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Meta-analysis of benzodiazepine use
in the treatment of acute alcohol
withdrawal
Anne M. Holbrook, MD, PharmD, MSc; Renée Crowther, MSc;
Ann Lotter, BA; Chiachen Cheng, MD; Derek King, BMath
Abstract
Objective: To analyse the evidence for the efficacy and potential harmful effects of
benzodiazepines compared with other therapies in the treatment of acute alco-
hol withdrawal.
Data sources: MEDLINE and the Cochrane Controlled Trials Registry were
searched for English-language articles published from 1966 to December 1997
that described randomized controlled trials (RCTs) of benzodiazepines in the
treatment of acute alcohol withdrawal. Key words included “benzodiazepines”
(exploded) and “randomized controlled trial.” Bibliographies of relevant articles
were reviewed for additional RCTs, and manufacturers of benzodiazepines were
asked to submit additional RCT reports not in the literature.
Study selection: Articles were considered for the meta-analysis if they were RCTs
involving patients experiencing acute alcohol withdrawal and comparing a ben-
zodiazepine available in Canada with placebo or an active control drug. Of the
original 23 trials identified, 11 met these criteria, representing a total of 1286
patients.
Data extraction: Data were extracted regarding the participants, the setting, details
of the intervention, the outcomes (including adverse effects) and the method-
ologic quality of the studies.
Data synthesis: The meta-analysis of benefit (therapeutic success within 2 days)
showed that benzodiazepines were superior to placebo (common odds ratio
[OR] 3.28, 95% confidence interval [CI] 1.30–8.28). Data on comparisons be-
tween benzodiazepines and other drugs, including β-blockers, carbamazepine
and clonidine, could not be pooled, but none of the alternative drugs was found
to be clearly more beneficial than the benzodiazepines. The meta-analysis of
harm revealed no significant difference between benzodiazepines and alterna-
tive drugs in terms of adverse events (common OR 0.67, 95% CI 0.34–1.32) or
dropout rates (common OR 0.68, 95% CI 0.47–0.97).
Interpretation: Benzodiazepines should remain the drugs of choice for the treat-
ment of acute alcohol withdrawal.
Résumé
Objectif : Analyser les données probantes relatives à l’efficacité et aux effets nocifs
possibles des benzodiazépines comparativement à d’autres thérapies utilisées
pour traiter le sevrage alcoolique aigu.
Sources de données : On a effectué, dans MEDLINE et le registre des études con-
trôlées Cochrane, une recherche d’articles en anglais publiés de 1966 à décem-
bre 1997 où l’on décrit des études contrôlées randomisées (ECR) portant sur
l’utilisation des benzodiazépines dans le traitement du sevrage alcoolique aigu.
On a utilisé comme mots clés «benzodiazepines» (développé) et «randomized
controlled trial». On a passé en revue les bibliographies d’articles pertinents
pour y trouver d’autres ECR et l’on a demandé aux fabricants de benzo-
Evidence
Études
From the Centre for
Evaluation of Medicines,
St. Joseph’s Hospital and
McMaster University,
Hamilton, Ont.
This article has been peer reviewed.
CMAJ 1999;160:649-55.
ß An overview of the diagnosis and
management of acute alcohol
withdrawal appears on page 675
CMAJ • MAR. 9, 1999; 160 (5) 649
© 1999 Canadian Medical Association (text and abstract/résumé)
B
enzodiazepines have been available for use in
Canada since 1960.
1
Few medications have been as
controversial in their clinical application.
2–11
To a d -
dress a perceived lack of summary data and to provide a
background paper for a practice guidelines initiative spon-
sored by the Canadian Pharmaceutical Association and
the Canadian Medical Association, we prepared a series of
meta-analyses of the benefits and harms of benzodi-
azepines for their common indications. In this article we
review studies of benzodiazepine use in the treatment of
acute alcohol withdrawal. Benzodiazepine use for anxiety
and insomnia will be addressed in future issues of CMAJ.
In an accompanying article in this issue (page 675) we re-
view the diagnosis and management of acute alcohol
withdrawal.
12
Methods
A comprehensive search of MEDLINE was conducted for
articles of randomized controlled trials published from 1966 to
December 1997 on the use of benzodiazepines in the treat-
ment of alcohol withdrawal. The search terms used were
“benzodiazepine” (exploded) or “benzodiazepine tranquilliz-
ers” (exploded) or “clonazepam”; “drug therapy”; “randomized
controlled trial” or “random allocation” or “all random”; “hu-
man” and “English language.” A similar search was carried out
in the Cochrane Controlled Trials Registry. Relevant articles
were retrieved and appraised for original data comparing ther-
apies for alcohol withdrawal. Bibliographies of retrieved arti-
cles were scanned for additional articles, and each manufac-
turer of a brand-name benzodiazepine was asked to contribute
reports of early trials not published in the medical literature.
Reports of randomized controlled trials of benzodiazepine
therapy for alcohol withdrawal were considered for the meta-
analysis if they compared the benzodiazepine with a placebo or
an alternative drug or mode of therapy available in Canada;
they involved actual patients rather than healthy volunteers;
and they measured at least one relevant clinical endpoint.
Studies in which a benzodiazepine was combined with another
drug were not included unless there was also a benzodi-
azepine-alone group.
Individual reports were rated for quality with the use of a
scale from 0 to 5; for therapeutic efficacy, this meant taking
into account the quality of randomization, blinding and follow-
up, and for harmful effects, it meant examining randomization,
blinding and control for baseline differences between groups.
13
Descriptive data were recorded on the conditions treated,
patient exclusion criteria, major coexisting disorders and con-
current interventions, patient age and sex, setting and duration
of the study, and side effects encountered during treatment
and follow-up. The study design (crossover, parallel group or
n of 1), the outcome measures and study day on which they
were measured, and the results (numbers of patients, outcome
means and measures of variability or numbers of patients with
events in each group, and the study investigators’ estimated p
values for differences between the groups) were recorded. In-
terrater reliability was checked through duplicate, independent
abstraction of the first 21 articles. Overall agreement on classi-
fication and descriptive data extracted from the studies was
98% (κ value 0.95). Agreement that all 5 validity criteria were
met for a study of therapy was 95% (κ value 0.90) and for a
study of harmful effects was 76% (κ value 0.51). Disagreement
was resolved by consensus, and subsequent abstraction was
carried out by one of us (A.L.).
Holbrook et al
diazépines de produire d’autres rapports d’ECR ne figurant pas dans les écrits.
Sélection d’études : On a envisagé d’utiliser pour la méta-analyse les articles qui
constituaient des ECR portant sur des patients vivant un sevrage alcoolique aigu
et comparant une benzodiazépine disponible au Canada à un placebo ou à un
médicament de contrôle actif. Sur les 23 études repérées à l’origine, 11 satisfai-
saient aux critères et représentaient au total 1286 patients.
Extraction des données : On a extrait des données portant sur les participants, le
contexte, les détails de l’intervention, les résultats (y compris les effets indési-
rables) et la qualité méthodologique des études.
Synthèse des données : La méta-analyse des avantages (réussite du traitement dans
les deux jours) a montré que les benzodiazépines donnaient de meilleurs résul-
tats que le placebo (coefficient de probabilité[CP] ordinaire de 3,28, intervalle
de confiance [IC] à 95 % de 1,30 à 8,28). On a pu regrouper des données por-
tant sur des comparaisons entre les benzodiazépines et d’autres médicaments, y
compris les β-bloquants, la carbamazépine et la clonidine, mais aucun des
autres médicaments ne présentait d’avantage clair sur les benzodiazépines. La
méta-analyse des préjudices n’a révélé aucune différence importante entre les
benzodiazépines et d’autres médicaments en ce qui concerne les effets indési-
rables (CP ordinaire de 0,67, IC à 95 % de 0,34 à 1,32) ou les taux d’abandon
(CP ordinaire de 0,68, IC à 95 % de 0,47 à 0,97).
Interprétation : Les benzodiazépines devraient demeurer les médicaments de
choix pour le traitement du sevrage alcoolique aigu.
650 JAMC • 9 MARS 1999; 160 (5)
The meta-analysis of the endpoints from the selected stud-
ies was necessarily limited to those presented in a comparable
way. Fixed-effects modelling was used, and heterogeneous
results were checked with a random-effects model.
14,15
Mantel–Haenszel common odds ratios, along with 95% confi-
dence intervals (CIs, calculated by the method of Cornfield
16
)
were obtained for discrete data (e.g., number of patients with
an outcome) with the use of the Metanal software program
(MS-DOS version 2.0; J. Julian, McMaster University, Hamil-
ton, Ont., 1993). The Breslow–Day test for homogeneity was
applied; if study results were heterogeneous, the studies were
subdivided into predefined groups and the common odds ra-
tios recalculated. Since the null hypothesis is homogeneity
among effect sizes, a significant p value suggests that hetero-
geneity exists among individual studies. Heterogeneity indi-
cates that a single, overall analysis of effect size may not be
valid and that previously identified important subgroups
should possibly be analysed separately. The subdivisions exam-
ined included individual benzodiazepine, dosage levels (e.g.,
high versus low), type of patient (e.g., primary care versus ter-
tiary care) and quality of methodology. For continuous vari-
ables (e.g., alcohol withdrawal assessment scales), effect sizes
were calculated for each study as the difference between the
outcome means of the groups divided by the pooled standard
deviations. An overall weighted effect size was obtained and
converted into natural units for the overall difference (along
with the 95% CI) in outcome between the benzodiazepine
groups and the control groups with the use of the Metanal
software program. Results were tested for homogeneity using
the Breslow–Day test as outlined above. If a measure of vari-
ability was not reported for study results, standard deviations
were calculated by means of substitution in the formula for the
coefficient of variation, using the study results most similar in
outcome means and numbers of patients to the study with
missing data.
17
In studies with a crossover desgn, the number
of patients was counted once for each arm in which they were
included.
Results
Of the 23 randomized controlled trials we identified, 9
were rejected: in 5 the alternative drug or drug formula-
tion was not available in Canada,
18–22
in 3 a random alloca-
tion of participants was not confirmed,
23–25
and in 1 benzo-
diazepines were included only as part of combination
therapy.
26
Of the remaining 14 studies, 13 examined acute
alcohol withdrawal
27–39
and 1 looked at long-term mainte-
nance of abstinence after alcohol withdrawal.
40
Two of the
13 studies of acute withdrawal
36,37
compared 2 benzodi-
azepines and therefore were not considered further. The
remaining 11 studies (representing a total of 1286 pa-
tients) compared a benzodiazepine with a placebo, active
control drug or both. Details of these studies are summa-
rized in Table 1.
Most of the 11 trials involved small samples. The mean
age of patients ranged from 35 to 45 years. In half of the
trials, patients with concomitant medical conditions were
excluded. Five of the studies involved chlordiazepoxide, 3
used diazepam, 2 involved oxazepam and 1 used lo-
razepam. Doses varied greatly once adjusted for equiva-
lent potency, from 2 to 18 diazepam dose equivalents per
day (a single dose equivalent = 5 mg of diazepam). Nine of
the trials followed patients for a week or less. Outcome
measures were different in virtually every study, rendering
meta-analysis of all studies impossible. The methodologic
quality of the trials was generally reasonable except for 2
trials.
33,34
Meta-analysis of the 3 studies of benzodiazepine versus
placebo that had a similar outcome measure yielded a
common odds ratio of 3.28 (95% CI 1.30–8.28) (Fig.
1).
27–29
This meant that the benzodiazepine studied was
rated as superior to placebo in relieving the symptoms of
alcohol withdrawal within the first 2 days of withdrawal.
Review of the individual benzodiazepines (diazepam,
chlordiazepoxide and lorazepam) used in these placebo-
controlled trials did not suggest differences in efficacy
among them. The 2 studies that specifically compared
benzodiazepines directly (chlordiazepoxide v. clobazam
36
and diazepam v. lorazepam
37
) did not show significant dif-
ferences in efficacy.
Nine of the trials compared benzodiazepines with
other drugs (bromocriptine,
28
carbamazepine,
31,32
chlorpromazine,
39
clonidine,
30
doxepin,
35
ethanol,
34
hy-
droxyzine,
39
paraldehyde,
33
propranolol
38
and thiamine
39
).
The heterogeneity of efficacy outcomes measured in
these trials precluded the combination of data, but there
was no evidence of overall superiority of any alternative
agent over benzodiazepines in these small trials. Propra-
nolol, as would be expected of β-blockers, lowered heart
rate, blood pressure and tremor more than placebo but
was less effective in the management of other symptoms
such as anxiety, difficulty sleeping and nausea within the
first 2 days. Carbamazepine appeared as efficacious as
relatively low doses of oxazepam.
Data could be pooled for meta-analysis of harm (ad-
verse effects and dropout rates). Three studies (repre-
senting a total 148 patients) reported on the number of
patients who had an adverse event (Fig. 2).
28,31,35
The
common odds ratio (0.67, 95% CI 0.34–1.32) suggested
no difference between benzodiazepines and the alterna-
tive drugs examined. Data on study dropout rates could
be combined from 5 trials (representing a total 633 pa-
tients) (Fig. 3).
30–33,39
The common odds ratio (0.68, 95%
CI 0.47–0.97) indicated that fewer patients in the benzo-
diazepine group than in the alternative drug group
dropped out within the first 7 days of treatment. Inclu-
sion of trials of alternative drugs not available in Canada,
such as chlormethiazole, tetrabamate and transdermal
clonidine,
18–20,22
resulted in virtually identical results.
Benzodiazepine use for alcohol withdrawal
CMAJ • MAR. 9, 1999; 160 (5) 651
One study followed patients long enough (6 months)
to be able to comment on therapy for maintenance of ab-
stinence from alcohol.
40
This study involved 78 patients
and compared chlordiazepoxide and metronidazole. The
authors found that both drugs were equally ineffective for
abstinence maintenance, as judged by dropout rates of
80% at 6 months.
A recent study of note compared different methods of
administration of benzodiazepine for acute alcohol with-
drawal.
41
This study was conducted in an alcohol detoxifi-
cation unit with staff trained in the management of alco-
hol withdrawal who used the Clinical Institute With-
drawal Assessment for Alcohol (CIWA-Ar) scale every 8
hours routinely and after each dose of benzodiazepine.
(The CIWA-Ar scale is reproduced in Appendix 2 of the
accompanying article on the diagnosis and management
of acute alcohol withdrawal
12
[page 680 of this issue].) The
authors found that a fixed dosage schedule of benzodi-
Holbrook et al
652 JAMC • 9 MARS 1999; 160 (5)
Baumgartner
et al, 1987
29
T 3
H 3
Tuppaeck et
al, 1992
30
T 4
H 4
Malcolm et
al, 1989
31
T 4
Thompson et
al, 1975
32
T 1
H 2
Funderburk
et al, 1978
33
Study
Study
quality*
T 1
H 1
Chlordiazepoxide (99.7 mg)
v. ethanol (358.8 mL)
Cumulative dose to endpoint:
diazepam (mean dose 46 mg)
(DTs only) v. paraldehyde
(mean dose 36 mL) (DTs only)
Sellers et al,
1983
26
T 4
H 4
Oxazepam (120 mg) v.
carbamazepine (800 mg)
Oxazepam (≤ 120 mg) v.
carbamazepine (≤ 800 mg)
Chlordiazepoxide (100 mg)
v. clonidine (0.4 mg)
Burroughs et
al, 1985
27
T 5
H 5
Lorazepam (6 mg) v. placebo
Chlordiazepoxide (250 mg
tapered to 25 mg) v.
bromocriptine (7.5 mg
tapered to 2.5 mg) v. placebo
Naranjo et
al, 1983
28
T 4
H 4
Diazepam (73 mg) v. placebo
Drugs compared
(and mean daily dose)
4–6 d
160 h
18/0
26/8
86/0
11/47
61/0
7 d
35/6
40/31
43/7
No. of
subjects
(male/female)
7 d
Table 1: Summary of randomized controlled trials of efficacy of benzodiazepines in the treatment of acute alcohol withdrawal
60 h
7 h
7 d
12–15 h
Treatment
duration
Improvement in withdrawal symptoms did not differ
significantly between groups
Severe withdrawal – all patients had DTs. Time to
calm and number of patients experiencing apnea,
agitation or death significantly reduced with
diazepam than with paraldehyde (p < 0.05)
Severe withdrawal. CIWA-Ar score and dropout rates
did not differ significantly between groups. Stable
improvement by 5 d
Improvement in withdrawal symptoms, complications,
adverse effect rates and dropout rates did not differ
significantly between groups. Continued improvement
over 7 d
Anxiety, cognitive capacity, self-rated severity of
withdrawal symptoms, adverse effects and dropout
rates did not differ significantly between groups.
Blood pressure and heart rate significantly reduced
with clonidine than with chlordiazepoxide (p < 0.05)
At 7 h, therapeutic success (CIWA-Ar score ≤ 10) was
significantly greater with lorazepam than with
placebo (p < 0.05)
Significant improvement in withdrawal symptoms and
therapeutic success at 2 d with chlordiazepoxide than
with bromocriptine or placebo (p < 0.05). Number of
patients reporting adverse events did not differ
significantly
Significant improvement in withdrawal symptoms
with diazepam than with placebo (p < 0.05).
Therapeutic success (CIWA-Ar score of ≤ 10) did not
differ significantly between groups
Main results
Gallant et al,
1969
34
T 4
H 4
Diazepam (15 mg) v. doxepin
(75 or 150 mg) v. placebo
100/0 21 d Clinical improvement and adverse effect rates did not
differ significantly between groups
Sellers et al,
1977
37
T 3
H 3
Chlordiazepoxide (100 mg)
v. propranolol (40 or 160 mg)
v. placebo
30/0 4 d Withdrawal symptoms at 2 d significantly improved
with chlordiazepoxide than with propranolol or
placebo (p < 0.05). Propranolol 160 mg decreased
tremor, heart rate and blood pressure
Kaim et al,
1969
38
T 4
H 4
Chlordiazepoxide (200 mg)
v. chlorpromazine (400 mg)
v. hydroxyzine (400 mg) v.
thiamine (400 mg) v. placebo
537 10 d Incidence rates of delirium and seizures significantly
reduced with chlordiazepoxide than with
chlorpromazine or placebo
Note: CIWA-Ar = Clinical Institute Withdrawal Assessment for Alcohol, DTs = delirium tremens.
*T = therapy (maximum score 5), H = harm (maximum score 5); see Methods.
azepines over 48 hours was less successful than a regimen
in which the benzodiazepine was administered as needed
on the basis of the CIWA-Ar score; this was true for both
the duration of benzodiazepine treatment and the total
number of milligrams given.
Interpretation
Our confirmation of the superiority of benzodiazepines
over placebo in the treatment of acute alcohol withdrawal
would probably not surprise most clinicians. However, al-
ternatives to benzodiazepines have attracted interest pri-
marily because of initial concerns about central nervous
system depression at high doses of benzodiazepines plus
the risk of benzodiazepine dependence. The former con-
cern was not borne out in the trials, and the latter should
not be an issue because of the short-term use recom-
mended in the treatment of alcohol withdrawal. Although
β-blockers may decrease the peripheral autonomic mani-
festations of alcohol withdrawal, they have no anti-epilep-
tic effect. Clonidine and carbamazepine remain second-
line or adjunctive choices if high doses of benzodiazepine
cannot be given.
42
Their impact on delirium and seizures
is unknown, given the small samples of the relevant stud-
ies. Carbamazepine has broader intuitive appeal than
clonidine because of its anticonvulsant activity. The addi-
tional alternatives studied that are not available in Canada
(chlormethiazole,
19,22
tetrabamate
20
and transdermal cloni-
dine
18
) were not found to be superior to benzodiazepines.
Our analysis revealed no evidence of superiority of one
Benzodiazepine use for alcohol withdrawal
CMAJ • MAR. 9, 1999; 160 (5) 653
Fig. 1: Odds ratio of trials analysing effect of benzodiazepine versus placebo in treatment of acute alcohol withdrawal. Success
was measured as reduction in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score within 2 days. Overall
odds ratio 3.28 (95% confidence interval [CI] 1.30 to 8.28; test for homogeneity, p > 0.05).
0.1
0.2
0.5
1
25
10
100
500
Odds ratio
Placebo better
Benzodiazepine better
Fig. 2: Odds ratio of trials analysing effect of benzodiazepine versus alternative drug treatment in terms of adverse effects
among patients with acute alcohol withdrawal. Overall odds ratio 0.67 (95% CI 0.34 to 1.32; test for homogeneity, p > 0.05).
0.1
0.2
0.5
1
25
10
100
500
Odds ratio
Benzodiazepine better
Alternative drug better
No. of patients
with adverse effect
Alternative
Study Treatment Benzodiazepine drug
Burroughs et al
27
Chlordiazepoxide v. bromocriptine 1/10 0/9
Gallant et al
34
Diazepam v. doxepin 75 mg 17/24 17/23
Diazepam v. doxepin 150 mg 17/24 20/24
Tuppaeck et al
30
Oxazepam v. carbamazepine 12/29 16/29
Total 47/87 53/85
No. of patients with
successful outcome
Study Treatment Benzodiazepine Placebo
Sellers et al
26
Diazepam v. placebo 18/25 14/25
Burroughs et al
27
Chlordiazepoxide v. placebo 9/10 4/11
Naranjo et al
28
Lorazepam v. placebo 20/21 17/20
Total 47/56 35/56
benzodiazepine over another. All benzodiazepines avail-
able orally in Canada are relatively long acting (effective
half-life over 12 hours
12
) except for triazolam. The ad-
vantage of a benzodiazepine with a longer half-life in
promoting a smoother withdrawal from alcohol
43,44
may
be partially offset by accumulation of the drug in pa-
tients who have significant hepatic impairment or who
are given prolonged treatment with inadequate doses.
44–46
We are unaware of other meta-analyses of benzodi-
azepines for their common uses. Recent evidence-based
guidelines from the American Society for Addiction Med-
icine support the use of benzodiazepines as first-line drug
therapy for alcohol withdrawal, with therapy individual-
ized according to the CIWA-Ar scores.
43
The guidelines
incorporated a meta-analysis, but nonrandomized trials
had been included.
This first article in our series of meta-analyses illus-
trates a number of deficiencies with the benzodiazepine
literature. Given that members of this family of drugs be-
gan appearing on the market in 1960,
1
there are surpris-
ingly few randomized controlled trials of their use in the
treatment of alcohol withdrawal. As with many areas of
therapeutics, the great variety of ways that benefit and
harm of therapies were expressed rendered the pooling of
data from different trials difficult. We were able to stan-
dardize dosing to a common measurement, the diazepam
dose equivalent,
12
but there were insufficient trials to ex-
amine dose–response relationships.
A potential limitation to our methodology was the re-
striction of our search to studies published in English.
47
Another potential limitation was our adoption of the
fixed-effects model, recommended by the Cochrane Col-
laboration.
14
Meta-analyses are undertaken using one of 2
main models, fixed effects or random effects.
48–50
Various
arguments have been put forth supporting one or the
other model. Although we used the fixed-effects model,
our results were virtually identical when we repeated the
analyses using a standard random-effects model.
Most of the studies included in our meta-analysis had
been conducted in inpatient alcohol detoxification units,
and the participants tended to be younger men with little
or no comorbidity. In contrast, comorbidity, particularly
lung and heart disease, is common in hospital patients,
and competing comorbidities may prevent the recogni-
tion of symptoms and signs of alcohol withdrawal at an
early stage. Furthermore, elderly patients or those with
known hepatic, cardiac or respiratory impairment tend to
be routinely excluded from trials; however, they may be
more sensitive to various adverse effects of benzodi-
azepines including respiratory suppression. Nonetheless,
the generalizability of the trial results to these individuals
at higher risk is cautiously recommended,
41,51,52
although
these patients must be closely monitored, particularly for
respiratory status.
Conclusions
Benzodiazepines appear to deserve a key role as first-
line drug therapy for the management of acute alcohol
withdrawal. The most important consideration is not
which benzodiazepine to use, but to ensure that adequate
doses are administered early in the course of withdrawal.
Early treatment coupled with close and regular monitor-
ing appears to be effective in avoiding prolonged with-
drawal, sedation-related morbidity and extra resource
utilization.
Holbrook et al
654 JAMC • 9 MARS 1999; 160 (5)
Fig. 3: Odds ratio of trials analysing effect of benzodiazepine versus alternative drug treatment in terms of dropout rates within
7 days after randomization among patients with acute alcohol withdrawal. Overall odds ratio 0.68 (95% CI 0.47 to 0.97; test
for homogeneity, p > 0.05).
0.1
0.2
0.5
1
25
10
100
500
Odds ratio
Benzodiazepine
better
Alternative
drug better
No. of patients who
dropped out
Alternative
Study Treatment Benzodiazepine drug
Baumgartner et al
29
Chlordiazepoxide v. clonidine 9/30 5/31
Malcolm et al
31
Oxazepam v. carbamazepine 4/30 4/30
Tuppaeck et al
30
Oxazepam v. carbamazepine 9/34 11/32
Thompson et al
32
Diazepam v. paraldehyde 0/17 0/17
Kaim et al
38
Chlordiazepoxide v. hydroxyzine 14/103 17/103
Chlordiazepoxide v. chlorpromazine 14/103 25/103
Chlordiazepoxide v. thiamine 14/103 24/103
Total 36/214 86/419
This study was funded in part by the Canadian Pharmaceutical
Association (CPhA) and the Canadian Medical Association
(CMA). The analysis was prepared for a CPhA–CMA clinical
practice guideline initiative on benzodiazepines. Dr. Holbrook
is a recipient of an Ontario Ministry of Health Research Person-
nel Award (no. 04698).
Competing interests: None declared.
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Reprint requests to: Dr. Anne M. Holbrook, Centre for Evaluation
of Medicine, St. Joseph’s Hospital, 50 Charlton Ave. E, Hamilton
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