptingthenumeroussearchesthatwouldberequired.
Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 18

Report No: 0610002R3

Hypnosedatives for anxiety, insomnia and muscle spasm 19

TableA1.4.Websitessearchedtoidentifyrelevantguidelines
GuidelineServices

NationalInstituteofClinicalStudies.Clinical
PracticeGuidelinesPortal

Therapeuticguidelinespsychotropicversion6(2008)

http://www.clinicalguidelines.gov.au/

http://www.clinicalguidelines.gov.au/browse.php?treePath=F.
D001520.D004644.D001007&pageType=2&fldglrID=466&

TherapeuticguidelinesRespiratoryversion4(2009)

Webpagereviewed:GuidelinePortal,Browseby
condition

http://www.clinicalguidelines.gov.au/search.php?pageType=2
&fldglrID=1600&
Myhandsshake:Classificationandtreatmentoftremor
http://www.racgp.org.au/afp/200909/200909sirisena.pdf
NationalHealthandMedicalResearchCouncil
(NHMRC)www.nhmrc.gov.au

Webpagereviewed:Guidelines,health
AustralianGuidelinesfortheTreatmentofAdultswithAcute
StressDisorderandPosttraumaticStressDisorder

http://www.nhmrc.gov.au/publications/synopses/mh13syn.ht
m

NationalInstituteforHealthandClinical
ExcellenceUK(NICE)
www.nice.org.uk

Anxiety:managementofanxiety(panicdisorder,withor
withoutagoraphobia,andgeneralisedanxietydisorder)in
adultsinprimary,secondaryandcommunitycare.
http://guidance.nice.org.uk/CG22

Webpagereviewed:Ourguidance,healthtopic,
Mentalhealthandbehaviouralconditions

Webpagereviewed:Ourguidance,healthtopic,
Musculoskeletal

Insomnianewerhypnoticdrugs:Zaleplon,zolpidemand
Hypnosedatives for anxiety, insomnia and muscle spasm 20


zopicloneforthemanagementofinsomnia
http://guidance.nice.org.uk/TA77
NewZealandGuidelineGroup(NZGG)
www.nzgg.org.nz

ScottishIntercollegiateGuidelinesNetwork(SIGN)
www.sign.ac.uk

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

Webpagereviewed:GuidelinesandReports

Earlymanagementofpatientswithaheadinjury

Webpagereviewed:GuidelinesMentalHealth

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

Webpagereviewed:GuidelinesOther

Australianguidelinesforthetreatmentofadultswithacute
stressdisorderandposttraumaticstressdisorder(MH13)
http://www.gin.net/membership/members/nhmrcau
nationalhealthandmedicalresearch/guidelines/australian
guidelinesforthetreatmentofadults

GuidelinesInternationalNetworkwww.gin.net

Effectivenessofnasalcontinuouspositiveairwaypressure
(nCPAP)inobstructivesleepapnoeainadults(HPR21,HPR22)
http://www.gin.net/membership/members/nhmrcau
nationalhealthandmedical
research/guidelines/effectivenessofnasalcontinuous
positiveairway

Webpagereviewed::InternationalGuidelineLibrary
(membersonly)
Searchedbykeywords:sedative,sedatives*,anxiety,
sleepORinsomnia,muscle,spasm,AlprazolamOR
bromazepamORclobazamORdiazepamOR
flunitrazepamORlorazepamORmidazolamOR
nitrazepamORoxazepamORtemazepamORtriazolam
ORzolpidemORzopiclone

GuidelinesAdvisoryCommittee
www.gacguidelines.ca

Anxiety
http://www.gacguidelines.ca/index.cfm?ACT=topics&Summary
_ID=233&Topic_ID=24

Webpagereviewed:Listalltopicsandsummaries

Hypnosedatives for anxiety, insomnia and muscle spasm 21

NationalGuidelineClearinghouseUS(NGC)
(1) searchedon07/02/1013Resultstotal
www.guidelines.gov

Guidelinesforthemanagementofseveretraumaticbrain
injury.Anesthetics,analgesics,andsedatives.
http://www.guidelines.gov/summary/summary.aspx?doc_id=1
0999&nbr=005779&string=%28Alprazolam+OR+Bromazepam+
OR+Clobazam+OR+Frisium+OR+Diazepam+OR+Flunitrazepam+
OR++Lorazepam+OR+Midazolam+OR+Nitrazepam+OR+Oxazep
am+OR+Temazepam+OR+Triazolam+OR+Zopiclone+or+Imovan
e+or+Imrest%29

Searchedby:
Keyword:(AlprazolamORBromazepamORClobazam
ORFrisiumORDiazepamORFlunitrazepamOR
LorazepamORMidazolamORNitrazepamOR
OxazepamORTemazepamORTriazolamORZopiclone
orImovaneorImrest)
Disease/Condition:(traumaORspinalORspineOR
brainORanxietyORsleepORinsomniaORmuscleOR
muscular))

Guidanceontheuseofzaleplon,zolpidemandzopiclonefor
theshorttermmanagementofinsomnia.
http://www.guidelines.gov/summary/summary.aspx?doc_id=8
641&nbr=004814&string=%28Alprazolam+OR+Bromazepam+O
R+Clobazam+OR+Frisium+OR+Diazepam+OR+Flunitrazepam+O
R++Lorazepam+OR+Midazolam+OR+Nitrazepam+OR+Oxazepa
m+OR+Temazepam+OR+Triazolam+OR+Zopiclone+or+Imovane
+or+Imrest%29

TRIPDatabase
(1) searchedon07/02/101,780Resultstotal
EvidenceBasedSynopses81
SystematicReviews114
Guidelines:
Aus.&NZ12
Canada5

AdultConditionedInsomnia:DiagnosistoManagement(CPD
access)

Searchedby:

Drugnames

RecommendationsfortheSafeTransferofPatientswithBrain
Injury2006
http://www.aagbi.org/publications/guidelines/docs/brain_inju
ry.pdf
Evidencebasedtreatmentforthepharmacologicaltreatment
ofanxietydisordersNationalLibraryofGuidelines(UK)2006
(CPDaccess)

Hypnosedatives for anxiety, insomnia and muscle spasm 22


UK58
USA8
Other4
www.tripdatabase.com

ImplementingandensuringSafeSedationPracticefor
healthcareproceduresinadults.ReportofanIntercollegiate
WorkingPartychairedbytheRoyalCollegeofAnaesthetists
http://www.rcoa.ac.uk/docs/safesedationpractice.pdf

AustralianGovernmentWebsitescontainingGuidelines
AustralianGovernmentDepartmentofHealthand
Ageingwww.health.gov.au

Webpagereviewed:HealthProfessionals
Treatments&TechniquesGuidelines

NSWHealthwww.health.nsw.gov.au

Webpagereviewed:Publications&Resources
PolicyDirectivesandGuidelines

Webpagereviewed:ResourcesReports,
GuidelinesandArticle

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

Webpagereviewed:Publications&ReportsMAA
GuidelinesGuidesforProfessionals

CentresofEvidenceBasedPracticeWebsites
WACentreforEvidenceBasedNursingand
Midwifery
http://wacebnm.curtin.edu.au

OtherAccidentCommissions
MotorAccidentsAuthorityNSW
www.maa.nsw.gov.au/
MAASGuidelines
MASGuidelines

MedicalAssessmentGuidelines1October2008
(2.1mb)
MedicalAssessmentGuidelinesMay2006 (77kb)(MS
Wordversion

929kb)

Hypnosedatives for anxiety, insomnia and muscle spasm 23


CARSGuidelines

ClaimsAssessmentGuidelines1October
2008(AmendedOctober12009) (260kb)
ClaimsAssessmentGuidelinesMay2006 (77kb)(MS
Wordversion

929kb)

InjuryManagementGuidelines

Guidesforprofessionals
Guidesforinjuredpeople

AccidentCompensationCorporation

Treatmentprofiles

www.acc.co.nz/index.htm

http://www.acc.co.nz/forproviders/clinicalbest
practice/PRV00053

Webpagereviewed::ForProvidersClinicalBest
PracticePublishedClinicalGuidelines

WorkSafeVIC

Webpagereviewed:Safety&Prevention;Health
andSafetyTopics

Webpagereviewed:Publications

Webpagereviewed:PublicationsPublicationsfor
healthproviders

www.workcover.vic.gov.au
WorkCoverNSW
www.workcover.nsw.gov.au
WorkCoverWA
www.workcover.wa.gov.au

Hypnosedatives for anxiety, insomnia and muscle spasm 24

APPENDIX2:INCLUDEDSTUDIES

Listofincludedsystematicreviews
1. BainKT.Managementofchronicinsomniainelderlypersons.AmericanJournalGeriatric
Pharmacotherapy.2006Jun;4(2):16892.
2. BlancoC,RazaMS,SchneierFR,LiebowitzMR.Theevidencebasedpharmacologicaltreatment
ofsocialanxietydisorder.InternationalJournalofNeuropsychopharmacology.2003
Dec;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.Theefficacyandsafety
ofdrugtreatmentsforchronicinsomniainadults:AmetaanalysisofRCTs.JournalofGeneral
InternalMedicine.2007Sep;22(9):133550.
5. BustoUE,PainT,LanctotKL,EinarsonTR,NaranjoCA.Assessmentoftheriskoftherapeuticdose
benzodiazepinewithdrawalreactionswithmetaanalysis.CanadianJournalofClinical
Pharmacology.1998Sep;5(3):1618.
6. CoxBJ,EndlerNS,LeePS,SwinsonRP.Ametaanalysisoftreatmentsforpanicdisorderwith
agoraphobia:Imipramine,alprazolam,andinvivoexposure.JournalofBehaviorTherapyand
ExperimentalPsychiatry.1992;23(3):17582.
7. CoxBJ,SwinsonRP,LeePS.Metaanalysisofanxietydisordertreatmentstudies[7].Journalof
ClinicalPsychopharmacology.1992;12(4):3001.
8. DundarY,BolandA,StroblJ,DoddS,HaycoxA,BagustA,etal.Newerhypnoticdrugsforthe
shorttermmanagementofinsomnia:Asystematicreviewandeconomicevaluation.Health
TechnologyAssessment.2004Jun;8(24):iii68.
9. FurukawaTA,StreinerDL,YoungLT.Antidepressantplusbenzodiazepineformajordepression.
CochraneDatabaseofSystematicReviews.2001(2):CD001026.
10. GlassJ,LanctotKL,HerrmannN,SprouleBA,BustoUE.Sedativehypnoticsinolderpeoplewith
insomnia:Metaanalysisofrisksandbenefits.BritishMedicalJournal.200519;331(7526):1169
73.
11. GouldRA,OttoMW,PollackMH,YapL.Cognitivebehavioralandpharmacologicaltreatmentof
generalizedanxietydisorder:Apreliminarymetaanalysis.BehaviorTherapy.1997
Mar;28(2):285305.

Hypnosedatives for anxiety, insomnia and muscle spasm 25


12. GradRM.Benzodiazepinesforinsomniaincommunitydwellingelderly:Areviewofbenefitand
risk.JournalofFamilyPractice.1995;41(5):47381.
13. HajakG,MullerWE,WittchenHU,PittrowD,KirchW.Abuseanddependencepotentialforthe
nonbenzodiazepinehypnoticszolpidemandzopiclone:Areviewofcasereportsand
epidemiologicaldata.Addiction.2003Oct;98(10):13718.
14. HidalgoRB,TuplerLA,DavidsonJRT.Aneffectsizeanalysisofpharmacologictreatmentsfor
generalizedanxietydisorder.JournalofPsychopharmacology.2007Nov;21(8):86472.
15. HolbrookAM,CrowtherR,LotterA,ChengC,KingD.Metaanalysisofbenzodiazepineuseinthe
treatmentofinsomnia.CanadianMedicalAssociationJournal.[Review].200025;162(2):22533.
16. HolmKJ,GoaKL.Zolpidem:Anupdateofitspharmacology,therapeuticefficacyandtolerability
inthetreatmentofinsomia.Drugs.2000;59(4):86589.
17. InadaT,NozakiS,InagakiA,FurukawaTA.Efficacyofdiazepamasanantianxietyagent:Meta
analysisofdoubleblind,randomizedcontrolledtrialscarriedoutinJapan.Human
Psychopharmacology.2003Aug;18(6):4837.
18. IpserJC,CareyP,DhansayY,FakierN,SeedatS,SteinDJ.Pharmacotherapyaugmentation
strategiesintreatmentresistantanxietydisorders.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.2009Aug
15;5(4):37783.
21. KaplanEM,DuPontRL.Benzodiazepinesandanxietydisorders:Areviewforthepracticing
physician.CurrentMedicalResearchandOpinion.2005;21(6)(pp941950)(2947).
22. KrystalAD.Treatingthehealth,qualityoflife,andfunctionalimpairmentsininsomnia.Journalof
ClinicalSleepMedicine.200715;3(1):6372.
23. MaheV,BaloghA.Longtermpharmacologicaltreatmentofgeneralizedanxietydisorder.
InternationalClinicalPsychopharmacology.2000;15(2):99105.
24. MartinJLR,SainzPardoM,FurukawaTA,MartinSanchezE,SeoaneT,GalanC.Review:
Benzodiazepinesingeneralizedanxietydisorder:Heterogeneityofoutcomesbasedona
systematicreviewandmetaanalysisofclinicaltrials.JournalofPsychopharmacology.2007
Sep;21(7):77482.
25. MitteK,NoackP,SteilR,HautzingerM.Ametaanalyticreviewoftheefficacyofdrugtreatment
ingeneralizedanxietydisorder.JournalofClinicalPsychopharmacology.2005Apr;25(2):14150.

Hypnosedatives for anxiety, insomnia and muscle spasm 26


26. NowellPD,MazumdarS,BuysseDJ,DewMA,ReynoldsICF,KupferDJ.Benzodiazepinesand
zolpidemforchronicinsomnia:Ametaanalysisoftreatmentefficacy.JournaloftheAmerican
MedicalAssociation.199724;278(24):21707.
27. RobinsonHM,HoodSD.SocialanxietydisorderAreviewofpharmacologicaltreatments.
CurrentPsychiatryReviews.2007May;3(2):95122.
28. SmithMT,PerlisML,ParkA,SmithMS,PenningtonJ,GilesDE,etal.Comparativemetaanalysis
ofpharmacotherapyandbehaviortherapyforpersistentinsomnia.AmericanJournalof
Psychiatry.2002Jan;159(1):511.
29. SoldatosCR,DikeosDG,WhiteheadA.Toleranceandreboundinsomniawithrapidlyeliminated
hypnotics:Ametaanalysisofsleeplaboratorystudies.InternationalClinical
Psychopharmacology.1999;14(5):287303.
30. SwainstonHarrisonT,KeatingGM.Zolpidem:areviewofitsuseinthemanagementofinsomnia.
CNSDrugs.2005;19(1):6589.
31. VanLiemptS,VermettenE,GeuzeE,WestenbergHGM.Pharmacotherapyfordisorderedsleep
inposttraumaticstressdisorder:Asystematicreview.InternationalClinical
Psychopharmacology.2006Jul;21(4):193202.
32. VersterJC,VeldhuijzenDS,PatatA,OlivierB,VolkertsER.Hypnoticsanddrivingsafety:meta
analysesofrandomizedcontrolledtrialsapplyingtheontheroaddrivingtest.CurrDrugSaf.
2006Jan;1(1):6371.
33. WatanabeN,ChurchillR,FurukawaTA.Combinedpsychotherapyplusbenzodiazepinesforpanic
disorder.CochraneDatabaseofSystematicReviews.2009;(1)(CD005335).
34. WetherellJL,LenzeEJ,StanleyMA.Evidencebasedtreatmentofgeriatricanxietydisorders.
PsychiatricClinicsofNorthAmerica.2005Dec;28(4):87196.

Listofincludedevidencebasedguidelines
1. AndrewsG.AustralianandNewZealandclinicalpracticeguidelinesforthetreatmentofpanic
disorderandagoraphobia.AustralianandNewZealandJournalofPsychiatry.2003
Dec;37(6):64156.
2. AACAP.Practiceparameterfortheassessmentandtreatmentofchildrenandadolescentswith
anxietydisorders.JournaloftheAmericanAcademyofChildandAdolescentPsychiatry.2007
Feb;46(2):26783.
3. BloomHG,AhmedI,AlessiCA,AncoliIsraelS,BuysseDJ,KrygerMH,etal.Evidencebased
recommendationsfortheassessmentandmanagementofsleepdisordersinolderpersons:
Supplement.JournaloftheAmericanGeriatricsSociety.2009May;57(5):76189.

Hypnosedatives for anxiety, insomnia and muscle spasm 27


4. MAAMACoN.Guidelinesforthemanagementofanxietyfollowingmotorvehicleaccidents.
2003.
5. McIntoshACA,TurnbullN,EsmondeL,DennisP,EatockJ,FeetamC,HagueJ,HughesI,KellyJ,
KoskyN,LearG,OwensL,RatcliffeJ,SalkovskisPClinicalGuidelinesandEvidenceReviewfor
PanicDisorderandGeneralisedAnxietyDisorder''.2004.
6. NationalInstituteofHealthandClinicalExcellence.Guidanceontheuseofzaleplon,zolpidem
andzopiclonefortheshorttermmanagementofinsomnia:TechnologyAppraisal77.NICE;April
2004[updatedApril2004;citedMay2010];Availablefrom:www.nice.org.uk/TA077guidance.
7. SwinsonRP.Clinicalpracticeguidelines:managementofanxietydisorders.Citation:CanJ
Psychiatry.2006;51(2):1S92S.

Hypnosedatives for anxiety, insomnia and muscle spasm 28