002 Benzodiazepines For Anxiety Summary of Systematic Reviews

TranspoortAcciden
ntCommission&W
WorkSafeV
Victoria
Benzodiazzepinesforaanxietyy
Summ
maryoffsystem
maticrevviews
June2011
EmmaaDonoghu
ue,DrissA
AitOuakrim
Reportn
number:0611002R6
Acccompanyinggdocumenttstothisrep
port
Title
Reportnum
mber
Benzodiaazepinesforanxiety
SummaryyofsystematiicreviewsPlainLanguagee
Summaryy
0611
1002R6.2
BeenzodiazepinesforAnxiety
ySummary ofSystematiccReviews
CONTEENTS
CONTENTTS..........................................................................................................................................................2
PLAINLA
ANGUAGESUM
MMARY.............................................................................................................................3
BACKGRO
OUND&METTHODS...............................................................................................................................4
FINDINGS............................................................................................................................................................5
SUMMAR
RY..........................................................................................................................................................8
SUMMAR
RYTABLES..............................................................................................................................................9
AMSTAR
RTABLE.................................................................................................................................................12
REFEREN
NCES......................................................................................................................................................14
APPENDIIX1:EXPAND
DEDSUMMAR
RYTABLES....................................................................................................15
APPENDIIX2:EVIDENC
CEMAPSUMM
MARY.........................................................................................................22
APPENDIIX3:EVIDENC
CEMAPMETH
HODS..........................................................................................................24
2
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TranspoortAcciden
ntCommission&W
WorkSafeV
Victoria
Benzodiazzepinesforaanxietyy
Plain
nlanguaagesummary
Anxiety disordersarrethemost commonmeentaldisorde
ers.AboutoneinfouraddultsinAusttraliahas
ananxieetydisorderaatsometime
eintheirlifee.Thiscanbe
eassociatedwithseveredistress.Itcanlead
todisrup
ptedsocialliifeandpoorhealth.
Benzodiazepinesareeusedbydoctorstotreaatanxiety.
Based o
on 118 studies, it is unclear if benzoodiazepines help to trea
at anxiety. Some studies found
benzodiazepineshellp,whileothersdidnot.TTheyweren
notgoodqua
alitystudies.
Allagreeedthatthereearepossibleharmswitthbenzodiazzepines.Theyysaythatdooctorsmustcarefully
judgeth
herisksandb
benefitsbefo
oreprescribi ngthem.
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BACKG
GROUND&
&METHO
ODS
Benzodiazepineshavvebeenwidelyusedincclinicalpracticesincethe
eirintroductiioninthe19
950sand
ofthemostconsumedaandhighlyprrescribedclassofdrugs.TTheirrangeofaction
continueetobeoneo
(sedative/hypnotic, anxiolytic,anticonvulsanntandmuscllerelaxant),combinedw
withtheirlow
wtoxicity
(1)
andcostthasgainedthempopularityamong physiciansaandpatients. Sincethe early1980ss,studies
have reggularly pointed out the risks relateed to long term use of benzodiazeppines. These
e include
physical dependence, withdra
awal sympt oms and other
o
adverse effects such as cognitive
c
(2)
mentsandanincreasedriiskoffallsanndfractures,particularlyinelderlypaatients.
impairm
The TAC
C and WorkkSafe Victorria requesteed an evidence review on the usee of hypnossedatives
(licensed
dforusein Australia)fo
oranxiety,innsomniaand
dmusclespasm.Toiden tifythescop
peofthe
research
h,anevidencemapwas developedaasafirstste
eptodeterm
minethequa ntityandco
omplexity
(33)
ofsystematicreview
ws(SR)and evidencebaasedguidelin
nes (EBG) on
nthetopic. Theevidence map
identifieed 34 SRs an
nd seven EB
BGs on hypnnosedatives for
f anxiety, insomnia orr muscle spa
asm (see
Table A
A2.2). A sum
mmary of the evidence map and a detailed de
escription off the eviden
nce map
ppendices2aand3,respe
ectively.
methodologycanbeefoundinAp
Given the breadth of the evid
dence indenntified, the topic was refined to aa review off SRs on
benzodiazepinesforranxietydiso
ordersrelateedtotraffic accidentsorrworkplace injuries.Th
hedetails
oftheseeSRsweressummarizedandtheirmeethodologicaalqualityasssessedusingameasurem
menttool
(4)
for asseessment of multiple
m
systematic reviiews (AMSTA
AR). The AMSTAR
A
is aan eleven ittem tool
designed
dtogiveanoverallqualityscorefor SRs.Thesesscoresgivea
anindicationnoftherisko
ofbiasof
each SR
R with 0/11 representin
ng lowest quuality (highe
est risk of bias),
b
and 111/11 highest quality
(lowestriskofbias).
In this rreport we present
p
a summary of tthe existing systematic reviews on the effectivveness of
benzodiazepines forr anxiety dissorders. Thiss is intended to provide
e an overvieew of the la
arge and
nlyprescribeddrugs.
complicaatedbodyoffevidenceunderlyingtheesecommon
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FINDIN
NGS
Atotalo
oftensystem
maticreview
wsoftheeffeectivenessoffbenzodiaze
epinesforannxietydisorderswere
identifieed. Five reviews investiggated the usse of benzo
odiazepines for
f generalizzed anxiety disorder
(Table11),tworeview
wsassessed theirusefoorpanicdiso
order(Table2)andthreeereviewsfoccusedon
othertypesofanxiety(Table3).
The num
mber of benzodiazepiness investigateed by each SR
S ranged from 1 to 5. Alprazolam was the
mostinvvestigateddrugappearinginalloftthe10SRs,ffollowedby Diazepam( n=8)andLo
orazepam
(n=6). O
Overall, the quality of th
he included systematic reviews wass low, with six studies having a
quality sscore of 5/1
11 or less (se
ee Table 4). Three revie
ews achieved
d an AMSTA
AR score higher than
7/11.Taable4presentsthemethodological qualityofeaachincluded
dSRwithreggardtothe different
AMSTAR
Rratingitem
ms.Characterristicsandre sultsoftheiincludedSRsarepresenttedinTabless13,and
ingreateerdetailinA
Appendix1.
GeneraalizedAnxiietydisord
der
FiveSRssconducted between19
997and20077(59)investiggatedtheefffectofbenzoodiazepines onGAD.
Thesereeviewsallad
ddressedslightlydifferenntresearchquestionsinrregardtodruugsstudied,duration
oftreatm
ment,compaarators,andoutcomesm
measured(se
eeTable1).
The dru
ugs and com
mparators sttudied acrosss the five SRs
S differed as follows.. Only one review(8)
focused exclusively onbenzodia
azepinesanddincludedR
RCTsthat com
mpareddiazzepam,lorazzepamor
(9))
alprazolam against placebo. One review compared the effectivveness of bbenzodiazepiines and
azapiron
nes against placebo. Tw
wo reviews(5,, 6) examined
d the effectiveness of bbenzodiazepines and
severalo
otherclassesofdrugsco
omparedto placebo,and
doneSR(7)in
ncludedplaccebocontrolledtrials
as well as trials com
mparing effectiveness beetween druggs. The review by Gould((5) also looke
ed at the
effectiveenessofpsycchologicaltreatmentsfo rGAD.
Therew
werealsodiffferencesinth
heoutcomessreportedin
neachSR.Th
hreeofthereeviews(5,6,9)reported
the effeectiveness off benzodiaze
epines as poooled effect sizes based on behaviooural tests of anxiety
(8)
scores. While, onee review measured eeffectivenesss as the riisk ratio off withdrawing from
ntscompareddtoplacebo.
benzodiazepinebasedtreatmen
Intermssofdurationoftreatmen
nt,thestudyybyMaheettal.(7)wastheonlySRto investigatetthelong
termefffectofbenzo
odiazepineso
onGADbyinncludingstud
diesofmore
ethan8weeeksduration. TwoSRs
(8, 9)
dreew conclusio
ons on the shortterm eeffects of benzodiazepines, with m
most of the included
(8)
studiesiinMartinet al. lasting4weeksor less,andanaveragedurationoftreeatmentof5.3weeks
forthesstudiesinclu
udedinMitte
eetal.(9).ThheremaininggtwoSRs,Go
ouldetal.(5) andHidalgo
oetal.(6),
included
dtrialsofvarriousduratio
onsrangingbbetween2to
o9weeks,an
nd4to12weeeks,respecctively.
We iden
ntified important differe
ences in metthodological quality betw
ween the fivve included SRs (see
(99)
Table4).Amongtheesereviews,Mitteetal. presentedthelowestriskofbiasw
withanAMST
TARscore
of 8/11 (see Table 1). This SR included 26 relevant studies (mostly on diazeppam, alprazo
olam and
lorazepaam vs. pill placebo).
p
The
e review coompared azaapirones, ben
nzodiazepinees and place
ebo, and
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found that both beenzodiazepin

nes and azappirones werre more effe
ective than placebo in reducing
anxiety and comorb
bid depressio
on in GAD. Although no difference
e in efficacy was found between
drug claasses, patien
nt compliancce was bettter with ben
nzodiazepine
ebased treaatment compared to
otherph
harmacologicalapproach
hes.Basedoon thisresult,thereview
wsuggests tthat benzodiazepines
aretob
bepreferred tootherdru
ugsasasho rttermtreatmentstrate
egy.Theaut horssuggesttlimiting
prescrip
ptionstosho
orttermuse duetothe increasingriiskofseriousadverseefffectsfollowinglong
term use such as physical depe
endence, witthdrawal, an
nd memory loss. They aalso highlight several
he included studies such
h as the lackk of doublebblindness, which
w
can
methodological limitations in th
n an overly positive
p
outccome and a biased estim
mation of effficacy. Anotther issue in most of
result in
thesestudiesconcernsthelack ofassessmeentofhowthetreatmen
ntimpactsonnpatientsq
qualityof
life.
Panicd
disorder
TwoSRssinvestigatedtheeffectofbenzodiaazepinesonp
panicdisorde
er(10,11)(see Table2).Th
hereview
(10)
byCoxeetal. assesssedtheefficacyofalpraazolam,imip
pramineandexposuretoophobicsituationsas
treatmeents for panic disorder with
w agorapphobia (PDA)). The review
w suggests tthat alprazo
olam and
exposurre therapies are both effective for PPDA. However, the study has nume rous methodological
orexample, nodetailsofftheincludeedstudiesarreprovidedm
meaningthaatitisnotpo
ossibleto
flaws;fo
determinethequaliityoftheresearchuponnwhichthe findingsare based.Ove ralltheSRb
byCoxet
(10)
al. hasahighriskofbias(AMSSTARscoreoof2/11),whichlimitsthevalidityofittsconclusion
ns.
The SR by Watanaabe et al.(11) comparedd the effectiveness of different ttreatment strategies
combining benzodiaazepines and psychotheerapy and presented
p
the lowest rrisk of bias with an
AMSTAR
R score of 10
0/11. The review
r
includded three trrials involving 166 particcipants and provided
data on 2 different benzodiazep
pines. No sttatistically siggnificant diffference wass found betw
ween the
ombinationoofpsychothe
erapyandbenzodiazepineesvs.psycho
otherapy
differentstrategiesaassessed(co
alone). TThe main co
onclusion fro
om the revieew was that there is ina
adequate evvidence to asssess the
effectiveenessofpsycchotherapyccombinedw
withbenzodiaazepinesforpanicdisordder.Thiswas duetoa
lackofh
highqualityttrials;threeRCTswereiddentified,on
nlytwoofwh
hichcouldcoontributedatatothe
primaryoutcomeso
ofthereview(seeTable22).
Otherttypesofan
nxiety
ThreeSR
Rsassessedttheeffective
enessofbenzzodiazepinessforothertyypesofanxieety(1214)(seeTable3).
The reviiew by Weth
herell et al.(114) investigatted all treatments of geriatric anxieety disorderss. Among
thepharmacologicalinterventio
onsidentifiedd,thereview
wfoundthre
eeRCTsinveestigatingtheimpact
odiazepines foranxietyd
disordersin laterlife,on
nlyoneofth
hesewasrellevanttothiisreport.
ofbenzo
This RCTT was stopped prematturely due tto concerns about adverse eventss and high attrition,
resultingg in sample sizes that were
w
too smaall to generaate solid con
nclusions aboout efficacy.. Overall,
the auth
hors of the SR noted the value of shortterm use of benzodiazepine s, and the potential
adverseeffectsasso
ociatedwithllongtermusse.
Inada ett al.(13) cond
ducted a systtematic reviiew of Japan
nese trials in
nvestigating the effectivveness of
diazepam
minimproviinganxietysstatesinpati entswithne
eurosisorpsychosomaticcdisease.Th
hereview
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included
d17placebo
ocontrolledRCTsconducctedbetween1970and1992.Thesttudyfoundd
diazepam
to be ssignificantly more effective than pplacebo with
h an optima
al treatmentt regimen of
o 12 or
18mg/daydoseoveeraperiodo
oftwoweekssormore.TTheauthorssstatedthattthequalityo
ofthe17
RCTssellectedwash
high.Howeve
er,theyalso notedthataanintentiontotreatanaalysisofthedatawas
perform
med in only seven studie
es and that several studies reporte
ed a large nnumber of dropouts.
d
Thesem
methodologiccalshortcom
mingswerennotaccounte
edforinthe metaanalyysisandreprresentan
importantsourceoffbiasforthe
epooledesttimatesrepo
ortedinthe SR.ThisSR hadhighrisskofbias
ARscoreof3//11),therefo
ore,thefindiingsandcon
nclusionsoftthisreviews houldbeinterpreted
(AMSTA
withcau
ution.
TherevviewbyFuru
ukawaetal.(112)hadthehhighestmeth
hodologicalq
qualitywith anAMSTAR scoreof
9/11. Itt investigateed the effects of com
mbining benzzodiazepiness with antiddepressants for the
treatmeent of adultts with anxiety associaated with major
m
depression. The review included 10
randomized controlled trials (RCTs) and meetaanalysed
d the resultss of 731 pattients. The included
ourintermeddiatequalityandtwo
RCTsvarriedintermssofquality,withtwocoonsideredhigghquality,fo
lowquality(duetou
uncertaintiessaboutblindding,orhighdropoutrattes).Theautthorsnotedtthatonly
one triaal followed patients be
eyond eight weeks, and that some of the inncluded stud
dies had
conflicting findings, making them hard to i nterpret and
d generalise. Overall, thhe review found that
with antidep
pressants
combining benzodiaazepines witth antidepreessants was superior to treatment w
alonein
ntermsofdeepressivesym
mptomsanddanxietysevverity.Thea
authorsalso emphasized
dtherisk
wal syndrom
me associate
ed with the
e use of bbenzodiazepines and
of depeendence and withdraw
recomm
mendedthat cliniciansca
arefully asse ssthebeneffitsandriskssbefore preescribingthiss classof
drugtoaapatient.
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SUMM
MARY
Overall, thereisalaackofconsisstency acrossstheSRsfiindingsand ahighriskoofbias(low AMSTAR
h SR aimed to answer a slightly different
d
queestion (i.e. different
scores) for most sttudies. Each
populatiions,drugs, comparatorss,oroutcom
messtudied)makingtheirrresultsdiffiiculttocombineinto
anoveraallansweron
ntheeffectivvenessofbeenzodiazepinesasatreatmentforanxxiety.
The fivee SRs assessing the effecct of benzoddiazepines on GAD included a total of 41 differe
ent trials
investigaating six ou
ut of the eleven typees of benzo
odiazepines registered in Australia
a. Three
(5,6,9)
multifaccetedreview
ws,
inclu
udingtheoneewiththeh
highestAMST
TARscore(88/11),conclu
udedthat
benzodiazepines weere an effecctive shortteerm treatme
ent for patients with G
GAD. Anothe
er review
(7
7)
found that the avaailable evide
ence was in conclusive. The only SR that excclusively foccused on
benzodiazepines waas unable to find convinncing evidence of their effectiveness
e
s. Using an outcome
(8)
measuree based on patients witthdrawal rattes, the reviiew by Marttin et al. s howed that subjects
receivingg benzodiazepines withdrew from ttreatment at the same rate as thosse receiving placebo
pills. It is importantt to note th
hat none of these revie
ews compare
ed effects bbenzodiazepines with
ogicaltreatm
ments,whichdonotcarryyariskofph
hysicaldepen
ndence.
psycholo
For panic disorder, a highquallity Cochran e SR(11) asse
essing the effectiveness
e
s of benzodiazepines
combineed with psyychotherapy was unablee to draw conclusions
c
due
d to the poor quality of the
availableeevidence.
Thesam
meuncertaintyexistsamongthereviiewsaddresssingtheeffe
ectsofbenzoodiazepinesfforother
typesoffanxiety.Forexample,theevidenceeofeffective
enessreporte
edbyInada etal.(13)islimitedby
theimpo
ortantmethodologicalshortcomingssoftheRCTssincludedin thereview.TheSRbyFFurukawa
(12)
et al. does not allow
a
us to draw
d
any coonclusion on
n the specific effect bennzodiazepine
es as the
reviewrreportstherresultsofacombination ofbenzodiazepinesandantidepress ants,ratherthanthe
effectso
ofbenzodiazepinesalone
e.
The maajor method
dological diffferences exxisting betw
ween the included SRs prevent an
n overall
interpreetationoftheeirfindings.FFurther,allppositiveresultsshouldbe
einterpreteddwithcautio
ondueto
themetthodological shortcominggsoftheinccludedRCTs,andthepottentialpubliicationbias((i.e.non
publicattion of nonsstatistically significant rresults) inherent to all SRs
S and mettaanalyses. Another
importantpointwhiichhasbeen
nconsistentlyydiscussediinalltheincludedSRscooncernsthepotential
essitytocareefullyassessbenefits
adverse effectsrelattedtotheuseofbenzoddiazepinesaandthenece
andpossibleharmsbeforepresccribingthem .
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SSUMMARYTA
ABLES
TTable1.Systematicreviewsofbenzod
diazepinesforGeneeralisedAnxietyDisorder
STTUDY
A
AMSTARRATING
BENZODIAZEPINES*
A
Alprazolam
Bromazepam
Clobazam
D
Diazepam
Fllunitrazepam
Lo
orazepam
M
Midazolam
N
Nitrazepam
O
Oxazepam
Teemazepam
Triazolam
COMPARATORSOF
IN
NTEREST
D
DURATIONOF
TREATMENT
O
OUTCOMES
RESULTSAND
CONCLUSIONS
COMMENTS
G
Gould1997(5)
4//11
3studies
3studies
1study
8studies
5studies
PharmacotherapyvsPlacebo
Hidalgo20007(6)
5/11
Mahe2000(7)
2/11
Martin2007(8)
M
6//11
1study
1sttudy
4studies
6studies
3studies
1study
1sttudy
7stu
udies
12studies
13studies
2studies
3stu
udies
7studies
7studies
Pharmaco
otherapyvsPlacebo
Totalinclu
udedstudies(n=21)
Relevantsstudies(n=4)
Irrelevantstudies(n=22)
Notspeciffied
Pharmacotherapyvsplaceboor
otherdrugs
Totalincludedstud
dies(n=13)
Relevantstudies(n=8)
Longterm(8week
ksorlonger)
Be
enzodiazepinevsplacebo
o
To
otalincludedstudies(n=23)
Re
elevantstudies(n=23)
Irrrelevantstudies(n=0)
Sh
hortterm(notdefined)
M
Measureofanxietyorworrry&
m
measureofdepression(efffectsize)
Measureo
ofanxiety(effectsize)
Benefitstopatientts/successfullong
termtreatmentofanxiety
Measureofanxiety
y
EFFECTIVE
(m
moreeffectivethanplace
ebo)
Benzosinorderofeffectivvenessfrom
m
mosttoleast:
D
Diazepam,Lorazepam,Bro
omazepam,
A
Alprazolam
th
hisreviewalsolookedat
psychologicaltreatmentsvvscontrol
n=13)
(n
EFFECTIVEE(lowtomoderate)
Orderofeeffectivenessfrommostto
o
least:Preggabalin,Hydroxyzine,
Venlafaxin
neSR,Benzos,SSRIs,
Buspironee,complementaryand
alternativeemedicines.
ded
Astudyoffbromazepamwasinclud
inthereviiew,butefficacydatawass
notreporttedandnotincludedinth
he
analysis
INCONCLUSIVE
Evidenceofeffectivenessis
inconclusive
Effficacy: asmeasuredbyw
withdrawals
fro
omstudy
Sid
deeffects:asmeasuredb
by
wiithdrawalsduetoadverseeevents
NO
OTEFFECTIVE
(notmoreeffectivethanplacebo)
Beenzosarenoteffectiveforthe
sh
horttermtreatmentofGA
AD(no
diffferencebetweenbenzossand
placebo)
Totalincludeddrugstudiess(n=22)
R
Irrrelevantstudies(n=5)
N
Notspecified
Thisreviewlooksa
atlongterm
treatmentofGAD(8weeksorlonger)
n.b.thisreviewalssolookedat
treatmentfornonwelldefined
anxietydisorder(n
n=5studies)
*fforsomeSRsthenumberssofstudiesforeachbenzo
odiazepinedonotaddup
ptothetotalnumberofreelevantstudies,assometrrialsstudiedmorethanon
netypeofbenzodiazepinee.
KEY:GAD=GeneralisedAn
nxietyDisorder
Benzzo/s=Benzodiazepine/s
SSRIs=SelectiveSeerotoninReuptakeInhibittors
9
9
R
Reportnumber:061
11002R6
Mitte2005
5(9)
8/11
1study
Pharmacottherapyvsplacebo
Totalincludedstudies(n=48)
Shortterm
m(notdefined)
Anxiety,de
epression,qualityoflife,o
or
clinicalsign
nificance(onlypertaining
toanxiety)).
EFFECTIVE
(moreeffe
ectivethanplacebo)
Benzosand
dazapironesequally
effective,b
bothclassesofdrugmoree
effectiveth
hanplaceboforshortterm
m
treatment
Thisreview
wlookedatbenzosvs
placebo,an
ndazapironesvsplacebo
andthencomparedeffectsizes

Benzod
diazepinesforAnxietySummaryofSystematicReview
ws
Table2.SSystematicre
eviewsofbenzodiazepinesforPanicDisorder
STUDY
AMSTARRA
ATING
BENZODIAZZPINES*
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepaam
Lorazepam
Midazolam
Nitrazepam
m
Oxazepam
Temazepam
m
Triazolam
COMPARATTORS
OFINTERESST
OUTCOMESS
Cox19
992(10)
Watanabe2
2009(11)
2/11
**
Thismetaanalysiscalculatedandcompareedeffectsizesof
alprazo
olam,Imipramineandexposurethe rapy
Includeedstudies(n=34)
**Nolistordetailsofinccludedstudieswerreprovided,
ore,itwasnotposssibletolisttheinccludedstudies
therefo
determ
minethenumbero
ofstudiesofalprazzolamordetermin
ne
thecom
mparatorsusedinthese
1/Dysp
phoriaordepressiion
2/Freq
quencyofpanicattacksperweek
3/Seveerityofpanicattaccks
4/Agoraphobicfear
5/Agoraphobicavoidanccebehaviour
6/Gen
neralizedanxiety
7/Oveerallimprovementratings
100/11
2sttudies
1sstudy
benzos +psy
ychotherapyvs(ppsychotherapyalo
oneorbenzo
treatment)
Totalinclude
edstudies(n=3)
Totalrelevantstudies(n=3)
CONCLUSIO
ONS
Primaryoutcome(s):
Response(asdefinedbyautthorsofincludedsstudies),ora
PanicDisord
derSeverityScale((PDSS)scoreof7o
orbelow.
Secondaryo
outcome(s):
1.Panicdiso
orderglobalseveriityonacontinuousscale
2.Frequency
yorseverityofpa nicattacks
3.Phobicavoidance
4.Generalanxiety
5.Depressio
on
6.Socialfunctioning
7.Qualityofflife
8.Patientsatisfactionwithtreeatment
9.Economic costs
INSUFFICIEN
NTEVIDENCE
Insufficiente
evidencetoassesssclinicaleffectsoff
benzodiazep
pines+psychotherrapyforpanicdiso
order
EFFECTTIVE
Alprazo
olamandexposuretherapiesbotheeffectiveforPDA
Alprazo
olamwassignificantlyeffectiveforppanicandanxiety
variabllesinPDA,whilee
exposurewassigniificantlyeffective
forpho
obiavariables.
Exposu
urehadthemostcconsistentlystronggeffectsizes
Alprazo
olamwasnoteffectiveforagoraphoobicdimensions
*forsomeSSRsthenumbersoffstudiesforeachb
benzodiazepinedoonotadduptotheetotalnumberofrrelevantstudies,aassometrialsstudiedmore
thanonetyppeofbenzodiazepine.
KEY:PDA=PanicDisorderwitthAgoraphobia Benzo/s=Benzoddiazepine/s
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Table3.SSystematicre
eviewsofbenzodiazepinesforothertyp
pesofanxiety
STUDY
AMSTARRA
ATING
TYPEOFAN
NXIETY
BENZODIAZZEPINES*
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepaam
Lorazepam
Midazolam
Nitrazepam
m
Oxazepam
Temazepam
m
Triazolam
COMPARATTORSOF
INTEREST
OUTCOMESS
CONCLUSIO
ONS
COMMENTSS
Furukkawa2001(12)
9/11
anxiettyassociatedwith
hmajor
depreession
1study
y
1study
y
1study
y
1study
y
Antidepressant+benzo
ovs
antideepressantalone
TotalIncludedstudies(n=10)
Relevantincludedstudiies(n=4)
Primaaryoutcome:Depressiveseverity,
(atleaastonemeasure)
Symptomseverity(selfreportor
obserrverrating)
Secon
ndaryoutcomes:
1.Ressponseindepressiion;2.
Accep
ptabilityoftreatment;3.Anxiety
severity;4.Insomniase
everity;5.Side
effectts
EFFEC
CTIVE,BUTBENEFITSSHOULDBE
WEIG
GHEDAGAINSTRIS
SKS
Thefo
ocusofthisstudywason
depreession
Inada2003(13)
3/11
neurosisorpsycchosomaticdiseasse
1study
2studies
2
17studies
1
1study
bothdiazepamandplacebowere
eused
ascontrolsonaallstudies
TotalIncludedsstudies(n=17)
Relevantincludedstudies(n=17)
FinalGlobalImp
provementRatingscale
(FGIR)usedtoccapturechangesinthe
overallseverityofpatientsympto
oms
expressedasaRelativeRiskafter
metaanalysis
EFFECTIVE(morreeffectivethan
placebo)
Diazepamismo
oreeffectivethan
placeboforneu
urosisorpsychosomatic
disease
OnlyJapanesesstudieswereincluded.
Wethreell2005(14)
5/11
anyanxxietydisorder
1study
Benzovvsantidepressantvvsplacebo
Totalinccludedpharmalog
gicalstudies
(n=8)
Relevanntincludedstudiess(n=1)
effectsiizeforeachoutcomemeasure
(includinng:CGI,ClinicalGllobal
Impresssion;HAMA,HamiltonAnxiety
Scale;STTAI,SpielbergerSttateTrait
Anxiety Inventory;VAS,V
Visual
AnaloguueScale)
EFFECTIIVE,BUTLONGTERM
TREATM
MENTNOTRECOM
MMENDED
DUETO
OPOTENTIALADVE
ERSEEVENTS
Thefocuusofthisstudywa
asongeriatric
anxiety disordersandalso
olookedat
studies ofcognitivebehavvioural
intervenntions
ThisrevviewalsoIncludedstudiesof
erventions
cognitivvebehaviouralinte
andphaarmacologicalinterventionsnot
relevantttoourquestion
*forsomeSSRsthenumbersoffstudiesforeachb
benzodiazepinedoonotadduptotheetotalnumberofrrelevantstudies,aassometrialsstudiedmore
thanonetyppeofbenzodiazepine.
o/s=Benzodiazepine/s
KEY:Benzo
11
number:0611002R6
Reportn
A
AMSTARTABLLE
TTable4.AMSTAR(4) ratingofincludedsystematicreviewss
Gould
A
AMSTARchecklistittems
1997(5)
Hidalgo
2007(6)
Mahe
2000(7)
Ma
artin
200
07(8)
Mitte
2005(9)
No
Yes
No
No
No
Cant
answer
es
Ye
Cant
answer
Yes
Yes
Cant
answer
a
Yes
Cant
answer
es
Ye
3
3.Wasacomprehen
nsiveliteraturesearchperformed?
Yes
Yes
No
Yes
Yes
Yes
Ye
es
4
4.Wasthestatusoffpublication(i.e.grreyliterature)
u
usedasaninclusion
ncriterion?
Yes
Yes
No
Yes
Yes
Cant
answer
5
5.Wasalistofstudiies(includedandexxcluded)
p
provided?
No
No
No
No
No
6
6.Werethecharactteristicsoftheinclu
udedstudies
p
provided?
Yes
Yes
Yes
No
7
7.Wasthescientificcqualityoftheinclu
udedstudies
assessedanddocum
mented?
No
No
No
8
8.Wasthescientificcqualityoftheinclu
udedstudies
u
usedappropriatelyiinformulatingconcclusions?
No
No
9
9.Werethemethod
dsusedtocombinethefindingsof
sttudiesappropriate??
Yes
1
10.Wasthelikelihoodofpublicationbiasassessed?
1
11.Wastheconflicttofinterestincludeed?
1
1.Wasan'apriori'd
designprovided?
2
2.Wasthereduplicaatestudyselectionanddata
eextraction?
A
AMSTARscore
Cox
1992(10)
Watan
nabe
2009(1
11)
Furukawa
2001(12)
Yes
Inada
2003(13)
Wethrell
2005(14)
No
No
No
Cant
answer
Yes
No
Yes
es
Ye
Yes
No
Cant
answer
No
Ye
es
Yes
No
No
Yes
No
Ye
es
Yes
Yes
Yes
Yes
Yes
No
Ye
es
Yes
Yes
No
No
Yes
Yes
No
Ye
es
Cant
answer
Yes
Yes
Yes
Cant
answer
Yes
Yes
Yes
Ye
es
Yes
No
N/A
No
Yes
No
Yes
Yes
No
Ye
es
Yes
No
N/A
No
No
No
No
No
No
No
No
No
Cant
answer
4/11
5/11
2/11
6/11
8/11
2/11
10//11
9/11
3/11
5/11
Yes
1
12
R
Reportnumber:061
11002R6
Benzod
diazepinesforAnxietySummaryofSystematicReview
ws
DISCLA
AIMER
Theinforrmationinthissreportisasummaryofthhatavailableaandisprimarilydesignedtoogivereadersastarting
point to consider currently availa
able researchh evidence. Whilst
W
apprecciable care h as been take
en in the
m
inclu
uded in this ppublication, the
t authors and
a the Natioonal Trauma Research
preparation of the materials
e
Institute do not warraant the accurracy of this doocument and deny any representation,, implied or expressed,
concerningtheefficaccy,appropriatenessorsuitaabilityofanyttreatmentorproduct.Inviiewoftheposssibilityof
ors and the National
N
Trauuma Research
h Institute
human eerror or advaances of medical knowledgge the autho
cannot aand do not warrant
w
that the
t informatiion contained
d in these pa
ages is in eveery aspect acccurate or
completee.Accordinglyy,theyareno
otandwillnottbeheldresp
ponsibleorlia
ableforanyerrrorsoromisssionsthat
maybeffoundinthis publication.Y
Youarethereeforeencouragedtoconsultothersourccesinordertoconfirm
the inforrmation contaained in this publication aand, in the evvent that med
dical treatme nt is required
d, to take
professio
onalexpertad
dvicefromale
egallyqualifieddandappropriatelyexperiencedmedicaalpractitionerr.
CONFLLICTOFIN
NTEREST
The TAC//WSV Evidence Service is provided by the Nationall Trauma Research Institutte. The NTRI does not
acceptfu
undingfromp
pharmaceuticalorbiotechnnologycompaaniesorotherrcommercial entitieswith potential
vestedin
nterestintheoutcomesofssystematicrevviews.
The TAC
C/WSV Health
h Services Group has enggaged the NTTRI for their objectivity a nd independence and
recognisee that any materials
m
deve
eloped must bbe free of influence from parties withh vested interrests. The
EvidenceeServicehasffulleditorialco
ontrol.
13
number:0611002R6
Reportn
REFER
RENCES
1.
BainKT.Managementofchronicinsomnniainelderlypersons.AmJJGeriatrPhar macother.20
006
Jun;4(2):16892.
midtA,BlancooJerezCR,MarshallRD,Sa
anchezLacayA
A,etal.
2.
BlancoC,SchneierFR,Schm
alanxietydisoorder:ametaanalysis.DeprressAnxiety.22003;18(1):29
940.
Pharmacologicaltreatmentofsocia
D.Hypnosedaativesforanxie
ety,insomniaandmusclesspasm:Eviden
nceMap.
3.
DonoghueE,AitOuakrimD
mpensationa ndRecoveryR
Research(ISCRR)2010(Unppublishedrep
port).
Melbourne:InstitutefforSafety,Com
SheaBJ,Grim
mshawJM,We
ellsGA,Boers M,Andersson
nN,HamelC, etal.DeveloppmentofAMSTAR:a
4.
ethodological qualityofsystematicreviews.BMCMeddResMethodol.
measurementtooltoaassesstheme
2007;7:10.
havioralandp
pharmacologiccaltreatmentof
GouldRA,OtttoMW,PollacckMH,YapL. Cognitivebeh
5.
haviorTherapy.1997;28(2) :285305.
generalizzedanxietydissorder:Aprelliminarymetaaanalysis.Beh
6.
HidalgoRB,TTuplerLA,DavvidsonJR.Aneeffectsizeanaalysisofpharm
macologictreaatmentsfor
1(8):86472.
generalizzedanxietydissorder.JPsychopharmacol .2007Nov;21
7.
MaheV,Balo
oghA.Longte
ermpharmacoologicaltreatm
mentofgeneralizedanxietyydisorder.IntClin
harmacol.200
00Mar;15(2):9
99105.
Psychoph
8.
MartinJL,SaiinzPardoM,FFurukawaTA,MartinSanch
hezE,SeoaneT,GalanC.Beenzodiazepinesin
ogeneityofouutcomesbase
edonasystem
maticreviewaandmetaanalysisof
generalizzedanxietydissorder:hetero
clinicaltrrials.JPsychopharmacol.20
007Sep;21(7)):77482.
9.
HautzingerM. Ametaanalyyticreviewoftheefficacyoofdrugtreatm
mentin
MitteK,NoacckP,SteilR,H
macol.2005Ap
pr;25(2):1415
50.
generalizzedanxietydissorder.JClinPsychopharm
10.
CoxBJ,EndlerNS,LeePS,SSwinsonRP.A
Ametaanalyssisoftreatmen
ntsforpanicddisorderwith
obia:imipram
mine,alprazola
am,andinvivooexposure.JBehavTherExpPsychiatry..1992Sep;23
3(3):175
agorapho
82.
WatanabeN,ChurchillR,FFurukawaTA. Combinedpsychotherapyplusbenzodiaazepinesforpanic
11.
Rev.2009(1):CCD005335.
disorder..CochraneDaatabaseSystR
12.
FurukawaTA,,StreinerDL,YoungLT.Anttidepressantp
plusbenzodiazepineformaajordepressio
on.
CochraneeDatabaseSyystRev.2001(2):CD001026..
13.
InadaT,NozaakiS,InagakiA
A,FurukawaTTA.Efficacyoff diazepamasanantianxiettyagent:metta
ofdoubleblin
nd,randomize
edcontrolledttrialscarriedo
outinJapan.H
HumPsychoppharmacol.2003
analysiso
Aug;18(66):4837.
14.
nleyMA.Eviddencebasedtreatmentofg
geriatricanxieetydisorders.Psychiatr
WetherellJL,LenzeEJ,Stan
Dec;28(4):87196.
ClinNortthAm.2005D
14
number:0611002R6
Reportn
APPEENDIX1:EXPA
ANDEDSUMM
MARYTABLES
TableA
A1.1SystematicreeviewsofbenzodiazepinesforGeneraalisedAnxietyDisorder
STUDY
AMSTAR
RRATING
BENZODIAZEPINES*
Alprazolaam
Bromazeepam
Clobazam
m
Diazepam
m
Flunitrazzepam
Lorazepaam
Midazolaam
Nitrazepam
Oxazepam
Temazep
pam
Triazolam
m
PATIENTTS
OUTCOM
MES
Gould19997(5)
4/11
3studies
3studies
1study
8studies
5studies
PatientswithGAD(APADSMIII,D
DSM
IIIR,orDSMIV)orpatientswhocllearly
wouldhaavemettheabovecriteriaaif
theyhad
dbeenapplied
Measureeofanxietyorworry&meeasure
ofdepresssion(effectsize)
15
2R6
Reporttnumber:0611002
Hidalgo2007((6)
5/11
Mahe2000(7)
2/11
Martin2007(8)
6/11
Mitte
e2005(9)
8/11
1study
1sstudy
4studiess
6studies
3studies
1study
1sstudy
7sttudies
12studie
es
13studies
2studies
3sttudies
7studiess
7studies
PatientswithG
GAD(DSMIIIR,DSMIV
andICD10)
patientswithcond
ditionsdescribedas
generalisedanxiety
ydisorder,anxiety
neurosisoranxietysymptoms
Measureofan
nxiety(effectsize)
Benefitstopatientss/successfullong
termtreatmentofa
anxiety
Measureofanxiety
y
PatientswithGAD(DSMIV,DSMIIIor
DSMIIIR)
Excluded:patientswithp
psychiatric
disordersorwhowereco
onsumingor
dependentonsubstanceesofabuseor
withothermedicalprobllems.
Efficacy: asmeasuredbyywithdrawals
fromstudy
Sideeffects:asmeasuredby
withdrawalsduetoadveerseevents
1study
Patie
entswithGAD(anydiagno
ostic
syste
em),oranexactdescriptio
onofthe
disorrderwaspresentedinclud
ding
durattionofsymptoms(i.e.insufficientif
patie
entsjustdescribedasanxxiousor
neurotic)
Selfrreport,observerratedmeeasures,or
behaviouraltestofanxiety,deepression,
qualityoflife,orclinicalsignificance
(onlyypertainingtoanxiety).
Benzodiazep
pinesforAnxietySummaryofSyste
ematicReviews

STUDY
COMPAR
RATORSOF
INTERESTT
Gould19997(5)
PharmaccotherapyvsPlacebo
Totalincludeddrugstudies(n=22))
Relevanttbenzostudies(n=17)
Alprazolaamvsplacebo(n=3)
Castillo(1987),Enkelmann(1991),
Fontainee(1984)
Bromazeepamvsplacebo(n=3)
Fontainee(1986),Fontaine(1984),
KraghSo
orensen(1990)
Clobazam
mvsplacebo(n=1)
Castillo(1987)
mvsplacebo(n=8)
Diazepam
Borison((1990),Cohn(1989),Fonttaine
(1987),O
Olajide(1987),Pecknold(1
1989),
Rickels(11993),Rickels(1982),Ross&
Matas(11987)
Lorazepaamvsplacebo(n=5)
Ansseau(1985),Ceulmans(1985),,Cutler
(1993),D
Diamond(1991),Fontainee(1986)
otherdru
ugstudies(n=5)
n.b.someebenzovsplacebostudieesalso
lookedattotherdrugsvsplacebo,ssome
studieslo
ookedatmorethanoned
drugvs
placebo
Hidalgo2007((6)
PharmacotherrapyvsPlacebo
dstudies(n=21)
Totalincluded
Relevantbenzzostudies(n=4)
Alprazolamvsplacebo(n=1)
Moller(2001)
Lorazepamvsplacebo(n=2)
Pande(2003),Feltner(2003)
Diazepam,plaacebo(n=1)
Hackett(20033)
otherdrugstu
udies(n=22)
SSRIstudies(n
n=8)
venlafaxinestudies(SNRI)(n=5)
hydroxyzinesttudies(AH)(n=3)
PGBstudies(n
n=2)
buspironearm
ms(n=2)
complementaryandalternative
medicinestud
dies(n=2)
o
n.b.somebenzovsplacebostudiesalso
lookedatotheerdrugsvsplacebo,somee
studieslooked
datmorethanonedrugvvs
placebo
Mahe2000(7)
Various
TotalGADstudies((n=8)
Relevantbenzostu
udies(n=4)
Alprazolamvsplace
ebo,lorazepamvs
placebo(n=1)
Cohn&Wilcox(198
84)
Diazepamvsplaceb
bo(n=1)
Power(1990)
Buspironevsdiazep
pam(n=1)
Murphy(1989)
parator(n=1)
Diazepam,nocomp
Rickels(1983)
Totalnonwelldefinedanxietydisorder
studies(n=5)
Relevantbenzostu
udies(n=4)
Clobazamvsdiazep
pam(n=1)
Schjonsby(1979)
pam(n=1)
Ketazolamvsdiazep
Fabre(1981)
am;openlabel(n=1)
Lorazepam,diazepa
Siassi(1975)
am;openlabel(n=1)
Lorazepam,diazepa
Gross(1977)
n.b.somebenzovssplacebostudiesalso
lookedatotherdrugsvsplacebo,some
studieslookedatm
morethanonedrugvs
placebo
Martin2007(8)
Benzodiazepinevsplace
ebo
Relevantbenzostudies((n=23)
diazepamvsplacebo(n=12)
lorazepamvsplacebo(n==7)
alprazolamvsplacebo(n
n=4)
Includedstudies:
Andreatini(2002),Ansseau(1991),
Boyer(1993),Castillo(19
987),Cutler
(1993),Diamond(1991),Enkelmann
ontaine(1983),
(1991),Feltner(2003),Fo
Fontaine(b)(1986),Hackkett(2003),
Laakmann(1998),Loo(1991),Lydiard
(1997),Moller(2001),Paande(2003),
Pecknold(1985),Pecknold(b)(1989),
Poumotabbed(1996),Ricckels(1993),
Rickels(b)(1997),Rickelss(c)(2000),Zung
(1986)
n.b.specificbenzousediineachstudynot
stated
Benzzodiazepines(bromazepaam,
diaze
epam)(n=1)
Fontaine(1984)
Brom
mazepamvsplacebo(n=2))
Fontaine(1983),Fontaine(1
1986)
Diaze
epamvsplacebo(n=12)
Boye
er&Feighner(1993),Fontaine
(1983),Fontaine(1987),Goldberg&
erty(1982),Pecknold(1
1989),
Finne
Pourrmotabbed(1996),Poweer(1989),
Powe
er(1990),Rickels(1982)),Rickels
(1993),Rickels(1997),Rickels(2000)
Lorazzepamvsplacebo(n=6)
Cohn
n&Wilcox(1984),Cutleer(1993),
Fontaine(1986),Fresquet(2
2000),
Laakmann(1998),LaboratorriosDr
Estevve*(unpublished)
Fontaine(1990)
NotspeccifiedinselectioncriteriafforSR.
Duration
noftreatmentforincluded
studiesvvariedbetween2and9weeks
NotspecifiedinselectioncriteriaforSR
R.
Durationoftreeatmentforincluded
studiesvariedbetween4and12weekss
Longterm(8weekssorlonger)
Notspecifiedinselection
ncriteriaforSR.
Conclusionsdrawnforsh
hortterm
treatment.
thetrialswereconducteedinthevery
shortterm,withmostlasstingjust4
weeks
Individualtrialdurationswerenot
specified
RESULTSS
Benzodiaazepines:
Benzodiazepin
nes:
Nooveralleffectsizzeorresult
Pooledanalysisindicated
dlessriskof
Castiillo(1987),Cohn&Wilco
ox(1984),
Enke
elmann(1991),Lydiard(1997),
McLe
eod(1982),Moller(2001)
Triazolamvsplacebo(n=1)
DURATIO
ONOF
TREATMENT
16
2R6
Mitte
e2005(9)
Pharmacotherapyvsplacebo
Totallincludedstudies(n=48)
Relevvantbenzostudies(n=25
5)
Alpraazolamvsplacebo(n=6)
n.b.ssomebenzovsplacebosttudiesalso
lookeedatotherdrugsvsplacebo,some
studiieslookedatmorethanon
nedrugvs
placeebo
SelecctioncriteriaforSRspecifieda
minim
mumof14daystreatmen
nt
Theaaveragedurationofthein
ncluded
benzostudieswas5.3weeks.
Fourstudiesinvestigatedtheedrugfor
lesstthan4weeks,however,eeffectsizes
forth
hosestudieswerecomparablewith
studiesinwhichthedrugswerre
invesstigatedforalongerperio
odoftime
Recommendationsweremadeeagainst
longtermuseduetotheincreeasingrisk
ofde
ependenceandwithdrawaalreported
elsew
where.
Forb
benzodiazepines,themeaneffect
Benzodiazep
ematicReviews

STUDY
Gould19997(5)
MeanES=0.70
Diazepam
m(11studies):ES=0.76
Lorazepaam(5studies):ES=0.66
Alprazolaam&bromazepam(2studies
each);ESS=0.44&0.61
Amongmedicationinterventionss,the
benzodiaazepinediazepamyielded
dthe
largestefffectsize(ES=0.76),follow
wedby
lorazepam(ES=0.66)
CONCLUSSIONS
Hidalgo2007((6)
ES+SD=0.38++0.15
pValue=p<0.0001
Ouranalysissshowedalowtomoderatte
overallES(0.339+0.06)fordrugtherapyin
thetreatmenttofGAD...Onthehigher
endofthespeectrumwefoundthe
anticonvulsantPGBandtheAH
hydroxyzine,ffollowedinorderby
venlafaxineXR
R,BZsandSSRIs
Mahe2000(7)
calculated,orconclusionsdrawnabout
anyspecificbenzido
oazepines,or
benzodiazepinesassawhole
theresultsoftherreportedlongterm
studiesinpatientsw
withGADare
inconclusive,andnoreferencedrughas
showntobeeffectiveinthelongterm
treatmentofthisco
ondition...although
longtermtreatmen
ntofgeneralized
anxietydisorderisa
anunmetmedical
need,noreferencedrughasyetbeen
anadequate
identified,norhasa
treatmentevaluatio
onofthiscondition
beenperformed
Martin2007(8)
treatmentdiscontinuatio
onduetolackof
efficacyforbenzodiazepiines,compared
toplacebo,RR=0.29(95%
%CI0.180.45;
p<0.00001).
Nevertheless,pooledanaalysisshowedno
conclusiveresultsforriskkofallcause
patientdiscontinuation,RR=0.78(95%CI
0.621.00;p=0.05).
theoutcomesobservedinthisreview
seemtoshowthat,basedontotal
withdrawalsfromclinicalstudies,
benzodiazepinesdonoteevenprove
definitivelysuperiortoplacebointhe
shortterm.Inaclinical(tthoughnot
experimental)setting,su
ubjectscould
withdrawfromtreatmen
ntafewweeks
afterthestartinthesam
meproportions
assubjectswhoreceiveaaplaceboina
clinicaltrial,indicatingth
hat
benzodiazepinesarenotaneffective
treatmentforGAD
NOTEFFECTIVE
(notmoreeffectivethan
nplacebo)
Benzosarenoteffectivefortheshort
termtreatmentofGAD(nodifference
betweenbenzosandplaccebo)
Wechosewithdrawalsffromtrialsfor
anyreasonastheprincip
paloutcome
measureinthisreview,aaswasdonein
therecentlypublishedlargetrialin
schizophreniacalledCATTIE(Liebermanet
al.,2005).Wearguethattwithdrawalfor
anyreasonrepresentsth
hemost
comprehensibleandcom
mprehensive
overallindexofeffectiveenessofany
intervention.
EFFECTIV
VE
EFFECTIVE(low
wtomoderate)
INCONCLUSIVE
(moreefffectivethanplacebo)
Orderofeffecctiveness(mosttoleast):
Evidenceofeffectiv
venessisinconclusive
Benzosin
norderofeffectivenessfrrom
Pregabalin,Hyydroxyzine,VenlafaxineSR,
mosttolleast:Diazepam,Lorazepaam,
Benzos,SSRIs,,Buspirone,
Bromazeepam,Alprazolam
complementaryandalternativemeds
Noindividualeeffectsizesreportedfor
Thisreviewlooksattlongtermtreatment
COMMEN
NTS
Thismetaanalysislookedat
AD,
thedifferentb
benzodiazepinesusedin
ofGAD(8weeksor longer)
pharmaccotherapyandCBTforGA
benzodiaazepineswereonlypartofthe
theincludedsstudies,justacombined
Aswellastreatmen
ntfornonwell
results.TTheauthorsnotethattheelong
overalleffectssizeforbenzodiazepines
definedanxietydiso
order(n=5studies)
termefficacyofpharmacologic
treatmen
ntwasattenuatedfollowiing
Astudyofbro
omazepam(Llorca(2002)
Thisreviewalsoloo
oksatdifferenttypes
medicationdiscontinuation
wasincludediinthereview,butefficacyy
ofpharmacotherap
pynotjustbenzos.
datawasnotrreportedandnotincluded
d
Theauthorsstatethatbenzosarenot
Aswellaslookingatpharmacotheerapy
intheanalysiss
bo,thisreviewalsolooked
dat
recommendedlong
gtermduetotherisk
vsplaceb
psycholo
ogicaltreatmentsvscontrrol
ofdependence
(n=13)
*forsomeSRsthenumbersofstud
diesforeachbenzodiazep
pinedonotadduptothettotalnumberofrelevantsstudies,assometrialsstu
udiedmorethanonetypeofbenzodiazepine.
KEY:GAD
D=GeneralisedAnxietyD
Disorder
Benzo/s=B
Benzodiazepine/s
SSSRIs=SelectiveSerotonin
nReuptakeInhibitors
17
2R6
Mitte
e2005(9)
sizefforanxietywasg =0.32.TTherewas
nosiggnificantdifferencebetweendrug
classes.
Ford
depressionthemeaneffecctsizefor
benzodiazepineswasg=0.28..Againno
drugclasswassuperior
Ourfindingsindicatethat
pharmacotherapyisaneffective
treatmentforGADinreducinggboth
anxie
etyandcomorbiddepresssive
symp
ptoms;superiorityoverplacebowas
given
n.Accordingtodrugclassees,no
differrencesinefficacybutincompliance
were
efound.So,resultssuggesstthat
benzodiazepinesaretobepreeferredat
leastwhenthedurationofthee
treatmentisshort
EFFEC
CTIVE
(morreeffectivethanplacebo))
Benzosandazapironesequalllyeffective,
bothclassesofdrugmoreeffeectivethan
place
eboforshorttermtreatm
ment
Thisrreviewlookedatbenzosvvs
place
ebo,andazapironesvsplaceboand
thencomparedeffectsizes
nownthat
Theaauthorsstatethatitiskn
there
eisanincreasingriskofp
physical
depe
endenceandwithdrawalaafterlong
termtreatmentwith
benzodiazepines...Inaddition,other
severreadverseeffectscanressultfrom
longtermuse...suchasimpairrmentof
mem
mory.Thereforeprescriptio
onsshould
belim
mitedtoshorttermuse
Benzodiazep
ematicReviews
TableA1.2SyystematicrevviewsofbenzodiazepinesfforPanicDiso
order
STUDY
AMSTARRATING
BENZODIAZPINESS*
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
PATIENTS
OUTCOMES
Cox1992(10)
Watanabe200
09(11)
2/11
Patientswith
hpanicdisorderorrpanicdisorderw
withagoraphobia
(agoraphobiaawithpanicattackksinDMSIII).Onnlystudiesthat
specificallysttatedtheycontain
nedalargepercenntageofsubjects
withbothpaanicattacksandag
goraphobicavoida ncewere
included.
1/Dysphoriaaordepression
2/Frequencyyofpanicattacksperweek
3/Severityo
ofpanicattacks
4/Agoraphobicfear
5/Agoraphobicavoidancebeh
haviour
6/Generalizeedanxiety
7/Overallim
mprovementrating
gs
10//11
2stuudies
1sttudy
Adultpatientswithpanicdisordeerwithorwithouttagoraphobia
(Feighnercriteria,ResearchDiaggnosticCriteria,DSSMIII,DSMIII
R,DSMIVorICD10)
COMPARATORS
OFINTEREST
Thismetaan
nalysiscalculateda
andcomparedeffeectsizesof
alprazolam,IImipramineandexxposuretherapy
Includedstud
dies(n=34)
#
Nolistordeetailsofincludedstudieswereprovi ded,therefore,it
wasnotposssibletolisttheincludedstudiesdeteerminethe
numberofsttudiesofalprazola
amordeterminethhecomparators
usedinthesee
RESULTS
Fewstudiesssatisfiedtheminimumcriteriaofinnclusionandthe
finaldatapoolconsistedof34
4treatmentstudiees.Imipramine
obegenerallyinefffectiveformostvaariables.
wasfoundto
Alprazolamw
wassignificantlyefffectiveforpanicaandanxiety
variablesinP
PDA,whileexposurewassignificantllyforphobia
variables.Exposurehadthemostconsistentlysttrongeffect
sizes.
Theresultsofthemetaanalyysisindicatethata lprazolamand
exposuretheerapiesarebothefffectiveforPDA,bbutalprazolam
wasnoteffecctiveforagorapho
obicdimensions.Im
mipraminewas
foundtobeggenerallyeffective
e
CONCLUSIONS
EFFECTIVE
AlprazolamaandexposuretherapiesbotheffectivveforPDA
18
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Primaryoutco
ome(s):
Response(adichotomisedouttcome)ineacharm
m,definedby
globaljudgeme
entoftheoriginalauthors,suchas:verymuch
ormuchimp
provement,noorminimalsymptom,oraPanic
DisorderSeverityScale(PDSS)sccoreof7orbelow.
Secondaryoutcome(s):
1.Panicdisorderglobalseverity onacontinuoussscale
2.Frequencyo
orseverityofpaniccattacks
3.Phobicavoid
dance
4.Generalanxiety
5.Depression
6.Socialfunctioning
7.Qualityofliffe
8.Patientsatisfactionwithtreat ment
9.Economicco
osts
benzos+psych
hotherapyvs(psyc
ychotherapyalone
eorbenzo
treatment)
Totalrelevantstudies(n=3)
Alprazolam+C
CBTvsPlacebopill+CBT(n=1)
Auerbach(1997)
alprazolamvsa
alprazolam+expossurevsdoubleplaccebovs
exposure(n=1))
Marks(1993)
Diazepam+ExposurevsPlaceboopill+Exposure(n
n=1)
Wardle(1994)
Twotrials(n=166)comparedcoombinationwithpsychotherapy
alone(bothusingbehaviourtherrapy).Nostatistica
allysignificant
differenceswereobservedinressponseduringtheintervention
(relativerisk(R
RR)forcombinatioon1.25,95%CI0.7
78to2.03,P=
0.35),attheen
ndoftheinterventtion(RR0.78,0.45
5to1.35,P=
0.37),oratthe
elastfollowuptim
mepointFollowup
pdata
suggestedthattthecombination mightbeinferiortobehaviour
therapyalone(RR0.62,0.36to11.07,P=0.08).
7)comparedcombbinationwithaben
nzodiazepine
Onetrial(n=77
alone.Nodiffe
erenceswerefoun dinresponseduringthe
intervention(R
RR1.57,0.83to2.998,P=0.17).Althoughthe
combinationappearedtobesupperiortothebenzo
odiazepine
ndoftreatment(RRR3.39,1.03to11
1.21,P=0.05).
aloneattheen
Nosignificantd
differenceswereoobservedatthe7monthfollow
up(RR2.31,0.79to6.74,P=0.112).
Thereviewesstablishedthepauucityofhighqualityyevidence
investigatingth
heefficacyofpsycchotherapycombinedwith
benzodiazepinesforpanicdisordder.Currently,thereis
of
inadequateeviidencetoassessthheclinicaleffectso
psychotherapy
ycombinedwithbbenzodiazepinesfo
orpatientswho
arediagnosedwithpanicdisordeer.
INSUFFICIENTEVIDENCE
Insufficientevidencetoassesscllinicaleffectsofbe
enzodiazepines
Benzoodiazepinesfo
orAnxietySu
ummaryofSyystematicRevviews
COMMENTS
Alprazolamw
wassignificantlyefffectiveforpanicaandanxiety
variablesinP
PDA,whileexposurewassignificantllyeffectivefor
phobiavariables.
Exposurehad
dthemostconsisttentlystrongeffecctsizes
Alprazolamw
wasnoteffectivefforagoraphobicdi mensions
+psychotherap
pyforpanicdisordder
Seearticlefordetailsonthescallesusedtomeasurethe
differentoutco
omesofthestudy..
*forsomeSRstheenumbersofstudieesforeachbenzod
diazepinedonotaadduptothetotal numberofrelevan
ntstudies,assomeetrialsstudiedmo
orethanonetype
ofbenzodiazepinee.
KEY:PDA=PanicDisorderwithAgo
oraphobia Benzo
o/s=Benzodiazepiine/s
19
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Benzoodiazepinesfo
orAnxietySu
TableA1.3Syystematicrevviewsofbenzodiazepinesfforothertype
esofanxiety
STUDY
AMSTARRATING
TYPEOFANXIETY
Y
BENZODIAZEPINEES*
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
PATIENTS
OUTCOMES
COMPARATORSO
OF
INTEREST
RESULTS
Furukawa2
2001(12)
9/11
anxietyasso
ociatedwithmajordepression
1study
1study
1study
1study
anxietyasso
ociatedwithmajo
or
depression
adults(aged
d18orolder)with
hmajor
depression,,diagnosedaccord
dingtoany
oneoftheFFeighnercriteria,R
RDC,DSMIII,
DSMIIIRorrDSMIV,orICD10
0.
Comorbiditieswithanxietydiisorders
included.
Primaryouttcome:Depressive
eseverity,
(atleastoneemeasure)
Symptomseeveritycouldbem
measuredby
eitherselfrreportorobserverrrating
Secondaryo
outcomes:
1.Responseeindepression;2.
Acceptabilittyoftreatment;3..Anxiety
severity;4.Insomniaseverity;5.Side
effects
Antidepresssants+benzosvs
antidepresssantsalone
TotalInclud
dedstudies(n=10)
Relevantinccludedstudies(n=
=4)
imipraime++triazolamvsimip
pramine
(n=1)
Dominguez(1984)
desipraminee+alprazolamvs
desipraminee(n=1)
Fawcett(19
987)
imipraminee+diazepamvsimipramine
(n=1)
Feet(1985)
(maprotilineeornortriptyline)+
(flunitrazep
pamorlormetazep
pam)vs
(maprotilineeornortriptyline)(n=1)
Nolen(1993
3b)
Theresultsssuggestthesupe
eriorityof
thecombinationtherapyinalleviating
anxietyevenuptosixtoeightweeks,
withstatistiicallysignificantSM
MDs
between0.50and0.64.
20
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Innada2003(13)
3//11
n eurosisorpsychossomaticdisease
1study
2sstudies
17sstudies
1study
TThesubjectswere
eallJapanesepatie
ents
suufferingfromneurosisor
p sychosomaticdise
ease,asdiagnosed
d
acccordingtotheJapanesediagnostic
syystembasedonIC
CD9...Morerecently,
suubjectswereselecctedbasedon
o perationaldiagnosticcriteriasuchas
ICCD10orDSMIV
FiinalGlobalImprovvementRatingscale
(FFGIR)usedtocaptturechangesinth
he
ovverallseverityofp
patientsymptoms
exxpressedasaRelaativeRiskaftermeta
annalysis
B enzovsdiazepamvsplacebo
(bbothdiazepamand
dplacebowereussed
asscontrolsinallinccludedstudies)
TootalIncludedstud
dies(n=17)
RRelevantincludedsstudies(n=17)
A
Alprazolamvsdiaze
epamvsplacebo(n=1)
Itto(1982)
CClobazamvsdiazep
pamvsplacebo(n=
=2)
K udo(1982),Mori(1982)
Loorazepamvsdiaze
epamvsplacebo(n
n=1)
Itto(1981)
O
Otherdrugvsdiaze
epamvsplacebo
(nn=13)
H
Hada(1979),Higuchi(1975),Ichimaru
(11970),Ito(1981),K
Kudo(1984),Kudo
o
(11983),Kurihara(19
992),Kurihara(1990),
K urihara(1977),Mori(1977),Namiki
(11974),Suematsu(1975),Suzuki(197
79)
M
Metaanalysisofthetotal17RCTs
d emonstrateddiazepamtobe
effectivethanplaccebo
siignificantlymoree
innthetreatmentoffneurosisor
p sychosomaticdise
ease(relativerisk1
1.35,
955%CI1.211.51,n
numberneededto
o
trreat9)...Theeffecctivenessofdiazep
pam
w
wasparticularlynotableatamaximu
um
d oseof12mg/dayorhigher,whileno
siignificantsuperiorritycomparedwith
hthe
p lacebowasobservvedatadoseof9
m
mg/dayorlower.
Wethrelll2005(14)
5/11
anyanxieetydisorder
1study
participanntswereatleast5
55yearsold,
withaprrincipalorcoprinccipaldiagnosis
ofanyannxietydisorderdiagnosed
accordinggtocriteriaoftheDiagnostic
andStatissticalManualofM
Mental
DisorderssIIIRorIV
Tocompaareclinicalsignificcanceacross
studies,eeffectsizeswerecalculated
wherepoossibleforeachou
utcome
measure (including:CGI,ClinicalGlobal
Impressioon;HAMA,HamiltonAnxiety
Scale;STAAI,SpielbergerSta
ateTrait
AnxietyInnventory;VAS,VissualAnalogue
Scale)witthineachstudy.
Benzovs antidepressantvssplacebo
Totalinclludedpharmalogiccalstudies
(n=8)
Relevant includedstudies((n=1)
Imipramiinevsalprazolamvvsplacebo
(n=1)
Sheikh&Swales(1999)pilo
otRCT
onlythre
reerandomizedco
ontrolledtrials
haveinveestigatedtheimpa
actof
benzodiaazepinesforanxiettydisordersin
laterlife.Twoofthesetrialshavefocused
onGAD,aandonetrialhassstudiedan
earlier,ppotentiallycomparrablecategory
ofanxietyyneurosis.Inallo
ofthese
studies,m
medicationwaseffficacious
relativettoplacebo,withtreatment
effectsevvidentwithinasea
arlyas7days.
Onlyone
estudyprovidedsu
ufficientdata
forthecaalculationofeffecttsize,withd
rangingfr
from0.79to0.95((meand,.85).
Responseeratestomedicationranged
from57%
%to83%.Attrition
nrateswere
Benzoodiazepinesfo
orAnxietySu
CONCLUSIONS
EFFECTIVE,BUTBENEFITSSHOULDBE
WEIGHEDA
AGAINSTRISKS
COMMENTS
Thefocuso
ofthisstudywaso
on
depression
Theauthorssstatethat:Thepotential
benefitsofaddingabenzodia
azepinetoan
antidepresssantmustbebalan
nced
judiciouslyaagainstpossibleha
arms
includingdeevelopmentofdep
pendence
andacciden
ntproneness,ontheone
hand,andaagainstcontinuedsuffering
followingno
oresponseanddropout,on
theother.
EFFFECTIVE(moree
effectivethanplacebo)
Resultsofthemetaanalysisofthe1
17
RRCTsselectedinthisstudysuggestth
hat
d iazepamissignificcantlymoreeffective
thhantheplaceboin
nthetreatmentof
n eurosisorpsychossomaticdisease.
O
OnlyJapanesestud
dieswereincluded.
generallyylow(%17%).
EFFECTIVVE,BUTLONGTER
RM
TREATMEENTNOTRECOMM
MENDEDDUE
TOPOTE NTIALADVERSEEVENTS
Thefocussofthisstudywassongeriatric
anxietyddisordersandalsolookedat
studiesoofcognitivebehavioural
interventtions
ThisrevieewalsoIncludedstudiesof
cognitiveebehaviouralinterrventionsand
pharmacoologicalinterventiionsnot
relevantttoourquestionTh
heauthors
statethaat:Overall,theda
atafromthese
trialssugg
ggestthevalueof
benzodiaazepinesfortreatin
nganxiety
disorderssinolderadults,H
However,
longerteermtreatmentwith
benzodiaazepinesgenerallyisnot
recommeended,particularlyyforolder
adults,giiventhepotentialformore
seriousa dverseevents.Benzodiazepines
canaffecctcognitivefunctio
oningand
psychom
motorperformance
e,leadingtoan
increaseddriskofhipfracturescausedby
falls,adeecreasedabilitytodrive,andan
increase inmemoryproble
ems.
*forsomeSRstheenumbersofstudieesforeachbenzod
diazepinedonotaadduptothetotalnumberofrelevan
ntstudies,assomeetrialsstudiedmo
orethanonetype
ofbenzodiazepinee.
KEY:Benzo/s=B
Benzodiazepine/s
21
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Benzoodiazepinesfo
orAnxietySu
APPENDIX
X2:EVIDEENCEMAP
PSUMMA
ARY
TheTACand
dWorkSafe VictoriarequestedanEvvidenceReviewontheu
useofsedat ivesinanxie
ety,insomniaa
andmuscle spasm.Thisprovedtobeanunfeasiiblylargetop
picwithsom
manydifferenntcombinationsofdrugs
onsneedinginvestigation
n.Itwasdeccidedthatinsstead,aneviidencemapw
evelopedasaa
andconditio
wouldbede
firststepto identify theeavailablehigherleveleevidenceand
dgetanideaofitsquanntityandco
omplexity.An
n
evidencemaapofsystem
maticreviewssandeviden cebasedguidelinesonh
hypnosedativvesforanxie
ety,insomniaa
and muscle spasm was developed(3
3). Drugs claassed as hyypnosedative
es for the p urposes of the
t evidencee
hoselicensedforuseinAustraliaan dlistedinM
MIMsaseithe
erantianxieetyagentso
orsedativess,
mapwereth
hypnotics(sseeTableA2
2.1)
TableA2.1.h
hypnosedative
esincludedin
nEvidenceMaap
Benzodiazep
pines
Alprazolam
Bromazepam
m
Clobazam
Diazepam
Flunitrazepaam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
m
Triazolam
Nonbenzodiazep
pineHypnottics
Zolpidem
Zopicclone
Searches of Medline an
nd Embase, and the intternet yielde
ed 1,943 potentially releevant studie
es. Screeningg
againstinclu
usionandexclusioncriteriaresulted inatotaloff41relevant studies(34 systematicrreviews[SRss]
and 7 evideencebased guidelines
g
[E
EBGs]). See A
Appendix 3 for detailed
d search meethodology and
a selection
n
criteria.
Forincluded
dstudies,theefollowingdatawasextrracted
Studytyype(systematicrevieworrevidencebaasedguideline)
Hypnoseedativesexamined
Indicatio
on
Whetherthestudyw
wasaboutbe
enefits,harm
msorboth
The extracteed data was tabulated in evidencee maps to allow

a
determ
mination of the volume
e of existingg
evidence,an
ndidentifyth
hegaps.Noq
qualityappraaisalwasund
dertakeninttheproducti onoftheEvidenceMap..
Therewere 18SRsand 5EBGsonhypnosedativvesforanxietty;17SRsan
nd2EBGsfoorinsomnia;and1SRfor
musclespassm.ThereweerenoEBGsonhypnoseedativesform
musclespasm
m(TableA1 .2).Thetotalnumbero
of
SRsidentifieed(34)islesssthanthesumofSRsfoortheindividualindicatiions(36)as oneSRcove
eredallthreee
indications.A
Allotherguid
delinesandssystematicreeviewswere
eaboutoneindicationonnly.
TableA2.2.Evidencemapforeachindiccation
Indication
22
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SyystematicReeviews
Evid
denceBaseddGuidelines
Benzoodiazepinesfo
orAnxietySu
18
Insomnia
17
Mu
usclespasm
Anxiety
ThebenzodiiazepineslisttedintheressearchquesttionarethosseusedinAu
ustralia,how
wever,manystudies
includedvarriousotherb
benzodiazepines(i.e.studdiesfromthe
eUKorUSoftenonlyinccludedbenzo
odiazepines
licensedforuseinthatccountry).Thisshouldbekkeptinmind
dwhenlookingatrecomm
mendationsorreported
benzodiazepines,asthelistofdrugs thatdifferen
ntauthorsarereferringttoarenotlikkelytobe
resultsforb
thesame.Fu
urtherdetailabouttheevidenceidenntified(i.e.suchasspecifficindicationnsorindividu
ualdrugs
includedineeachstudy),seeEvidenceMapreporrt(3).
23
ber:0611002R6
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Benzoodiazepinesfo
orAnxietySu
APPEN
NDIX3:EV
VIDENCEM
MAPMETH
HODS
Inclusio
onandexcclusioncritteria
Inclusion
nandexclusioncriteriaw
wereestablisshedapriori(TableA3.1)andwereaappliedbytw
wo
reviewers.Anydiscrrepancieswe
erediscusseddandresolve
ed.
TableA33.1.Inclusionaandexclusioncriteria
Patient/
I
Inclusion:pat
tientswith:
populatio
on
Anxiety(iincludinganxiietydisorders)
Insomnia,or
Musclesp
pasm
A
Allages
E
Exclusion:Co
nditionsoccu rringintheco
ontextofcanccer,StiffMan Syndrome,Atthetosis,
A
Alcoholwithd
drawal,Tetanuus,Statusepilepticus,Allerg
gytreatment (urticaria,pru
uritis),
S
Spasticitydue
etouppermootorneuronlesion,Migraine
e,Dementia, Bipolardisord
der,
S
Schizophrenia
a,Psychosis,N
Neurodegenerrativedisorders,Delirium,BBorderlinepersonality
d
disorder,Dysp
pnoea,Detoxiificationorwiithdrawalfrom
mbenzodiaze pineaddiction
n.
P
Patientsrecei
vingsedativessforthefollowingpurpose
es:preoperativvemedication
n,
i
inductionofa
anaesthesia,seedationinintensivecareunit,asananti emetic.
Interventtion/
I
Inclusion:Stu
udieswherethhefocusisatleastoneofthefollowinghhypnosedatives:
B
Benzodiazepin
nes
indicatorr
A
Alprazolam,B
Bromazepam, Clobazam,Diazepam,Flunitrazepam,Loorazepam,Mid
dazolam,
N
Nitrazepam,O
Oxazepam,Teemazepam,Triazolam
N
Nonbenzodia
azepineHypnootics
Z
Zolpidem,Zop
piclone
E
Exclusion:Stu
udieswherethheincludedhyypnosedativeswereonlyreeportedonassa
c
comparator
Comparisson/
I
Inclusion:An
y
control
E
Exclusion:Nil
Outcomees
I
Inclusion:Ou
utcomesrelateedtoresolutio
on orreductio
onofproblem
mbeingtreated.
O
Outcomesrel
atedtotheefffectoftreatm
mentonfunction(abilitytoconductdailyy
a
activities),QO
OL,othermed icationuse,re
eturntowork
k.Adverseeffeects
E
Exclusion:stu
udiesonpharm
macokinetics
Setting
I
Inclusion:All
healthcaressettingsnoton
ntheexclusionlist(e.g.acuute,primarycare,
r
rehabilitation
)
E
Exclusion:
Intensive careunit
Nursingh
homes
Palliativecare
Studydeesign
I
Inclusion:Evi
idencebased guidelinesorrSystematicre
eviews
E
Exclusion:No
nEBGs,nonssystematicrevviews,random
misedcontrollledtrials,controlled
c
clinicaltrials,
cohortstudie s,casecontro
olstudies,caseseries,editoorials,letters,
c
commentarie
s.
Publicatiiondetails Inclusion:Stu
I
udiesinEnglisshandconducctedonhumans
E
Exclusion:Stu
udiesinlanguaagesotherthaanEnglishand
d/orconducteedonanimalss
Timeperriod
I
Inclusion:Any
ypublicationddate
E
Exclusion:Nil
24
number:0611002R6
Reportn
For a sttudy to be in
ncluded, at least one off the hypnosedatives ha
ad to be speecified in the search
strategyytoensurethatallrefere
encesabout thatdrugw
weresought.Whereaninncludeddruggwasnot
the focu
us of the sttudy, but results of thee drug as a comparatorr were repoorted, the sttudy was
excluded
d.
Dataexxtraction
Dataoncharacteristticsofthestu
udieswereeextractedand
dsummarise
edforevidenncemapping.
Searchstrategy
A highlyy sensitive search
s
in Medline and Embase as detailed below was un dertaken fo
or all the
generic and Australlian productt drug namees to be revviewed. A further
f
highlly sensitive filter for
synthesiizedevidenccewasapplie
edandthereesultslimited
dtothoseinEnglish.TheelargerEmb
baseyield
wasfurttherreduced
dbylimiting theresults tothethree
econditionsunderreview
w;anxiety,iinsomnia
andmussclespasm.
TableA33.2.Databasessaccessed
Databaseename
Datescovere
ed
Datesearche
ed
Refs
Embase
1980to2010
0Week04
05/02/2010
1,4444
Medline
1950toJanuaryWeek32 010
05/02/2010
595
TOTAL
1,9211
TableA33.3.Searchstrrategiesused
Databaseename
Strategy
Embase
1.expAnxietty/
2.(anxietyorranxious).ti,a b.
3.or/12
4.exp"Sleep
pInitiationanddMaintenancceDisorders"//
5.(insomniaorsleep*).ti,aab.
6.or/45
7.expSpasm
m/
8.((muscularrormuscle*) adj5spasm*).ti,ab.
9.or/78
10.Alprazola
am/
11.(AlpraxorAlprazolam orKalmaorX
XanaxorXanaxorZamhexa l).ti,ab.
12.or/1011
13.Bromazepam/
14.Lexotan.tti,ab.
15.or/1314
16.(Clobazam
morFrisium)..ti,ab.
17.Diazepam
m/
18.(AntenexxorDiazepam orDuceneorrRanzepamorValiumorVaalpam).ti,ab.
19.or/1718
20.Flunitraze
epam/
21.Hypnodorm.ti,ab.
22.or/2021
25
number:0611002R6
Reportn
23.Lorazepam/
24.Ativan.ti,ab.
25.or/2324
26.Midazolam/
27.Hypnovel.ti,ab.
28.or/2627
29.Nitrazepa
am/
30.(Alodorm
morMogadonn).ti,ab.
31.or/2930
32.Oxazepam
m/
33.(AlepamorMurelaxorrSerepax).ti,aab.
34.or/3233
35.Temazepam/
36.(Temazep
pamorNormiisonorTemazzeorTemtabss).ti,ab.
37.or/3536
38.Triazolam
m/
39.Halcion.ti,ab.
40.or/3839
41.(Zolpidem
mtartrateorD
DormizolorSo
omidemorStildemorStiln oxorZolpibell
orZolpidem).ti,ab.
42.(Zopiclon
neorImovaneeorImrest).ti,ab.
43.or/12,1516,19,22,25,228,31,34,37,4
4042
44.hypnosed
dative*.ti,ab.
45.43or44
46."review"//orreview.ptt.orreview.ti..
47.(systematicorevidencce$ormethod
dol$orquantitativ$oranallys$or
assessment$).ti,sh,ab.
48.46and47
7
49.MetaAna
alysis/
50.metaana
alysis.mp.
51."systema
aticreview"/
52.(metaanaly$ormetannaly$ormetaaanaly$ormetaanaly$).mpp.
53.((systema
atic$orevide nce$ormethodol$orquan
ntitativ$)adj55(review$or
survey$orovverview$)).ti,aab,sh.
54.((pool$orcombinedoorcombining)adj2(dataortrialsorstudiiesor
results)).ti,ab
b.
55.or/4854
56.exppractticeguideline//
57.(clinicala
adj3guideline *).ti,ab.
58.or/5557
59.45and58
8
60.3and59
61.6and59
62.9and59
63.60or61o
or62
Englisharticlesonly
Medline
1."review"/orreview.pt. orreview.ti.
2.(systematicorevidencee$ormethodo
ol$orquantita
ativ$oranalyys$or
assessment$).ti,sh,ab.
3.1and2
4.metaanalyysis.pt.
5.MetaAnallysis/
6."systematiicreview*".ti,,ab.
26
number:0611002R6
Reportn
7.(metaanaly$ormetanaaly$ormetaanaly$ormeta
a analy$).mp.
8.((systemattic$orevidencce$ormetho
odol$orquanttitativ$)adj5((review$or
survey$orovverview$)).ti,aab,sh.
9.((pool$orcombinedor combining)adj2(dataortrrialsorstudieesor
results)).ti,ab
b.
10.practicegguideline/
11.(clinicala
adj3guideline *).ti,ab.
12.or/311
13.Alprazola
am/
14.(AlpraxorAlprazolam orKalmaorX
XanaxorXanaxorZamhexa l).ti,ab.
15.or/1314
16.Bromazepam/
17.Lexotan.tti,ab.
18.or/1617
19.(Clobazam
morFrisium)..ti,ab.
20.Diazepam
m/
21.(AntenexxorDiazepam orDuceneorrRanzepamorValiumorVaalpam).ti,ab.
22.or/2021
23.Flunitraze
epam/
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
32.Nitrazepa
am/
33.(Alodorm
morMogadonn).ti,ab.
34.or/3233
35.Oxazepam
m/
36.(AlepamorMurelaxorrSerepax).ti,aab.
37.or/3536
38.Temazepam/
39.(Temazep
pamorNormiisonorTemazzeorTemtabss).ti,ab.
40.or/3839
41.Triazolam
m/
42.Halcion.ti,ab.
43.or/4142
44.(Zolpidem
mtartrateorD
DormizolorSo
omidemorStildemorStiln oxorZolpibell
orZolpidem).ti,ab.
45.(Zopiclon
neorImovaneeorImrest).ti,ab.
46.or/15,1819,22,25,28,331,34,37,40,4
4345
47.hypnosed
dative*.ti,ab.
48.46or47
49.12and48
8
Englisharticlesonly
Websittesearchestoidentifyrelevan tevidence
ebasedguidelines
Thereviiewerswere awareofwebsitesofguuidelinecleaaringhouses,guidelinedeevelopers,ce
entresof
evidenceebased pracctice, Austra
alian governm
ment health
h services an
nd websites of specific relevance
(eg.acciidentcompeensationgrou
ups)knownttocontainevvidencebase
edresourcess.
27
number:0611002R6
Reportn
The 17 websites previously

p
id
dentified by the review
w team (9 guideline
g
seervices, 2 Australian
A
governm
ment websitees and 1 centre of eviddencebased practice, an
nd 5 other aaccident com
mmission
websitess)weresearchedforrele
evantEBGs. Detailsofwe
ebsitessearcchedcanbeffoundinTab
bleA1.4.
Where aan internal search engin
ne was avai lable, websiites were se
earched usinng the search strings
detailed
d in the tablee below. If no search eengine was available,list
a
ts of EBGs, ppublications or other
resourceesidentifiedonthesitew
werescanneedforrelevan
ntdocumentts.
TableA33.4.Websitessearchedtoidentifyrelevaantguideliness
GuidelineeServices
NationalInstituteofClinicalStudiess.Clinical
GuidelinesPo
ortal
PracticeG
http://w
www.clinicalgu
uidelines.gov.a
au/
NationalHealthandM
MedicalResearrchCouncil
(NHMRC)www.nhmrcc.gov.au
NationalInstituteforH
HealthandCliinical
ExcellencceUK(NICE)
www.nice.org.uk
Webpaggereviewed: GuidelinePorrtal,Browseby
conditio
on
Webpaggereviewed: Guidelines,heealth
NewZealandGuidelineGroup(NZG
GG)
www.nzggg.org.nz
ScottishIIntercollegiateeGuidelinesN
Network(SIGN
N)
www.sign.ac.uk
GuidelineesInternation
nalNetworkw
www.gin.net
(memberrsonly)
GuidelineesAdvisoryCo
ommittee
www.gaccguidelines.caa
NationalGuidelineCleearinghouseU
US(NGC)
www.guiidelines.gov
Webpaggereviewed:Ourguidancee,healthtopic,Mental
healthandbehaviourralconditions
Webpaggereviewed:Ourguidancee,healthtopic,
Musculo
oskeletal
Webpaggereviewed:GuidelinesanndReports
Webpaggereviewed:GuidelinesM
MentalHealth
Webpaggereviewed:GuidelinesOtther
Webpaggereviewed:International GuidelineLibrary
Searchedbykeywords:sedative,seedatives*,anxxiety,
Rinsomnia,m
muscle,spasm,,AlprazolamO
OR
sleepOR
bromaze
epamORclob
bazamORdia zepamOR
flunitrazzepamORlora
azepamORm
midazolamOR
nitrazep
pamORoxazepamORtemaazepamORtriiazolam
ORzolpiidemORzopicclone
Webpaggereviewed:Listalltopics andsummaries
Searchedby:
d:(Alprazolam
mORBromazeepamORClob
bazamOR
Keyword
FrisiumORDiazepam ORFlunitrazeepamORLora
azepamOR
emazepam
MidazollamORNitrazepamOROxaazepamORTe
ORTriazzolamORZopicloneorImovvaneorImrest)
Disease//Condition:(ttraumaORsppinalORspineORbrain
ORanxieetyORsleepO
ORinsomniaO
ORmuscleOR
muscula
ar))
Searchedby:Drugnames
TRIPDataabasewww.trripdatabase.com
AustraliaanGovernmen
ntWebsitesccontainingGuuidelines
AustralianGovernmen
ntDepartmentofHealthannd
www.health.go
ov.au
Ageingw
NSWHeaalthwww.heaalth.nsw.gov.a
au
Webp
pagereviewed
d:HealthProfeessionalsTreatments
&Tech
hniquesGuidelines
Webp
pagereviewed
d:Publicationss&Resourcess Policy
DirectiivesandGuidelines
Centreso
ofEvidenceB
BasedPractice
eWebsites
WACenttreforEvidencceBasedNurssingand
Midwiferryhttp://waccebnm.curtin.e
edu.au
OtherAcccidentComm
missions
28
number:0611002R6
Reportn
Webp
pagereviewed
d:ResourcesReports,Guidelines
andArrticle

MotorAcccidentsAuthorityNSW
www.maaa.nsw.gov.au
u/
AccidentCompensatio
onCorporation
www.accc.co.nz/index.htm
WorkSafeeVICwww.wo
orkcover.vic.ggov.au
WorkCovverNSWwww
w.workcover.n
nsw.gov.au
WorkCovverWAwww.workcover.w
wa.gov.au
Webp
pagereviewed
d:Publicationss&ReportsMAA
GuidellinesGuidessforProfessioonals
Webp
pagereviewed
d::ForProvideersClinicalB
Best
PracticcePublished
dClinicalGuiddelines
Webp
page reviewed
d:Safety&Preevention;Hea
althand
Safety Topics
Webp
pagereviewed
d:Publicationss
Webp
pagereviewed
d:PublicationssPublication
nsfor
healthproviders
29
number:0611002R6
Reportn

002 Benzodiazepines For Anxiety Summary of Systematic Reviews

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found that both beenzodiazepin

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The 17 websites previously

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