Ben zodiaz epines for anxiety - TACSecure Site · Ben Summ June Emma ‐R6 zodiaz ary of 2011...

0611‐0021

Ben

Summ

June

Emma

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mary of

2011

a Donoghu

zepine

f system

ue, Driss A

Acc

Title

N/A

Transpo

s for a

matic rev

Ait Ouakri

companying

Benzodi

ort Acciden

anxiety

views

m

g document

iazepines for A

nt Commi

y

ts to this rep

Anxiety – Sum

ssion & W

port

Report num

mmary of Sys

WorkSafe V

mber

tematic Revie

Victoria

ews

0611‐0022

CONTE

CONTENT

BACKGRO

FINDING

SUMMAR

SUMMAR

AMSTAR

REFEREN

APPENDI

APPENDI

APPENDI

2‐R6

ENTS

TS ................

OUND & MET

S ..................

RY ................

RY TABLES ....

R TABLE .........

NCES ..............

IX 1: EXPAND

IX 2: EVIDENC

IX 3: EVIDENC

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THODS ..........

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DED SUMMAR

CE MAP SUMM

CE MAP METH

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RY TABLES ......

MARY ...........

HODS ............

Benzodi

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iazepines for A

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Anxiety – Sum

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mmary of Sys

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tematic Revie

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ews

0611‐0023

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

2‐R6

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

& 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

ODS

ely used in c

consumed a

nticonvulsan

arity among

risks relate

awal sympt

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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

Benzodi

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

iazepines for A

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

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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.

mmary of Sys

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

tematic Revie

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

ews

0611‐0024

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

2‐R6

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

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

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

Benzodi

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

iazepines for A

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

Anxiety – Sum

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

mmary of Sys

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

tematic Revie

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

ews

0611‐0025

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

2‐R6

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

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

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

Benzodi

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

iazepines for A

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

Anxiety – Sum

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

mmary of Sys

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

tematic Revie

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

ews

0611‐0026

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

2‐R6

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.

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

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

Benzodi

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

iazepines for A

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

Anxiety – Sum

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

mmary of Sys

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

tematic Revie

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

ews

0611‐0027

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

2‐R6

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

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

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

Benzodi

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

.

iazepines for A

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

Anxiety – Sum

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

mmary of Sys

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

tematic Revie

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

ews

08

S

TST

A

B

A

B

C

D

Fl

Lo

M

N

O

Te

T

CIN

DT

O

RC

C

*fK

0611‐002‐R6 8

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

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 ofMeasure 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 EFFECTIVEot 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

0611‐0029

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 =

2‐R6

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

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

0611‐00210

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

2‐R6

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

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 measurelobal lton Anxiety tate‐Trait Visual

RM MMENDED ERSE EVENTS

as on geriatric o looked at vioural

studies of erventions rventions not

ied more

01

A

T

A

1

2e

3

4u

5p

6p

7a

8u

9st

1

1

A

0611‐002‐R6 11

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

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

0611‐00212

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

2‐R6

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

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

0611‐00213

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

14. Clin Nort

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Blanco C, Schological treat

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Gould RA, Ottzed anxiety dis

Hidalgo RB, Tzed anxiety dis

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Martin JL, Saized anxiety disrials. J Psycho

Mitte K, Noaczed anxiety dis

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Watanabe N,. Cochrane Da

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Inada T, Nozaof double‐blin6):483‐7.

Wetherell JL, th Am. 2005 D

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neier FR, Schmment of socia

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mshaw JM, Weassess the me

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aki S, Inagaki And, randomize

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hronic insomn

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ck MH, Yap L. liminary meta

vidson JR. An ehopharmacol

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Hautzinger M. Psychopharm

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Furukawa TA. Rev. 2009(1):C

Young LT. Ant2):CD001026.

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nley MA. Evid‐96.

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nia in elderly

o‐Jerez CR, Morder: a meta‐

atives for anxiend Recovery R

M, Anderssonquality of sys

Cognitive beha‐analysis. Beh

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Martin‐Sanchutcomes base):774‐82.

A meta‐analymacol. 2005 Ap

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Combined psCD005335.

tidepressant p.

TA. Efficacy oftrials carried o

dence‐based t

es for Anxiety

persons. Am J

arshall RD, Saanalysis. Depr

ety, insomnia Research (ISC

n N, Hamel C,tematic revie

havioral and phavior Therap

alysis of pharm1(8):864‐72.

ment of gener

hez E, Seoaneed on a system

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

y – Summary

J Geriatr Phar

anchez‐Lacay Aress Anxiety. 2

and muscle sRR) 2010 (Unp

et al. Developws. BMC Med

pharmacologicy. 1997;28(2)

macologic trea

alized anxiety

T, Galan C. Bematic review a

the efficacy o50.

nts for panic dxp Psychiatry.

plus benzodia

zepine for ma

an anti‐anxietHum Psychop

geriatric anxie

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macother. 20

A, et al. 2003;18(1):29

spasm: Evidenpublished rep

pment of AMd Res Method

cal treatment:285‐305.

atments for

y disorder. Int

enzodiazepinand meta‐ana

of drug treatm

disorder with . 1992 Sep;23

azepines for p

ajor depressio

ty agent: metpharmacol. 20

ety disorders.

c Reviews

006

9‐40.

nce Map. port).

STAR: a ol.

of

Clin

es in lysis of

ment in

3(3):175‐

anic

on.

ta‐03

Psychiatr

0611‐014

APPE

Table ASTUDY

AMSTAR

BENZOD

Alprazola

Bromaze

Clobazam

Diazepam

Flunitraz

Lorazepa

Midazola

Nitrazep

Oxazepa

Temazep

Triazolam

PATIENT

OUTCOM

COMPARINTEREST

002‐R6

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

RATORS OF T

Pharmac Total incRelevantAlprazolaCastillo (FontaineBromazeFontaineKragh‐SoClobazamCastillo (DiazepamBorison ((1987), ORickels (1Matas (1LorazepaAnsseau (1993), D

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)

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

MARY TABLES

zepines for GeneraHidalgo 2007(

5/11

DSM‐learly a if

Patients with Gand ICD‐10)

easure Measure of an

)

,

taine 1989), s &

, Cutler e (1986)

Pharmacother Total includedRelevant benzAlprazolam vsMoller (2001) Lorazepam vs Pande (2003),Diazepam, plaHackett (2003 other drug stuSSRI studies (nvenlafaxine sthydroxyzine stPGB studies (nbuspirone armcomplementamedicine stud

alised Anxiety Diso(6)

1 study

1 study

2 studies

GAD (DSM‐III‐R, DSM‐IV

nxiety (effect size)

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)

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

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)

Benzodiazep

study

study

tudies

tudies

ditions described as y disorder, anxiety symptoms”

s/ successful long‐anxiety y

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)

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

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)

– 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

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

Phar TotalRelevAlpra

CastiEnkeMcLe‘Benzdiaze

FontBrom

FontDiaze

Boye(198FinnePourPowe

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).

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)

ostic on of the ding ufficient if xious’ or

easures, or epression, icance

5)

ox (1984), 1997), 1) am,

)

1986)

ntaine dberg & 1989), er (1989), ), Rickels

0611‐015

STUDY

DURATIOTREATM

RESULTS

002‐R6

Gould 19

other drun.b. somelooked atstudies loplacebo

ON OF ENT

Not specDurationstudies v

S BenzodiaMean ESDiazepamLorazepaAlprazolaeach); ES “Among benzodialargest eflorazepa

997(5)

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: = 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)”

Hidalgo 2007(

es also some drug vs

n.b. some benlooked at othestudies lookedplacebo

for SR.d eeks

Not specified Duration of trestudies varied

dies

s, the d the wed by

Benzodiazepin ES+SD = 0.38+ p‐Value = p<0 “Our analysis s

overall ES (0.3

the treatment

end of the spe

anticonvulsan

hydroxyzine, f

(6)

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:

+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

Mahe 2000(7)

o e vs

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

te

in

No overall effect sizcalculated, 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

Benzodiazep

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 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


Martin 2007(8)

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 indicatedtreatment 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 e


Mitte

in each study not (199Loraz

CohnFontLaakEstevTriaz

Font n.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 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

For bsize fno sigclassFor dbenzdrug “Our phartreatanxiesympgiven

ematic Reviews

e 2005(9)

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 meafor 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 classe

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 There was een drug

ct size for . Again no

ve g both sive acebo was es, no

0611‐016

CONCLUS

COMMEN

*for somKEY: GAD

002‐R6

SIONS EFFECTIV(more efBenzos inmost to lDiazepamAlprazola

NTS This metpharmacbenzodiaresults. Tterm effitreatmenmedicati As well avs placebpsycholo(n=13)

e SRs the numbers of studD = Generalised Anxiety D

VEffective than placebo) n order of effectiveness frleast: m, Lorazepam, Bromazepaam

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

venlafaxine XR

rom

am,

EFFECTIVE (lowOrder of effecPregabalin, HyBenzos, SSRIs,complementamedicines.

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

R, BZs and SSRIs”

w to moderate)ctiveness (most to least): ydroxyzine, Venlafaxine S, Buspirone, ry and alternative

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

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

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


definitively 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.


lacebo in the though not ubjects could nt a few weeks me proportions a placebo in a hat an effective

differwerebenzleast 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

rences in efficacy but in ce found. So, results suggesodiazepines are to be prewhen the duration of thement is short”

CTIVEre 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”

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

0611‐002‐R6 17

Table A1.2 SySTUDY

AMSTAR RATING

BENZODIAZPINES

Alprazolam

Bromazepam

Clobazam

Diazepam

Flunitrazepam

Lorazepam

Midazolam

Nitrazepam

Oxazepam

Temazepam

Triazolam

PATIENTS

OUTCOMES

COMPARATORS OF INTEREST

RESULTS

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

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

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”

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

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

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

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.”

views

t agoraphobiaSM‐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

0611‐002‐R6 18

CONCLUSIONS

COMMENTS

*for some SRs theof benzodiazepineKEY: PDA = Panic

EFFECTIVE Alprazolam aAlprazolam wvariables in Pphobia variaExposure hadAlprazolam w

e numbers of studiee. Disorder with Ago

and exposure therwas significantly efPDA, while exposubles. d the most consistwas not effective f

es for each benzod

oraphobia Benzo

Benzo

apies both effectivffective for panic are was significantl

tently strong effecfor agoraphobic di

diazepine do not a

o/s = Benzodiazepi

odiazepines fo

ve for PDA and anxiety ly effective for

ct sizes mensions

add up to the total

ine/s

or Anxiety – Su

INSUFFICIENT Insufficient evi+ psychotherap

See article for different outco

number of relevan

ummary of Sy

EVIDENCEdence to assess clpy for panic disord

details on the scalomes of the study.

nt studies, as some

ystematic Rev

linical effects of beder

les used to measu.

e trials studied mo

views

enzodiazepines

re the

ore than one type

0611‐002‐R6 19

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

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

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%generally

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%. Attritiony low (%17%).”

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

0611‐002‐R6 20

CONCLUSIONS

COMMENTS

*for some SRs theof benzodiazepine KEY: Benzo/s = B

EFFECTIVE, WEIGHED A

The focus odepression The authorsbenefits of antidepressjudiciously aincluding deand accidenhand, and afollowing nothe other.”

e numbers of studiee.

Benzodiazepine/s

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

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

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

0611‐002‐R6 21

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

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

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

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

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

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

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

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.

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

0611‐002‐R6 22

Table A2.2. E

Indication

I

Mu

The benzodi

included var

licensed for

results for ‘b

the same. Fu

included in e

vidence map

Anxiety

nsomnia

uscle spasm

iazepines list

rious other b

use in that c

benzodiazep

urther detail

each study),

for each indic

Sy

ted in the res

benzodiazepi

country). Thi

ines’, as the

about the e

see Evidenc

Benzo

cation

ystematic Re

search quest

nes (i.e. stud

s should be k

list of drugs

vidence iden

e Map repor

odiazepines fo

eviews

18

17

1

tion are thos

dies from the

kept in mind

that differen

ntified (i.e. s

rt(3).

or Anxiety – Su

Evid

se used in Au

e UK or US o

d when looki

nt authors a

uch as specif

ummary of Sy

dence Based

ustralia, how

ften only inc

ng at recomm

re referring t

fic indication

ystematic Rev

d Guidelines

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

0611‐00223

APPEN

Inclusio

Inclusion

reviewe

Table A3

Patient/ populatio

Intervent

indicator

Comparis

control

Outcome

Setting

Study de

Publicati

Time per

For a st

strategy

2‐R6

NDIX 3: EV

on and exc

n and exclus

rs. Any discr

3.1. Inclusion a

on I

A

EASSdPi

tion/

r

IB

A

N

N

Z

E

c

son/ I

E

es I

O

a

E

Ir

E

esign I

E

c

c

ion details I

E

riod I

E

tudy to be in

y to ensure t

VIDENCE M

clusion crit

ion criteria w

repancies we

and exclusion

Inclusion: pat

Anxiety (i

Insomnia

Muscle spAll ages

Exclusion: CoAlcohol withdSpasticity dueSchizophreniadisorder, DyspPatients receiinduction of a

Inclusion: StuBenzodiazepin

Alprazolam, B

Nitrazepam, O

Non‐benzodia

Zolpidem, Zop

Exclusion: Stu

comparator

Inclusion: An

Exclusion: Nil

Inclusion: Ou

Outcomes rel

activities), QO

Exclusion: stu

Inclusion: All rehabilitation

Exclusion:

Intensive

Nursing h

Palliative

Inclusion: Evi

Exclusion: No

clinical trials,

commentarie

Inclusion: Stu

Exclusion: Stu

Inclusion: Any

Exclusion: Nil

ncluded, at

hat all refere

Be

MAP METH

teria

were establis

ere discussed

criteria

tients with:

including anxi

, or

pasm

nditions occudrawal, Tetanue to upper moa, Psychosis, Npnoea, Detoxiving sedativesanaesthesia, se

udies where thnes

Bromazepam,

Oxazepam, Te

azepine Hypno

piclone

udies where th

y

utcomes relate

ated to the ef

OL, other med

udies on pharm

health care s)

care unit

homes

care

idence‐based

n‐EBGs, non‐s

cohort studie

s.

udies in Englis

udies in langua

y publication d

least one of

ences about

enzodiazepin

HODS

shed a priori

d and resolve

iety disorders

rring in the cous, Status epilotor neuron leNeurodegenerification or wis for the folloedation in int

he focus is at

Clobazam, Di

emazepam, Tr

otics

he included hy

ed to resolutio

ffect of treatm

ication use, re

macokinetics

settings not on

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0611‐00225

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Ben zodiaz epines for anxiety - TACSecure Site · Ben Summ June Emma ‐R6 zodiaz ary of 2011...

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