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1
Ben
Summ
June
Emma
Report n
BenzodiaSummarySummary
zodiaz
mary of
2011
a Donoghu
number: 0611‐
azepines for ay of systematiy
zepine
f system
ue, Driss A
‐002‐R6
Acc
Title
nxiety ic reviews – P
Be
Transpo
s for a
matic rev
Ait Ouakri
companying
lain Language
enzodiazepin
ort Acciden
anxiety
views
m
g document
e 0611
es for Anxiety
nt Commi
y
ts to this rep
1‐002‐R6.2
y – Summary
ssion & W
port
Report num
of Systematic
WorkSafe V
mber
c Reviews
Victoria
2 Report n
CONTE
CONTENT
PLAIN LA
BACKGRO
FINDING
SUMMAR
SUMMAR
AMSTAR
REFEREN
APPENDI
APPENDI
APPENDI
number: 0611‐
ENTS
TS ................
ANGUAGE SUM
OUND & MET
S ..................
RY ................
RY TABLES ....
R TABLE .........
NCES ..............
IX 1: EXPAND
IX 2: EVIDENC
IX 3: EVIDENC
‐002‐R6
.....................
MMARY ........
THODS ..........
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DED SUMMAR
CE MAP SUMM
CE MAP METH
Be
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RY TABLES ......
MARY ...........
HODS ............
enzodiazepin
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.....................
es for Anxiety
.....................
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y – Summary
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of Systematic
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c Reviews
............. 2
............. 3
............. 4
............. 5
............. 8
............. 9
........... 12
........... 14
........... 15
........... 22
........... 24
3 Report n
Ben
Plain
Anxiety
an anxie
to disrup
Benzodi
Based o
benzodi
All agree
judge th
number: 0611‐
zodiaz
n langua
disorders ar
ety disorder a
pted social li
azepines are
on 118 studi
azepines hel
ed that there
he risks and b
‐002‐R6
zepine
age sum
re the most
at some time
ife and poor
e used by do
es, it is unc
lp, while oth
e are possib
benefits befo
Be
Transpo
s for a
mary
common me
e in their life
health.
ctors to trea
lear if benzo
ers did not. T
le harms wit
ore prescribi
enzodiazepin
ort Acciden
anxiety
ental disorde
e. This can be
at anxiety.
odiazepines
They were n
th benzodiaz
ng them.
es for Anxiety
nt Commi
y
ers. About o
e associated
help to trea
not good qua
zepines. They
y – Summary
ssion & W
ne in four ad
with severe
at anxiety.
ality studies.
y say that do
of Systematic
WorkSafe V
dults in Aust
distress. It
Some studi
octors must
c Reviews
Victoria
tralia has
can lead
es found
carefully
4 Report n
BACKG
Benzodi
continue
(sedativ
and cost
have reg
physical
impairm
The TAC
(licensed
research
of syste
identifie
Table A
method
Given t
benzodi
of these
for asse
designed
each SR
(lowest
In this r
benzodi
complica
number: 0611‐
GROUND &
azepines hav
e to be one o
e/hypnotic,
t has gained
gularly poin
dependen
ments and an
C and Work
d for use in
h, an eviden
matic review
ed 34 SRs an
A2.2). A sum
ology can be
he breadth
azepines for
e SRs were s
essment of m
d to give an
R with 0/11
risk of bias).
report we p
azepines for
ated body of
‐002‐R6
& METHO
ve been wid
of the most
anxiolytic, a
them popul
ted out the
ce, withdra
increased ri
kSafe Victor
Australia) fo
ce map was
ws (SR) and
nd seven EB
mmary of th
e found in Ap
of the evid
r anxiety diso
summarized
multiple sys
overall qual
representin
present a su
r anxiety dis
f evidence u
Be
ODS
ely used in c
consumed a
nticonvulsan
arity among
risks relate
awal sympt
isk of falls an
ria requeste
or anxiety, in
developed a
evidence‐ba
BGs on hypn
e evidence
ppendices 2 a
dence inden
orders relate
and their me
tematic revi
ity score for
ng lowest qu
mmary of t
sorders. This
nderlying the
enzodiazepin
clinical pract
and highly pr
nt and muscl
physicians a
ed to long t
oms and o
nd fractures,
ed an evide
nsomnia and
as a first ste
ased guidelin
nosedatives f
map and a
and 3, respe
ntified, the
ed to traffic
ethodologica
iews (AMSTA
SRs. These s
uality (highe
the existing
s is intende
ese common
es for Anxiety
ice since the
rescribed cla
le relaxant),
and patients
erm use of
other adve
particularly
nce review
d muscle spa
ep to determ
nes (EBG) on
for anxiety,
detailed de
ectively.
topic was
accidents or
al quality ass
AR).(4) The A
scores give a
est risk of b
systematic
d to provide
nly prescribe
y – Summary
eir introducti
ss of drugs. T
combined w
.(1) Since the
benzodiazep
rse effects
in elderly pa
on the use
sm. To iden
mine the qua
n the topic.(3
insomnia or
escription of
refined to a
r workplace
sessed using
AMSTAR is a
an indication
bias), and 11
reviews on
e an overvie
d drugs.
of Systematic
ion in the 19
Their range
with their low
early 1980’s
pines. These
such as c
atients.(2)
e of hypnos
tify the scop
ntity and co3) The evide
r muscle spa
f the eviden
a review of
injuries. Th
a measurem
an eleven it
n of the risk o
1/11 highes
the effectiv
ew of the la
c Reviews
950’s and
of action
w toxicity
s, studies
e include
cognitive
sedatives
pe of the
omplexity
nce map
asm (see
nce map
f SRs on
he details
ment tool
tem tool
of bias of
t quality
veness of
arge and
5 Report n
FINDIN
A total o
identifie
(Table 1
other ty
The num
most inv
(n=6). O
quality s
7/11. Ta
AMSTAR
in greate
Genera
Five SRs
These re
of treatm
The dru
focused
alprazol
azapiron
several o
as well
effective
There w
the effe
scores.
benzodi
In terms
term eff(8, 9) dre
studies i
for the s
included
We iden
Table 4)
of 8/11
lorazepa
number: 0611‐
NGS
of ten system
ed. Five revi
1), two review
pes of anxie
mber of ben
vestigated d
Overall, the
score of 5/1
able 4 prese
R rating item
er detail in A
alized Anxi
s conducted
eviews all ad
ment, compa
ugs and com
exclusively
am against
nes against
other classe
as trials com
eness of psyc
were also diff
ectiveness of
While, one
azepine‐bas
s of duration
fect of benzo
ew conclusio
in Martin et
studies inclu
d trials of var
ntified impo
. Among the
(see Table
am vs. pill p
‐002‐R6
matic review
ews investig
ws assessed
ty (Table 3).
zodiazepines
rug appeari
quality of th
11 or less (se
nts the met
ms. Character
Appendix 1.
iety disord
between 19
ddressed slig
arators, and
mparators st
on benzodia
placebo. O
placebo. Tw
s of drugs co
mparing effe
chological tr
ferences in th
f benzodiaze
e review(8)
ed treatmen
of treatmen
odiazepines o
ons on the
al.(8) lasting
uded in Mitte
rious duratio
rtant differe
ese reviews,
1). This SR
placebo). The
Be
ws of the effe
gated the us
their use fo
s investigate
ng in all of t
he included
ee Table 4).
hodological
ristics and re
der
997 and 2007
htly differen
outcomes m
tudied acros
azepines and
ne review(9)
wo reviews(5,
ompared to
ctiveness be
eatments fo
he outcomes
epines as po
measured e
nts compared
nt, the study
on GAD by in
short‐term e
4‐weeks or
e et al.(9). Th
ons ranging b
ences in met
Mitte et al.(9
included 26
e review co
enzodiazepin
ectiveness of
se of benzo
or panic diso
ed by each S
the 10 SRs, f
systematic
Three revie
quality of ea
sults of the i
7(5‐9) investig
nt research q
measured (se
ss the five S
d included R) compared, 6) examined
placebo, and
etween drug
r GAD.
s reported in
ooled effect
effectiveness
d to placebo
y by Mahe et
ncluding stud
effects of b
less, and an
he remaining
between 2 to
thodological9) presented
relevant st
ompared aza
es for Anxiety
f benzodiaze
odiazepines f
order (Table
SR ranged fr
followed by
reviews was
ews achieved
ach included
included SRs
gated the eff
uestions in r
ee Table 1).
SRs differed
RCTs that com
the effectiv
d the effect
d one SR(7) in
gs. The revie
n each SR. Th
sizes based
s as the ri
.
t al.(7) was th
dies of more
enzodiazepi
average du
g two SRs, Go
o 9 weeks, an
quality betw
the lowest r
udies (most
apirones, ben
y – Summary
epines for an
for generaliz
2) and three
om 1 to 5.
Diazepam (
s low, with
d an AMSTA
d SR with reg
are present
fect of benzo
regard to dru
as follows.
mpared diaz
veness of b
iveness of b
ncluded plac
w by Gould(
hree of the re
on behavio
isk ratio of
e only SR to
e than 8 wee
nes, with m
ration of tre
ould et al.(5)
nd 4 to 12 we
ween the fiv
isk of bias w
ly on diazep
nzodiazepine
of Systematic
nxiety disord
zed anxiety
e reviews foc
Alprazolam
n=8) and Lo
six studies
AR score hig
gard to the
ted in Tables
odiazepines
ugs studied,
. Only one
zepam, loraz
benzodiazepi
benzodiazep
cebo‐control(5) also looke
eviews(5, 6, 9)
oural tests o
f withdrawi
investigate t
eks duration.
most of the
eatment of 5
and Hidalgo
eeks, respec
ve included
with an AMST
pam, alprazo
es and place
c Reviews
ers were
disorder
cused on
was the
orazepam
having a
her than
different
s 1‐3, and
on GAD.
duration
review(8)
zepam or
ines and
ines and
led trials
ed at the
reported
f anxiety
ng from
the long‐
Two SRs
included
.3 weeks
o et al.(6),
ctively.
SRs (see
TAR score
olam and
ebo, and
6 Report n
found t
anxiety
drug cla
other ph
are to b
prescrip
term us
method
result in
these st
life.
Panic d
Two SRs
by Cox e
treatme
exposur
flaws; fo
determi
al.(10) ha
The SR
combini
AMSTAR
data on
differen
alone). T
effective
lack of h
primary
Other t
Three SR
The revi
the pha
of benzo
This RCT
resulting
the auth
adverse
Inada et
diazepam
number: 0611‐
hat both be
and comorb
asses, patien
harmacologi
be preferred
ptions to sho
e such as p
ological limi
n an overly p
udies conce
disorder
s investigate
et al.(10) asses
ents for pan
re therapies
or example,
ne the quali
s a high risk
by Watana
ng benzodia
R score of 10
2 different
t strategies a
The main co
eness of psyc
high‐quality t
outcomes o
types of an
Rs assessed t
iew by Weth
rmacologica
odiazepines
T was stop
g in sample
hors of the
effects asso
t al.(13) cond
m in improvi
‐002‐R6
enzodiazepin
bid depressio
nt complianc
cal approach
to other dru
ort‐term use
hysical depe
tations in th
positive outc
rns the lack
d the effect
ssed the effi
ic disorder w
are both ef
no details of
ity of the re
of bias (AMS
abe et al.(1
azepines an
0/11. The r
benzodiazep
assessed (co
onclusion fro
chotherapy c
trials; three
of the review
nxiety
the effective
herell et al.(1
l interventio
for anxiety d
ped premat
sizes that w
SR noted t
ociated with l
ducted a syst
ing anxiety s
Be
nes and azap
on in GAD.
ce was bett
hes. Based o
ugs as a sho
due to the
endence, wit
he included
come and a
of assessme
of benzodia
cacy of alpra
with agorap
fective for P
f the include
search upon
STAR score o
1) compared
d psychothe
review includ
pines. No st
ombination o
om the revie
combined w
RCTs were id
(see Table 2
eness of benz14) investigat
ons identified
disorders in
turely due t
were too sma
he value of
long‐term us
tematic revi
states in pati
enzodiazepin
pirones wer
Although n
ter with ben
on this resul
rt term trea
increasing ri
thdrawal, an
studies such
biased estim
ent of how t
azepines on p
azolam, imip
phobia (PDA)
PDA. Howev
ed studies ar
n which the
of 2/11), whi
d the effec
erapy and p
ded three tr
tatistically sig
of psychothe
ew was that
with benzodia
dentified, on
2).
zodiazepines
ted all treat
d, the review
later life, on
to concerns
all to genera
short‐term
se.
iew of Japan
ents with ne
es for Anxiety
re more effe
o difference
nzodiazepine
t, the review
tment strate
isk of seriou
nd memory
h as the lack
mation of ef
he treatmen
panic disorde
pramine and
). The review
er, the stud
re provided m
findings are
ch limits the
tiveness of
presented t
rials involvin
gnificant diff
erapy and be
there is ina
azepines for
nly two of wh
s for other ty
ments of ge
w found thre
nly one of th
about adv
ate solid con
use of ben
nese trials in
eurosis or ps
y – Summary
ective than
e in efficacy
e‐based trea
w suggests t
egy. The aut
s adverse ef
loss. They a
k of double‐b
fficacy. Anot
nt impacts on
er(10, 11) (see
exposure to
w suggests t
y has nume
meaning tha
based. Ove
validity of it
different t
he lowest r
g 166 partic
ference was
nzodiazepine
adequate ev
panic disord
hich could co
ypes of anxie
riatric anxie
ee RCTs inve
hese was rel
erse events
nclusions abo
zodiazepine
nvestigating
ychosomatic
of Systematic
placebo in
was found
atment com
that benzodi
hors suggest
ffects follow
also highligh
blindness, w
ther issue in
n patients’ q
Table 2). Th
o phobic situ
that alprazo
rous metho
at it is not po
rall the SR b
ts conclusion
treatment s
risk of bias
cipants and
s found betw
es vs. psycho
vidence to as
der. This was
ontribute da
ety(12‐14) (see
ety disorders
estigating th
levant to thi
s and high
out efficacy.
s, and the
the effectiv
c disease. Th
c Reviews
reducing
between
pared to
azepines
t limiting
ing long‐
t several
which can
most of
quality of
he review
ations as
olam and
dological
ossible to
by Cox et
ns.
trategies
with an
provided
ween the
otherapy
ssess the
due to a
ta to the
Table 3).
s. Among
e impact
is report.
attrition,
. Overall,
potential
veness of
he review
7 Report n
included
to be s
18mg/d
RCTs sel
perform
These m
importa
(AMSTA
with cau
The rev
9/11. It
treatme
random
RCTs var
low qua
one tria
conflicti
combini
alone in
of depe
recomm
drug to a
number: 0611‐
d 17 placebo
significantly
ay dose ove
lected was h
med in only
methodologic
nt source of
AR score of 3/
ution.
view by Furu
t investigate
ent of adult
ized control
ried in terms
lity (due to u
al followed
ng findings,
ng benzodia
n terms of de
endence an
mended that
a patient.
‐002‐R6
o‐controlled
more effec
er a period o
high. Howeve
seven studie
cal shortcom
f bias for the
/11), therefo
ukawa et al.(1
ed the effe
ts with anx
led trials (R
s of quality,
uncertainties
patients be
making the
azepines wit
epressive sym
d withdraw
clinicians ca
Be
RCTs conduc
tive than p
of two weeks
er, they also
es and that
mings were n
e pooled est
ore, the findi
12) had the h
cts of com
iety associa
CTs) and me
with two co
s about blind
eyond eight
m hard to i
th antidepre
mptoms and
wal syndrom
arefully asse
enzodiazepin
cted betwee
placebo with
s or more. T
noted that a
several stu
not accounte
timates repo
ings and con
highest meth
mbining benz
ated with m
eta‐analysed
onsidered hig
ding, or high
weeks, an
nterpret and
essants was
d anxiety sev
me associate
ss the benef
es for Anxiety
n 1970 and
h an optima
The authors s
an intention
dies reporte
ed for in the
orted in the
nclusions of t
hodological q
zodiazepines
major depre
d the results
gh quality, fo
drop‐out rat
d that som
d generalise
superior to
verity. The a
ed with the
fits and risks
y – Summary
1992. The st
al treatment
stated that t
to treat ana
ed a large n
meta‐analy
SR. This SR
this review s
quality with
s with antid
ssion. The
s of 731 pat
our intermed
tes). The aut
e of the in
. Overall, th
treatment w
authors also
e use of b
s before pre
of Systematic
tudy found d
t regimen o
the quality o
alysis of the
number of d
ysis and repr
had high ris
hould be int
an AMSTAR
depressants
review incl
tients. The
diate quality
thors noted t
ncluded stud
he review fo
with antidep
emphasized
benzodiazepi
escribing this
c Reviews
diazepam
of 12 or
of the 17
data was
dropouts.
resent an
sk of bias
erpreted
score of
for the
uded 10
included
and two
that only
dies had
und that
pressants
d the risk
nes and
s class of
8 Report n
SUMM
Overall,
scores)
populati
an overa
The five
investiga
multifac
benzodi
found t
benzodi
measure
receiving
pills. It
psycholo
For pan
combine
available
The sam
types of
the impo
et al.(12)
review r
effects o
The ma
interpre
the met
publicat
importa
adverse
and pos
number: 0611‐
MARY
there is a la
for most st
ions, drugs,
all answer on
e SRs assessi
ating six ou
ceted review
azepines we
hat the ava
azepines wa
e based on
g benzodiaz
is important
ogical treatm
ic disorder,
ed with psy
e evidence.
me uncertain
f anxiety. Fo
ortant meth
does not a
reports the r
of benzodiaz
ajor method
etation of the
thodological
tion of non‐s
nt point whi
effects relat
sible harms
‐002‐R6
ack of consis
tudies. Each
comparators
n the effectiv
ng the effec
ut of the
ws,(5, 6, 9) inclu
ere an effec
ailable evide
as unable to
patients’ wit
epines with
t to note th
ments, which
a high‐qual
ychotherapy
ty exists am
r example, t
odological s
allow us to d
results of a c
epines alone
dological dif
eir findings. F
shortcoming
statistically
ich has been
ted to the u
before presc
Be
stency acros
h SR aimed
s, or outcom
veness of be
ct of benzod
eleven type
uding the one
ctive short‐te
ence was in
find convin
thdrawal rat
drew from t
hat none of
do not carry
lity Cochran
was unable
ong the revi
he evidence
hortcomings
draw any co
ombination
e.
fferences ex
Further, all p
gs of the inc
significant r
n consistently
se of benzod
cribing them
enzodiazepin
ss the SRs’ fi
to answer
mes studied)
enzodiazepin
diazepines o
es of benzo
e with the h
erm treatme
conclusive.(7
ncing eviden
tes, the revi
treatment a
these revie
y a risk of ph
e SR(11) asse
e to draw c
iews address
e of effective
s of the RCTs
onclusion on
of benzodia
xisting betw
positive resu
cluded RCTs,
results) inhe
y discussed i
diazepines a
.
es for Anxiety
indings and
a slightly d
making their
es as a treat
n GAD inclu
odiazepines
highest AMST
ent for pati7) The only
ce of their e
iew by Mart
t the same
ews compare
hysical depen
essing the e
conclusions d
sing the effe
eness reporte
s included in
n the specifi
zepines and
ween the in
lts should be
and the pot
rent to all S
in all the inc
and the nece
y – Summary
a high risk o
different que
r results diffi
ment for anx
ded a total
registered
TAR score (8
ents with G
SR that exc
effectiveness
tin et al.(8) s
rate as thos
ed effects b
ndence.
effectiveness
due to the
ects of benzo
ed by Inada
the review.
c effect ben
antidepress
cluded SRs
e interpreted
tential publi
SRs and met
luded SRs co
essity to care
of Systematic
of bias (low
estion (i.e.
icult to com
xiety.
of 41 differe
in Australia
8/11), conclu
GAD. Anothe
clusively foc
s. Using an
howed that
se receiving
benzodiazepi
s of benzodi
poor qualit
odiazepines f
et al.(13) is li
The SR by F
nzodiazepine
ants, rather
prevent an
d with cautio
ication bias (
ta‐analyses.
oncerns the
efully assess
c Reviews
AMSTAR
different
bine into
ent trials
a. Three
uded that
er review
cused on
outcome
subjects
placebo
nes with
azepines
y of the
for other
mited by
Furukawa
es as the
than the
n overall
on due to
(i.e. non‐
Another
potential
benefits
9R
S
TST
A
B
A
B
C
D
Fl
Lo
M
N
O
Te
T
CIN
DT
O
RC
C
*fK
9 Report number: 061
SUMMARY TA
Table 1. Systematic TUDY G
AMSTAR RATING 4/
ENZODIAZEPINES*
Alprazolam
romazepam
lobazam
Diazepam
lunitrazepam
orazepam
Midazolam
Nitrazepam
Oxazepam
emazepam
riazolam
OMPARATORS OF NTEREST
P
TRIr
DURATION OF REATMENT
N
OUTCOMES Mm
ESULTS AND ONCLUSIONS
E(mBmDA
OMMENTS thp(n
for some SRs the numbersEY: GAD = Generalised An
11‐002‐R6
ABLES
reviews of benzodGould 1997(5)
/11
3 studies
3 studies
1 study
8 studies
5 studies
harmacotherapy vs Plac
otal included drug studiesRelevant studies (n= 17) rrelevant studies (n=5)
Not specified
Measure of anxiety or wormeasure of depression (eff
FFECTIVE more effective than placeenzos in order of effectiv
most to least: Diazepam, Lorazepam, BroAlprazolam
his review also looked at sychological treatments vn=13)
s of studies for each benzonxiety Disorder Benz
diazepines for GeneHidalgo 20
5/11
ebo
s (n=22)
Pharmaco Total incluRelevant sIrrelevant
Not specif
rry & fect size)
Measure o
ebo) veness from
omazepam,
EFFECTIVEOrder of eleast: PregVenlafaxinBuspironealternative
vs control A study ofin the revinot reportanalysis”
odiazepine do not add upzo/s = Benzodiazepine/s
eralised Anxiety Di007(6)
1 study
1 study
2 studies
otherapy vs Placebo
uded studies (n=21) studies (n= 4) studies (n=22)
fied
of anxiety (effect size)
E (low to moderate)effectiveness from most togabalin, Hydroxyzine, ne SR, Benzos, SSRIs, e, complementary and e medicines.
f bromazepam was includiew, but efficacy data wasted and not included in th
p to the total number of reSSRIs = Selective Se
sorder Mahe 2000(7)
2/11
1 st
1 st
7 stu
3 stu
Pharmacotherapy other drugs Total included studRelevant studies ( Irrelevant studies
Long‐term (8 week
Benefits to patientterm treatment of Measure of anxiety
o INCONCLUSIVEEvidence of effectiinconclusive
ded s he
This review looks atreatment of GAD n.b. this review alstreatment for non anxiety disorder (n
elevant studies, as some trerotonin Reuptake Inhibit
Benzod
M
6/
tudy
tudy
udies
udies
vs placebo or
dies (n=13) n=8) (n=5)
Be ToReIrr
ks or longer) Sh
ts/ successful long‐anxiety y
EffroSidwi
veness is NO(nBeshdifpl
at long‐term (8 weeks or longer) so looked at well‐defined n=5 studies)
rials studied more than ontors
diazepines for Anx
Martin 2007(8)
/11
4 studies
12 studies
7 studies
enzodiazepine vs placebo
otal included studies (n=2elevant studies (n= 23) relevant studies (n=0)
hort‐term (not defined)
fficacy: as measured by wom study de effects: as measured bithdrawals due to adverse
OT EFFECTIVE ot more effective than penzos are not effective fohort‐term treatment of GAfference between benzosacebo)
ne type of benzodiazepine
iety – Summary of
Mitte 2005
8/11
o
3)
Pharmacot Total incluRelevant sIrrelevant
Short‐term
withdrawals
by e events
Anxiety, declinical signto anxiety)
lacebo) r the AD (no s and
EFFECTIVE (more effeBenzos andeffective, beffective thtreatment
This reviewplacebo,anand then c
e.
Systematic Review
5(9)
6 studies
3 studies
13 studies
7 studies
1 study
therapy vs placebo
ded studies (n=48) tudies (n=26) studies (n=22)
m (not defined)
epression, quality of life, onificance (only pertaining ).
ective than placebo) d azapirones equally both classes of drug morehan placebo for short‐term
w looked at benzos vs nd azapirones vs placebo ompared effect sizes
ws
or
e m
10 Report n
Table 2. SSTUDY
AMSTAR RA
BENZODIAZ
Alprazolam
Bromazepa
Clobazam
Diazepam
Flunitrazepa
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
COMPARATOF INTERES
OUTCOMES
CONCLUSIO
*for some Sthan one typ KEY: PDA =
number: 0611‐
Systematic reCox 19
ATING
ZPINES*
m
am
m
m
TORS ST
This malprazoInclude **No ltherefodetermthe com
S 1/ Dysp2/ Freq3/ Seve4/ Ago5/ Ago6/ Gen7/ Ove
ONS EFFECTAlprazoAlprazovariablfor phoExposuAlprazo
SRs the numbers ofpe of benzodiazep
Panic Disorder wit
‐002‐R6
eviews of ben992(10)
eta‐analysis calcuolam, Imipramine ed studies (n=34)
ist or details of incore, it was not posmine the number omparators used in
phoria or depressiquency of panic aterity of panic attacraphobic fear raphobic avoidancneralized anxiety erall improvement
TIVE olam and exposurolam was significales in PDA, while eobia variables. ure had the most colam was not effe
f studies for each bine.
th Agoraphobia
Be
zodiazepines
2/11
**
lated and compareand exposure the
cluded studies werssible to list the incof studies of alpraz these
ion tacks per week cks
ce behaviour
ratings
e therapies both ently effective for pexposure was signi
consistently strongctive for agorapho
benzodiazepine do
Benzo/s = Benzod
enzodiazepin
for Panic Dis
ed effect sizes of rapy
re provided, cluded studies zolam or determin
effective for PDApanic and anxiety ificantly effective
g effect sizes obic dimensions
o not add up to the
diazepine/s
es for Anxiety
order Watanabe 2
ne
benzos + psytreatment) Total includeTotal relevaIrrelevant st
Primary out“Response” Panic DisordSecondary o1. Panic diso2. Frequency3. Phobic av4. General a5. Depressio6. Social fun7. Quality of8. Patient sa9. Economic
INSUFFICIENInsufficient ebenzodiazep
e total number of r
y – Summary
2009(11)
10
2 st
1 s
ychotherapy vs (p
ed studies (n=3) nt studies (n=3) udies (n=0)
come(s):(as defined by autder Severity Scale (outcome(s): order global severiy or severity of paoidance nxiety on ctioning f life tisfaction with trecosts
NT EVIDENCEevidence to assesspines + psychother
relevant studies, a
of Systematic
0/11
tudies
study
psychotherapy alo
thors of included s(PDSS) score of 7 o
ity on a continuounic attacks
eatment
s clinical effects ofrapy for panic diso
as some trials stud
c Reviews
one or benzo
studies), or a or below.
s scale
f order
ied more
11 Report n
Table 3. SSTUDY
AMSTAR RA
TYPE OF AN
BENZODIAZ
Alprazolam
Bromazepa
Clobazam
Diazepam
Flunitrazepa
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
COMPARATINTEREST
OUTCOMES
CONCLUSIO
COMMENTS
*for some Sthan one typ KEY: Benzo
number: 0611‐
Systematic reFuruk
ATING 9/11
NXIETY anxietdepre
ZEPINES*
m
am
m
m
TORS OF Antidantide Total Relev
S Prima(at leaSympobserSecon1. ResAccepsevereffect
ONS EFFECWEIG
S The fodepre
SRs the numbers ofpe of benzodiazep
o/s = Benzodiazep
‐002‐R6
eviews of benkawa 2001(12)
ty associated withession
1 study
1 study
1 study
1 study
epressant + benzoepressant alone
Included studies (ant included studi
ary outcome: Depast one measure) tom severity (self‐rver‐rating) ndary outcomes: sponse in depressiptability of treatmity; 4. Insomnia sets
CTIVE, BUT BENEFGHED AGAINST RIS
ocus of this study ession
f studies for each bine.
ine/s
Be
zodiazepines
h major
y
y
y
y
o vs
n=10) ies (n= 4)
ressive severity,
‐report or
ion; 2. ent; 3. Anxiety everity; 5. Side
ITS SHOULD BE SKS
was on
benzodiazepine do
enzodiazepin
for other typInada 2003(13)
3/11
neurosis or psyc
2
1
both diazepam as controls on a Total Included sRelevant includ
Final Global Imp(FGIR) used to coverall severity expressed as a meta‐analysis
EFFECTIVE (morplacebo) Diazepam is moplacebo for neudisease
Only Japanese s
o not add up to the
es for Anxiety
pes of anxiety
chosomatic diseas
1 study
2 studies
17 studies
1 study
and placebo wereall studies
studies (n=17) ed studies (n= 17)
provement Rating capture “changes iof patient symptoRelative Risk after
re effective than
ore effective than urosis or psychoso
studies were inclu
e total number of r
y – Summary
Wethre
5/11
se any anx
e used
Benzo v Total inc(n=8) Relevan
scale n the oms”
effect si(includinImpressScale; STAnxiety Analogu
matic
EFFECTITREATMDUE TO
ded. The focuanxiety studies interven This revcognitivand pharelevant
relevant studies, a
of Systematic
ell 2005(14)
xiety disorder
1 study
vs antidepressant v
cluded pharmalog
nt included studies
ize for each outcong: CGI, Clinical Glsion; HAMA, HamiTAI, Spielberger StInventory; VAS, Vue Scale)
IVE, BUT LONG TEMENT NOT RECOMO POTENTIAL ADVE
us of this study wadisorders and alsoof cognitive behavntions
view also Included ve behavioural intearmacological intet to our question
as some trials stud
c Reviews
vs placebo
gical studies
s (n=1)
me measure lobal lton Anxiety tate‐Trait Visual
RM MMENDED ERSE EVENTS
as on geriatric o looked at vioural
studies of erventions rventions not
ied more
1R
A
T
A
1
2e
3
4u
5p
6p
7a
8u
9st
1
1
A
12 Report number: 061
AMSTAR TABL
Table 4. AMSTAR(4)
AMSTAR checklist it
1. Was an 'a priori' d
2. Was there duplicaextraction?
3. Was a comprehen
4. Was the status ofused as an inclusion
5. Was a list of studiprovided?
6. Were the charactprovided?
7. Was the scientificssessed and docum
8. Was the scientificused appropriately i
9. Were the methodtudies appropriate?
10. Was the likeliho
11. Was the conflict
AMSTAR score
11‐002‐R6
LE
rating of included
tems
design provided?
ate study selection
nsive literature sea
f publication (i.e. grn criterion?
ies (included and ex
teristics of the inclu
c quality of the inclumented?
c quality of the incluin formulating conc
ds used to combine?
od of publication b
t of interest include
systematic reviews
and data
rch performed?
rey literature)
xcluded)
uded studies
uded studies
uded studies clusions?
the findings of
ias assessed?
ed?
s Gould 1997(5)
Hidalgo 2007(6)
No Yes
Can’t answer
Yes
Yes Yes
Yes Yes
No No
Yes Yes
No No
No No
Yes Yes
No Yes
No No
4/11 5/11
Mahe 2000(7)
Ma200
No
Yes a
No
No
No
Yes
No
No
Can’t answer
No
No
2/11
Benzod
artin 07(8)
Mitte 2005(9)
No No
Can’t answer
Yes
Yes Yes
Yes Yes
No No
No Yes
Yes Yes
Yes Yes
Yes Yes
Yes Yes
No No
6/11 8/11
diazepines for Anx
Cox 1992(10)
Watan2009(1
Can’t answer
Ye
Can’t answer
Ye
Yes Ye
Can’t answer
Ye
No Ye
No Ye
No Ye
No Ye
Yes Ye
No Ye
No N
2/11 10/
iety – Summary of
nabe 11)
Furukawa 2001(12)
es Yes
es Yes
es Yes
es Yes
es Yes
es Yes
es Yes
es Can’t answer
es Yes
es Yes
o No
/11 9/11
Systematic Review
Inada 2003(13)
Wethrell 2005(14)
No No
No Can’t answe
No Yes
No Can’t answe
No No
Yes Yes
Yes No
Yes Yes
No N/A
No N/A
No Can’t answe
3/11 5/11
ws
r
r
r
13 Report n
DISCLA
The infor
point to
preparat
Institute
concerni
human e
cannot a
complete
may be f
the infor
professio
CONFL
The TAC/
accept fu
vested in
The TAC
recognise
Evidence
number: 0611‐
AIMER
rmation in this
consider cu
ion of the m
do not warra
ng the efficac
error or adva
and do not w
e. Accordingly
found in this
rmation conta
onal expert ad
LICT OF IN
/WSV Eviden
unding from p
nterest in the
C/WSV Health
e that any m
e Service has f
‐002‐R6
s report is a s
rrently availa
materials inclu
ant the accur
cy, appropriat
ances of med
warrant that t
y, they are no
publication. Y
ained in this
dvice from a le
NTEREST
ce Service is
pharmaceutic
outcomes of s
h Services Gr
materials deve
full editorial co
Be
ummary of th
able research
uded in this p
racy of this do
eness or suita
ical knowledg
the informati
ot and will not
You are there
publication a
egally qualified
provided by
al or biotechn
systematic rev
oup has eng
eloped must b
ontrol.
enzodiazepin
hat available a
h evidence. W
publication, t
ocument and
ability of any t
ge the autho
ion contained
t be held resp
efore encoura
and, in the ev
d and approp
the National
nology compa
views.
gaged the NT
be free of in
es for Anxiety
and is primaril
Whilst apprec
the authors a
deny any re
treatment or
ors and the N
d in these pa
ponsible or lia
ged to consu
vent that med
riately experi
l Trauma Res
anies or other
TRI for their
fluence from
y – Summary
y designed to
ciable care h
and the Natio
presentation,
product. In vi
National Trau
ages is in eve
able for any er
lt other sourc
dical treatme
enced medica
earch Institut
r commercial
objectivity a
parties with
of Systematic
o give readers
as been take
onal Trauma
, implied or e
iew of the pos
uma Research
ery aspect ac
rrors or omiss
ces in order t
nt is required
al practitioner
te. The NTRI
entities with
nd independ
h vested inter
c Reviews
a starting
en in the
Research
expressed,
ssibility of
h Institute
ccurate or
sions that
o confirm
d, to take
r.
does not
potential
ence and
rests. The
14 Report n
REFER1. Jun;4(2):
2. Pharmac
3. Melbour
4. measure2007;7:1
5. generaliz
6. generaliz
7. Psychoph
8. generalizclinical tr
9. generaliz
10. agorapho82.
11. disorder.
12. Cochrane
13. analysis oAug;18(6
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Blanco C, Schological treat
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Shea BJ, Grimment tool to a0.
Gould RA, Ottzed anxiety dis
Hidalgo RB, Tzed anxiety dis
Mahe V, Baloharmacol. 200
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Watanabe N,. Cochrane Da
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‐002‐R6
agement of c
neier FR, Schmment of socia
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mshaw JM, Weassess the me
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inz‐Pardo M, Fsorder: heteropharmacol. 20
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ells GA, Boers ethodological
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vidson JR. An ehopharmacol
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Furukawa TA. Rev. 2009(1):C
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enzodiazepin
nia in elderly
o‐Jerez CR, Morder: a meta‐
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tidepressant p.
TA. Efficacy oftrials carried o
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arshall RD, Saanalysis. Depr
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ytic review of pr;25(2):141‐5
sis of treatmenBehav Ther E
ychotherapy
plus benzodia
f diazepam as out in Japan. H
reatment of g
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anchez‐Lacay Aress Anxiety. 2
and muscle sRR) 2010 (Unp
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atments for
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ajor depressio
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ety disorders.
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nce Map. port).
STAR: a ol.
of
Clin
es in lysis of
ment in
3(3):175‐
anic
on.
ta‐03
Psychiatr
15 Report
APPE
Table ASTUDY
AMSTAR
BENZOD
Alprazola
Bromaze
Clobazam
Diazepam
Flunitraz
Lorazepa
Midazola
Nitrazep
Oxazepa
Temazep
Triazolam
PATIENT
OUTCOM
t number: 0611‐002
ENDIX 1: EXPA
A1.1 Systematic reGould 19
R RATING 4/11
IAZEPINES*
am
epam
m
m
zepam
am
am
am
m
pam
m
TS Patients IIIR, or Dwould hathey had
MES Measureof depres
2‐R6
ANDED SUMM
eviews of benzodia997(5)
3 studies
3 studies
1 study
8 studies
5 studies
with GAD (APA DSM‐III, DSM‐IV) or patients who clave met the above criteriad been applied
e of anxiety or worry & mession (effect size)
MARY TABLES
zepines for GeneraHidalgo 2007(
5/11
DSM‐learly a if
Patients with Gand ICD‐10)
easure Measure of an
alised Anxiety Diso(6)
1 study
1 study
2 studies
GAD (DSM‐III‐R, DSM‐IV
nxiety (effect size)
rder Mahe 2000(7)
2/11
1 s
1 s
7 st
3 st
“patients with condgeneralised anxietyneurosis or anxiety
Benefits to patientsterm treatment of aMeasure of anxiety
Benzodiazep
study
study
tudies
tudies
ditions described as y disorder, anxiety symptoms”
s/ successful long‐anxiety y
pines for Anxiety –
Martin 2007(8)
6/11
4 studies
12 studie
7 studies
Patients with GAD (DSM‐DSM‐III‐R)
Excluded: patients with pdisorders or who were codependent on substancewith other medical probl
Efficacy: as measured byfrom study Side effects: as measurewithdrawals due to adve
– Summary of Syste
Mitte
8/11
s
es
s
‐IV, DSM‐III or
psychiatric onsuming or es of abuse or lems.
Patiesystedisorduratpatie“neu
y withdrawals
d by erse events
Self‐rbehaquali(only
ematic Reviews
e 2005(9)
6 studies
3 studies
13 studies
7 studies
1 study
ents with GAD (any diagnoem), or an exact descriptiorder was presented includtion of symptoms (i.e. insents just described as ‘anxrotic”)
report, observer rated mevioural test of anxiety, dety of life, or clinical signify pertaining to anxiety).
ostic on of the ding ufficient if xious’ or
easures, or epression, icance
16 Report
STUDY
COMPARINTEREST
DURATIOTREATM
RESULTS
t number: 0611‐002
Gould 19
RATORS OF T
Pharmac Total incRelevantAlprazolaCastillo (FontaineBromazeFontaineKragh‐SoClobazamCastillo (DiazepamBorison ((1987), ORickels (1Matas (1LorazepaAnsseau (1993), D other drun.b. somelooked atstudies loplacebo
ON OF ENT
Not specDurationstudies v
S Benzodia
2‐R6
997(5)
cotherapy vs Placebo
luded drug studies (n=22)t benzo studies (n= 17) am vs placebo (n=3) 1987), Enkelmann (1991)e (1984) epam vs placebo (n=3) e (1986), Fontaine (1984), orensen (1990) m vs placebo (n=1) 1987) m vs placebo (n=8) (1990), Cohn (1989), FontOlajide (1987), Pecknold (11993), Rickels (1982), Ros1987) am vs placebo (n=5) (1985), Ceulmans (1985),
Diamond (1991), Fontaine
ug studies (n=5) e benzo vs placebo studiet other drugs vs placebo, sooked at more than one d
cified in selection criteria fn of treatment for includevaried between 2 and 9 w
azepines:
Hidalgo 2007(
)
,
taine 1989), s &
, Cutler e (1986)
es also some drug vs
Pharmacother Total includedRelevant benzAlprazolam vsMoller (2001) Lorazepam vs Pande (2003),Diazepam, plaHackett (2003 other drug stuSSRI studies (nvenlafaxine sthydroxyzine stPGB studies (nbuspirone armcomplementamedicine stud n.b. some benlooked at othestudies lookedplacebo
for SR.d eeks
Not specified Duration of trestudies varied
Benzodiazepin
(6)
rapy vs Placebo
d studies (n=21) zo studies (n= 4) placebo (n=1) placebo (n=2) Feltner (2003) acebo (n=1) 3)
udies (n=22) n=8) udies (SNRI) (n=5) tudies (AH) (n=3) n=2) ms (n=2) ry and alternative dies (n=2)
zo vs placebo studies alsoer drugs vs placebo, somed at more than one drug v
in selection criteria for SReatment for included between 4 and 12 weeks
nes:
Mahe 2000(7)
o e vs
Various Total included studTotal GAD studies (Relevant benzo stuAlprazolam vs placeplacebo (n=1) Cohn & Wilcox (198Diazepam vs placebPower (1990) Buspirone vs diazepMurphy (1989) Diazepam, no compRickels (1983) Total non well‐defistudies (n=5) Relevant benzo stuClobazam vs diazepSchjonsby (1979) Ketazolam vs diazepFabre (1981) Lorazepam, diazepaSiassi (1975) Lorazepam, diazepaGross (1977) n.b. some benzo vslooked at other drustudies looked at mplacebo
R.
s
Long‐term (8 weeks
No overall effect siz
Benzodiazep
ies (n=13) (n=8) udies (n= 4) ebo, lorazepam vs
84) bo (n=1)
pam (n=1)
parator (n=1)
ned anxiety disorder
udies (n=4) pam (n=1)
pam (n=1)
am; open label (n=1)
am; open label (n=1)
s placebo studies also gs vs placebo, some
more than one drug vs
s or longer)
ze or result
pines for Anxiety –
Martin 2007(8)
Benzodiazepine vs place Total included studies (nRelevant benzo studies (diazepam vs placebo (n=lorazepam vs placebo (n=alprazolam vs placebo (n Included studies: Andreatini (2002), AnsseBoyer (1993), Castillo (19(1993), Diamond (1991), (1991), Feltner (2003), FoFontaine(b) (1986), HackLaakmann (1998), Loo (1(1997), Moller (2001), PaPecknold (1985), PecknoPoumotabbed (1996), RicRickels(b) (1997), Rickels(1986) n.b. specific benzo used istated
Not specified in selectionConclusions drawn for shtreatment. “the trials were conducteshort‐term, with most lasweeks” Individual trial durations specified
Pooled analysis indicated
– Summary of Syste
Mitte
ebo
=23) (n= 23) 12) =7) n=4)
au (1991), 987), Cutler Enkelmann ontaine (1983), kett (2003), 991), Lydiard ande (2003), ld(b) (1989), ckels (1993), s(c) (2000), Zung
in each study not
Phar TotalRelevAlpra
CastiEnkeMcLe‘Benzdiaze
FontBrom
FontDiaze
Boye(198FinnePourPowe(199Loraz
CohnFontLaakEstevTriaz
Fontn.b. slookestudiplace
n criteria for SR.hort‐term
ed in the very sting just 4
were not
SelecminimThe abenz“Fouless tfor thstudiinvesRecolong‐of deelsew
d less risk of For b
ematic Reviews
e 2005(9)
macotherapy vs placebo
l included studies (n=48) vant benzo studies (n=25azolam vs placebo (n=6)
illo (1987), Cohn & Wilcoelmann (1991), Lydiard (eod (1982), Moller (200zodiazepines’ (bromazepaepam) (n=1)
aine (1984) mazepam vs placebo (n=2)
aine (1983), Fontaine (1epam vs placebo (n=12)
er & Feighner (1993), Fo3), Fontaine (1987), Golerty (1982), Pecknold (1rmotabbed (1996), Poweer (1990), Rickels (1982)3), Rickels (1997), Rickezepam vs placebo (n=6)
n & Wilcox (1984), Cutleaine (1986), Fresquet (2mann (1998), Laboratorve* (unpublished) olam vs placebo (n=1)
aine (1990) some benzo vs placebo sted at other drugs vs placeies looked at more than onebo
ction criteria for SR specifmum of 14 days treatmenaverage duration of the ino studies was 5.3 weeks. r studies investigated thethan 4‐weeks, however, ehose studies were compaes in which the drugs werstigated for a longer periommendations were made‐term use due to the increependence and withdrawawhere.
benzodiazepines, the mea
5)
ox (1984), 1997), 1) am,
)
1986)
ntaine dberg & 1989), er (1989), ), Rickels ls (2000)
er (1993), 2000), rios Dr
tudies also bo, some ne drug vs
ied a nt ncluded
e drug for effect sizes rable with re od of time” e against easing risk al reported
n effect
17 Report
STUDY
CONCLUS
COMMEN
*for somKEY: GAD
t number: 0611‐002
Gould 19
Mean ESDiazepamLorazepaAlprazolaeach); ES “Among benzodialargest eflorazepa
SIONS EFFECTIV(more efBenzos inmost to lBromaze
NTS This metpharmacbenzodiaresults. Tterm effitreatmenmedicati As well avs placebpsycholo(n=13)
e SRs the numbers of studD = Generalised Anxiety D
2‐R6
997(5)
= 0.70 m (11 studies): ES=0.76 am (5 studies): ES=0.66 am & bromazepam (2 stuS=0.44 & 0.61
medication interventionsazepine diazepam yieldedffect size (ES=0.76), followm (ES=0.66)”
VE ffective than placebo) n order of effectiveness frleast: Diazepam, Lorazepaepam, Alprazolam
a‐analysis looked at cotherapy and CBT for GAazepines were only part oThe authors note that “thecacy of pharmacologic nt was attenuated followion discontinuation”
s looking at pharmacothebo, this review also lookedogical treatments vs contr
dies for each benzodiazepDisorder Benzo/s = B
Hidalgo 2007(
dies
s, the d the wed by
ES+SD = 0.38+ p‐Value = p<0 “Our analysis s
overall ES (0.3
the treatment
end of the spe
anticonvulsan
hydroxyzine, f
venlafaxine XR
rom am,
EFFECTIVE (lowOrder of effecPregabalin, HyBenzos, SSRIs,complementa
AD, f the e long‐
ing
erapy d at rol
No individual ethe different bthe included soverall effect s A study of browas included idata was not rin the analysis
pine do not add up to the tBenzodiazepine/s S
(6)
+0.15
.0001
showed a low to moderat
39+0.06) for drug therapy
t of GAD... On the higher
ectrum we found the
t PGB and the AH
followed in order by
R, BZs and SSRIs”
w to moderate)ctiveness (most to least): ydroxyzine, Venlafaxine S, Buspirone, ry and alternative meds
effect sizes reported for benzodiazepines used in studies, just a combined size for benzodiazepines
omazepam (Llorca (2002) in the review, but efficacyreported and not includeds
total number of relevant sSSRIs = Selective Serotonin
Mahe 2000(7)
te
in
calculated, or conclany specific benzidobenzodiazepines as “the results of the rstudies in patients winconclusive, and nshown to be effectitreatment of this colong‐term treatmenanxiety disorder is aneed, no reference identified, nor has atreatment evaluatiobeen performed”
R,
INCONCLUSIVEEvidence of effectiv
y d
This review looks atof GAD (8 weeks orAs well as treatmendefined anxiety diso This review also looof pharmacotherap The authors state trecommended longof dependence
studies, as some trials stun Reuptake Inhibitors
Benzodiazep
usions drawn about oazepines, or s a whole
reported long‐term with GAD are o reference drug has ve in the long‐term ondition... although nt of generalized an unmet medical drug has yet been an adequate on of this condition
veness is inconclusive
t long‐term treatment longer)
nt for non well‐order (n=5 studies)
oks at different types py – not just benzos.
hat benzos are not g‐term due to the risk
udied more than one type
pines for Anxiety –
Martin 2007(8)
treatment discontinuatioefficacy for benzodiazepito placebo, RR=0.29 (95%p<0.00001). Nevertheless, pooled anaconclusive results for riskpatient discontinuation, 0.62–1.00; p=0.05). “the outcomes observedseem to show that, basewithdrawals from clinicabenzodiazepines do not edefinitively superior to pshort term. In a clinical (texperimental) setting, suwithdraw from treatmenafter the start in the samas subjects who receive aclinical trial, indicating thbenzodiazepines are not treatment for GAD”
NOT EFFECTIVE (not more effective thanBenzos are not effective term treatment of GAD (between benzos and plac
“We chose withdrawals fany reason as the principmeasure in this review, athe recently published laschizophrenia called CATal., 2005). We argue thatany reason represents thcomprehensible and comoverall index of effectiveintervention.”
of benzodiazepine.
– Summary of Syste
Mitte
on due to lack of ines, compared % CI 0.18–0.45;
alysis showed no k of all‐cause RR=0.78 (95% CI
in this review d on total l studies, even prove lacebo in the though not ubjects could nt a few weeks me proportions a placebo in a hat an effective
size fno sigclassFor dbenzdrug “Our phartreatanxiesympgivendifferwerebenzleast treat
n placebo) for the short‐no difference cebo)
EFFEC(morBenzboth place
from trials for pal outcome as was done in rge trial in TIE (Lieberman et t withdrawal for he most mprehensive eness of any
This rplacethen The atheredepetermbenzseverlong‐membe lim
ematic Reviews
e 2005(9)
for anxiety was g = 0.32. Tgnificant difference betwes. depression the mean effecodiazepines was g = 0.28.class was superior findings indicate that macotherapy is an effectiment for GAD in reducingety and comorbid depressptoms; superiority over pln. According to drug classerences in efficacy but in ce found. So, results suggesodiazepines are to be prewhen the duration of thement is short”
CTIVE re effective than placebo)os and azapirones equallclasses of drug more effeebo for short‐term treatm
review looked at benzos vebo,and azapirones vs placompared effect sizes authors state that “it is kne is an increasing risk of pendence and withdrawal a treatment with odiazepines...In addition,re adverse effects can res‐term use...such as impairmory. Therefore prescriptiomited to short‐term use”
There was een drug
ct size for . Again no
ve g both sive acebo was es, no ompliance st that eferred at e
) ly effective, ective than ment
vs cebo and
nown that physical after long‐
other sult from rment of ons should
18 Report numb
Table A1.2 SySTUDY
AMSTAR RATING
BENZODIAZPINES
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
PATIENTS
OUTCOMES
COMPARATORS OF INTEREST
RESULTS
CONCLUSIONS
ber: 0611‐002
ystematic revCox 1992(10
S*
Patients with(agoraphobiaspecifically stwith both paincluded.”
1/ Dysphoria2/ Frequency3/ Severity o4/ Agorapho5/ Agorapho6/ Generalize7/ Overall im
This meta‐analprazolam, IIncluded stud #No list or dewas not possnumber of stused in these
“Few studiesfinal data powas found toAlprazolam wvariables in Pvariables. Exsizes.” “The results exposure thewas not effecfound to be g
EFFECTIVE Alprazolam a
‐R6
views of benz)
h panic disorder ora with panic attacktated they containanic attacks and ag
a or depression y of panic attacks of panic attacks bic fear bic avoidance behed anxiety mprovement rating
nalysis calculated aImipramine and exdies (n=34)
etails of included ssible to list the inctudies of alprazolae
s satisfied the minol consisted of 34o be generally inefwas significantly efPDA, while exposuposure had the m
of the meta‐analyerapies are both efctive for agoraphogenerally effective
and exposure ther
Benzo
odiazepines f
2/11
#
r panic disorder wks in DMS‐III). “Onned a large percengoraphobic avoida
per week
haviour
gs
and compared effexposure therapy
tudies were proviluded studies deteam or determine th
imum criteria of in4 treatment studieffective for most vaffective for panic are was significantlost consistently st
ysis indicate that affective for PDA, bobic dimensions. Ime”
apies both effectiv
odiazepines fo
for Panic Diso
with agoraphobia nly studies that ntage of subjects nce were
ect sizes of
ded, therefore, it ermine the he comparators
nclusion and the es. Imipramine ariables. and anxiety ly for phobia trong effect
lprazolam and but alprazolam mipramine was
ve for PDA
or Anxiety – Su
order Watanabe 200
Adult patients (Feighner criteR, DSMIV or IC
“Primary outco“Response” (a global judgemeor “much” impDisorder SeverSecondary out1. Panic disord2. Frequency o3. Phobic avoid4. General anx5. Depression6. Social functi7. Quality of lif8. Patient satis9. Economic co
benzos + psychtreatment) Total included Total relevant Irrelevant stud Alprazolam + CAuerbach (199alprazolam vs aexposure (n=1)Marks (1993)Diazepam + ExWardle (1994)
“Two trials (n=alone (both usdifferences we(relative risk (R0.35), at the en0.37), or at thesuggested thattherapy alone One trial (n=77alone. No diffeintervention (Rcombination aalone at the enNo significant dup (RR 2.31, 0.“The review esinvestigating thbenzodiazepininadequate evipsychotherapyare diagnosed
INSUFFICIENT Insufficient evi
ummary of Sy
09(11)
10/
2 stu
1 st
with panic disorderia, Research DiagD‐10)
ome(s):dichotomised outent of the original provement, “no or ity Scale (PDSS) sccome(s): er global severity or severity of panicdance iety
oning fe faction with treatosts”
hotherapy vs (psyc
studies (n=3) studies (n=3) ies (n=0)
CBT vs Placebo pill 7) alprazolam+expos)
posure vs Placebo
166) compared coing behaviour therre observed in resRR) for combinationd of the intervente last follow‐up timt the combination (RR 0.62, 0.36 to 17) compared comberences were founRR 1.57, 0.83 to 2.9ppeared to be supnd of treatment (Rdifferences were o79 to 6.74, P = 0.1stablished the pauhe efficacy of psyces for panic disordidence to assess thy combined with bwith panic disorde
EVIDENCEdence to assess cl
ystematic Rev
/11
udies
tudy
er with or withoutgnostic Criteria, DS
tcome) in each arm authors, such as: minimal” symptocore of 7 or below
on a continuous sc attacks
ment
ychotherapy alone
+ CBT (n=1)
sure vs double plac
o pill + Exposure (n
ombination with prapy).No statisticasponse during the on 1.25, 95% CI 0.7tion (RR 0.78, 0.45me point Follow‐upmight be inferior 1.07, P = 0.08). bination with a bend in response dur98, P = 0.17). Althperior to the benzoRR 3.39, 1.03 to 11observed at the 7‐12).” ucity of high qualitychotherapy combider. “Currently, thhe clinical effects obenzodiazepines foer.”
linical effects of be
views
t agoraphobia SM‐III, DSM‐III‐
m, defined by “very much” m, or a Panic .
scale
e or benzo
cebo vs
n=1)
sychotherapy ally significant intervention 78 to 2.03, P = 5 to 1.35, P = p data to behaviour
nzodiazepine ing the ough the odiazepine 1.21, P = 0.05). ‐month follow‐
y evidence ned with ere is of or patients who
enzodiazepines
19 Report numb
COMMENTS
*for some SRs theof benzodiazepineKEY: PDA = Panic
ber: 0611‐002
Alprazolam wvariables in Pphobia variaExposure hadAlprazolam w
e numbers of studiee. Disorder with Ago
‐R6
was significantly efPDA, while exposubles. d the most consistwas not effective f
es for each benzod
oraphobia Benzo
Benzo
ffective for panic are was significantl
tently strong effecfor agoraphobic di
diazepine do not a
o/s = Benzodiazepi
odiazepines fo
and anxiety ly effective for
ct sizes mensions
add up to the total
ine/s
or Anxiety – Su
+ psychotherap
See article for different outco
number of relevan
ummary of Sy
py for panic disord
details on the scalomes of the study.
nt studies, as some
ystematic Rev
der
les used to measu.
e trials studied mo
views
re the
ore than one type
20 Report numb
Table A1.3 SySTUDY
AMSTAR RATING
TYPE OF ANXIETY
BENZODIAZEPINE
Alprazolam
Bromazepam
Clobazam
Diazepam
Flunitrazepam
Lorazepam
Midazolam
Nitrazepam
Oxazepam
Temazepam
Triazolam
PATIENTS
OUTCOMES
COMPARATORS OINTEREST
RESULTS
ber: 0611‐002
ystematic revFurukawa 2
9/11
Y anxiety asso
ES*
anxiety assodepression adults (ageddepression,one of the FDSMIII‐ R orComorbiditincluded.
Primary out(at least oneSymptom seeither self‐rSecondary o1. ResponseAcceptabilitseverity; 4. effects
OF Antidepressantidepress Total IncludRelevant inc imipraime +(n=1) Dominguez desipraminedesipramineFawcett (19imipramine(n=1) Feet (1985)(maprotiline(flunitrazep(maprotilineNolen (1993
“The resultsthe combinanxiety evewith statistibetween ‐0
‐R6
views of benz2001(12)
ociated with majo
1 study
1 study
1 study
1 study
ociated with majo d 18 or older) with, diagnosed accordFeighner criteria, RrDSM‐IV, or ICD‐10ies with anxiety di
tcome: Depressivee measure) everity could be mreport or observeroutcomes: e in depression; 2.ty of treatment; 3.Insomnia severity
sants + benzos vs sants alone
ded studies (n=10) cluded studies (n=
+ triazolam vs imip
(1984) e + alprazolam vs e (n=1) 987) e + diazepam vs im
e or nortriptyline) pam or lormetazepe or nortriptyline) 3b)
s suggest the supeation therapy in an up to six to eighically significant SM.50 and ‐ 0.64.”
Benzo
odiazepines fIn
3/
r depression n
or
h major ding to any RDC, DSM‐III, 0. isorders
“TsupacsysuoIC
e severity,
measured by r‐rating
. Anxiety ; 5. Side
Fi(Fovexan
= 4)
pramine
ipramine
+ pam) vs (n=1)
B(bas
ToR
AItCKLoItO(nH(1(1K(1
eriority of lleviating t weeks, MDs
“Mdsiinp95trwdsipm
odiazepines fo
for other typenada 2003(13)
/11
eurosis or psychos
1
2 s
17 s
1
The subjects wereuffering from neusychosomatic diseccording to the Jaystem based on ICubjects were selecperational diagnoCD‐10 or DSM‐IV”
inal Global ImprovFGIR) used to captverall severity of pxpressed as a Relanalysis
enzo vs diazepamboth diazepam ands controls in all inc
otal Included studRelevant included s
Alprazolam vs diazeto (1982) Clobazam vs diazepudo (1982), Mori orazepam vs diazeto (1981) Other drug vs diazen=13) Hada (1979), Higuc1970), Ito (1981), K1983), Kurihara (19urihara (1977), M1974), Suematsu (
Meta‐analysis of temonstrated diazignificantly more en the treatment ofsychosomatic dise5% CI 1.21–1.51, nreat 9)... The effecwas particularly noose of 12 mg/day ignificant superiorlacebo was observ
mg/day or lower.”
or Anxiety – Su
es of anxiety
somatic disease
study
studies
studies
study
e all Japanese patierosis or ease, as diagnosedpanese diagnosticCD‐9... More recencted based on stic criteria such a
vement Rating scature “changes in thpatient symptomsative Risk after me
vs placebod placebo were uscluded studies)
dies (n=17) studies (n= 17)
epam vs placebo (
pam vs placebo (n=(1982) epam vs placebo (n
epam vs placebo
hi (1975), IchimarKudo (1984), Kudo992), Kurihara (19ori (1977), Namiki1975), Suzuki (197
he total 17 RCTs epam to be effective than placf neurosis or ease (relative risk 1number needed toctiveness of diazeptable at a maximuor higher, while nrity compared withved at a dose of 9
ummary of Sy
Wethrell
5/11
any anxie
ents
d tly,
s
participanwith a prof any anaccordingand StatisDisorders
le he ” ta‐
To compastudies, ewhere pomeasure ImpressioScale; STAAnxiety InScale) wit
sed
n=1)
=2)
n=1)
u o 90), 79)
Benzo vs Total incl(n=8) Relevant Imiprami(n=1) Sheikh &
cebo
1.35, o pam um o h the
“only threhave invebenzodialater life. on GAD, aearlier, pof anxietystudies, mrelative teffects evOnly one for the caranging frResponsefrom 57%
ystematic Rev
l 2005(14)
ety disorder
1 study
nts were at least 5rincipal or co‐princnxiety disorder diag to criteria of thestical Manual of Ms III‐R or IV
are clinical significeffect sizes were cossible for each ou(including: CGI, Con; HAMA, HamiltAI, Spielberger Stanventory; VAS, Visthin each study.
antidepressant vs
luded pharmalogic
included studies (
ine vs alprazolam v
Swales (1999) pilo
ree randomized coestigated the impaazepines for anxiet Two of these triaand one trial has spotentially compary neurosis. In all omedication was efto placebo, with trvident within as eae study provided sualculation of effectfrom 0.79 to 0.95 (e rates to medicat% to 83%. Attrition
views
55 years old, cipal diagnosis gnosed Diagnostic
Mental
cance acrossalculated utcome linical Global on Anxiety ate‐Trait sual Analogue
s placebo
cal studies
(n=1)
vs placebo
ot RCT
ontrolled trials act of ty disorders in ls have focused studied an rable category of these fficacious eatment arly as 7 days. ufficient data t size, with d (mean d, .85). ion ranged n rates were
21 Report numb
CONCLUSIONS
COMMENTS
*for some SRs theof benzodiazepine KEY: Benzo/s = B
ber: 0611‐002
EFFECTIVE, WEIGHED A
The focus odepression The authorsbenefits of antidepressjudiciously aincluding deand accidenhand, and afollowing nothe other.”
e numbers of studiee.
Benzodiazepine/s
‐R6
BUT BENEFITS SHAGAINST RISKS
of this study was o
s state that: “The adding a benzodiasant must be balanagainst possible haevelopment of depnt proneness, on tagainst continued o response and dr
es for each benzod
Benzo
OULD BE EF “Rdthn
on
potential azepine to an nced arms pendence he one suffering op out, on
O
diazepine do not a
odiazepines fo
FFECTIVE (more e“Results of the meRCTs selected in thiazepam is significhan the placebo ineurosis or psychos
Only Japanese stud
add up to the total
or Anxiety – Su
effective than plactaanalysis of the 1is study suggest thcantly more effectn the treatment ofsomatic disease.”
dies were included
number of relevan
ummary of Sy
generally
ebo)17 hat ive
EFFECTIVTREATMETO POTE
. The focusanxiety dstudies ointervent This reviecognitivepharmacorelevant tstate thatrials suggbenzodiadisorderslonger‐tebenzodiarecommeadults, giserious acan affecpsychomincreasedfalls, a deincrease
nt studies, as some
ystematic Rev
y low (%17%).”
VE, BUT LONG TERENT NOT RECOMMNTIAL ADVERSE E
s of this study wasdisorders and also of cognitive behavitions
ew also Included se behavioural interological interventito our questionThat: “Overall, the daggest the value of azepines for treatins in older adults, Herm treatment witazepines generally ended, particularlyiven the potential dverse events. Bect cognitive functiomotor performanced risk of hip fractuecreased ability toin memory proble
e trials studied mo
views
RM MENDED DUE VENTS
s on geriatric looked at oural
tudies of rventions and ions not he authors ata from these
ng anxiety However, h is not y for older for more nzodiazepines oning and e, leading to an res caused by drive, and an ems.”
ore than one type
22 Report numb
APPENDIXThe TAC and
and muscle
and conditio
first step to
evidence ma
and muscle
map were th
hypnotics’ (s
Table A2.1. h
Benzodiazep
Alprazolam BromazepamClobazam Diazepam FlunitrazepaLorazepam Midazolam Nitrazepam Oxazepam TemazepamTriazolam
Searches of
against inclu
and 7 evide
criteria.
For included
Study ty
Hypnose
Indicatio
Whethe
The extracte
evidence, an
There were
muscle spas
SRs identifie
indications.A
Table A2.2. E
Indication
ber: 0611‐002
X 2: EVIDEd WorkSafe
spasm. This
ons needing
identify the
ap of system
spasm was
hose license
see Table A2
hypnosedative
pines
m
am
m
Medline an
usion and ex
ence‐based g
d studies, the
ype (systema
edatives exa
on
r the study w
ed data wa
nd identify th
18 SRs and
sm. There we
ed (34) is les
All other guid
vidence map
‐R6
ENCE MAPVictoria req
proved to b
investigation
e available h
matic reviews
developed(3
d for use in
2.1)
es included in
nd Embase,
clusion crite
guidelines [E
e following d
tic review or
mined
was about be
s tabulated
he gaps. No q
5 EBGs on h
ere no EBGs
ss than the s
delines and s
for each indic
Sy
Benzo
P SUMMAuested an Ev
e an unfeasi
n. It was dec
igher level e
s and eviden
3). Drugs cla
Australia an
n Evidence Ma
and the int
ria resulted
EBGs]). See A
ata was extr
r evidence ba
enefits, harm
in evidence
quality appra
ypnosedativ
on hypnose
um of SRs fo
systematic re
cation
ystematic Re
odiazepines fo
ARY vidence Rev
ibly large top
cided that ins
evidence and
ce‐based gu
assed as ‘hy
d listed in M
ap
Non‐
ZolpiZopic
ternet yielde
in a total of
Appendix 3
racted
ased guideli
ms or both
e maps to a
aisal was und
ves for anxiet
edatives for m
or the indivi
eviews were
eviews
or Anxiety – Su
iew on the u
pic with so m
stead, an evi
d get an ide
idelines on h
ypnosedative
MIMs as eithe
‐benzodiazep
dem clone
ed 1,943 po
f 41 relevant
for detailed
ne)
allow determ
dertaken in t
ty; 17 SRs an
muscle spasm
dual indicati
e about one i
Evid
ummary of Sy
use of sedat
many differen
idence map w
a of its quan
hypnosedativ
es’ for the p
er ‘anti‐anxie
pine Hypnot
tentially rele
studies (34
d search me
mination of
the producti
nd 2 EBGs fo
m (Table A1
ions (36) as
ndication on
dence Based
ystematic Rev
ives in anxie
nt combinat
would be de
ntity and co
ves for anxie
urposes of t
ety agents’ o
tics
evant studie
systematic r
ethodology a
the volume
on of the Ev
or insomnia;
.2). The tot
one SR cove
nly.
d Guidelines
views
ety, insomnia
ions of drug
eveloped as a
omplexity. An
ety, insomnia
the evidence
or ‘sedatives
es. Screening
reviews [SRs
and selection
e of existing
idence Map.
and 1 SR fo
al number o
ered all three
a
s
a
n
a
e
s,
g
s]
n
g
.
r
of
e
23 Report numb
I
Mu
The benzodi
included var
licensed for
results for ‘b
the same. Fu
included in e
ber: 0611‐002
Anxiety
nsomnia
uscle spasm
iazepines list
rious other b
use in that c
benzodiazep
urther detail
each study),
‐R6
ted in the res
benzodiazepi
country). Thi
ines’, as the
about the e
see Evidenc
Benzo
search quest
nes (i.e. stud
s should be k
list of drugs
vidence iden
e Map repor
odiazepines fo
18
17
1
tion are thos
dies from the
kept in mind
that differen
ntified (i.e. s
rt(3).
or Anxiety – Su
se used in Au
e UK or US o
d when looki
nt authors a
uch as specif
ummary of Sy
ustralia, how
ften only inc
ng at recomm
re referring t
fic indication
ystematic Rev
5
2
0
wever, many
cluded benzo
mendations
to are not lik
ns or individu
views
studies
odiazepines
or reported
kely to be
ual drugs
24 Report n
APPEN
Inclusio
Inclusion
reviewe
Table A3
Patient/ populatio
Intervent
indicator
Comparis
control
Outcome
Setting
Study de
Publicati
Time per
number: 0611‐
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