Art. Cefalea

Propranolol for migraine prophylaxis (Review)
Linde K, Rossnagel K
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 11
http://www.thecochranelibrary.com

Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Propranolol versus placebo, Outcome 1 Responders (parallel-group and 1st period crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Responders (parallel-group and pooled crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Propranolol versus placebo, Outcome 3 Attack frequency measures (parallel-group and 1st
period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Propranolol versus placebo, Outcome 4 Attack frequency measures (parallel-group and pooled
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Propranolol versus placebo, Outcome 5 Number of patients with adverse events (parallelgroup; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Propranolol versus placebo, Outcome 6 Number of patients with adverse events (parallel-group
and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.7. Comparison 1 Propranolol versus placebo, Outcome 7 Number of dropouts due to adverse events (parallelgroup and 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.8. Comparison 1 Propranolol versus placebo, Outcome 8 Number of dropouts due to adverse events (parallelgroup and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Propranolol versus calcium antagonists, Outcome 1 Responders (all trials parallel-group).
Analysis 2.2. Comparison 2 Propranolol versus calcium antagonists, Outcome 2 Attack frequency measures (all trials
parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.3. Comparison 2 Propranolol versus calcium antagonists, Outcome 3 Number of patients with adverse events
(all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.4. Comparison 2 Propranolol versus calcium antagonists, Outcome 4 Number of patients with adverse events
(vs. flunarizine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.5. Comparison 2 Propranolol versus calcium antagonists, Outcome 5 Number of dropouts due to adverse events
(all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(vs. flunarizine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . .
(vs. nifedipine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Propranolol versus other beta-blockers, Outcome 1 Responders (parallel-group; no 1st period
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Propranolol versus other beta-blockers, Outcome 2 Responders (parallel-group and pooled
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Propranolol versus other beta-blockers, Outcome 3 Responders (vs. nadolol; parallel-group and
pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.4. Comparison 3 Propranolol versus other beta-blockers, Outcome 4 Responders (vs. metoprolol; parallel-group
and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
1
2
2
2
2
5
7
8
8
9
13
61
70
71
73
74
75
76
77
78
80
82
83
85
86
88
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93
i
Analysis 3.5. Comparison 3 Propranolol versus other beta-blockers, Outcome 5 Attack frequency measures (pooled
crossover only; no parallel-group or 1st period crossover data). . . . . . . . . . . . . . . . . .
Analysis 3.6. Comparison 3 Propranolol versus other beta-blockers, Outcome 6 Number of patients with adverse events
(parallel-group; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.7. Comparison 3 Propranolol versus other beta-blockers, Outcome 7 Number of patients with adverse events
(parallel-group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.8. Comparison 3 Propranolol versus other beta-blockers, Outcome 8 Number of dropouts due to adverse events
(parallel-group; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.9. Comparison 3 Propranolol versus other beta-blockers, Outcome 9 Number of dropouts due to adverse events
(parallel-group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Propranolol versus other drugs, Outcome 1 Responders (parallel-group and 1st period crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.2. Comparison 4 Propranolol versus other drugs, Outcome 2 Responders (parallel-group and pooled crossover
data [one 1st period]). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.3. Comparison 4 Propranolol versus other drugs, Outcome 3 Attack frequency measures (parallel-group and 1st
period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.4. Comparison 4 Propranolol versus other drugs, Outcome 4 Attack frequency measures (parallel-group and
pooled crossover data [two 1st period]). . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.5. Comparison 4 Propranolol versus other drugs, Outcome 5 Number of patients with adverse events (parallelgroup; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse events (parallelgroup and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to adverse events (parallelgroup; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to adverse events (parallelgroup and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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94
95
95
97
98
101
102
103
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105
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107
108
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118
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[Intervention Review]
Propranolol for migraine prophylaxis

Klaus Linde1 , Karin Rossnagel2
1 Centre for Complementary Medicine Research, Department of Internal Medicine II, Technical University Munich, Munich, Germany.
2 Institute
of Social Medicine & Epidemiology, Charit University Hospital, Berlin, Germany
Contact address: Anna Hobson, Cochrane Pain, Palliative & Supportive Care Group, Pain Research Unit, The Churchill Hospital,
Old Road, Oxford, OX3 7LE, UK. anna.hobson@ndcn.ox.ac.uk.
Editorial group: Cochrane Pain, Palliative and Supportive Care Group.
Publication status and date: Edited (no change to conclusions), published in Issue 11, 2012.
Review content assessed as up-to-date: 15 May 2003.
Citation: Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database of Systematic Reviews 2004, Issue 2. Art.
No.: CD003225. DOI: 10.1002/14651858.CD003225.pub2.
ABSTRACT
Background
Propranolol is one of the most commonly prescribed drugs for migraine prophylaxis.
Objectives
We aimed to determine whether there is evidence that propranolol is more effective than placebo and as effective as other drugs for the
interval (prophylactic) treatment of patients with migraine.
Search methods
Potentially eligible studies were identified by searching MEDLINE/PubMed (1966 to May 2003) and the Cochrane Central Register
of Controlled Trials (Issue 2, 2003), and by screening bibliographies of reviews and identified articles.
Selection criteria
We included randomised and quasi-randomised clinical trials of at least 4 weeks duration comparing clinical effects of propranolol with
placebo or another drug in adult migraine sufferers.
Data collection and analysis
Two reviewers extracted information on patients, methods, interventions, outcomes measured, and results using a pre-tested form.
Study quality was assessed using two checklists (Jadad scale and Delphi list). Due to the heterogeneity of outcome measures and
insufficient reporting of the data, only selective quantitative meta-analyses were performed. As far as possible, effect size estimates were
calculated for single trials. In addition, results were summarised descriptively and by a vote count among the reviewers.
Main results
A total of 58 trials with 5072 participants met the inclusion criteria. The 58 selected trials included 26 comparisons with placebo and
47 comparisons with other drugs. The methodological quality of the majority of trials was unsatisfactory. The principal shortcomings
were high dropout rates and insufficient reporting and handling of this problem in the analysis. Overall, the 26 placebo-controlled trials
showed clear short-term effects of propranolol over placebo. Due to the lack of studies with long-term follow up, it is unclear whether
these effects are stable after stopping propranolol. The 47 comparisons with calcium antagonists, other beta-blockers, and a variety of
other drugs did not yield any clear-cut differences. Sample size was, however, insufficient in most trials to establish equivalence.
Authors conclusions
Although many trials have relevant methodological shortcomings, there is clear evidence that propranolol is more effective than placebo
in the short-term interval treatment of migraine. Evidence on long-term effects is lacking. Propranolol seems to be as effective and safe
as a variety of other drugs used for migraine prophylaxis.
PLAIN LANGUAGE SUMMARY

Propranolol, a beta-blocker, is one of the most commonly prescribed drugs for the prevention of migraine. This systematic review
identified 58 trials, and these provide evidence that propranolol reduces migraine frequency significantly more than placebo. We did
not find any clear differences between propranolol and other migraine-preventing drugs, but firm conclusions cannot be drawn about
the relative efficacy of propranolol and other drugs due to the small sample size of most of the trials.
BACKGROUND
Migraine is a common disabling condition. It typically manifests
as attacks of severe, pulsating, one-sided headache and is often
accompanied by nausea, phonophobia, or photophobia. Population-based studies from the US and elsewhere suggest that six to
seven per cent of men and 15% to 18% of women experience migraine headaches (Lipton 2001; Stewart 1994). Preventive drugs
are used by a small proportion of migraineurs. Available guidelines commonly recommend beta-blockers as the first choice for
migraine prophylaxis (e.g., Pryse-Phillips 1997). It is not certain
exactly how beta-blockers decrease the frequency of migraine attacks, but they may affect the central catecholaminergic system
and brain serotonin receptors.
Among the many different beta-blockers, propranolol is one of the
most commonly prescribed for migraine prophylaxis (Ramadan
1997). It has been subjected to a number of placebo-controlled
trials and is now sometimes used as a comparator drug when testing newer agents for migraine prophylaxis (Gray 1999; Holroyd
1991). While propranolol is well-tolerated in general, it is associated with a variety of adverse effects (such as bradycardia, hypotension, bronchospasm, gastrointestinal complaints, vertigo, hypoglycaemia, etc).
1. more effective than placebo;

2. as effective as other pharmacological agents.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised and quasi-randomised (using methods such as alternation) clinical trials were included. Trials that did not make an
explicit statement about the allocation method, but were described
as double-blind (referring to blinding of patients and blinding of
recruiting, treating, and evaluating staff ), were included unless
there were clear reasons to assume that allocation was not randomised.
Types of participants
OBJECTIVES
We aimed to systematically review the available randomised and
quasi-randomised controlled trials of propranolol for migraine
prophylaxis. Specifically, we aimed to determine whether there is
evidence that propranolol is:
Study participants were required to be adult migraine sufferers.

Trials including individual participants under 18 years of age were
included provided that the mean age of trial participants clearly
indicated that the majority of patients were adults (e.g., if the
age range was 16 to 61 years, with a mean age of 41 years). Trials conducted among patients who suffered from other types of
headaches in addition to migraine were included. Trials studying
patients with migraine and patients with other types of headache

were included only if results for the subgroup of migraine sufferers

were presented separately.
trials with children or on non-migraine headaches). Full copies of

all remaining articles were obtained. Two independent reviewers
then checked whether trials met inclusion criteria using a special
form. Disagreements were resolved by discussion.
Types of interventions
Included studies were required to have at least one arm in which
oral propranolol was used for migraine prophylaxis. Acceptable
control groups included other migraine-prophylactic drugs (e.g.,
flunarizine, metoprolol, cyclandelate) and placebo. Trials comparing only different doses of propranolol, without a non-propranolol
group, were excluded. Trials comparing propranolol solely with
non-drug interventions (e.g., biofeedback or relaxation) were also
excluded.
Types of outcome measures

At least one of the following outcomes must have been measured
(but not necessarily reported in sufficient detail to allow effect
size calculation): number of migraine attacks, number of headache
days, pain intensity, headache index, or global response. Trials reporting only physiological or laboratory parameters were excluded,
as were trials focusing on the treatment of acute migraine attacks
and trials with an observation period of less than 4 weeks after the
start of treatment.
Search methods for identification of studies

We searched the following sources:
The basic search was performed in MEDLINE (1966
through September 2001) using the search terms propranolol or
propanolol and headache (exploded) combined with the
optimal search strategy for randomised controlled trials described
in the Cochrane Reviewers Handbook (Clarke 2003). To update
this search, we regularly screened citations from the search
migraine AND propranolol in PubMed for eligible studies or
reviews that might include eligible studies (last update May
2003; limited to publication date 2000 or later).
The Cochrane Central Register of Controlled Trials
(CENTRAL) was searched using the terms propranolol or
propanolol and migraine or headache (last update Issue 2,
2003).
In addition, we screened bibliographies of reviews and
identified articles.
Data collection and analysis
Eligibility
One reviewer screened titles and abstracts of all references identified and excluded all citations that were clearly ineligible (e.g.,
Data extraction
Two independent reviewers extracted the following information
using a pre-tested form:
On the patient population:
number randomised and analysed;
diagnoses (and headache classification systems used);
age;
sex;
duration of disease;
setting.
On methods:
study design;
use of a headache diary;
duration of baseline, therapy, and follow-up periods; for
crossover studies, we also documented washout periods;
randomisation;
concealment;
handling of dropouts and withdrawals.
On interventions:
type of intervention;
dosage;
regimen;
duration.
Outcomes and results:
withdrawals and dropouts due to adverse events, lack of
efficacy, or other reasons, with total number;
results for headache days, attack frequency, pain intensity,
medication use, headache index, and other outcomes at baseline,
after up to 4 weeks of treatment, after more than 4 weeks of
treatment, and at follow-up after completion of treatment;
number of responders, with definition of response;
number of patients reporting adverse events
Assessment of quality
Methodological quality was assessed using the scale by Jadad et
al. (Jadad 1996) and the Delphi list (Verhagen 1998). The Jadad
scale has three items and a maximum score of 5: randomisation
(statement that the study was randomised = 1 point; if the method
used to generate the random sequence was described, an additional point is given), double-blinding (statement that the study
was double-blind = 1 point; additional point if a credible description of how blinding was achieved was given), and dropouts and
withdrawals (a point was given if the number and reasons for dropouts and withdrawals were presented for each group separately).

The Delphi list has nine questions, which concern randomisation;

concealment of randomisation; baseline comparability; specification of eligibility criteria; blinding of the care provider, patients,
and outcome evaluator; adequacy of reporting of main results; and
analysis according to the intention-to-treat principle. Each question can be answered yes = 1, no = 0, or unclear = ?.
In addition, the adequacy of observation and reporting of key
clinical issues was assessed using a checklist developed by one of the
reviewers. It included questions on: description of the sampling
strategy (source of patients, recruitment); description of headache
diagnoses (description of specific diagnoses, use of transparent
diagnostic criteria); description of patient characteristics (age, sex,
duration, baseline severity); inclusion of a baseline period (of at
least 4 weeks); description of co-interventions (amount of analgesic
use); use of a headache diary; detailed presentation of data on
headache frequency and intensity (central tendency, variability);
completeness of follow up at 2 months (results for at least 90% of
included patients 2 months after the start of treatment) and at 6
months (follow up of at least 6 months after start of the treatment,
with results available for at least 80% of patients). Each item could
be scored as met (yes = 1) or not met or unclear (no/unclear =
0).
Summarising the results

As anticipated, the reporting of the complex outcome data in the
included trials was highly variable (various measurement methods, different time points) and often insufficient (lack of variance
measures, unclear number of observations). The only outcomes
reported in a substantial number of papers were:
various headache frequency measures (number of migraine
attacks, number of migraine days, and number of headache days;
mostly reported for the last 4 weeks of treatment, but sometimes
for other time frames);
headache indices;
number of responders (with response most often defined
as at least a 50% reduction in number of migraine attacks, but
also sometimes as at least a 50% reduction in headache index or
by global patient assessment); and
number of patients reporting adverse events.
Furthermore, a relevant proportion of trials had a crossover design
and reported results only in a pooled manner for both treatment
periods.
Using RevMan 4.2, we calculated standardized mean differences
for headache frequency, and relative risks for number of responders, number of patients with adverse events, and number of dropouts due to adverse events for individual trials. As the measure
for headache frequency we used, if available, the number of migraine attacks in the last 4 weeks or the last month of (full-dose)
treatment. However, a number of trials presented data either for
different time frames (for example, 8 weeks) or for another frequency measure (migraine or headache days). For the calculation
of the relative risk of response to treatment (here referred to as the

responder ratio) we used, if available, the number of patients with
a reduction of at least 50% in the number of migraine attacks.
If this was not available, we used the number of patients with a
reduction of at least 50% in the number of headache days, the
number of patients with a reduction of at least 50% in headache
index, or global response measures. In the Characteristics of included studies table, we indicate which measures were actually
used for each trial. As denominators we used the number of patients included in the analysis for responder ratios and the relative risk of adverse events, and the number of patients randomised
for the relative risk of dropouts due to adverse events. In many
instances there was uncertainty about precise numbers, for example, when only percentage values were reported for proportion of
responders, with denominators not fully clear, or when the total
number of patients randomised was presented but not the number
randomised to each group. In other cases, standard deviations had
to be calculated from standard errors or 95% confidence intervals. We tried to calculate effect sizes for single trials as often as
possible despite these uncertainties. Therefore, the effect size estimates must be interpreted with caution. In the Characteristics of
included studies table, we generally describe the data as reported
in the publications.
For effect size calculation we used, in the first instance, only data
from trials with a parallel-group design and first-period data from
those crossover studies that reported data for the first treatment
period separately. As many crossover trials did not present separate
data for the first treatment period, we calculated, in a second step,
effect size estimates for all trials providing data, including crossover
trials that reported only pooled data (data from all treatment
periods combined as if they were from a parallel-group trial). If
crossover trials reported both first-period and pooled data, then
we used the first-period data for the first analyses and pooled data
for the second; if crossover trials reported data only for separate
phases, with no pooled data, then we used first-period data for
both analyses. Comparisons of propranolol versus placebo, versus
calcium antagonists, versus other beta-blockers, and versus other
drugs were included.
In our protocol we prespecified that we would not perform quantitative meta-analysis for a given comparison if fewer than half of
the included trials provided usable data. For the comparison of
propranolol versus placebo, fewer than half of the trials in fact provided sufficient data for effect size calculation. However, because
the descriptive results, simple vote counts (see next paragraph),
and Jadad scores were similar for trials providing data for effect
size calculation and those not providing data, we decided post hoc
to perform quantitative meta-analyses for the propranolol versus
placebo comparison to get at least a crude estimate of the overall
effect sizes. Quantitative meta-analyses were also performed for
the comparisons with calcium antagonists and other beta-blockers. We calculated both fixed-effect and random-effects estimates,
but only fixed-effect estimates (which give more weight to larger

trials) are presented in the Results section. Due to the heterogeneity of trials (regarding patients, dosages, observation periods,
and methods for outcome measurements), the lack of detailed data
for a relevant proportion of the trials, and the problem of pooled
crossover data (described in the preceding paragraph), all overall
effect size estimates presented below must be interpreted with great
caution. Because of these problems, we did not calculate measures
like numbers-needed-to-treat, which suggest direct applicability
of effect size estimates to routine use in practice.
Because of the difficulties with the quantitative analysis, we also
provide a systematic descriptive summary of results for each study
in the table on the Characteristics of included studies. If available, results were summarized for the following outcomes: response, headache frequency, analgesic use, headache indices, adverse events, and dropouts due to adverse events. In addition, we
performed a simple vote count to provide a crude estimate of the
overall outcome of each study. For this vote count, each reviewer
independently categorized the results of each study using the following scale: + = propranolol significantly better than control (primary or most clinically relevant outcome measures statistically significantly better with propranolol than with control); (+) = propranolol trend better than control (significant differences for only
some clinically relevant outcomes, or no statistically significant
differences, but potentially clinically relevant trends in favour of
propranolol); 0 = no difference; (-) = control trend better than
propranolol; - = control significantly better than propranolol. Disagreements were resolved by discussion and consensus was reached
on each study.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
We identified 96 potentially relevant publications. Seventy-two
publications describing 58 separate trials met the inclusion criteria (see table on the Characteristics of included studies). One
publication presented separate data on patients suffering from migraine alone and patients suffering from migraine plus interval
headaches, but no analysis of all patients together; it was, therefore,
analysed as two separate trials (Mathew 1981-Study 1; Mathew
1981-Study 2).
Twenty-four publications were excluded: six were review articles (Amery 1988; Anonymous 1979; Montastruc 1992; RaveauLandon 1988; Tfelt-Hansen 1986; Turner 1984); nine described
studies that were not randomised or quasi-randomised (Cortelli
1985; de Bock 1997; Diamond 1987; Julien 1976; Rosen 1983;
Schmidt 1991; Verspeelt 1996a; Verspeelt 1996b; Wober 1991);
one unblinded trial did not describe the method of allocation
to groups (Steardo 1982); two trials were on the treatment of

acute attacks (Banerjee 1991; Fuller 1990); one had an observation period of less than 4 weeks (Winther 1990); and five were
randomised trials, but did not include placebo or another drug
as a control (Carroll 1990; Havanka-Kann. 1988; Holroyd 1995;
Penzien 1990; Sovak 1981) (for details see table on the Characteristics of excluded studies). We have so far been unable to obtain a
copy of two articles (Bernik 1978; Rao 2000); they are categorized
here as studies awaiting assessment.
The 58 trials included a total of 73 comparisons relevant to this
review: 26 trials included a comparison with placebo, and 40 trials
included a total of 47 comparisons of propranolol with another
drug. Eight trials had both a placebo and an active comparator
group. Three trials additionally included comparisons of propranolol alone versus propranolol in combination with another drug,
one a comparison with another propranolol dose, and one a comparison with d-propranolol. There were 15 comparisons with calcium antagonists (10 flunarizine, three nifedipine, one nimodipine, one verapamil), 12 with other beta-blockers (five metoprolol,
five nadolol, one atenolol, one timolol), and 20 with various other
agents (three amitriptyline, two femoxetine, two methysergide,
two cyclandelate, two divalproex sodium, two tolfenamic acid,
one dihydroergotamine, one dihydroergocryptine, one mefenamic
acid, one acetylsalicylic acid, one clonidine, one 5-hydroxytryptophan, one naproxen). Thirty-three trials had a crossover design.
The included trials were published between 1972 and 2002; four
were available only as abstracts. Ten studies reported the source of
funding.
The median number of patients per trial was 49 (range 9 to 810),
and the total number of included patients was 5072. The proportion of patients excluded from analysis varied from zero to 50%.
Eight trials were restricted to patients with migraine without aura,
and one to patients with migraine with aura. Twelve studies used
the International Headache Societys criteria (IHS 1988) for confirming the diagnosis, 20 the Ad Hoc Committees criteria (Ad
Hoc 1962), and nine other criteria; in 17 trials, the diagnostic
criteria used were not reported. Propranolol doses ranged from 60
to 320 mg per day. Baseline periods varied from 0 to 10 weeks
(median 4 weeks), and treatment phases from 4 to 30 weeks (median 12 weeks). Only a few studies included a follow-up period
after completion of treatment, and dropout rates in these studies
were high, making any interpretation difficult.
Risk of bias in included studies

The Jadad score for each study is given in the Characteristics of
included studies table, results of the assessment with the Delphi
list are reported in Table 1, and results of the assessment of the
adequacy of observation are described in Table 2 and Table 3.
The methodological quality of studies and the observation and
reporting of key clinical issues were unsatisfactory in the majority
of trials. The main shortcoming was the reporting and handling

of dropouts and withdrawals. Twenty-five studies reported numbers of and reasons for dropouts and withdrawals, but only three
included an intention-to-treat (ITT) analysis, even as a secondary
analysis. In comparisons between active drugs, an ITT analysis
would seem highly desirable as a sensitivity analysis given the high
dropout rates in most studies. Only two studies adequately described allocation concealment, and none tested the success of
blinding. Fifty-one studies were described as double-blind. The
median Jadad score was 2 (range 1 to 5); the median number
of criteria met on the Delphi list was 5 (range 1 to 9). A transparent description of patient recruitment was available for only
nine studies. Forty-seven trials used headache diaries, but only 29
presented detailed results (means and standard deviations, or median and ranges, etc.) for frequency measures, and 15 for intensity
measures. Eleven trials had data for at least 90% of randomised
patients for a period of at least 2 months, and three for 80% of
patients for at least 6 months. Crossover studies rarely reported
analyses of carryover or period effects.
Effects of interventions
Comparisons with placebo

Twenty-six trials compared propranolol with placebo.
Four trials reported data on response (with variable definitions)
that could be used to estimate effect sizes, nine if crossover trials
with pooled data are included. In all nine trials, the proportion of
responders was higher with propranolol than with placebo, and
in five trials the difference between the two interventions was statistically significant. The overall relative risk of response to treatment (here called the responder ratio) was 1.94 (95% confidence
interval [CI] 1.61 to 2.35) for all nine trials (see Comparison No.
01 02), and 1.73 (95% CI 1.23 to 2.42) for the four trials with
parallel-group or first-period crossover data (Comparison No. 01
01), indicating a significant effect of propranolol over placebo.
Results were statistically rather heterogeneous (I = 50.1%) in the
set of four trials, but not in the set of nine trials (I = 13.8%).
Responder ratios tended to be higher in trials with higher dosages
of propranolol, but the trial with the lowest dosage (80 mg) had
the most positive result (Weber 1972).
Four trials, or 10 if pooled crossover trials are included, reported
sufficient data on headache frequency. Here, too, all 10 trials
showed at least a trend in favour of propranolol. The overall standardized mean difference was -0.45 (95% CI -0.75 to -0.14) for
the four trials with parallel-group or first-period crossover data
(Comparison No. 01 03), and -0.40 (95% CI -0.56 to -0.24) for
all 10 trials (Comparison No. 01 04). The results suggest that propranolol 160 mg may be slightly more effective than 120 mg, but
the results from the four trials using 160 mg were highly heterogeneous (I = 60.8%).
Data on headache intensity were reported inconsistently, but effects over placebo seemed minor at best. There was no consistent
trend for larger effects with higher doses.
Only two trials, or six if pooled crossover trials are included, reported data on the number of patients with adverse events. Adverse
events were more often reported by patients receiving propranolol
(relative risk 1.33, 95% CI 0.97 to 1.82 for the two studies reporting parallel-group or first-period crossover data [Comparison
No. 01 05]; and 1.43, 95% CI 1.12 to 1.81 for all six trials [Comparison No. 01 06]).
For three, respectively 13, trials the number of patients dropping
out due to adverse events was reported. Patients receiving propranolol dropped out more often than patients receiving placebo
(relative risk 1.90, 95% CI 0.36 to 10.14 in the three trials with
parallel-group or first-period crossover data [Comparison No. 01
07]; and 2.11, 95% CI 1.09 to 4.08 in all 13 trials [Comparison
No. 01 08]).
Both for the number of patients reporting adverse events and the
number of patients dropping out due to adverse events, the results
of trials with parallel-group or first-period crossover data were statistically highly heterogeneous (Comparisons No. 01 05 and No.
01 07), while this heterogeneity strongly decreased when pooled
crossover data were considered (Comparisons No. 01 06 and No.
01 08).
The descriptive review of the placebo-controlled trials confirms
the impression that propranolol is significantly more effective than
placebo, mainly by reducing headache frequency. Any effect on
headache intensity seems at best minor. According to our vote
count, 17 trials showed a significant superiority over placebo, seven
a trend in favour of propranolol, and two no difference. All these
results apply only to effects during the treatment phase (most often
during the last month).
Comparisons with calcium antagonists

This category included 13 trials with 15 comparisons, plus one trial
comparing propranolol alone with a combination of propranolol
and flunarizine. All trials providing data for effect size calculations
in this subset had a parallel-group design.
Responder data were available for 11 comparisons between propranolol in variable doses and calcium antagonists (flunarizine in
nine cases), and for one comparison between propranolol alone
and a combination of propranolol and flunarizine. No trial found
a significant difference; in most studies response rates were very
similar in both groups. The overall responder ratio was 1.00 (95%
CI 0.93 to 1.09; Comparison No. 02 01).
Attack frequency data were available for seven comparisons and
indicated no statistically significant differences between groups.
The pooled standardized mean difference was -0.02 (95% CI 0.12 to 0.08; Comparison No. 02 02).
Nine trials comparing propranolol with a calcium antagonist (flunarizine in seven cases), and the trial comparing propranolol alone

with a combination of propranolol and flunarizine reported the

number of patients experiencing adverse events. These were similar in propranolol and flunarizine groups, but tended to be higher
with nifedipine and nimodipine. The overall relative risk for all
trials was 1.02 (95% CI 0.91 to 1.15; Comparison No. 02 03);
for comparisons of propranolol and flunarizine, the overall relative
risk was 1.06 (95% CI 0.94 to 1.20; Comparison No. 02 04).
Results were similar for the number of patients dropping out due
to adverse events in the 12 trials describing this outcome (Comparison No. 02 05). The overall relative risk for trials comparing propranolol and flunarizine was 0.98 (95% CI 0.67 to 1.44;
Comparison No. 02 06). Patients receiving nifedipine dropped
out more often due to side effects (relative risk 0.37, 95% CI 0.19
to 0.72; Comparison No. 02 07).
The vote count yielded the following result: two comparisons with
a trend in favour of propranolol, 12 showing no difference, one
with a trend in favour of flunarizine, and one with a trend in favour
of the combination of propranolol and flunarizine.
Comparisons with other beta-blockers

This category included 10 trials with 12 comparisons, plus one
trial comparing propranolol with d-propranolol.
Responder data were reported for four comparisons (Comparison
No. 03 01), or seven when including crossover trials with pooled
data (Comparison No. 03 02). In one trial, nadolol 160 mg was
significantly superior to propranolol 160 mg (Sudilovsky 1987);
the other six trials did not yield significant differences. As trial
results were statistically heterogeneous (I = 53.5% for the fourand 48.0% for the seven-trial set), and comparator drugs were
nadolol in three trials and metoprolol in three trials, we did not
combine results for all trials, but instead performed separate analyses for comparisons with nadolol (Comparison No. 03 03) and
metoprolol (Comparison No. 03 04). In the three trials comparing propranolol and nadolol, the overall responder ratio favoured
nadolol (0.60, 95% CI 0.37 to 0.97), but the results of the three
trials were contradictory (I = 68.8%). The three trials comparing propranolol and metoprolol had more consistent results (I
= 0%), but did not show significant differences (responder ratio
0.78, 95% CI 0.56 to 1.09).
Only four trials, all crossover in design, reported attack frequency
data, all pooled, and none reported significant differences; the
overall standardized mean difference was -0.01 (95% CI -0.24
to 0.22; Comparison No. 03 05). There were also no clearcut
differences in the number of patients with adverse events (one,
respectively three, trials; Comparisons No. 03 06 and No. 03 07)
or the number of patients dropping out due to adverse events (six,
respectively 11, comparisons; Comparisons No. 03 08 and No. 03
09).
The vote count results were as follows: seven comparisons showing
no difference, three with a trend in favour of the other beta-blocker,
one significantly in favour of the other beta-blocker (vs. nadolol),
and one not interpretable. Compared to d-propranolol there was

a trend in favour of propranolol.
Comparisons with other drugs

This category included 20 trials with 20 comparisons, plus two
trials comparing propranolol alone with a combination of propranolol and amitriptyline. We did not perform quantitative metaanalyses for the comparisons of propranolol and other drugs due to
the great variety of comparator drugs used. Therefore, we provide
only a descriptive summary of results here. Readers are referred
to the Characteristics of included studies table and the graphs in
MetaView for further information.
Five trials, or 10 if pooled crossover trials are included, provided
responder data that could be used for effect size calculation (Comparisons No. 04 01 and No. 04 02). None found a significant
difference. Both trials comparing propranolol 160 mg and femoxetine 400 mg reported a possibly relevant trend in favour of propranolol (Andersson 1981; Kangasniemi 1983). Attack frequency
data were reported in eight, respectively 10, trials (Comparisons
No. 04 03 and No. 04 04). Our calculations yielded a significant
superiority of propranolol 120 mg in one of two trials comparing it with tolfenamic acid 300 mg (Kjaersgard 1994) and to 5hydroxytryptophan 300 mg (Maissen 1991). Both comparisons
with femoxetine again showed a trend in favour of propranolol.
No differences were observed in other trials.
Four, respectively 10, trials described the number of patients reporting adverse events (Comparisons No. 04 05 and No. 04 06).
The trial comparing propranolol 120 mg and naproxen 1100
mg reported significantly fewer adverse events with propranolol
(Sargent 1985). Apart from the comparisons with cyclandelate
(trend in favour of cyclandelate [Diener 1996]) and divalproex
sodium (trend in favour of propranolol [Kaniecki 1997]), the
numbers of patients reporting adverse events with propranolol and
comparator drugs were very similar. The number of patients dropping out due to adverse events was reported for seven, respectively
18, comparisons (including the two comparisons of propranolol
alone with a combination of propranolol and amitriptyline). There
were no significant differences, but confidence intervals were wide
due to the low number of events (Comparisons No. 04 07 and
No. 04 08).
The vote count yielded the following result: one trial significantly
in favour of propranolol (vs. amitriptyline), five with a trend in
favour of propranolol, 11 showing no difference, two with a trend
in favour of the comparator drug, and one not interpretable; one
of the two comparisons of propranolol alone and propranolol in
combination with amitriptyline was classified as no difference, and
the other as showing a trend in favour of the combination.
DISCUSSION

Despite the methodological limitations of the majority of the available trials, there is clear and consistent evidence that propranolol
is superior to placebo in the interval treatment of patients suffering from migraine. Based on the available trials, it is not possible
to draw reliable conclusions on whether different doses of propranolol have different effectiveness, or whether the prophylactic
effects continue after propranolol is stopped. Propranolol seems to
be as effective as other pharmacological agents used for migraine
prophylaxis, and seems to have similar safety and tolerability, but
definitive conclusions are not possible due to small sample sizes
and the inconsistent reporting of results, which precluded a reliable meta-analysis of the available studies.
The major problem encountered in this review was the highly variable and often insufficient reporting of the complex outcome data.
Migraine prophylaxis trials typically use headache diaries to monitor the course of the disease. From these headache diaries a variety
of outcomes can be extracted (headache days, migraine days, migraine attacks, days with a defined headache intensity, attack intensity, mean headache intensity, headache indices, headache hours,
days with medication, use of analgesics, etc.). These outcomes can
be assessed over different time frames (most often 4 weeks, but
there were trials using 3 weeks, 8 weeks, total treatment periods,
etc.) and presented in different manners (values at a certain time
interval presented as means with standard deviations, standard errors, confidence intervals, or often no measure of variance; medians with range, quartiles, or nothing; as mean or median per
cent change compared to baseline, etc.). The data reported in the
included studies represent a highly heterogeneous mixture of these
different options. This not only makes quantitative meta-analysis
technically difficult, but raises the question of why certain results
have been presented and others not. Due to these problems, all
overall effect size estimates from the quantitative meta-analyses
reported here must be interpreted with great caution.
Another problem was the high dropout rates reported. The majority of the trials were performed at a time when intention-totreat analyses were not mandatory. Therefore, dropouts and withdrawals were typically excluded from analysis, which probably led
to overly optimistic response rates (regardless of study group) and
possibly to an over-estimation of effects over placebo.
Due to the small sample size of most trials, the comparisons of
propranolol with other drugs must be interpreted with great caution. Clinically relevant differences might exist but have not been
detected. On the other hand, as there are very few trials or often
only a single trial comparing a defined dose of propranolol with
a comparator drug in a defined dose, any significant differences
found in our effect size calculations also have to be interpreted
with great care.
Taking all these problems into account, there is considerable uncertainty about the actual size of the effect of propranolol over
placebo and effect sizes for propranolol in comparison with other
pharmacological agents.
The main shortcoming of the available trials from a practical perspective is the lack of adequate follow up after stopping treatment.
The few studies that had such a follow up reported very high withdrawal rates.
Our findings are very similar to those of a systematic review on drug
treatments for the prevention of migraine headache performed
for the US Agency of Health Care Policy and Research (now the
US Agency for Healthcare Research and Quality) in 1999 (Gray
1999).
AUTHORS CONCLUSIONS
Implications for practice
Based on the available evidence, the use of propranolol for the
prophylactic treatment of migraine is justified.
Implications for research

Since propranolol has been on the market for a long time, it
seems unlikely that major studies will be performed in the future
with propranolol as the primary experimental treatment. However, it will probably still be used as a comparator drug when
new agents or uncommon dosing schemes are tested (as, e.g., in
Diener 2002). We recommend that new trials follow the International Headache Societys guidelines for controlled trials of drugs
for migraine (Tfelt-Hansen 2000), so that future studies will be
conducted according to a high methodological standard and will
more readily permit quantitative meta-analysis. However, as these
guidelines recommend quite narrow inclusion criteria, it seems
unclear whether the findings of such trials will be directly applicable to migraine treatment in primary care. Major topics for future research include the question of how stable the preventive
effects of prophylactic drug treatment is once the treatment has
been stopped and the extent to which migraine patients comply
with prophylactic treatment in routine practice.
ACKNOWLEDGEMENTS
The authors would like to thank Dr HJ Jaster for extracting data
from several studies, and Rebecca Gray and Douglas McCrory for
their great help and input at various stages of the review.

REFERENCES
References to studies included in this review

Ahuja 1985 {published data only}
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Albers 1989 {published data only}
Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine
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Al-Qassab 1993 {published data only}
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Andersson 1981 {published data only}
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Baldrati 1983 {published data only}
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G, DAlessandro R, Baruzzi A, et al.Propranolol and
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Behan 1980 {published data only}
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Diener 1989 {published data only}
Diener HC, Scholz E, Dichgans J, Gerber WD, Jck

A, Bille A, et al.Central effects of drugs used in migraine
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treatment of migraine with propranolol. A clinical trial.
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Gawel 1992 {published data only}

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Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS.

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Dahlf 1987 {published data only}

Dahlf C. No clearcut longterm prophylactic effect of
one month of treatment with propranolol in migraineurs.
Cephalalgia 1987;7 Suppl 6:45960.
Gerber 1995 {published data only}
Gerber WD, Schellenberg R, Thom M, Haufe C, Blsche

F, Wedekind W, et al.Cyclandelate versus propranolol in the
prophylaxis of migraine - a double-blind placebo-controlled
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Schellenberg R, Schwarz A, Niederberger U, Blsche F,
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cyclandelate and propranolol in migraine after stopping a

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einer viermonatigen medikamentsen Prophylaxe].
Nervenheilkunde 1997;16:1837.
Klapper 1994 {published data only}

Klapper JA. An open label cross-over comparison of
divalproex sodium and propranolol HCl in the prevention
of migraine headaches. Headache Quarterly 1994;5(1):
503.
Grotemeyer 1987 {published data only}

Grotemeyer KH, Husstedt IW, Schlake HP. Betablocker vs
placebo in vasomotor headache. A double-blind crossover
study [Betablocker vs Placebo bei vasomotorischem
Kopfschmerz. Eine doppelblinde CrossoverStudie].
Deutsche Medizinische Wochenschrift 1987;112(45):17403.
Kuritzky 1987 {published data only}

Kuritzky A, Hering R. Prophylactic treatment of migraine
with long acting propranolol - a comparison with placebo.
Hedman 1986 {published data only}

Hedman C, Winther K, Knudsen JB. The difference
between non-selective and beta 1-selective beta-blockers in
their effect on platelet function in migraine patients. Acta
Neurologica Scandinavica 1986;74(6):4758.
Holdorff 1977 {published data only}
Holdorff B, Sinn M, Roth G. Propranolol for migraine
prophylaxis: a double-blind study [Propranolol in der
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Klinik 1977;72(25):11158.
Johnson 1986 {published data only}
Johnson RH, Hornabrook RW, Lambie DG. Comparison of
mefenamic acid and propranolol with placebo in migraine
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4902.
Kangasniemi 1983 {published data only}
Kangasniemi PJ, Nyrke T, Lang AH, Petersen E. Femoxetine
- a new 5-HT uptake inhibitor - and propranolol in the
prophylactic treatment of migraine. Acta Neurologica
Scandinavica 1983;68(4):2627.
Kangasniemi 1984 {published data only}
Kangasniemi P, Hedman C. Metoprolol and propranolol

in the prophylactic treatment of classical and common
migraine. A double-blind study. Cephalalgia 1984;4(2):
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Nyrke T, Kangasniemi P, Lang AH, Petersen E. Steady-state
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propranolol and femoxetine. Acta Neurologica Scandinavica
1984;69(1):914.
Kaniecki 1997 {published data only}
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Kass 1980 {published data only}
Kass B, Nestvold K. Propranolol (Inderal) and clonidine
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Kjaersgard 1994 {published data only}
Kjaersgard Rasmussen MJ, Holt Larsen B, Borg L, Soelberg
Sorensen P, Hansen PE. Tolfenamic acid versus propranolol
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Scandinavica 1994;89(6):44650.
Lcking 1988a {published data only}
Lcking CH, Oestreich W, Schmidt R, Soyka D.

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Lcking 1988b {published data only}
Lcking CH, Oestreich W, Schmidt R, Soyka D.

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Ludin 1989 {published data only}
Ludin HP. Flunarizine and propranolol in the treatment of
migraine. Headache 1989;29(4):21924.
Maissen 1991 {published data only}
Maissen CP, Ludin HP. Comparative efficacy of
5-hydroxytryptophan and propranolol in interval
treatment of migraine [Vergleich der Wirksamkeit von
5Hydroxytrypthophan und von Propranolol in der
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Wochenschrift. Journal Suisse de Medecine 1991;121(43):
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Malvea 1973 {published data only}
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Mathew 1981-Study 1 {published data only}
Mathew NT. Prophylaxis of migraine and mixed headache.
A randomized controlled study. Headache 1981;21(3):1059. [Study 1 included patients with migraine only].
Mathew 1981-Study 2 {published data only}
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10
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Micieli 2001 {published data only}
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Mikkelsen B, Pedersen KK, Christiansen LV. Prophylactic
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placebo. Acta Neurologica Scandinavica 1986;73(4):4237.
Nadelmann 1986 {published data only}
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the prophylaxis of migraine. Headache 1986;26(4):17582.
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Olsson 1984 {published data only}
Olsson JE, Behring HC, Forssman B, Hedman C, Hedman
G, Johansson F, et al.Metoprolol and propranolol in
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Acta Neurologica Scandinavica 1984;70(3):1608.
Palferman 1983 {published data only}
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propranolol in the treatment of headache. British Journal of
Clinical Practice 1983;37(1):289.
Pita 1977 {published data only}
Pita E, Higueras A, Bolanos J, Perez N, Mundo A.
Propranolol and migraine. A clinical trial. Archivos de
Farmacologia y Toxicologia 1977;3(3):2738.
Pradalier 1989 {published data only}
Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J,
Masson M, et al.Beta-blockers and migraine. Efficacy of
time-release propranolol versus placebo [Betabloquants
et migraine. Efficacit, contre placebo, du propranolol a
libration prolonge]. Thrapie 1990;45(5):4415.
Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J,
Masson M, et al.Double-blind placebo controlled study of
the use of long-acting propranolol in migraine prophylaxis.
Pradalier A, Serratrice G, Collard M, Hirsch E, Feve

J, Masson M, et al.Long-acting propranolol in migraine
prophylaxis: results of a double-blind, placebo-controlled
study. Cephalalgia 1989;9(4):24753.
Ryan 1984 {published data only}
Ryan RE Sr. Comparative study of nadolol and propranolol
in prophylactic treatment of migraine. American Heart
Journal 1984;108(4 Pt 2):11569.
Sargent 1985 {published data only}

Sargent J, Solbach P, Damasio H, Baumel B, Corbett
J, Eisner L, et al.A comparison of naproxen sodium to
propranolol hydrochloride and a placebo control for the
prophylaxis of migraine headache. Headache 1985;25(6):
3204.
Scholz 1987 {published data only}
Scholz E, Gerber WD, Diener HC, Langohr HD, Reinecke
M. Dihydroergotamine vs flunarizine vs nifidepine vs
metoprolol vs propranolol in migraine prophylaxis: a
comparative study based on time series analysis. In: Rose
CF editor(s). Advances in headache research: proceedings of
the 6th International Migraine Symposium. London: John
Libbey, 1987:13945.
Shimell 1990 {published data only}
Shimell CJ, Fritz VU, Levien SL. A comparative trial of
flunarizine and propranolol in the prevention of migraine.
South African Medical Journal 1990;77(2):757.
Solomon 1986 {published data only}
Solomon GD, Scott AFB. Verapamil and propranolol in
migraine prophylaxis: a double-blind, crossover study.
Headache 1986;26(6):325.
Stensrud 1976 {published data only}
Stensrud P, Sjaastad O. Short-term clinical trial of
propranolol in racemic form (Inderal), D-propranolol and
placebo in migraine. Acta Neurologica Scandinavica 1976;
53(3):22932.
Stensrud 1980 {published data only}
Stensrud P, Sjaastad O. Comparative trial of Tenormin

(atenol) and Inderal (propranolol) in migraine. Headache
1980;20(4):2047.
Stensrud P, Sjaastad O. Comparative trial of Tenormin
(atenolol) and Inderal (propranolol) in migraine. Upsala
Journal of Medical Sciences - Supplement 1980;31:3740.
Sudilovsky 1987 {published data only}
Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA,
Meyer JH. Comparative efficacy of nadolol and propranolol
in the management of migraine. Headache 1987;27(8):
4216.
Tfelt-Hansen 1984 {published data only}
Standnes B. The prophylactic effect of timolol versus
propranolol and placebo in common migraine: betablockers in migraine. Cephalalgia 1982;2(3):16570.
Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen

H, Olesen J. Timolol vs propranolol vs placebo in common
migraine prophylaxis: a double-blind multicenter trial. Acta
Neurologica Scandinavica 1984;69(1):18.
Weber 1972 {published data only}
Weber RB, Reinmuth OM. The treatment of migraine with
propranolol. Neurology 1972;22(4):3669.
Wideroe 1974 {published data only}
Wideroe TE, Vigander T. Propranolol in the treatment of
migraine. BMJ 1974;2(921):699701.
Ziegler 1987 {published data only}
Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz

HA, Preskorn SH, Manson J. Migraine prophylaxis. A

11
comparison of propranolol and amitriptyline. Archives of

Neurology 1987;44(5):4869.
Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, Seim
J. Propranolol and amitriptyline in the prophylaxis of
migraine. Pharmacokinetic and therapeutic effects. Archives
of Neurology 1993;50(8):82530.
References to studies excluded from this review

Amery 1988 {published data only}
Amery WK. Onset of action of various migraine
prophylactics. Cephalalgia 1988;8 Suppl 8:113.
Anonymous 1979 {published data only}
Anonymous. Propranolol for prevention of migraine
headaches. Medical Letter on Drugs & Therapeutics 1979;21
(19):778.
Banerjee 1991 {published data only}
Banerjee M, Findley L. Propranolol in the treatment of
acute migraine attacks. Cephalalgia 1991;11(4):1936.
Carroll 1990 {published data only}
Carroll JD, Reidy M, Savundra PA, Cleave N, McAinsh J.
Long-acting propranolol in the prophylaxis of migraine: a
comparative study of two doses. Cephalalgia 1990;10(2):
1015.
Cortelli 1985 {published data only}
Cortelli P, Sacquegna T, Albani F, Baldrati A, DAlessandro
R, Baruzzi A, et al.Propranolol plasma levels and relief of
migraine. Relationship between plasma propranolol and
4-hydroxypropranolol concentrations and clinical effects.
Archives of Neurology 1985;42(1):468.
traitement prophylactique des migraines par le propranolol].

Nouvelle Presse Mdicale 1976;5(10):653.
Montastruc 1992 {published data only}
Montastruc JL, Senard JM. Calcium channel blockers and
prevention of migraine [Medicaments anticalciques et
prophylaxie de la migraine]. Pathologie et Biologie 1992;40
(4):3818.
Penzien 1990 {published data only}
Penzien D, Johnson C, Carpenter D, Holroyd K. Drug vs.
behavioral treatment of migraine: long-acting propranolol
vs. home-based self-management training. Headache 1990;
30(5):300.
Raveau-Landon 1988 {published data only}
Raveau-Landon C, Bousser MG. Metoprolol, a new effective
antimigraine agent [Le metoprolo, nouvel antimigraineux
de fond]. Presse Medicale 1988;17(35):18059.
Rosen 1983 {published data only}
Rosen JA. Observations on the efficacy of propranolol for
the prophylaxis of migraine. Annals of Neurology 1983;13
(1):923.
Schmidt 1991 {published data only}
Schmidt R, Oestreich W. Flunarizine in migraine
prophylaxis: the clinical experience. Journal of
Cardiovascular Pharmacology 1991;18 Suppl 8:S216.
Sovak 1981 {published data only}
Sovak M, Kunzel M, Sternbach RA, Dalessio DJ.
Mechanism of the biofeedback therapy of migraine:
volitional manipulation of the psychophysiological
background. Headache 1981;21(3):8992.
de Bock 1997 {published data only}

de Bock GH, Eelhart J, van Marwijk HW, Tromp TP,
Springer MP. A postmarketing study of flunarizine in
migraine and vertigo. Pharmacy World & Science 1997;19
(6):26974.
Steardo 1982 {published data only}

Steardo L, Bonuso S, Di Stasio E, Marano E. Selective and
non-selective beta-blockers: are both effective in prophylaxis
of migraine? A clinical trial versus methysergide. Acta
Neurologica 1982;4(3):196204.

Diamond S, Solomon GD, Freitag FG, Mehta ND. Longacting propranolol in the prophylaxis of migraine. Headache
1987;27(2):702.
Tfelt-Hansen 1986 {published data only}

Tfelt-Hansen P. Efficancy of beta-blockers in migraine. A
critical review. Cephalalgia 1986;6 Suppl 5:1524.
Fuller 1990 {published data only}

Fuller GN, Guiloff RJ. Propranolol in acute migraine: a
controlled study. Cephalalgia 1990;10(5):22933.
Havanka-Kann. 1988 {published data only}
Havanka-Kanniainen H, Hokkanen E, Myllyl VV.
Long acting propranolol in the prophylaxis of migraine.
Comparison of the daily doses of 80 mg and 160 mg.
Headache 1988;28(9):60711.
Holroyd 1995 {published data only}
Holroyd KA, France JL, Cordingley GE, Rokicki LA,
Kvaal SA, Lipchik GL, et al.Enhancing the effectiveness of
relaxation-thermal biofeedback training with propranolol
hydrochloride. Journal of Consulting & Clinical Psychology
1995;63(2):32730.
Julien 1976 {published data only}
Julien J, Vallat JM, Lagueny A, Darriet M. Preventive
treatment of migraine with propranolol (letter) [Le
Turner 1984 {published data only}

Turner P. Beta-blocking drugs in migraine. Postgraduate
Medical Journal 1984;60 Suppl 2:515.
Verspeelt 1996a {published data only}
Verspeelt J, De Locht P, Amery WK. Post-marketing cohort
study comparing the safety and efficacy of flunarizine and
propranolol in the prophylaxis of migraine. Cephalalgia
1996;16(5):32836.
Verspeelt 1996b {published data only}
Verspeelt J, De Locht P, Amery WK. Postmarketing study of
the use of flunarizine in vestibular vertigo and in migraine.
European Journal of Clinical Pharmacology 1996;51(1):
1522.
Winther 1990 {published data only}
Winther K, Hedman C, Flodgaard H. Platelet P1, P4-Di
(adenosine-51) tetraphosphate (AP4A) in migraine patients
before and during beta-adrenoceptor blockade. European
Journal of Clinical Investigation 1990;20(3):3368.

12
Wober 1991 {published data only}

Wober C, Wober-Bingel C, Koch G, Wessely P. Long-term
results of migraine prophylaxis with flunarizine and betablockers. Cephalalgia 1991;11(6):2516.
References to studies awaiting assessment

Bernik 1978 {published data only}
Bernik V, Maia E. The use of propranolol on migraine
prophylaxis: a double-blind clinical trials comparing
propranolol with an analgesic drug (acetaminophen) and
placebo [Uso do propranolol na profilaxia da enxacequa:
Estudo duplocego comparando propranolol a um
analgesico (acetaminofen) e placebo]. Folha mdica (Rio de
Janeiro) 1978;77(4):5018.
Rao 2000 {published data only}
Rao BS, Das DG, Taraknath VR, Sarma Y. A double blind
controlled study of propranolol and cyproheptadine in
migraine prophylaxis. Neurology India 2000;48(3):2236.
Additional references
IHS 1988
Headache Classification Committee of the International
Headache Society. Classification and diagnostic criteria
for headache disorders, cranial neuralgias and facial pain.
Jadad 1996
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds
DJ, Gavaghan DJ, et al.Assessing the quality of reports of
randomized clinical trials: is blinding necessary?. Controlled
Clinical Trials 1996;17(1):112.
Lipton 2001
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed
M. Prevalence and burden of migraine in the United States:
data from the American Migraine Study II. Headache 2001;
41(7):64657.
Pryse-Phillips 1997
Pryse-Phillips WEM, Dodick DW, Edmeads JG, Gawel
MJ, Nelson RF, Purdy RA, et al.Guidelines for the diagnosis
and management of migraine in clinical practice [published
erratum appears in CMAJ 1997;157(10):1354]. CMAJ
1997;156(9):127387.
Ad Hoc 1962
Ad Hoc Committee on the Classification of Headache of the
National Institute of Neurological Diseases and Blindness.
Classification of headache. JAMA 1962;179(9):7178.
Ramadan 1997
Ramadan NM, Schultz LL, Gilkey SJ. Migraine prophylactic
drugs: proof of efficacy, utilization and cost. Cephalalgia
1997;17(2):7380.
Clarke 2003
Clarke M, Oxman AD, editors. Optimal search strategy for
RCTs. Cochrane Reviewers Handbook 4.1.6 [updated January
2003]; Appendix 5c. In: The Cochrane Library, Issue 1, 2003.
Oxford: Update Software.
Stewart 1994
Stewart WF, Shechter A, Rasmussen BK. Migraine
prevalence. A review of population-based studies. Neurology
1994;44(6 Suppl 4):S17S23.
Gray 1999
Gray RN, Goslin RE, McCrory DC, Eberlein K, Tulsky
J, Hasselblad V. Drug treatments for the prevention of
migraine headache. Technical review 2.3. February 1999.
Prepared for the Agency for Health Care Policy and Research
under Contract No. 290-94-2025. Available at: http://
www.clinpol.mc.duke.edu (accessed 20 February 2004).
Holroyd 1991
Holroyd KA, Penzien DB, Cordingley GE. Propranolol in
the management of recurrent migraine: a meta-analytic
review. Headache 1991;31(5):33340.
Tfelt-Hansen 2000
Tfelt-Hansen P, Block G, Dahlf C, Diener HC, Ferrari
MD, Goadsby PJ, et al.Guidelines for controlled trials of
drugs for migraine: second edition. Cephalalgia 2000;20
(9):76586.
Verhagen 1998
Verhagen AP, de Vet HCW, de Bie RA, Kessels AG, Boers M,
Bouter LM, et al.The Delphi list: a criteria list for quality
assessment of randomized clinical trials for conducting
systematic reviews developed by Delphi consensus. Journal
of Clinical Epidemiology 1998;51(12):123541.
Indicates the major publication for the study

13
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Ahuja 1985
Methods
D: crossover
C: unclear
B: double
WD: unclear
J: 1-1-0
DU: -/2x8w (no washout)/-
Participants
N: 26/unclear
D: migraine
C: Ad Hoc
F: 46%
A: 17-55
DU: unclear
S: neurology clinic in India
Interventions
P: 120 mg
C: Placebo
Outcomes
R: not reported
F: 8.6 (sd 5.9) vs. 14.5 (13.1) attacks in 8 weeks
AU: not reported
HI: 20.7 (sd 16.8) vs. 38.0 (39.1)
AEs: no significant side effects
Dropouts-AEs: not reported
V: +
Notes
Dropouts/withdrawals unclear
Risk of bias
Bias
Authors judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear

14
Al-Qassab 1993
Methods
D: crossover
C: unclear
B: double
WD: 15/45
J: 1-1-1
DU: 4w/3x2mo (1w)/-
Participants
N: 45/30
D: 27 migraine with, 17 without aura (1 unclear)
C: unclear
F: 80%
A: 17-55 years
DU: 1-49 years
S: general neurology clinic in London
Interventions
P1: 160 mg (long-acting)

P2: 80 mg (long-acting)
C: Placebo
Outcomes
R: not reported
F: median attack frequency 3.8 (P1) vs. 3.8 (P2) vs. 3.2 (C)
AU: similar in all 3 groups
HI: not reported
AEs: not reported
V: 0
Notes
High dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Albers 1989
Methods
D: parallel
C: unclear
B: unblinded
WD: 20/40
J: 2-0-1
DU: -/6m/-
Participants
N: 40/20
D: migraine
C: Ad Hoc
F: 89%
A: 23-47 years

15
Albers 1989
(Continued)
DU: not reported

S: probably neurological university outpatient clinic in the US
Interventions
P: 120-180 mg
C: Nifedipine 60-90 mg
Outcomes
R: 12/13 vs. 6/7 (subjective rating of at least 50% improvement)

F: 2.2 (sd 3.2) vs. 1.5 (4.0) attacks/month during months 4-6
AU: not reported
HI: not reported
AEs: 15/20 vs. 20/20
Dropouts-AEs: 5/20 vs. 13/20
V: (+)
Notes
Very high dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Andersson 1981
Methods
D: crossover
C: unclear
B: double
WD: 12/49
J: 1-1-1
DU: 1m/2x3m (no washout)/-
Participants
N: 49/37
D: 31 migraine with, 18 without aura
C: unclear
F: 69%
A: 22-68 years
DU: 2-40 years
S: probably neurological practice in Denmark
Interventions
P: 160 mg
C: Femoxetine 400 mg
Outcomes
R: 11/28 vs. 4/28 (reported only for 28 patients with baseline data)
F: 1st period: 3.1 (sem 0.5) vs. 4.2 (0.3); pooled: 3.4 (sem 0.3) vs. 4.1 (0.3) attacks per 30
days in last 2 months
AU: not reported
HI: 15.4 vs. 18.0
AEs: more side effects with propranolol (30 vs. 14)

16
Andersson 1981
(Continued)

V: (+)
Notes
Baseline data for 28 patients only
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Baldrati 1983
Methods
D: crossover
C: unclear
B: double
WD: 6/18
J: 1-1-1
DU: 1m/2x3m (2w)/-
Participants
N: 18/12
D: all migraine without aura
C: Ad Hoc
F: 89%
A: 18-49 years
DU: 3-38 years
S: probably neurological university outpatient clinic in Italy
Interventions
P: 1.8 mg/kg
C: Acetylsalicylic acid 13.5 mg/kg
Outcomes
R: 9/12 vs. 9/12 (at least 50% index reduction)

F: not reported
AU: not reported
HI: 65% reduction in both groups
AEs: 6/12 vs. 6/12
V: 0
Notes
Small trial with relatively high dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

17
Behan 1980
Methods
D: crossover
C: unclear
B: double
WD: 20/56
J: 0-1-0
DU: -/2x3m (1m)/-
Participants
N: 56/36
C: unclear
F: 66%
A: 18-56 years
DU: 1-33 years
S: probably neurology clinic in Glasgow
Interventions
P: 120 mg
C: Methysergide 3 mg
Outcomes
R: 19/36 vs. 13/36

F: frequency lower with propranolol
AU: not reported
HI: not reported
AEs: 12/36 vs. 16/36
V: (+)
Notes
High dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Bonuso 1998
Methods
D: parallel
C: unclear
B: unclear
WD: 8/50
J: 1-0-0
DU: unclear/2m/4m
Participants
N: 50/42
C: IHS
F: 68%
A: 20-45 years
DU: unclear

18
Bonuso 1998
(Continued)
S: unclear, Italy
Interventions
P: 80 mg
C: Flunarizine 10 mg
Outcomes
R: 15/19 vs. 18/23

F: not reported
AU: not reported
HI: not reported
AEs: 4 AEs vs. 7
Dropouts-AEs: 0 vs. 0 (number of patients randomised to groups not fully clear)
V: 0
Notes
Study focusing on the fronto-temporal nitrogylcerin test and reporting only responder data
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Bordini 1997
Methods
D: parallel
C: unclear
B: double
WD: 7/52
J: 1-1-0
DU: 3w/17w/6w
Participants
N: 52/45
C: IHS
F: 91%
A: 17-48 years
DU: not reported
S: outpatient department of a university hospital in Brazil
Interventions
P: 60 mg
C1: Flunarizine 10 mg
C2: Propranolol + flunarizine
Outcomes
R: 15/15 vs. 14/15 vs. 14/15 (global assessment at least good)

F: 1.3 vs. 1.2 vs. 1.1 attacks/20 days (no variance data)
AU: not reported
HI: 23.4 vs. 18.7 vs. 14.4
AEs: 2/15 vs. 3/15 vs. 4/15
Dropouts-AEs: 0 vs. 0 vs. 0 (number of patients randomized to groups not fully clear)

19
Bordini 1997
(Continued)
V: 0 vs. C1, (-) vs. C2

Notes
Small groups, low propranolol dose
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Borgesen 1974
Methods
D: crossover
C: unclear
B: double
WD: 15/45
J: 1-1-0
DU: 4w/2x3m/-
Participants
N: 45/30
C: Ad Hoc
F: 83%
A: 18-59 years
DU: 1-50 years
S: neurology department in Denmark
Interventions
P: 120 mg
C: Placebo
Outcomes
R: 14/30 vs. 9/30

F: 1.03 (sd 1.02) vs. 1.33 (1.15) attacks per week
AU: similar in both groups
HI: not reported
AEs: not reported
V: +
Notes
High dropout rate

Responder rates and attack frequency calculated from single patient data presented in the
publication
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

20
Dahlf 1987
Methods
D: crossover
C: unclear
B: double
WD: none
J: 1-1-1
DU: 4w/2x1m/2x5m (5m washout)
Participants
N: 28/28
C: World Federation of Neurology Research Group
F: 83%
A: 18-60 years
DU: > 2 years
S: Sweden
Interventions
P: 120 mg
C: Placebo
Outcomes
R: not reported
F: significantly better than placebo
AU: significantly better than placebo
HI: significantly better than placebo
AEs: more with propranolol
V: +
Notes
Available only as expanded abstract

Long follow up suggesting no long-lasting benefit of 1-month treatment
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Diamond 1976
Methods
D: crossover
C: unclear
B: double
WD: 21/83
J: 1-1-0
DU-/2x4-8w (no washout)/-
Participants
N: 83/62
D: Migraine with or without aura
C: unclear
F: 81%
A: 21-62 years

21
Diamond 1976
(Continued)
DU: not reported

S: neurology department in Chicago, USA
Interventions
P: 80-160 mg
C: Placebo
Outcomes
R: 34/62 preferred propranolol, 17/62 placebo

F: not reported
AU: not reported
HI: not reported
AEs: 16/62 vs. 10/62
V: +
Notes
High dropout rate, unclear presentation
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Diamond 1982
Methods
D: parallel (with optional crossover)

C: unclear
B: double
WD: 48/148
J: 1-1-0
DU: 2m/4w/optional crossover for 6-12 m
Participants
N: 148/100
D: migraine
C: Ad Hoc
F: not reported
A: not reported
DU: not reported
S: unclear, USA
Interventions
P: 80-160 mg
C: Placebo
Outcomes
R: not reported
F: not reported
AU: not reported
HI: not reported
AEs: not reported
V: not interpretable

22
Diamond 1982
(Continued)
Notes
Trial meets the inclusion criteria, but primarily investigates long-term treatment with propranolol and includes only a 4-week RCT, whose results, however, are not presented in
detail
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Diener 1989
Methods
D: parallel
C: unclear
B: double
WD: 8/58
J: 1-1-0
DU: 2m/7m/1-2m
Participants
N: 58/50
C: Ad Hoc
F: 81
A: mean age 43 years
DU: 1-55 years
S: unclear, Germany
Interventions
P: 80-160 mg
C1: Metoprolol 100-200 mg
C2: Nifedipine 20-40 mg
Outcomes
R: 6/19 vs. 12/22 vs. 1/17 (according to time series analysis)

F: greater reduction in metoprolol group, but relevant baseline differences
AU: no significant differences
HI: not measured
AEs: more circulatory disturbances with propanolol, more fatigue with metoprolol
V: (-) vs. C1, (+) vs. C2
Notes
Rigorous study
Dropout rates not fully clear
Risk of bias
Bias
Authors judgement

23
Diener 1989
(Continued)
Unclear risk
B - Unclear
Diener 1996
Methods
D: parallel
C: unclear
B: double
WD: 40/214
J: 1-1-1
DU: 4w/16w/-
Participants
N: 214/214 (174 in per protocol analysis)

D: 58 migaine with, 156 without aura
C: IHS
F: 78%
A: 39 (SD 12) years
DU: 19 (SD 12) years
S: multiple centers in Germany and Italy
Interventions
P: 120 mg
C1: Placebo
C2: Cyclandelate 1200 mg
Outcomes
R: 33/78 vs. 17/55 vs. 30/81

F: not reported
AU: not reported
HI: not reported
AEs: 19/78 vs. 5/55 vs. 13/81
Dropouts-AEs: 4/78 vs. 0/55 vs. 5/81
V: (+) vs. C1, 0 vs. C2
Notes
Good quality trial

Intent-to-treat analysis
Presentation of results lacks detail
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

24
Diener 2002
Methods
D: parallel
C: adequate
B: double
WD: 144/810
J: 2-2-1
DU: 4w/16w/-
Participants
N: 810/783 (in intent-to-treat analysis, 808 in safety analysis)

D: 72% migraine without aura
C: IHS
F: 81%
A: 17-66 years
DU: 0.8 to 57 years
S: 130 centres in 8 countries
Interventions
P: 160 mg (slow-release)
Outcomes
R: 125/258 vs. 141/264 vs. 118/259

F: 1.7 (sd 1.6) vs. 1.6 (1.6) vs. 1.8 (1.2)
AU: 0.9 vs. 1.1 vs. 1.1 migraine attacks treated symptomatically
AEs: 88/270 vs. 88/275 vs. 88/263
V: 0 vs. C1, 0 vs. C2
Notes
Excellent, large, multicentre study

Standard deviations for frequency calculated from reported 95% CIs
Risk of bias
Bias
Authors judgement
Low risk
A - Adequate
Formisano 1991
Methods
D: parallel
C: unclear
B: none
WD: 3/22
J: 1-0-1
DU: 4w/16w/4w
Participants
N: 22/19
D: migraine with and without aura
C: IHS
F: 55%
A: mean 39 years

25
Formisano 1991
(Continued)
DU: mean 20 years

S: unclear, Italy
Interventions
P: 120 mg
C: Nimodipine 120 mg
Outcomes
R: not reported
F: 2.6 (sd 1.5) vs. 2.9 (1.7)
AU: not reported
HI: not reported
AEs: probably 6/10 vs. 11/12 (numbers not fully clear)
V: 0
Notes
Small study focusing on endocrinological effects
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Forssman 1976
Methods
D: crossover
C: unclear
B: double
WD: 8/40
J: 1-2-1
DU: 10w/2x12w (no washout)/-
Participants
N: 40/32
D: 27 common, 5 classic migraine
C: unclear
F: 97%
A: 17-51 years
DU: 2-40 years
S: probably university outpatient clinic in Sweden
Interventions
P: 240 mg
C: Placebo
Outcomes
R: 11 responders in propranolol phase, no data for placebo

F: not reported
AU: significantly lower during propranolol phase
HI: significantly better during propranolol phase
AEs: more frequent in propranolol phase

26
Forssman 1976
(Continued)
V: +
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Gawel 1992
Methods
D: parallel
C: unclear
B: double
WD: 18/94
J: 1-1-0
DU: 1m/4m/-
Participants
N: 94/76 (89 in safety analysis)

D: 37 migraine with and 57 without aura
F: 90%
A: mean 36 years
DU: mean 17 years
S: 4 Canadian centers
Interventions
P: 160 mg
Outcomes
R: 20/39 vs. 25/37 (patient global assessment; threshold used to define positive response
not specified; denominators not fully clear, only percentages given)
F: slightly better reduction with flunarizine
AU: similar reduction
HI: not reported
AEs: 36/45 vs. 33/44
V: (-)
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

27
Gerber 1995
Methods
D: parallel
C: unclear
B: double
WD: 22/84
J: 1-1-0
DU: 8w/16w/-
Participants
N: 84/62 (84 in safety analysis)

D: 19 migraine with and 43 without aura
C: IHS
F: 90%
A: mean 41 years
DU: mean 20 years
S: unclear, Germany
Interventions
P: 120-160 mg
C: Cyclandelate 1200-1600 mg
Outcomes
R: 18/34 vs. 20/28

F: Slightly more reduction with propranolol
AEs: 6/42 vs. 4/42
V: 0
Notes
High dropout rate

A second publication reports on a follow-up study, which is, however, uninterpretable due
to a very high dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Grotemeyer 1987
Methods
D: crossover
C: unclear
B: double
WD: 6/30
J: 0-1-0
Participants
N: 30/24
D: migraine without aura
C: Ad Hoc and other
F: 73%
A: 36 (sd 11) years

28
Grotemeyer 1987
(Continued)
DU: not reported

S: probably neurological university outpatient department in Germany
Interventions
P: 120 mg
C: Placebo
Outcomes
R: not reported
F: 19 (sd 16) attacks during 8 weeks vs. 22 (16)
AU: not reported
HI: not reported
AEs: not reported
V: (+)
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Hedman 1986
Methods
D: crossover
C: unclear
B: double
WD: unclear
J: 1-1-0
DU: 2w/2x1m (2w)/-
Participants
N: 12/12 (numbers not fully clear)

D: migraine with aura
F: 67%
A: 30-49 years
DU: unclear
S: unclear, Denmark
Interventions
P: 80 mg
C: Metoprolol 100 mg
Outcomes
R: not reported
F: 2.4 (sem 0.3) vs. 3.1 (0.6)
AU: not reported
HI: not reported
AEs: 0 vs. 0
V: uninterpretable

29
Hedman 1986
(Continued)
Notes
Small study focusing on laboratory parameters
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Holdorff 1977
Methods
D: parallel
C: unclear
B: double
WD: 26/53
J: 1-1-0
DU: -/3m/-
Participants
N: 53/27
D: mostly migraine without aura
C: Ad Hoc
F: unclear
A: unclear
DU: unclear
S: probably neurological university hospital outpatient department in Germany
Interventions
P: 80-120 mg
C: Placebo
Outcomes

F: not reported
AU: not reported
HI: no difference
AEs: not reported
V: 0
Notes
Very high dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

30
Johnson 1986
Methods
D: crossover
C: adequate
B: double
WD: 12/29
J: 1-2-1
DU: 1m/3x3m (no washout)/-
Participants
N: 29/17 (22-24 for adverse events)

C: unclear
F: 69%
A: 22-80 years
DU: 4-50 years
S: probably university outpatient department in New Zealand
Interventions
P: 240 mg
C1: Placebo
C2: Mefenamic acid 1500 mg
Outcomes
R: not reported
F: 13.8 (sd 12.0) vs. 20.1 (18.0) vs. 12.9 (10.8) attacks in 3 months
AU: not reported
HI: median migraine hours 75 vs. 138 vs. 66
AEs: 2/23 vs. 1/24 vs. 2/22
V: + vs. C1; 0 vs. C2
Notes
High dropout rate; otherwise rigorous crossover trial
Risk of bias
Bias
Authors judgement
Low risk
A - Adequate
Kangasniemi 1983
Methods
D: crossover
C: unclear
B: double
WD: 5/29
J: 1-1-0
DU: 4w/2x8w (4w)/-
Participants
N: 29/24
C: unclear
F: 86%

31
Kangasniemi 1983
(Continued)
A: 24-47 years
DU: 4-40 years
S: private practice, Finland
Interventions
P: 160 mg
C: Femoxetine 400 mg
Outcomes
R: 3/11 vs. 1/11 (1st period; no pooled data)

F: 1st period: 5.00 (sem 0.71) vs. 6.81 (1.12); pooled: 4.67 (sem 0.64) vs. 6.16 (0.82)
AU: propranolol better
HI: propranolol significantly better
AEs: more side effects with propranolol
V: (+)
Notes
Responder data presented only for separate phases; frequency data reported for separate
phases and for both phases pooled
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Kangasniemi 1984
Methods
D: crossover
C: unclear
B: double
WD: 3/36
J: 1-2-1
DU: 4w/2x3m (no washout)/1m (placebo)
Participants
N: 36/33
F: 89%
A: 18-51 years
DU: mean 16 years
S: unclear
Interventions
P: 160 mg
Outcomes
R: 15/33 vs. 17/33 (at least 50% severity score reduction)

F: 3.0 (sd 1.9) vs. 3.0 (1.8)
AU: 4.7 vs. 4.7
HI: 5.4 vs. 4.9

32
Kangasniemi 1984
(Continued)
AEs: similar in both groups

V: 0
Notes
Well-reported crossover study with low dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Kaniecki 1997
Methods
D: crossover
C: unclear
B: probably none
WD: 5/37
J: 1-0-1
DU: 8w/2x12w (4w)/-
Participants
N: 37/32
C: IHS
F: 81%
A: not reported
DU: not reported
S: neurological practice, USA
Interventions
P: 60-240 mg
C: Divalproex sodium 1000-2000 mg
Outcomes
R: 1st period: 12/17 vs. 9/15; pooled: 20/32 vs. 21/32

F: similar reduction
AU: not reported
HI: not reported
AEs: 11/32 vs. 16/32
V: 0
Notes
Pragmatic crossover study with some reporting shortcomings
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

33
Kass 1980
Methods
D: crossover
C: unclear
B: double
WD: 2/23
J: 1-1-0
Participants
N: 23/21
F: 70%
A: 22-62 years
DU: not reported
S: neurology department, Norway
Interventions
P: 160 mg
C: Clonidine 100 mcg
Outcomes
R: 13/21 vs. 8/21 (at least 50% headache days reduction)

F: 12.7 (sd 11.2) vs. 13.0 (11.7) headache days during last 12 treatment weeks
AU: less with propranolol
HI: not reported
AEs: 11/21 vs. 11/21
V: (+)
Notes
Small crossover trial with interesting outcome measures and data presentation
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Kjaersgard 1994
Methods
D: crossover
C: unclear
B: double
WD: 20/76
J: 1-2-1
DU: 4w/2x12w (4w)/-
Participants
N: 76/56
C: IHS
F: 79%
A: 19-65 years

34
Kjaersgard 1994
(Continued)
DU: 1-40 years

S: 2 outpatient neurology departments in Denmark
Interventions
P: 120 mg
C: Tolfenamic acid 300 mg
Outcomes
R: not reported
F: reduction migraine days vs. baseline 1.7 (sd 1.9) vs. 0.6 (1.6) (1st period; no pooled
data)
AU: not reported
HI: not reported
AEs: 28 vs. 26 adverse effects
V: 0
Notes
High dropout rate

Unclear statistics
No significant carryover effect detected
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Klapper 1994
Methods
D: crossover
C: unclear
B: double
WD: 12/24
J: 1-0-1
DU: -/2x2m (2w)/-
Participants
N: 24/12
D: migraine
C: IHS
F: unclear
A: unclear
DU: unclear
S: unclear, USA
Interventions
P: 80-240 mg
C: Divalproex sodium 750-1500 mg
Outcomes
R: not reported
F: divalproex significantly better
AU: not reported

35
Klapper 1994
(Continued)
HI: not reported

AEs: not reported
V: uninterpretable
Notes
Extremely high dropout rate, insufficient reporting
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Kuritzky 1987
Methods
D: crossover
C: unclear
B: unclear
WD: 7/38
J: 1-0-0
DU: -/2x8w (unclear whether washout)/-
Participants
N: 38/31
C: unclear
F: unclear
A: 17-53 years
DU: mean 14 years
S: unclear, Israel
Interventions
P: 160 mg (long-acting)
C: Placebo
Outcomes
R: not reported
F: 3.23 vs. 5.56 attacks (p = 0.014; no variance data presented)
AU: not reported
HI: not reported
AEs: not reported
V: +
Notes
Available only as an abstract
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

36
Ludin 1989
Methods
D: parallel
C: unclear
B: double
WD: 12/59
J: 1-2-1
DU: 1m/4m/-
Participants
N: 59/59 (intent-to-treat analysis)

C: unclear
F: 71%
A: mean 34 years
DU: not reported
S: 15 neurological practices in Switzerland
Interventions
P: 120 mg
Outcomes
R: 16/32 vs. 13/27

F: 3.7 (sd 4.2) vs. 4.8 (6.2)
AU: 3.4 (sd 5.5) vs. 4.1 (6.9, number of analgesics)
HI: 67 (sd 74) vs. 93 (154)
AEs: 15/32 vs. 13/27
V: 0
Notes
Well-reported study
In flunarizine group, either good response or deterioration; with propranolol, fewer strong
responders, but better on average
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Lcking 1988a
Methods
D: parallel
C: unclear
B: double
WD: 18/87
J: 1-1-0
DU: -/4m/-
Participants
N: 87/69
D: mainly migraine with aura
C: Ad Hoc
F: 74%

37
Lcking 1988a
(Continued)
A: mean 42 years
DU: not reported
S: 12 hospital outpatient departments (probably in Germany)
Interventions
P: 120 mg
Outcomes
R: 24/34 vs. 24/35 (investigator global assessment very good or good)

F: 3 (sd 5) vs. 4 (5)
AU: decreased in 16/34 vs. 18/35
HI: not reported
AEs: 21/34 vs. 16/35
V: 0
Notes
Relevant dropout; no intent-to-treat analysis
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Lcking 1988b
Methods
D: parallel
C: unclear
B: double
WD: 98/434
J: 1-1-0
DU: -/4m/-
Participants
N: 434/336
D: mainly migraine with aura
C: Ad Hoc
F: 82%
A: mean 42 years
DU: not reported
S: 99 medical practices (probably in Germany)
Interventions
P: 120 mg
Outcomes
R: 105/170 vs. 104/166 (investigator global assessment very good or good)

F: 4 (sd 5) vs. 4 (4)
AU: decreased in 83/170 vs. 95/166
HI: not reported
AEs: 66/170 vs. 52/166

38
Lcking 1988b
(Continued)

V: 0
Notes
Large study with high dropout rate; no intent-to-treat analysis
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Maissen 1991
Methods
D: parallel
C: unclear
B: double
WD: 7/39
J: 0-2-1
DU: 1m/4m/3m
Participants
N: 39/38
C: own
F: 67%
A: mean 39 years
DU: not reported
S: 7 neurologists in Switzerland
Interventions
P: 120 mg
C: 5-hydroxytryptophan 300 mg
Outcomes
R: 7/20 vs. 8/19

F: reduction from 7.1 (sd 5.8) vs. 9.4 (5.7) to 4.4 (4.0) vs. 7.3 (7.4)
AU: reduction from 16.3 (sd 20.1) vs. 9.1 (7.4) to 4.3 (3.4) vs. 5.0 (5.5)
HI: not reported
AEs: 7/20 vs. 7/19
V: 0
Notes
Relevant baseline differences, high attack frequency
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

39
Malvea 1973
Methods
D: crossover
C: unclear
B: double
WD: 2/31
J: 1-1-0
DU: 1m/2x6w (no washout)/-
Participants
N: 31/29
C: unclear
F: 87%
A: 25-57 years
DU: not reported
S: headache clinic in Boston, USA
Interventions
P: Dose unclear
C: Placebo
Outcomes
R: 16 preferred propranolol, 8 placebo, 5 none

F: not reported
HI: 18.6 vs. 23.3
AEs: listed only for propranolol
V: +
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Mathew 1981-Study 1
Methods
D: parallel
C: unclear
B: none
WD: 67/340
J: 1-0-1
DU: 1m/6m/-
Participants
N: 340/273
D: migraine (no interval headaches allowed)
C: unclear
F: 90%
A: mean 35 years
DU: not reported

40
Mathew 1981-Study 1
(Continued)
S: unclear, USA
Interventions
P: 120-160 mg
C1: No prophylactic therapy
C2: Amitriptyline 50-75 mg
C3: Biofeedback
C4: Propranolol + biofeedback
C5: Amitriptyline + biofeedback
C6: Amitriptyline + propranolol
C7: Propranolol + amitriptyline + biofeedback
Outcomes
R: not reported
F: not reported
AU: not reported
HI: index reduction 62% vs. 20% (C1), 42% (C2), 35% (C3), 64% (C4), 74% (C5), 48%
(C6), 73% (C7)
AEs: not reported
Dropouts-AEs: 1/44 (P) vs. 4/45 (C1) vs. 4/42 (C2) vs. 0/48 (C3) vs. 2/39 (C4) vs. 2/43
(C5) vs 2/41 (C6) vs. 3/38 (C7)
V: + vs. C2
Notes
Uncommon 8-armed trial

Dropout rates highly variable between groups
Only headache indices presented
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Mathew 1981-Study 2
Methods
D: parallel
C: unclear
B: none
WD: 94/375
J: 1-0-1
DU: 1m/6m/-
Participants
N: 375/281
D: migraine + interval headaches
C: unclear
F: 95%
A: mean 40 years
DU: not reported
S: unclear, USA

41
Mathew 1981-Study 2
(Continued)
Interventions
P: 120-160 mg
C1: No prophylactic therapy
C3: Biofeedback
C4: Propranolol + biofeedback
C5: Amitriptyline + biofeedback
C6: Amitriptyline + propranolol
C7: Propranolol + amitriptyline + biofeedback
Outcomes
R: not reported
F: not reported
AU: not reported
HI: index reduction 52% vs. 18% (C1), 60% (C2), 48% (C3), 69% (C4), 62% (C5), 66%
(C6), 76% (C7)
AEs: not reported
Dropouts-AEs: 3/48 (P) vs. 9/49 (C1) vs. 3/44 (C2) vs. 1/52 (C3) vs. 3/43 (C4) vs. 4/46
(C5) vs. 2/47 (C6) vs. 4/46 (C7)
V: (-) vs. C2
Notes
Uncommon 8-armed trial

Dropout rates highly variable between groups
Only headache indices presented
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Micieli 2001
Methods
D: crossover
C: unclear
B: double
WD: 10/40
J: 1-1-1
DU: 1m/2x3m (1m)/3m
Participants
N: 40/30
D: migraine without aura
C: IHS
F: 75%
A: 35 (sd 10) years
DU: 18 years
S: unclear, Italy
Interventions
P: 80 mg
C: Alpha-dihydroergocryptine 20 mg

42
Micieli 2001
(Continued)
Outcomes
R: not reported
F: reduction from 5.2 (sd 1.4) to 1.3 (1.2) vs. 5.4 (1.3) to 1.3 (1.2) (1st period; no pooled
data)
AU: reduction from 8.5 (sd 4.2) to 2.2 (2.1) vs. 7.7 (3.0) to 2.0 (2.1; analgesic doses)
HI: not reported
AEs: not reported Dropouts-AEs: 5/40 vs. 4/40
V: 0
Notes
High dropout rate

Significant baseline differences in duration of attacks and psychological profile
No significant carryover effect
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Mikkelsen 1986
Methods
D: crossover
C: unclear
B: double
WD: 8/39
J: 1-2-1
Participants
N: 39/31
C: Ad Hoc
F: 84%
A: 15-65 years
DU: not reported
S: neurology outpatient department of a hospital in Denmark
Interventions
P: 120 mg
C1: Placebo
C2: Tolfenamic acid 300 mg
Outcomes
R: not reported
F: 1st period: 6.4 (sd 4.1) vs. 7.6 (6.1) vs. 10.2 (6.8); pooled: 6.6 (sd 4.9) vs. 8.8 (6.9) vs.
6.9 (6.1)
AU: trend in favor of tolfenamic acid
HI: not reported
AEs: 3/31 vs. 3/31 vs. 2/31
V: + vs. C1, (-) vs. C2

43
Mikkelsen 1986
(Continued)
Notes
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Nadelmann 1986
Methods
D: crossover
C: unclear
B: double
WD: 21/64
J: 1-2-1
DU: 4w/6+2x12w (no washout)/-
Participants
N: 57/41 (67 entered baseline, 57 entered treatment phases)

D: 35 migraine with, 27 migraine with and without aura
C: Ad Hoc
F: 83%
A: 18-60 years
DU: not reported
S: unclear, USA
Interventions
P: 80-320 mg
C: Placebo
Outcomes
R: not reported
F: not reported
AU: better with propranolol
HI: better with propranolol
AEs: more frequent with propranolol
Dropouts-AEs: 1st period: 0/28 vs. 0/29; pooled: 0/57 vs. 0/57
V: +
Notes
Detailed subgroup analyses
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

44
Nicolodi 1997
Methods
D: parallel
C: unclear
B: double
WD: unclear
J: 1-1-0
DU: 1m/3m/-
Participants
N: 256/unclear
D: migraine
C: unclear
F: 76%
A: mean 35 years
DU: mean 4 years
S: unclear
Interventions
P: 1230 mcg/kg
C: Methysergide 30.8 mcg/kg
Outcomes
R: not reported
F: 3.1 (sd 1.4) vs. 3.1 (1.4)
AU: not reported
HI: not reported
AEs: not reported
V: 0
Notes
Large trial, reported briefly with other studies in one publication
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Olerud 1986
Methods
D: parallel
C: unclear
B: double
WD: 1/28
J: 1-1-1
DU: 4-17w/24w/-
Participants
N: 28/27
C: Ad Hoc
F: 79%
A: 17-61 years
DU: 2-45 years

45
Olerud 1986
(Continued)
S: unclear, Sweden
Interventions
P: 80-160 ng
C: Nadolol 40-160 mg
Outcomes
R: 8/14 vs. 5/13

F: reduction from 3.6 to 1.9 vs. 5.6 to 2.7 (sd not reported)
AU: reduction from 11.5 to 4.1 vs. 17.1 to 9.2
HI: not reported
AEs: 5/14 vs. 6/13
V: 0
Notes
Small, rigorous trial with relevant baseline imbalances
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Olsson 1984
Methods
D: crossover
C: unclear
B: double
WD: 3/56
J: 1-2-1
DU: 4w/2x8w (4w)/-
Participants
N: 56/53
F: 73%
A: 19-59 years
DU: 5-43 years
S: 6 neurology clinics in Sweden
Interventions
P: 80 mg
Outcomes

F: reduction from 5.4 to 4.2 in both groups (sd not reported)
AU: reduction from 9.1 to 5.7 vs. 7.6 tablets/4 weeks
HI: reduction from 12.4 to 8.7 vs. 9.7
V: 0

46
Olsson 1984
(Continued)
Notes
Well-reported crossover study

Strong deterioration during washout phase between the two treatment phases
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Palferman 1983
Methods
D: crossover
C: unclear
B: double
WD: 6/16
J: 1-1-0
DU: -/2x8 (no washout)/-
Participants
N: 16/10
D: migraine
C: unclear
F: 80%
A: mean 41 years
DU: mean 17 years
S: outpatient department, UK
Interventions
P: 120 mg
C: Placebo
Outcomes
R: not reported
F: 21 vs. 24 headache days in 56 days (sd not reported)
AU: not reported
HI: 47 vs. 52
AEs: not reported
V: (+)
Notes
Small study with high dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

47
Pita 1977
Methods
D: crossover
C: unclear
B: double
WD: 1/9
J: 1-1-1
DU: -/2x2m (no washout)/-
Participants
N: 9/8
C: Ad Hoc
F: 78%
A: 23-39 years
DU: 1-27 years
S: clinical pharmacology department in Granada, Spain
Interventions
P: 160 mg
C: Placebo
Outcomes
R: 4/8 vs. 2/8; 7 preferred propranolol, 1 no preference

F: significantly fewer attacks with propranolol
AU: not reported
HI: not reported
AEs: unclear
V: +
Notes
Extremely small trial with very positive results
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Pradalier 1989
Methods
D: parallel
C: unclear
B: double
WD: 14/55, additional 19 patients dropped out in post-randomisation baseline
J: 1-2-1
DU: 4w/12w/-
Participants
N: 74/41
D: 8 migraine with, 61 without, 5 both
C: IHS
F: 76%
A: mean 37 years
DU: mean 17 years

48
Pradalier 1989
(Continued)
S: muliple centers in France

Interventions
P: 160 mg (long-acting)
C: Placebo
Outcomes
R: not reported
F: 3.15 (sem 0.77) vs. 6.4 (1.70)
AU: not reported
HI: not reported
V: +
Notes
Uncommon design with randomisation before baseline

High dropout rate
Intent-to-treat analysis unclear
No placebo effect
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Ryan 1984
Methods
D: parallel
C: unclear
B: double
WD: 3/48
J: 1-1-1
DU: 4w/12w/-
Participants
N: 48/45
D: migraine
C: unclear
F: 73%
A: 21-60 years
DU: not reported
S: unclear, USA
Interventions
P: 120 mg
C1: Nadolol 80 mg
C2: Nadolol 160 mg
Outcomes
R: not reported
F: reduction 2.88 vs. 3.39 vs. 2.63 (sd not reported)
AU: not reported

49
Ryan 1984
(Continued)
HI: reduction 6.70 vs. 7.89 vs. 4.60

AEs: not reported
Dropouts-AEs: 0/16 vs. 1/16 vs. 0/16 (denominators not fully clear)
V: (-) vs. C1, 0 vs. C2
Notes
Insufficient reporting
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Sargent 1985
Methods
D: parallel
C: unclear
B: double
WD: 20/149, additional 21 dropped before treatment started
J: 1-1-0
DU: 2w/15w/-
Participants
N: 149/129
D: migraine with and without aura
C: unclear
F: 79%
A: 18-62 years
DU: mean 20 years
S: unclear, USA
Interventions
P: 120 mg
C1: Placebo
C2: Naproxen 1100 mg
Outcomes
R: patient rating (1 = poor to 4 = excellent) 2.80 vs. 2.38 vs. 2.86

F: Decrease in headache days per week 0.21 (sd 1.86) vs. -0.25 (1.57) vs. -0.48 (2.02)
AU: not reported
HI: not reported
AEs: 30/44 vs. 28/43 vs. 38/42
V: (+) vs. C1, 0 vs. C2
Notes
Insufficient reporting
Results seem partly contradictory
Small effects
Risk of bias

50
Sargent 1985
(Continued)
Bias
Authors judgement
Unclear risk
B - Unclear
Scholz 1987
Methods
D: parallel
C: unclear
B: double
WD: 45/109
J: 1-1-0
DU: 8w/24w/3m
Participants
N: 83/83? (109 patients entered the study, 26 dropped out in the baseline period, 19
stopped treatment early - not clear whether fully analyzed)
C: unclear
F: 77%
A: mean 40 years
DU: mean 19 years
S: unclear, Germany
Interventions
P: 160 mg
C1: Metoprolol 200 mg
C3: Nifedipine 40 mg
C4: Dihydroergotamine 10 mg
Outcomes
R: 33% vs. 60% vs. 17% vs. 31% vs. 8% (single case statistics)
F: reduction of headache days by 30% vs. 54% vs. 11% vs. 5% vs. 37%
AU: reduction by 40% vs. 40% vs. 41% vs. 45% vs. 33%
HI: not reported
AEs: not reported
Dropouts-AEs: 3/19 vs. 6/22 vs. 2/12 vs. 8/17 vs. 0/13
V: (-) vs. C1, 0 vs. C2, 0 vs. C3, (+) vs. C4
Notes
Complex five-armed trial

Dropout reporting difficult to follow
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

51
Shimell 1990
Methods
D: parallel
C: unclear
B: double
WD: 10 /58
J: 1-2-1
DU: -/4m/-
Participants
N: 58/57
D: IHS
F: 70%
A: 16-61 years
DU: mean 27 years
S: neurology outpatient clinic in Johannesburg, South Africa
Interventions
P: 180 mg
Outcomes
R: 94% vs. 70% (patient global rating excellent/good)

F: reduction from 5.7 to 1.2 vs. 4.6 to 1.4 (sd not presented)
AU: not reported
HI: not reported
V: 0
Notes
No headache diary
Possibly intent-to-treat analysis
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Solomon 1986
Methods
D: crossover
C: unclear
B: double
WD: unclear
J: 0-1-0
DU: unclear/3x2m (unclear whether washout)/unclear
Participants
N: unclear/15
D: migraine with or without aura
C: unclear
F: unclear
A: unclear

52
Solomon 1986
(Continued)
DU: unclear
S: unclear
Interventions
P: 120 mg
C1: Placebo
C2: Verapamil 240 mg
Outcomes
R: not reported
F: 4.5 vs. 5.0 vs. 4.5 (sd not presented)
AU: not reported
HI: not reported
AEs: unclear
V: + vs. C1, 0 vs. C2
Notes
Small crossover study, available only as an abstract
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Stensrud 1976
Methods
D: crossover
C: unclear
B: double
WD: 1/20
J: 1-1-1
DU: -/3x4w (1w)/-
Participants
N: 20/19
C: Ad Hoc
F: 70%
A: 15-60 years
DU: not reported
S: unclear, Norway
Interventions
P: 160 mg
C1: Placebo
C2: d-propranolol 160 mg
Outcomes
R: not reported
F: 5.0 (sd 3.7) vs. 6.1 (4.1) vs. 6.2 (4.6)
AU: not reported
HI: 7.5 vs. 12.3 vs. 10.9

53
Stensrud 1976
(Continued)
AEs: not reported

V: + vs. C1, (+) vs. C2
Notes
No headache diary
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Stensrud 1980
Methods
D: crossover
C: unclear
B: double
WD: 7/35
J: 1-2-0
DU: -/2x6w (1w)/-
Participants
N: 35/28
C: Ad Hoc
F: 69%
A: 25-60 years
DU: not reported
S: unclear, Norway
Interventions
P: 160 mg
C1: Placebo
C2: Atenolol 100 mg
Outcomes
R: not reported
F: 9.2 vs. 10.3 vs. 8.8 (headache days; sd not reported)
AU: not reported
HI: not reported
AEs: more with propranolol
V: (+) vs. C1, 0 vs. C2
Notes
Results reported insufficiently
Risk of bias
Bias
Authors judgement

54
Stensrud 1980
(Continued)
Unclear risk
B - Unclear
Sudilovsky 1987
Methods
D: parallel
C: unclear
B: double
WD: 42/140
J: 1-2-0
DU: 4-8w/12w/-
Participants
N: 140/98
D: migraine with or without aura
C: Ad Hoc
F: 76%
A: mean 39 years
DU: mean 21 years
S: 6 centers in the USA
Interventions
P: 160 mg
C1: Nadolol 80 mg
C2: Nadolol 160 mg
Outcomes
R: 5/27 vs. 11/33 vs. 18/33

F: not reported
AU: at least 50% reduction in 11/26 vs. 10/33 vs. 16/32
HI: 1.31 vs. 1.24 vs. 2.22 (higher values indicate better response)
AEs: not reported
V: 0 vs. C1, - vs. C2
Notes
High dropout rate
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear

55
Tfelt-Hansen 1984
Methods
D: crossover
C: unclear
B: double
WD: 16/96
J: 1-2-0
Participants
N: 96/80 (83 for adverse events; 90 started placebo and 89 both active treatments)
D: migraine
C: Ad Hoc
F: 74%
A: mean 40 years
DU: mean 21 years
Interventions
P: 160 mg
C1: Placebo
C2: Timolol 20 mg
Outcomes
R: 48/80 vs. 24/80 vs. 44/80

F: 3.69 (sd 3.44) vs. 4.84 (3.85) vs. 3.35 (3.13)
AU: not reported
HI: 6.66 (sd 5.87) vs. 9.03 (7.28) vs. 5.71 (5.14)
AEs: 35/83 vs. 23/83 vs. 38/83
V: + vs. C1, 0 vs. C2
Notes
Rigorous, well-reported crossover trial

Probably subgroup analysis in publication by Standnes (see references)
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Weber 1972
Methods
D: crossover
C: unclear
B: double
WD: 6/25
J: 1-1-0
Participants
N: 25/19
C: Ad Hoc
F: 52%
A: 19-61 years

56
Weber 1972
(Continued)
DU: not reported

S: unclear, USA
Interventions
P: 80 mg
C: Placebo
Outcomes

F: not reported
AU: not reported
HI: not reported
AEs: unclear
V: +
Notes
Small crossover trial with extremely positive results
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Wideroe 1974
Methods
D: crossover
C: unclear
B: double
WD: 4/30
J: 1-1-0
Participants
N: 30/26
C: Ad Hoc
F: 87%
A: 18-55 years
DU: not reported
S: neurology outpatient department in Trondheim, Norway
Interventions
P: 160 mg
C: Placebo
Outcomes

F: mean monthly attack frequency, 1st period: 0.44 (sd 0.52) vs. 1.64 (1.30); pooled: 0.39
(sd 0.48) vs. 1.70 (1.40)
AU: not reported
HI: not reported
AEs: not reported

57
Wideroe 1974
(Continued)
V: +
Notes
Included only patients who had responded to propranolol before
Risk of bias
Bias
Authors judgement
Unclear risk
B - Unclear
Ziegler 1987
Methods
D: crossover
C: unclear
B: double
WD: 24/54
J: 1-1-0
DU: 4-8w/3x8w (4w)/-
Participants
N: 54/30
D: migraine
C: Ad Hoc
F: 73%
A: 22-57 years
DU: not reported
S: unclear, USA
Interventions
P: 80-240 mg
C1: Placebo
Outcomes
R: 12/30 vs. unclear vs. 10/30 (at least 50% index reduction)
F: not reported
AU: not reported
HI: 405 vs. 511 vs. 429
AEs: not reported
V: + vs. C1, 0 vs. C2
Notes
High dropout rate

Insufficient presentation of results
Complex design
Risk of bias
Bias
Authors judgement

58
Ziegler 1987
(Continued)
Unclear risk
B - Unclear
Abbreviations:
Methods column: D = design; C = concealment of allocation; B = blinding; WD = dropouts and withdrawals; J = Jadad score; DU
= duration of baseline/treament (in case of crossover studies, washout period in parentheses)/follow-up period in m = months or w =
weeks
Participants column: N = number of patients randomized/analyzed; D = diagnoses; C = classification of headaches (IHS = International
Headache Society; ad hoc = Ad Hoc Committee); F = percentage of female participants; A = age (range or mean); DU = duration
(migraine since); S = setting (if unclear, the country of the first author is provided)
Interventions column: P = propranolol dosage; C = control intervention
Outcomes column: R = responder (at least 50% reduction in number of migraine attacks, unless otherwise indicated); F = attack
frequency (number of migraine attacks in the last 4 weeks/month of treatment, unless otherwise indicated); AU = analgesic use (typically
tablets/time period); HI = headache index; AEs = adverse events (unless otherwise indicated, number of patients with at least one adverse
event); Dropouts-AEs = number of patients dropping out due to adverse events; V = vote count (+ = propranolol significantly better,
(+) = propranolol trend better, 0 = no difference, (-) = control trend better, - = control significantly better). If numbers are presented,
the first number always refers to the propranolol group, the second to the control group. If there was more than one control group, the
order of results follows the numbering of control groups in the Interventions column.
Allocation concealment column: A = adequate, B = unclear, C = inadequate, D = not used
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Amery 1988
No original data - review
Anonymous 1979
Banerjee 1991
Study on treatment of acute migraine attacks
Carroll 1990
Did not include a comparison with placebo or another drug
Cortelli 1985
Not randomised or quasi-randomised clinical study
de Bock 1997
Diamond 1987
Fuller 1990
Study on treatment of acute migraine attacks
Havanka-Kann. 1988
Holroyd 1995

59
(Continued)
Julien 1976
Montastruc 1992
Penzien 1990
Raveau-Landon 1988
Rosen 1983
Schmidt 1991
Sovak 1981
Steardo 1982
Open trial with unclear method of allocation
Tfelt-Hansen 1986
Turner 1984
Verspeelt 1996a
Verspeelt 1996b
Winther 1990
Observation period less than 4 weeks
Wober 1991

60
DATA AND ANALYSES
Comparison 1. Propranolol versus placebo
Outcome or subgroup title

1 Responders (parallel-group and
1st period crossover data)
1.1 Propranolol 160 mg
1.3 Propranolol 80-120 mg
pooled crossover data)
2.6 Propranolol, dose unclear
3 Attack frequency measures
(parallel-group and 1st period
crossover data)
(parallel-group and pooled
crossover data)
5 Number of patients with adverse
events (parallel-group; no 1st
period crossover data)
events (parallel-group and
7 Number of dropouts due to
adverse events (parallel-group
and 1st period crossover data)
No. of
studies
No. of
participants
205
Risk Ratio (M-H, Fixed, 95% CI)
1.72 [1.23, 2.40]
1
1
1
1
9
26
133
27
19
668

2.62 [1.34, 5.14]

1.37 [0.85, 2.20]
1.23 [0.63, 2.42]
14.67 [0.93, 232.44]
1.94 [1.61, 2.35]
3
1
2
1
1
1
4
228
124
193
27
38
58
172

Std. Mean Difference (IV, Fixed, 95% CI)
2.14 [1.59, 2.87]

2.0 [1.26, 3.18]
1.43 [0.97, 2.10]
1.23 [0.63, 2.42]
7.5 [1.98, 28.40]
2.0 [1.02, 3.93]
-0.45 [-0.75, -0.14]
2
2
10
67
105
634

-0.77 [-1.27, -0.27]

-0.26 [-0.64, 0.13]
-0.40 [-0.56, -0.24]
1
4
5
2
34
291
309
220

-0.40 [-1.08, 0.28]

-0.49 [-0.72, -0.25]
-0.32 [-0.55, -0.10]
1.33 [0.97, 1.82]
2
6
220
619

1.33 [0.97, 1.82]

1.43 [1.12, 1.81]
1
1
1
3
3
47
166
124
282
264

2.09 [0.20, 21.48]

1.52 [0.99, 2.34]
1.6 [0.79, 3.25]
1.30 [0.95, 1.77]
1.90 [0.36, 10.14]
1
1
1
57
74
133

0.0 [0.0, 0.0]

0.28 [0.01, 6.77]
6.38 [0.35, 116.13]
Statistical method

Effect size
61

and pooled crossover data)
13
1150
2.11 [1.09, 4.08]
1
2
5
1
3
1
114
138
381
166
301
50

0.0 [0.0, 0.0]

1.0 [0.21, 4.78]
2.15 [0.77, 6.01]
6.0 [0.74, 48.75]
1.88 [0.51, 6.91]
0.0 [0.0, 0.0]
Comparison 2. Propranolol versus calcium antagonists

1 Responders (all trials
parallel-group)
1.1 Propranolol 180 mg vs.
flunarizine 10 mg
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
flunarizine 10 mg
flunarizine 10 mg
vs. nifedipine 60-90 mg
vs. propranolol 60 mg +
flunarizine 10 mg
2 Attack frequency measures (all
trials parallel-group)
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
nimodipine 120 mg
No. of
studies
No. of
participants
10
1794
1.00 [0.93, 1.09]
57
1.30 [1.01, 1.68]
598
0.88 [0.76, 1.03]
517
1.06 [0.89, 1.28]
464
1.00 [0.87, 1.15]
42
1.01 [0.73, 1.38]
30
1.07 [0.89, 1.28]
20
1.08 [0.77, 1.51]
36
5.37 [0.72, 40.20]
30
1.07 [0.89, 1.28]
1543
-0.02 [-0.12, 0.08]
524
0.06 [-0.11, 0.23]
518
-0.07 [-0.24, 0.10]
462
-0.05 [-0.24, 0.13]
20
0.19 [-0.73, 1.11]
19
-0.18 [-1.09, 0.74]
Statistical method

Effect size
62

events (all trials parallel-group)
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
flunarizine 10 mg
nimodipine 120 mg
propanolol 60 mg + flunarizine
10 mg
events (vs. flunarizine; all trials
parallel-group)
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
flunarizine 10 mg
5 Number of dropouts due
to adverse events (all trials
parallel-group)
flunarizine 10 mg
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
flunarizine 10 mg
flunarizine 10 mg
nimodipine 120 mg
nifedipine 40 mg
1753
1.02 [0.91, 1.15]
634
1.03 [0.86, 1.24]
533
0.97 [0.76, 1.24]
464
1.22 [0.97, 1.52]
30
0.67 [0.13, 3.44]
40
0.76 [0.58, 0.98]
22
0.65 [0.38, 1.12]
30
0.5 [0.11, 2.33]
1661
1.06 [0.94, 1.20]
634
1.03 [0.86, 1.24]
533
0.97 [0.76, 1.24]
464
1.22 [0.97, 1.52]
30
0.67 [0.13, 3.44]
1533
0.82 [0.59, 1.13]
58
1.5 [0.27, 8.32]
665
1.05 [0.61, 1.78]
533
0.83 [0.46, 1.53]
59
1.27 [0.23, 7.03]
50
0.0 [0.0, 0.0]
35
0.0 [0.0, 0.0]
22
2.4 [0.25, 22.75]
36
0.34 [0.11, 1.06]
40
0.38 [0.17, 0.88]

63
vs. propranolol 60 mg +
flunarizine 10 mg
adverse events (vs. flunarizine;
all trials parallel-group)
flunarizine 10 mg
flunarizine 10 mg
flunarizine 5 mg
flunarizine 10 mg
flunarizine 10 mg
flunarizine 10 mg
adverse events (vs. nifedipine;
all trials parallel-group)
nifedipine 40 mg
35
0.0 [0.0, 0.0]
1400
0.98 [0.67, 1.44]
58
1.5 [0.27, 8.32]
665
1.05 [0.61, 1.78]
533
0.83 [0.46, 1.53]
59
1.27 [0.23, 7.03]
50
0.0 [0.0, 0.0]
35
0.0 [0.0, 0.0]
76
0.37 [0.19, 0.72]
36
0.34 [0.11, 1.06]
40
0.38 [0.17, 0.88]
Comparison 3. Propranolol versus other beta-blockers

1 Responders (parallel-group; no
nadolol 160 mg
nadolol 80 mg
vs. nadolol 40-160 mg
vs. metoprolol 100-200 mg
nadolol 160 mg
nadolol 80 mg
No. of
studies
No. of
participants
Statistical method
Effect size
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]

64

metoprolol 200 mg
metoprolol 100 mg
timolol 20 mg
3 Responders (vs. nadolol;
parallel-group and pooled
crossover data)
nadolol 160 mg
nadolol 80 mg
4 Responders (vs. metoprolol;
parallel-group and pooled
crossover data)
metoprolol 200 mg
metoprolol 100 mg
(pooled crossover only; no
parallel-group or 1st period
crossover data)
metoprolol 200 mg
metoprolol 100 mg
timolol 20 mg
d-propranolol 160 mg
timolol 20 mg
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
147
0.60 [0.37, 0.97]
60
0.34 [0.15, 0.79]
60
0.56 [0.22, 1.40]
27
1.49 [0.65, 3.39]
216
0.78 [0.56, 1.09]
66
0.88 [0.54, 1.45]
41
0.58 [0.27, 1.24]
109
0.81 [0.47, 1.37]
290
-0.01 [-0.24, 0.22]
68
0.0 [-0.48, 0.48]
24
-0.43 [-1.24, 0.38]
160
0.10 [-0.21, 0.41]
38
-0.27 [-0.91, 0.37]
Totals not selected
0.0 [0.0, 0.0]
217
0.90 [0.65, 1.24]
166
0.92 [0.65, 1.30]

65

metoprolol 100 mg
adverse events (parallel-group;
no 1st period crossover data)
nadolol 160 mg
nadolol 80 mg
nadolol 160 mg
nadolol 80 mg
metoprolol 200 mg
nadolol 160 mg
nadolol 80 mg
nadolol 160 mg
nadolol 80 mg
metoprolol 200 mg
metoprolol 100 mg
atenolol 100 mg
timolol 20 mg
d-propranolol 160 mg
27
0.77 [0.31, 1.93]
24
0.0 [0.0, 0.0]
317
1.00 [0.48, 2.10]
91
2.14 [0.41, 11.09]
93
2.23 [0.43, 11.57]
32
0.0 [0.0, 0.0]
32
0.33 [0.01, 7.62]
28
0.29 [0.01, 6.60]
41
0.58 [0.17, 2.01]
789
1.05 [0.61, 1.80]
91
2.14 [0.41, 11.09]
93
2.23 [0.43, 11.57]
32
0.0 [0.0, 0.0]
32
0.33 [0.01, 7.62]
28
0.29 [0.01, 6.60]
113
0.94 [0.33, 2.72]
112
0.0 [0.0, 0.0]
70
3.0 [0.13, 71.22]
178
0.67 [0.25, 1.79]
40
3.0 [0.13, 69.52]

66
Comparison 4. Propranolol versus other drugs

femoxetine 400 mg
vs. cyclandelate 1200-1600 mg
cyclandelate 1200 mg
1.4 Propranolol 60-240 mg vs.
divalproex sodium 1000-2000
mg
5-hydroxytryptophan 300 mg
pooled crossover data [one 1st
period])
femoxetine 400 mg
mg
methysergide 3 mg
clonidine 100 mcg
vs. amitriptyline 50-150 mg
2.9 Propranolol 1.8 mg/kg vs.
ASA 13.5 mg/kg
(parallel-group and 1st period
crossover data)
femoxetine 400 mg
tolfenamic acid 300 mg
No. of
studies
No. of
participants
Statistical method
Effect size
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
10
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]

67

naproxen 1100 mg
3.5 Propranolol 1230 mcg/kg
vs. methysergide 30.8 mcg/kg
alpha-dihydroergocryptine 20
mg
(parallel-group and pooled
crossover data [two 1st period])
femoxetine 400 mg
naproxen 1100 mg
4.5 Propranolol 1230 mcg/kg
vs. methysergide 30.8 mcg/kg
mefenamic acid 1500 mg
clonidine 100 mcg
mg
naproxen 1100 mg
naproxen 1100 mg
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
10
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
10
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]

68

methysergide 3 mg
clonidine 100 mcg
mg
6.9 Propranolol 1.8 mg/kg vs.
ASA 13.5 mg/kg
adverse events (parallel-group;
no 1st period crossover data)
dihydroergotamine 10 mg
vs. amitriptyline 50-75 mg +
propranolol 120-160 mg
femoxetine 400 mg
mg
mg
methysergide 3 mg
dihydroergotamine 10 mg
mg
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
16
Totals not selected
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]

69

clonidine 100 mcg
8.12 Propranolol 1.8 mg/kg
vs. ASA 13.5 mg/kg
vs. amitriptyline 50-75 mg +
propranolol 120-160 mg
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
0.0 [0.0, 0.0]
Analysis 1.1. Comparison 1 Propranolol versus placebo, Outcome 1 Responders (parallel-group and 1st
period crossover data).
Review:
Comparison: 1 Propranolol versus placebo

Outcome: 1 Responders (parallel-group and 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
12/12
5/14
15.9 %
2.62 [ 1.34, 5.14 ]
12
14
15.9 %
2.62 [ 1.34, 5.14 ]
33/78
17/55
61.9 %
1.37 [ 0.85, 2.20 ]
78
55
61.9 %
1.37 [ 0.85, 2.20 ]
8/13
7/14
20.9 %
1.23 [ 0.63, 2.42 ]
13
14
20.9 %
1.23 [ 0.63, 2.42 ]
5/8
0/11
1.3 %
14.67 [ 0.93, 232.44 ]
11
1.3 %
14.67 [ 0.93, 232.44 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Propranolol 160 mg
Wideroe 1974
Subtotal (95% CI)

Total events: 12 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.80 (P = 0.0050)

Diener 1996
Subtotal (95% CI)

3 Propranolol 80-120 mg
Holdorff 1977
Subtotal (95% CI)


4 Propranolol 80 mg
Weber 1972
Subtotal (95% CI)

0.1 0.2
0.5
Favours control
10
Favours treatment
(Continued . . . )
70
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Total (95% CI)
111
94
100.0 %
1.72 [ 1.23, 2.40 ]

Heterogeneity: Chi2 = 5.64, df = 3 (P = 0.13); I2 =47%
Test for subgroup differences: Chi2 = 5.52, df = 3 (P = 0.14), I2 =46%
0.1 0.2
0.5
Favours control
10
Favours treatment
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Responders (parallel-group and pooled
crossover data).
Review:

Outcome: 2 Responders (parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
4/8
2/8
2.0 %
2.00 [ 0.50, 8.00 ]
Tfelt-Hansen 1984
48/80
24/80
24.3 %
2.00 [ 1.37, 2.92 ]
Wideroe 1974
25/26
10/26
10.1 %
2.50 [ 1.53, 4.09 ]
114
114
36.5 %
2.14 [ 1.59, 2.87 ]
34/62
17/62
17.2 %
2.00 [ 1.26, 3.18 ]
62
62
17.2 %
2.00 [ 1.26, 3.18 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Pita 1977
Subtotal (95% CI)

Heterogeneity: Chi2 = 0.52, df = 2 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 5.04 (P < 0.00001)
Diamond 1976
Subtotal (95% CI)

0.1 0.2
0.5
Favours control
10
Favours treatment
(Continued . . . )

71
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Borgesen 1974
14/30
9/30
9.1 %
1.56 [ 0.80, 3.03 ]
Diener 1996
33/78
17/55
20.2 %
1.37 [ 0.85, 2.20 ]
108
85
29.3 %
1.43 [ 0.97, 2.10 ]
8/13
7/14
6.8 %
1.23 [ 0.63, 2.42 ]
13
14
6.8 %
1.23 [ 0.63, 2.42 ]
15/19
2/19
2.0 %
7.50 [ 1.98, 28.40 ]
19
19
2.0 %
7.50 [ 1.98, 28.40 ]
16/29
8/29
8.1 %
2.00 [ 1.02, 3.93 ]
29
29
8.1 %
2.00 [ 1.02, 3.93 ]
323
100.0 %
1.94 [ 1.61, 2.35 ]
Subtotal (95% CI)

Holdorff 1977
Subtotal (95% CI)

5 Propranolol 80 mg
Weber 1972
Subtotal (95% CI)


6 Propranolol, dose unclear
Malvea 1973
Subtotal (95% CI)

Total (95% CI)
345

0.1 0.2
0.5
Favours control
10
Favours treatment

72
Analysis 1.3. Comparison 1 Propranolol versus placebo, Outcome 3 Attack frequency measures (parallelgroup and 1st period crossover data).
Review:

Outcome: 3 Attack frequency measures (parallel-group and 1st period crossover data)
Study or subgroup
Treatment
Std.
Mean
Difference
Control
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
Mean(SD)
Mean(SD)
IV,Fixed,95% CI
Pradalier 1989
22
3.15 (3.61)
19
6.41 (7.41)
23.7 %
-0.56 [ -1.19, 0.07 ]
Wideroe 1974
12
0.44 (0.52)
14
1.64 (1.3)
13.2 %
-1.14 [ -1.98, -0.30 ]
36.9 %
-0.77 [ -1.27, -0.27 ]
Subtotal (95% CI)
34
33

Mikkelsen 1986
Sargent 1985
Subtotal (95% CI)
6.4 (4.1)
7.6 (6.1)
10.8 %
-0.22 [ -1.15, 0.71 ]
44
-0.21 (1.86)
43
0.25 (1.57)
52.3 %
-0.26 [ -0.69, 0.16 ]
52
63.1 %
-0.26 [ -0.64, 0.13 ]
85
100.0 %
-0.45 [ -0.75, -0.14 ]
53

Total (95% CI)
87

-4
-2
Favours treatment

Favours control
73
Analysis 1.4. Comparison 1 Propranolol versus placebo, Outcome 4 Attack frequency measures (parallelgroup and pooled crossover data).
Review:

Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data)
Study or subgroup
Treatment
Std.
Mean
Difference
Control
Mean(SD)
Mean(SD)
17
13.8 (12)
17
20.1 (18)
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI
Johnson 1986
Subtotal (95% CI)
17
17
5.4 %
-0.40 [ -1.08, 0.28 ]
5.4 %
-0.40 [ -1.08, 0.28 ]

Pradalier 1989
22
3.15 (3.61)
19
6.41 (7.41)
6.4 %
-0.56 [ -1.19, 0.07 ]
Stensrud 1976
19
5 (3.7)
19
6.11 (4.05)
6.1 %
-0.28 [ -0.92, 0.36 ]
Tfelt-Hansen 1984
80
3.69 (3.44)
80
4.84 (3.85)
25.7 %
-0.31 [ -0.63, 0.00 ]
Wideroe 1974
26
0.39 (0.48)
26
1.7 (1.4)
7.0 %
-1.23 [ -1.83, -0.64 ]
45.2 %
-0.49 [ -0.72, -0.25 ]
Subtotal (95% CI)
147
144

Ahuja 1985
26
8.58 (5.92)
26
14.46 (13.05)
8.1 %
-0.57 [ -1.13, -0.02 ]
Borgesen 1974
30
1.03 (1.02)
30
1.33 (1.15)
9.7 %
-0.27 [ -0.78, 0.24 ]
Grotemeyer 1987
24
19 (16)
24
22 (16)
7.8 %
-0.18 [ -0.75, 0.38 ]
Mikkelsen 1986
31
6.6 (4.9)
31
8.8 (6.9)
9.9 %
-0.36 [ -0.87, 0.14 ]
Sargent 1985
44
-0.21 (1.86)
43
0.25 (1.57)
14.0 %
-0.26 [ -0.69, 0.16 ]
154
49.4 %
-0.32 [ -0.55, -0.10 ]
315
100.0 %
-0.40 [ -0.56, -0.24 ]
Subtotal (95% CI)
155

Total (95% CI)
319

Test for subgroup differences: Chi2 = 0.97, df = 2 (P = 0.62), I2 =0.0%
-4
-2
Favours treatment

Favours control
74
Analysis 1.5. Comparison 1 Propranolol versus placebo, Outcome 5 Number of patients with adverse
events (parallel-group; no 1st period crossover data).
Review:

Outcome: 5 Number of patients with adverse events (parallel-group; no 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
Diener 1996
19/78
5/55
17.2 %
2.68 [ 1.06, 6.74 ]
Sargent 1985
30/44
28/43
82.8 %
1.05 [ 0.78, 1.41 ]
Total (95% CI)
122
98
100.0 %
1.33 [ 0.97, 1.82 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Test for subgroup differences: Not applicable
0.1 0.2
0.5
Favours treatment
10
Favours control

75
Analysis 1.6. Comparison 1 Propranolol versus placebo, Outcome 6 Number of patients with adverse
events (parallel-group and pooled crossover data).
Review:

Outcome: 6 Number of patients with adverse events (parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
2/23
1/24
1.4 %
2.09 [ 0.20, 21.48 ]
23
24
1.4 %
2.09 [ 0.20, 21.48 ]
35/83
23/83
32.3 %
1.52 [ 0.99, 2.34 ]
83
83
32.3 %
1.52 [ 0.99, 2.34 ]
16/62
10/62
14.1 %
1.60 [ 0.79, 3.25 ]
62
62
14.1 %
1.60 [ 0.79, 3.25 ]
19/78
5/55
8.2 %
2.68 [ 1.06, 6.74 ]
3/31
3/31
4.2 %
1.00 [ 0.22, 4.58 ]
30/44
28/43
39.8 %
1.05 [ 0.78, 1.41 ]
153
129
52.3 %
1.30 [ 0.95, 1.77 ]
298
100.0 %
1.43 [ 1.12, 1.81 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
Johnson 1986
Subtotal (95% CI)

Tfelt-Hansen 1984
Subtotal (95% CI)


Diamond 1976
Subtotal (95% CI)

Diener 1996
Mikkelsen 1986
Sargent 1985
Subtotal (95% CI)

Total (95% CI)
321

0.1 0.2
0.5
Favours treatment
10
Favours control

76
Analysis 1.7. Comparison 1 Propranolol versus placebo, Outcome 7 Number of dropouts due to adverse
events (parallel-group and 1st period crossover data).
Review:

Outcome: 7 Number of dropouts due to adverse events (parallel-group and 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
Nadelmann 1986
0/28
0/29
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)
28
29
0.0 [ 0.0, 0.0 ]
0/40
1/34
0.28 [ 0.01, 6.77 ]
40
34
0.28 [ 0.01, 6.77 ]
4/78
0/55
6.38 [ 0.35, 116.13 ]
78
55
6.38 [ 0.35, 116.13 ]
146
118
1.90 [ 0.36, 10.14 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Pradalier 1989
Subtotal (95% CI)

Diener 1996
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours treatment

10
Favours control
77
Analysis 1.8. Comparison 1 Propranolol versus placebo, Outcome 8 Number of dropouts due to adverse
Review:

Outcome: 8 Number of dropouts due to adverse events (parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
Nadelmann 1986
0/57
0/57
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)
57
57
0.0 [ 0.0, 0.0 ]
Forssman 1976
2/40
2/40
1.00 [ 0.15, 6.76 ]
Johnson 1986
1/29
1/29
1.00 [ 0.07, 15.24 ]
69
69
1.00 [ 0.21, 4.78 ]
1/9
0/9
3.00 [ 0.14, 65.16 ]
Pradalier 1989
0/40
1/34
0.28 [ 0.01, 6.77 ]
Stensrud 1976
1/20
0/20
3.00 [ 0.13, 69.52 ]
Stensrud 1980
1/35
0/35
3.00 [ 0.13, 71.22 ]
Tfelt-Hansen 1984
6/89
2/90
3.03 [ 0.63, 14.63 ]
Subtotal (95% CI)
193
188
2.15 [ 0.77, 6.01 ]
6/83
1/83
6.00 [ 0.74, 48.75 ]
83
83
6.00 [ 0.74, 48.75 ]
0/45
2/45
0.20 [ 0.01, 4.05 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtotal (95% CI)


Pita 1977

Diamond 1976
Subtotal (95% CI)

Borgesen 1974
0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

78
(. . .
Study or subgroup
Treatment
Control
Risk Ratio
n/N
n/N
Diener 1996
4/78
0/55
6.38 [ 0.35, 116.13 ]
Mikkelsen 1986
2/39
0/39
5.00 [ 0.25, 100.89 ]
162
139
1.88 [ 0.51, 6.91 ]
0/25
0/25
0.0 [ 0.0, 0.0 ]
25
25
0.0 [ 0.0, 0.0 ]
589
561
2.11 [ 1.09, 4.08 ]
Subtotal (95% CI)
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

6 Propranolol 80 mg
Weber 1972
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours treatment

10
Favours control
79
Analysis 2.1. Comparison 2 Propranolol versus calcium antagonists, Outcome 1 Responders (all trials
parallel-group).
Review:
Comparison: 2 Propranolol versus calcium antagonists

Outcome: 1 Responders (all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Propranolol 180 mg vs. flunarizine 10 mg

Shimell 1990
27/29
20/28
4.1 %
1.30 [ 1.01, 1.68 ]
29
28
4.1 %
1.30 [ 1.01, 1.68 ]
Subtotal (95% CI)


Diener 2002
125/258
141/264
27.9 %
0.91 [ 0.77, 1.07 ]
Gawel 1992
20/39
25/37
5.1 %
0.76 [ 0.52, 1.11 ]
297
301
33.0 %
0.88 [ 0.76, 1.03 ]
125/258
118/259
23.5 %
1.06 [ 0.89, 1.28 ]
258
259
23.5 %
1.06 [ 0.89, 1.28 ]
Subtotal (95% CI)

Diener 2002
Subtotal (95% CI)

Ludin 1989
16/32
13/27
2.8 %
1.04 [ 0.62, 1.75 ]
Lucking 1988a
24/34
24/35
4.7 %
1.03 [ 0.75, 1.41 ]
Lucking 1988b
105/170
104/166
21.0 %
0.99 [ 0.83, 1.16 ]
236
228
28.6 %
1.00 [ 0.87, 1.15 ]
15/19
18/23
3.3 %
1.01 [ 0.73, 1.38 ]
19
23
3.3 %
1.01 [ 0.73, 1.38 ]
Subtotal (95% CI)

Bonuso 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours control
10
Favours treatment
(Continued . . . )

80
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Bordini 1997
15/15
14/15
2.9 %
1.07 [ 0.89, 1.28 ]
15
15
2.9 %
1.07 [ 0.89, 1.28 ]
12/13
6/7
1.6 %
1.08 [ 0.77, 1.51 ]
13
1.6 %
1.08 [ 0.77, 1.51 ]
6/19
1/17
0.2 %
5.37 [ 0.72, 40.20 ]
19
17
0.2 %
5.37 [ 0.72, 40.20 ]
Subtotal (95% CI)

7 Propranolol 120-180 mg vs. nifedipine 60-90 mg

Albers 1989
Subtotal (95% CI)


Diener 1989
Subtotal (95% CI)

9 Propranolol 60 mg vs. propranolol 60 mg + flunarizine 10 mg

Bordini 1997
15/15
14/15
2.9 %
1.07 [ 0.89, 1.28 ]
15
15
2.9 %
1.07 [ 0.89, 1.28 ]
901
893
100.0 %
1.00 [ 0.93, 1.09 ]
Subtotal (95% CI)

Total (95% CI)

0.1 0.2
0.5
Favours control
10
Favours treatment

81
Analysis 2.2. Comparison 2 Propranolol versus calcium antagonists, Outcome 2 Attack frequency measures
(all trials parallel-group).
Review:

Outcome: 2 Attack frequency measures (all trials parallel-group)
Study or subgroup
Treatment
N
Std.
Mean
Difference
Control
Mean(SD)
Mean(SD)
1.7 (1.6)
265
1.6 (1.6)
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI

Diener 2002
Subtotal (95% CI)
259
259
265
34.0 %
0.06 [ -0.11, 0.23 ]
34.0 %
0.06 [ -0.11, 0.23 ]
33.6 %
-0.07 [ -0.24, 0.10 ]
33.6 %
-0.07 [ -0.24, 0.10 ]

Diener 2002
Subtotal (95% CI)
259
1.7 (1.6)
259
259
1.8 (1.2)
259

Ludin 1989
32
3.7 (4.2)
27
4.8 (6.2)
3.8 %
-0.21 [ -0.72, 0.31 ]
Lucking 1988a
32
3 (5)
35
4 (5)
4.3 %
-0.20 [ -0.68, 0.28 ]
Lucking 1988b
170
4 (5)
166
4 (4)
21.8 %
0.0 [ -0.21, 0.21 ]
29.9 %
-0.05 [ -0.24, 0.13 ]
1.2 %
0.19 [ -0.73, 1.11 ]
1.2 %
0.19 [ -0.73, 1.11 ]
1.2 %
-0.18 [ -1.09, 0.74 ]
11
1.2 %
-0.18 [ -1.09, 0.74 ]
770
100.0 %
-0.02 [ -0.12, 0.08 ]
Subtotal (95% CI)
234
228

Albers 1989
Subtotal (95% CI)
13
2.2 (3.24)
13
1.5 (3.97)

5 Propranolol 120 mg vs. nimodipine 120 mg
Formisano 1991
Subtotal (95% CI)
2.6 (1.5)
11
2.9 (1.7)

Total (95% CI)
773

-4
-2
Favours treatment

Favours control
82
Analysis 2.3. Comparison 2 Propranolol versus calcium antagonists, Outcome 3 Number of patients with
adverse events (all trials parallel-group).
Review:

Outcome: 3 Number of patients with adverse events (all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Diener 2002
88/270
88/275
26.4 %
1.02 [ 0.80, 1.30 ]
Gawel 1992
36/45
33/44
10.1 %
1.07 [ 0.85, 1.34 ]
315
319
36.6 %
1.03 [ 0.86, 1.24 ]
88/270
88/263
27.0 %
0.97 [ 0.76, 1.24 ]
270
263
27.0 %
0.97 [ 0.76, 1.24 ]
Subtotal (95% CI)

Diener 2002
Subtotal (95% CI)

Ludin 1989
15/32
13/27
4.3 %
0.97 [ 0.57, 1.67 ]
Lucking 1988a
21/34
16/35
4.8 %
1.35 [ 0.86, 2.11 ]
Lucking 1988b
66/170
52/166
16.0 %
1.24 [ 0.92, 1.66 ]
236
228
25.0 %
1.22 [ 0.97, 1.52 ]
2/15
3/15
0.9 %
0.67 [ 0.13, 3.44 ]
15
15
0.9 %
0.67 [ 0.13, 3.44 ]
15/20
20/20
6.2 %
0.76 [ 0.58, 0.98 ]
20
20
6.2 %
0.76 [ 0.58, 0.98 ]
Subtotal (95% CI)

Bordini 1997
Subtotal (95% CI)


Albers 1989
Subtotal (95% CI)
0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

83
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Formisano 1991
6/10
11/12
3.0 %
0.65 [ 0.38, 1.12 ]
10
12
3.0 %
0.65 [ 0.38, 1.12 ]
Subtotal (95% CI)

7 Propranolol 60 mg vs. propanolol 60 mg + flunarizine 10 mg

Bordini 1997
2/15
4/15
1.2 %
0.50 [ 0.11, 2.33 ]
15
15
1.2 %
0.50 [ 0.11, 2.33 ]
881
872
100.0 %
1.02 [ 0.91, 1.15 ]
Subtotal (95% CI)

Total (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control

84
Analysis 2.4. Comparison 2 Propranolol versus calcium antagonists, Outcome 4 Number of patients with
adverse events (vs. flunarizine; all trials parallel-group).
Review:

Outcome: 4 Number of patients with adverse events (vs. flunarizine; all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Diener 2002
88/270
88/275
29.5 %
1.02 [ 0.80, 1.30 ]
Gawel 1992
36/45
33/44
11.3 %
1.07 [ 0.85, 1.34 ]
315
319
40.8 %
1.03 [ 0.86, 1.24 ]
88/270
88/263
30.2 %
0.97 [ 0.76, 1.24 ]
270
263
30.2 %
0.97 [ 0.76, 1.24 ]
Subtotal (95% CI)

Diener 2002
Subtotal (95% CI)

Ludin 1989
15/32
13/27
4.8 %
0.97 [ 0.57, 1.67 ]
Lucking 1988a
21/34
16/35
5.3 %
1.35 [ 0.86, 2.11 ]
Lucking 1988b
66/170
52/166
17.8 %
1.24 [ 0.92, 1.66 ]
236
228
27.9 %
1.22 [ 0.97, 1.52 ]
2/15
3/15
1.0 %
0.67 [ 0.13, 3.44 ]
15
15
1.0 %
0.67 [ 0.13, 3.44 ]
836
825
100.0 %
1.06 [ 0.94, 1.20 ]
Subtotal (95% CI)

Bordini 1997
Subtotal (95% CI)

Total (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control

85
Analysis 2.5. Comparison 2 Propranolol versus calcium antagonists, Outcome 5 Number of dropouts due to
adverse events (all trials parallel-group).
Review:

Outcome: 5 Number of dropouts due to adverse events (all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
3/29
2/29
1.50 [ 0.27, 8.32 ]
29
29
1.50 [ 0.27, 8.32 ]
Diener 2002
18/270
19/275
0.96 [ 0.52, 1.80 ]
Gawel 1992
5/45
3/44
1.63 [ 0.41, 6.41 ]
Scholz 1987
3/19
2/12
0.95 [ 0.18, 4.87 ]
334
331
1.05 [ 0.61, 1.78 ]
18/270
21/263
0.83 [ 0.46, 1.53 ]
270
263
0.83 [ 0.46, 1.53 ]
3/32
2/27
1.27 [ 0.23, 7.03 ]
32
27
1.27 [ 0.23, 7.03 ]
0/25
0/25
0.0 [ 0.0, 0.0 ]
25
25
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Shimell 1990
Subtotal (95% CI)

Subtotal (95% CI)


Diener 2002
Subtotal (95% CI)

Ludin 1989
Subtotal (95% CI)

Bonuso 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

86
(. . .
Study or subgroup
Risk Ratio
Continued)
Risk Ratio
Treatment
Control
n/N
n/N
0/18
0/17
0.0 [ 0.0, 0.0 ]
18
17
0.0 [ 0.0, 0.0 ]
2/10
1/12
2.40 [ 0.25, 22.75 ]
10
12
2.40 [ 0.25, 22.75 ]
3/19
8/17
0.34 [ 0.11, 1.06 ]
19
17
0.34 [ 0.11, 1.06 ]
5/20
13/20
0.38 [ 0.17, 0.88 ]
20
20
0.38 [ 0.17, 0.88 ]
0/18
0/17
0.0 [ 0.0, 0.0 ]
18
17
0.0 [ 0.0, 0.0 ]
775
758
0.82 [ 0.59, 1.13 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Bordini 1997
Subtotal (95% CI)

Formisano 1991
Subtotal (95% CI)

8 Propranolol 160 mg vs. nifedipine 40 mg
Scholz 1987
Subtotal (95% CI)


Albers 1989
Subtotal (95% CI)

10 Propranolol 60 mg vs. propranolol 60 mg + flunarizine 10 mg

Bordini 1997
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours treatment

10
Favours control
87
adverse events (vs. flunarizine; all trials parallel-group).
Review:

Outcome: 6 Number of dropouts due to adverse events (vs. flunarizine; all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
3/29
2/29
1.50 [ 0.27, 8.32 ]
29
29
1.50 [ 0.27, 8.32 ]
Diener 2002
18/270
19/275
0.96 [ 0.52, 1.80 ]
Gawel 1992
5/45
3/44
1.63 [ 0.41, 6.41 ]
Scholz 1987
3/19
2/12
0.95 [ 0.18, 4.87 ]
334
331
1.05 [ 0.61, 1.78 ]
18/270
21/263
0.83 [ 0.46, 1.53 ]
270
263
0.83 [ 0.46, 1.53 ]
3/32
2/27
1.27 [ 0.23, 7.03 ]
32
27
1.27 [ 0.23, 7.03 ]
0/25
0/25
0.0 [ 0.0, 0.0 ]
25
25
0.0 [ 0.0, 0.0 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Shimell 1990
Subtotal (95% CI)

Subtotal (95% CI)


Diener 2002
Subtotal (95% CI)

Ludin 1989
Subtotal (95% CI)

Bonuso 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

88
(. . .
Study or subgroup
Risk Ratio
Continued)
Risk Ratio
Treatment
Control
n/N
n/N
0/18
0/17
0.0 [ 0.0, 0.0 ]
18
17
0.0 [ 0.0, 0.0 ]
708
692
0.98 [ 0.67, 1.44 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Bordini 1997
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours treatment
10
Favours control
adverse events (vs. nifedipine; all trials parallel-group).
Review:

Outcome: 7 Number of dropouts due to adverse events (vs. nifedipine; all trials parallel-group)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
3/19
8/17
39.4 %
0.34 [ 0.11, 1.06 ]
19
17
39.4 %
0.34 [ 0.11, 1.06 ]
5/20
13/20
60.6 %
0.38 [ 0.17, 0.88 ]
20
20
60.6 %
0.38 [ 0.17, 0.88 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nifedipine 40 mg

Scholz 1987
Subtotal (95% CI)


Albers 1989
Subtotal (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

89
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Total (95% CI)
39
37
100.0 %
0.37 [ 0.19, 0.72 ]

0.1 0.2
0.5
Favours treatment
10
Favours control
Analysis 3.1. Comparison 3 Propranolol versus other beta-blockers, Outcome 1 Responders (parallelgroup; no 1st period crossover data).
Review:
Comparison: 3 Propranolol versus other beta-blockers

Outcome: 1 Responders (parallel-group; no 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
5/27
18/33
0.34 [ 0.15, 0.79 ]
5/27
11/33
0.56 [ 0.22, 1.40 ]
5/13
1.49 [ 0.65, 3.39 ]
12/22
0.58 [ 0.27, 1.24 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg

Sudilovsky 1987
Sudilovsky 1987
3 Propranolol 80-160 mg vs. nadolol 40-160 mg

Olerud 1986
8/14
4 Propranolol 80-160 mg vs. metoprolol 100-200 mg

Diener 1989
6/19
0.1 0.2
0.5
Favours control

10
Favours treatment
90
Analysis 3.2. Comparison 3 Propranolol versus other beta-blockers, Outcome 2 Responders (parallel-group
and pooled crossover data).
Review:

Outcome: 2 Responders (parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
5/27
18/33
0.34 [ 0.15, 0.79 ]
5/27
11/33
0.56 [ 0.22, 1.40 ]
8/14
5/13
1.49 [ 0.65, 3.39 ]
15/33
17/33
0.88 [ 0.54, 1.45 ]
6/19
12/22
0.58 [ 0.27, 1.24 ]
16/53
21/56
0.81 [ 0.47, 1.37 ]
48/80
44/80
1.09 [ 0.84, 1.42 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Sudilovsky 1987
Sudilovsky 1987

Olerud 1986
4 Propranolol 160 mg vs. metoprolol 200 mg
Kangasniemi 1984

Diener 1989
Olsson 1984
7 Propranolol 160 mg vs. timolol 20 mg
Tfelt-Hansen 1984
0.1 0.2
0.5
Favours control

10
Favours treatment
91
Analysis 3.3. Comparison 3 Propranolol versus other beta-blockers, Outcome 3 Responders (vs. nadolol;
parallel-group and pooled crossover data).
Review:

Outcome: 3 Responders (vs. nadolol; parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
5/27
18/33
51.8 %
0.34 [ 0.15, 0.79 ]
27
33
51.8 %
0.34 [ 0.15, 0.79 ]
5/27
11/33
31.6 %
0.56 [ 0.22, 1.40 ]
27
33
31.6 %
0.56 [ 0.22, 1.40 ]
8/14
5/13
16.6 %
1.49 [ 0.65, 3.39 ]
14
13
16.6 %
1.49 [ 0.65, 3.39 ]
68
79
100.0 %
0.60 [ 0.37, 0.97 ]
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Sudilovsky 1987
Subtotal (95% CI)


Sudilovsky 1987
Subtotal (95% CI)


Olerud 1986
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours control
10
Favours treatment

92
Analysis 3.4. Comparison 3 Propranolol versus other beta-blockers, Outcome 4 Responders (vs.
metoprolol; parallel-group and pooled crossover data).
Review:

Outcome: 4 Responders (vs. metoprolol; parallel-group and pooled crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Risk Ratio
M-H,Fixed,95% CI

Kangasniemi 1984
15/33
17/33
35.0 %
0.88 [ 0.54, 1.45 ]
33
33
35.0 %
0.88 [ 0.54, 1.45 ]
6/19
12/22
22.9 %
0.58 [ 0.27, 1.24 ]
19
22
22.9 %
0.58 [ 0.27, 1.24 ]
16/53
21/56
42.1 %
0.81 [ 0.47, 1.37 ]
53
56
42.1 %
0.81 [ 0.47, 1.37 ]
105
111
100.0 %
0.78 [ 0.56, 1.09 ]
Subtotal (95% CI)


Diener 1989
Subtotal (95% CI)


Olsson 1984
Subtotal (95% CI)

Total (95% CI)

0.1 0.2
0.5
Favours control
10
Favours treatment

93
Analysis 3.5. Comparison 3 Propranolol versus other beta-blockers, Outcome 5 Attack frequency measures
(pooled crossover only; no parallel-group or 1st period crossover data).
Review:

Outcome: 5 Attack frequency measures (pooled crossover only; no parallel-group or 1st period crossover data)
Study or subgroup
Treatment
Std.
Mean
Difference
Control
Mean(SD)
Mean(SD)
3 (1.9)
34
3 (1.8)
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI

Kangasniemi 1984
34
Subtotal (95% CI)
34
23.5 %
0.0 [ -0.48, 0.48 ]
23.5 %
0.0 [ -0.48, 0.48 ]
8.1 %
-0.43 [ -1.24, 0.38 ]
8.1 %
-0.43 [ -1.24, 0.38 ]
55.3 %
0.10 [ -0.21, 0.41 ]
55.3 %
0.10 [ -0.21, 0.41 ]
13.0 %
-0.27 [ -0.91, 0.37 ]
19
13.0 %
-0.27 [ -0.91, 0.37 ]
145
100.0 %
-0.01 [ -0.24, 0.22 ]
34

Hedman 1986
Subtotal (95% CI)
12
2.4 (1)
12
12
3.1 (2)
12

Tfelt-Hansen 1984
80
Subtotal (95% CI)
80
3.69 (3.44)
80
3.35 (3.13)
80

4 Propranolol 160 mg vs. d-propranolol 160 mg
Stensrud 1976
Subtotal (95% CI)
19
5 (3.7)
19
19
6.16 (4.6)

Total (95% CI)
145

-4
-2
Favours treatment

Favours control
94
Analysis 3.6. Comparison 3 Propranolol versus other beta-blockers, Outcome 6 Number of patients with
adverse events (parallel-group; no 1st period crossover data).
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Olerud 1986
5/14
6/13
0.77 [ 0.31, 1.93 ]
0.1 0.2
0.5
Favours treatment
10
Favours control
Analysis 3.7. Comparison 3 Propranolol versus other beta-blockers, Outcome 7 Number of patients with
adverse events (parallel-group and pooled crossover data).
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
35/83
38/83
0.92 [ 0.65, 1.30 ]
83
83
0.92 [ 0.65, 1.30 ]
5/14
6/13
0.77 [ 0.31, 1.93 ]
14
13
0.77 [ 0.31, 1.93 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Tfelt-Hansen 1984
Subtotal (95% CI)

Olerud 1986
Subtotal (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

95
(. . .
Study or subgroup
Risk Ratio
Continued)
Risk Ratio
Treatment
Control
n/N
n/N
0/12
0/12
0.0 [ 0.0, 0.0 ]
12
12
0.0 [ 0.0, 0.0 ]
109
108
0.90 [ 0.65, 1.24 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Hedman 1986
Subtotal (95% CI)

Total (95% CI)


0.1 0.2
0.5
Favours treatment

10
Favours control
96
Analysis 3.8. Comparison 3 Propranolol versus other beta-blockers, Outcome 8 Number of dropouts due to
Review:

Outcome: 8 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
4/44
2/47
2.14 [ 0.41, 11.09 ]
44
47
2.14 [ 0.41, 11.09 ]
4/44
2/49
2.23 [ 0.43, 11.57 ]
44
49
2.23 [ 0.43, 11.57 ]
0/16
0/16
0.0 [ 0.0, 0.0 ]
16
16
0.0 [ 0.0, 0.0 ]
0/16
1/16
0.33 [ 0.01, 7.62 ]
16
16
0.33 [ 0.01, 7.62 ]
0/15
1/13
0.29 [ 0.01, 6.60 ]
15
13
0.29 [ 0.01, 6.60 ]
3/19
6/22
0.58 [ 0.17, 2.01 ]
19
22
0.58 [ 0.17, 2.01 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Sudilovsky 1987
Subtotal (95% CI)

Sudilovsky 1987
Subtotal (95% CI)

Ryan 1984
Subtotal (95% CI)

Ryan 1984
Subtotal (95% CI)


Olerud 1986
Subtotal (95% CI)

Scholz 1987
Subtotal (95% CI)
0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

97
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
154
163
Risk Ratio
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Total (95% CI)
1.00 [ 0.48, 2.10 ]

0.1 0.2
0.5
Favours treatment
10
Favours control
Analysis 3.9. Comparison 3 Propranolol versus other beta-blockers, Outcome 9 Number of dropouts due to
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
4/44
2/47
2.14 [ 0.41, 11.09 ]
44
47
2.14 [ 0.41, 11.09 ]
4/44
2/49
2.23 [ 0.43, 11.57 ]
44
49
2.23 [ 0.43, 11.57 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Sudilovsky 1987
Subtotal (95% CI)

Sudilovsky 1987
Subtotal (95% CI)

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

98
(. . .
Study or subgroup
Treatment
Control
Risk Ratio
n/N
n/N
0/16
0/16
0.0 [ 0.0, 0.0 ]
16
16
0.0 [ 0.0, 0.0 ]
0/16
1/16
0.33 [ 0.01, 7.62 ]
16
16
0.33 [ 0.01, 7.62 ]
0/15
1/13
0.29 [ 0.01, 6.60 ]
15
13
0.29 [ 0.01, 6.60 ]
Kangasniemi 1984
2/36
0/36
5.00 [ 0.25, 100.63 ]
Scholz 1987
3/19
6/22
0.58 [ 0.17, 2.01 ]
55
58
0.94 [ 0.33, 2.72 ]
0/56
0/56
0.0 [ 0.0, 0.0 ]
56
56
0.0 [ 0.0, 0.0 ]
1/35
0/35
3.00 [ 0.13, 71.22 ]
35
35
3.00 [ 0.13, 71.22 ]
Tfelt-Hansen 1984
6/89
9/89
0.67 [ 0.25, 1.79 ]
Subtotal (95% CI)
89
89
0.67 [ 0.25, 1.79 ]
Ryan 1984
Subtotal (95% CI)
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Ryan 1984
Subtotal (95% CI)


Olerud 1986
Subtotal (95% CI)

Subtotal (95% CI)


Olsson 1984
Subtotal (95% CI)

8 Propranolol 160 mg vs. atenolol 100 mg
Stensrud 1980
Subtotal (95% CI)


0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )
99
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

10 Propranolol 160 mg vs. d-propranolol 160 mg
Stensrud 1976
Subtotal (95% CI)
1/20
0/20
3.00 [ 0.13, 69.52 ]
20
20
3.00 [ 0.13, 69.52 ]
390
399
1.05 [ 0.61, 1.80 ]

Total (95% CI)


0.1 0.2
0.5
Favours treatment

10
Favours control
100
Analysis 4.1. Comparison 4 Propranolol versus other drugs, Outcome 1 Responders (parallel-group and 1st
period crossover data).
Review:
Comparison: 4 Propranolol versus other drugs

Outcome: 1 Responders (parallel-group and 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
3/11
1/11
3.00 [ 0.37, 24.58 ]
20/28
0.74 [ 0.50, 1.10 ]
30/81
1.14 [ 0.78, 1.68 ]
9/15
1.18 [ 0.70, 1.97 ]
8/19
0.83 [ 0.37, 1.84 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg

Kangasniemi 1983
2 Propranolol 120-160 mg vs. cyclandelate 1200-1600 mg

Gerber 1995
18/34
3 Propranolol 120 mg vs. cyclandelate 1200 mg

Diener 1996
33/78
4 Propranolol 60-240 mg vs. divalproex sodium 1000-2000 mg

Kaniecki 1997
12/17
5 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg

Maissen 1991
7/20
0.1 0.2
0.5
Favours control

10
Favours treatment
101
Analysis 4.2. Comparison 4 Propranolol versus other drugs, Outcome 2 Responders (parallel-group and
pooled crossover data [one 1st period]).
Review:

Outcome: 2 Responders (parallel-group and pooled crossover data [one 1st period])
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
Andersson 1981
11/28
4/28
2.75 [ 0.99, 7.61 ]
Kangasniemi 1983
3/11
1/11
3.00 [ 0.37, 24.58 ]
20/28
0.74 [ 0.50, 1.10 ]
30/81
1.14 [ 0.78, 1.68 ]
21/32
0.95 [ 0.66, 1.38 ]
7/20
8/19
0.83 [ 0.37, 1.84 ]
19/36
13/36
1.46 [ 0.86, 2.49 ]
13/21
8/21
1.63 [ 0.86, 3.08 ]
12/30
10/30
1.20 [ 0.61, 2.34 ]
9/12
9/12
1.00 [ 0.63, 1.59 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Gerber 1995
18/34

Diener 1996
33/78

Kaniecki 1997
20/32

Maissen 1991
6 Propranolol 120 mg vs. methysergide 3 mg
Behan 1980
7 Propranolol 160 mg vs. clonidine 100 mcg
Kass 1980
8 Propranolol 80-240 mg vs. amitriptyline 50-150 mg

Ziegler 1987
9 Propranolol 1.8 mg/kg vs. ASA 13.5 mg/kg
Baldrati 1983
0.1 0.2
0.5
Favours control

10
Favours treatment
102
Analysis 4.3. Comparison 4 Propranolol versus other drugs, Outcome 3 Attack frequency measures
(parallel-group and 1st period crossover data).
Review:

Outcome: 3 Attack frequency measures (parallel-group and 1st period crossover data)
Study or subgroup
Treatment
N
Std.
Mean
Difference
Control
Mean(SD)
Mean(SD)
Std.
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI

Andersson 1981
20
3.1 (3)
17
4.2 (1.2)
-0.46 [ -1.11, 0.20 ]
Kangasniemi 1983
11
5 (2.35)
13
6.81 (4.04)
-0.52 [ -1.34, 0.30 ]
2 Propranolol 120 mg vs. tolfenamic acid 300 mg

Kjaersgard 1994
29
-1.7 (1.9)
27
-0.6 (1.6)
-0.62 [ -1.15, -0.08 ]
Mikkelsen 1986
6.4 (4.1)
13
10.2 (6.8)
-0.62 [ -1.50, 0.25 ]
4.4 (4)
19
7.3 (7.4)
-0.48 [ -1.12, 0.17 ]
-0.21 (1.86)
42
0.48 (2.02)
-0.35 [ -0.78, 0.07 ]
128
3.06 (1.4)
0.03 [ -0.22, 0.27 ]
15
1.3 (1.2)
0.0 [ -0.72, 0.72 ]

Maissen 1991
19
4 Propranolol 120 mg vs. naproxen 1100 mg

Sargent 1985
44
5 Propranolol 1230 mcg/kg vs. methysergide 30.8 mcg/kg

Nicolodi 1997
128
3.1 (1.4)
6 Propranolol 80 mg vs. alpha-dihydroergocryptine 20 mg

Micieli 2001
15
1.3 (1.2)
-4
-2
Favours treatment

Favours control
103
Analysis 4.4. Comparison 4 Propranolol versus other drugs, Outcome 4 Attack frequency measures
(parallel-group and pooled crossover data [two 1st period]).
Review:

Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data [two 1st period])
Study or subgroup
Treatment
Std.
Mean
Difference
Control
Mean(SD)
Mean(SD)
Std.
Mean
Difference
IV,Fixed,95% CI
IV,Fixed,95% CI

Andersson 1981
37
3.4 (1.8)
37
4.1 (1.8)
-0.38 [ -0.84, 0.08 ]
Kangasniemi 1983
24
4.67 (2.31)
24
6.16 (4.02)
-0.45 [ -1.02, 0.13 ]

Kjaersgard 1994
29
-1.7 (1.9)
27
-0.6 (1.6)
-0.62 [ -1.15, -0.08 ]
Mikkelsen 1986
31
6.6 (4.9)
31
6.9 (6.1)
-0.05 [ -0.55, 0.44 ]
4.4 (4)
19
7.3 (7.4)
-0.48 [ -1.12, 0.17 ]
-0.21 (1.86)
42
0.48 (2.02)
-0.35 [ -0.78, 0.07 ]
3.1 (1.4)
128
3.06 (1.4)
0.03 [ -0.22, 0.27 ]
13.8 (12)
17
12.9 (10.8)
0.08 [ -0.60, 0.75 ]
12.67 (11.15)
21
13 (11.65)
-0.03 [ -0.63, 0.58 ]
15
1.3 (1.2)
0.0 [ -0.72, 0.72 ]

Maissen 1991
19

Sargent 1985
44
5 Propranolol 1230 mcg/kg vs. methysergide 30.8 mcg/kg

Nicolodi 1997
128
6 Propranolol 240 mg vs. mefenamic acid 1500 mg

Johnson 1986
17

Kass 1980
21

Micieli 2001
15
1.3 (1.2)
-4
-2
Favours treatment

Favours control
104
Analysis 4.5. Comparison 4 Propranolol versus other drugs, Outcome 5 Number of patients with adverse
events (parallel-group; no 1st period crossover data).
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Gerber 1995
6/42
4/42
1.50 [ 0.46, 4.93 ]
13/81
1.52 [ 0.81, 2.86 ]
7/19
0.95 [ 0.41, 2.20 ]
38/42
0.75 [ 0.60, 0.94 ]

Diener 1996
19/78

Maissen 1991
7/20

Sargent 1985
30/44
0.1 0.2
0.5
Favours treatment

10
Favours control
105
Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Gerber 1995
6/42
4/42
1.50 [ 0.46, 4.93 ]
13/81
1.52 [ 0.81, 2.86 ]
7/19
0.95 [ 0.41, 2.20 ]
38/42
0.75 [ 0.60, 0.94 ]
2/31
1.50 [ 0.27, 8.36 ]
16/36
0.75 [ 0.42, 1.35 ]
11/21
1.00 [ 0.56, 1.78 ]
16/32
0.69 [ 0.38, 1.24 ]
6/12
1.00 [ 0.45, 2.23 ]
2/22
0.96 [ 0.15, 6.21 ]

Diener 1996
19/78

Maissen 1991
7/20

Sargent 1985
30/44

Mikkelsen 1986
3/31

Behan 1980
12/36

Kass 1980
11/21

Kaniecki 1997
11/32

Baldrati 1983
6/12

Johnson 1986
2/23
0.1 0.2
0.5
Favours treatment

10
Favours control
106
Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to
Review:

Outcome: 7 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
4/78
5/81
0.83 [ 0.23, 2.98 ]
0/19
4.76 [ 0.24, 93.19 ]
0/13
4.90 [ 0.27, 87.59 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Diener 1996

Maissen 1991
2/20
3 Propranolol 160 mg vs. dihydroergotamine 10 mg

Scholz 1987
3/19

Mathew 1981-Study 1
1/44
4/42
0.24 [ 0.03, 2.05 ]
Mathew 1981-Study 2
3/48
3/44
0.92 [ 0.20, 4.31 ]
5 Propranolol 120-160 mg vs. amitriptyline 50-75 mg + propranolol 120-160 mg

Mathew 1981-Study 1
1/44
2/41
0.47 [ 0.04, 4.95 ]
Mathew 1981-Study 2
3/48
2/47
1.47 [ 0.26, 8.40 ]
0.1 0.2
0.5
Favours treatment

10
Favours control
107
Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to
Review:

Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
Risk Ratio
Andersson 1981
2/49
2/49
1.00 [ 0.15, 6.82 ]
Kangasniemi 1983
3/29
0/29
7.00 [ 0.38, 129.74 ]
4/78
5/81
0.83 [ 0.23, 2.98 ]
9/24
0.33 [ 0.10, 1.08 ]
4/37
0.25 [ 0.03, 2.13 ]
0/19
4.76 [ 0.24, 93.19 ]
1/29
1.00 [ 0.07, 15.24 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Diener 1996

Klapper 1994
3/24

Kaniecki 1997
1/37

Maissen 1991
2/20

Johnson 1986
1/29

Kjaersgard 1994
9/76
5/76
1.80 [ 0.63, 5.12 ]
Mikkelsen 1986
2/39
2/39
1.00 [ 0.15, 6.75 ]
0/56
3/56
0.14 [ 0.01, 2.70 ]
0/13
4.90 [ 0.27, 87.59 ]
5/40
4/40
1.25 [ 0.36, 4.32 ]
0/23
0/23
0.0 [ 0.0, 0.0 ]
2/18
3/18
0.67 [ 0.13, 3.53 ]

Behan 1980
9 Propranolol 160 mg vs. dihydroergotamine 10 mg

Scholz 1987
3/19

Micieli 2001
Kass 1980
Baldrati 1983

Mathew 1981-Study 1
1/44
4/42
0.24 [ 0.03, 2.05 ]
Mathew 1981-Study 2
3/48
3/44
0.92 [ 0.20, 4.31 ]

0.1 0.2
0.5
Favours treatment
10
Favours control
(Continued . . . )

108
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Risk Ratio
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI
14 Propranolol 120-160 mg vs. amitriptyline 50-75 mg + propranolol 120-160 mg

Mathew 1981-Study 1
1/44
2/41
0.47 [ 0.04, 4.95 ]
Mathew 1981-Study 2
3/48
2/47
1.47 [ 0.26, 8.40 ]
0.1 0.2
0.5
Favours treatment
10
Favours control
ADDITIONAL TABLES
Table 1. Methodological quality - Delphi list
Study
Randomisation
Concealment
BaseInclusion
line com- criteria
parab.
Blind
evaluators
Blind care Blind pa- Reporting

providers tients
of results
Intent-totreat
Ahuja
1985
Al-Qassab
1993
Albers
1989
Andresson
1981
Baldrati
1983
Behan
1980
Bonuso
1998
Bordini
1997
Borgesen
1974

109
(Continued)
Dahlf
1987
Diamond
1976
Diamond
1982
Diener
1996
Diener
2002
Diener
1989
Formisano
1991
Forssman
1976
Gawel
1991
Gerber
1995
Grotemeyer
1987
Hedman
1986
Holdorff
1977
Johnson
1986
Kangasniemi
1983
Kangasniemi
1984

110
(Continued)
Kaniecki
1997
Kass 1980
Kjaesgard- 1
Rasmussen
1994
Klapper
1994
Kuritzky
1987
Lcking
1988a
Lcking
1998b
Ludin
1989
Maissen
1985
Malvea
1973
Mathew
1981Study 1
Mathew
1981Study 2
Micieli
2001
Mikkelsen
1986
Nadelmann
1986

111
(Continued)
Nicolodi
1997
Olerud
1986
Olsson
1984
Palferman
1983
Pita 1977
Pradalier
1989
Ryan 1984 1
Sargent
1985
Scholz
1987
Shimell
1990
Solomon
1986
Stensrud
1976
Stensrud
1980
Sudilovski
1987
TfeltHasen
1984
Weber
1972
Wideroe
1976

112
Ziegler
1987
(Continued)
Table 2. Adequacy of observation and reporting of key clinical issues (questions 1-5)
Study
Sampling
described
Clear diagnosis
Patient character.
> 4 weeks baseline
Co-interventions
Ahuja 1985
Al-Qassab 1993
Albers 1989
Andersson 1981
Baldrati 1983
Behan 1980
Bonuso 1998
Bordini 1997
Borgesen 1974
Dahlf 1987
Diamond 1976
Diamond 1982
Diener 1996
Diener 2002
Diener 1989
Formisano 1991
Forssman 1976
Gawel 1992
Gerber 1995
Grotemeyer 1987

113
(Continued)
Hedman 1986
Holdroff 1977
Johnson 1986
Kangasniemi 1983
Kangasniemi 1984
Kaniecki 1997
Kass 1980
KjaesgardRasmussen 1994
Klapper 1994
Kuritzky 1987
Lcking 1988a
Lcking 1988b
Ludin 1989
Maissen 1985
Malvea 1973
Mathew
study 1
1981- 0
Mathew
study 2
1981- 0
Micieli 2001
Mikkelsen 1986
Nadelmann 1986
Nicolodi 1997
Olerud 1986
Olsson 1984

114
(Continued)
Palferman 1983
Pita 1977
Pradlier 1989
Ryan 1984
Sargent 1985
Scholz 1987
Shimell 1990
Solomon 1986
Stensrud 1976
Stensrud 1980
Sudilovsky 1987
Tfelt-Hansen 1984
Weber 1972
Wideroe 1976
Ziegler 1987
Study
Diary used
Frequency data
Intensity data
2-month follow up
6-month follow up
Ahuja 1985
Al-Qassab 1993
Albers 1989
Andersson 1981
Baldrati 1983
Behan 1980
Bonuso 1998

115
(Continued)
Bordini 1997
Borgesen 1974
Dahlf 1974
Diamond 1976
Diamond 1982
Diener 1996
Diener 2002
Diener 1989
Formisano 1991
Forssman 1976
Gawel 1992
Gerber 1995
Grotemeyer 1987
Hedman 1986
Holdorff 1977
Johnson 1986
Kangasniemi 1983
Kangasniemi 1984
Kaniecki 1997
Kass 1980
KjaesgardRasmussen 1994
Klapper 1994
Kuritzky 1987
Lcking 1988a

116
(Continued)
Lcking 1988b
Ludin 1989
Maissen 1985
Malvea 1973
Mathew
study 1
1981- 1
Mathew
study 2
1981- 1
Micieli 2001
Mikkelsen 1986
Nadelmann 1986
Olerud 1986
Olsson 1984
Palferman 1983
Pita 1977
Pradalier 1989
Ryan 1984
Sargent 1985
Scholz 1987
Shimell 1990
Solomon 1986
Stensrud 1976
Stensrud 1980
Sudilovsky 1987
Tfelt-Hansen 1984
Weber 1972

117
(Continued)
Wideroe 1976
Ziegler 1987
Nicolodi 1997
WHATS NEW
Last assessed as up-to-date: 15 May 2003.
Date
Event
Description
1 October 2012
Amended
Contact details updated.
HISTORY
Protocol first published: Issue 3, 2001
Review first published: Issue 2, 2004
Date
Event
Description
12 March 2012
Amended
Information about the updating of this review has been added to the Published notes section.
10 August 2009
Amended
29 January 2009
Amended
26 August 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
Klaus Linde conceived the review, collected the literature, extracted data, performed analyses, and wrote the manuscript.
Karin Rossnagel contributed to the protocol, extracted data, and contributed to the manuscript.

118
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
No sources of support supplied
External sources
Karl and Veronica Carstens Foundation, Germany.
International Headache Society (for administrative costs associated with editorial review and peer review), Not specified.
NOTES
The original authors of this review are unable to update it. The Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS)
is seeking new authors for the update. If you are interested, please contact the Managing Editor of PaPaS (contact details provided
under Contact Person).
INDEX TERMS
Medical Subject Headings (MeSH)
Adrenergic beta-Antagonists [ therapeutic use]; Calcium Channel Blockers [therapeutic use]; Migraine Disorders [ prevention &
control]; Propranolol [ therapeutic use]; Randomized Controlled Trials as Topic; Treatment Refusal
MeSH check words

Adult; Humans

119

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Propranolol for migraine prophylaxis (Review)

Propranolol for migraine prophylaxis (Review)

Propranolol for migraine prophylaxis (Review)

Propranolol for migraine prophylaxis

of Social Medicine & Epidemiology, Charit University Hospital, Berlin, Germany

PLAIN LANGUAGE SUMMARY

1. more effective than placebo;

Criteria for considering studies for this review

Study participants were required to be adult migraine sufferers.

Propranolol for migraine prophylaxis (Review)

were included only if results for the subgroup of migraine sufferers

trials with children or on non-migraine headaches). Full copies of

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Propranolol for migraine prophylaxis (Review)

The Delphi list has nine questions, which concern randomisation;

Summarising the results

of the relative risk of response to treatment (here referred to as the

Propranolol for migraine prophylaxis (Review)

to groups (Steardo 1982); two trials were on the treatment of

Risk of bias in included studies

Propranolol for migraine prophylaxis (Review)

Comparisons with placebo

Comparisons with calcium antagonists

Propranolol for migraine prophylaxis (Review)

with a combination of propranolol and flunarizine reported the

Comparisons with other beta-blockers

and one not interpretable. Compared to d-propranolol there was

Comparisons with other drugs

Propranolol for migraine prophylaxis (Review)

Implications for research

Propranolol for migraine prophylaxis (Review)

References to studies included in this review

Diamond 1982 {published data only}

Diener HC, Scholz E, Dichgans J, Gerber WD, Jck

Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath

Borgesen 1974 {published data only}

Borgesen SE, Nielsen JL, Moller CE. Prophylactic

Gawel 1992 {published data only}

Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS.

Dahlf 1987 {published data only}

Gerber 1995 {published data only}

Gerber WD, Schellenberg R, Thom M, Haufe C, Blsche

Diamond 1976 {published data only}

Propranolol for migraine prophylaxis (Review)

cyclandelate and propranolol in migraine after stopping a

Klapper 1994 {published data only}

Grotemeyer 1987 {published data only}

Kuritzky 1987 {published data only}

Hedman 1986 {published data only}

Kangasniemi P, Hedman C. Metoprolol and propranolol

Lcking 1988a {published data only}

Lcking CH, Oestreich W, Schmidt R, Soyka D.

Lcking CH, Oestreich W, Schmidt R, Soyka D.

Propranolol for migraine prophylaxis (Review)

105-9 [Study 2 included patients with migraine + interval

Pradalier A, Serratrice G, Collard M, Hirsch E, Feve

Sargent 1985 {published data only}

Stensrud P, Sjaastad O. Comparative trial of Tenormin

Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen

Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz

Propranolol for migraine prophylaxis (Review)

comparison of propranolol and amitriptyline. Archives of