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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 Library2012, Issue 11
http://www.thecochranelibrary.com
Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Propranolol versus placebo, Outcome 1 Responders (parallel-group and 1st period crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Responders (parallel-group and pooled crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Analysis 1.3. Comparison 1 Propranolol versus placebo, Outcome 3 Attack frequency measures (parallel-group and 1st
period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 1.4. Comparison 1 Propranolol versus placebo, Outcome 4 Attack frequency measures (parallel-group and pooled
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Analysis 1.5. Comparison 1 Propranolol versus placebo, Outcome 5 Number of patients with adverse events (parallel-
group; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Analysis 1.6. Comparison 1 Propranolol versus placebo, Outcome 6 Number of patients with adverse events (parallel-group
and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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). . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Analysis 1.8. Comparison 1 Propranolol versus placebo, Outcome 8 Number of dropouts due to adverse events (parallel-
group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Analysis 2.1. Comparison 2 Propranolol versus calcium antagonists, Outcome 1 Responders (all trials parallel-group). 80
Analysis 2.2. Comparison 2 Propranolol versus calcium antagonists, Outcome 2 Attack frequency measures (all trials
parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Analysis 2.3. Comparison 2 Propranolol versus calcium antagonists, Outcome 3 Number of patients with adverse events
(all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis 2.4. Comparison 2 Propranolol versus calcium antagonists, Outcome 4 Number of patients with adverse events
(vs. flunarizine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . 85
Analysis 2.5. Comparison 2 Propranolol versus calcium antagonists, Outcome 5 Number of dropouts due to adverse events
(all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Analysis 2.6. Comparison 2 Propranolol versus calcium antagonists, Outcome 6 Number of dropouts due to adverse events
(vs. flunarizine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . 88
Analysis 2.7. Comparison 2 Propranolol versus calcium antagonists, Outcome 7 Number of dropouts due to adverse events
(vs. nifedipine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . 89
Analysis 3.1. Comparison 3 Propranolol versus other beta-blockers, Outcome 1 Responders (parallel-group; no 1st period
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Analysis 3.2. Comparison 3 Propranolol versus other beta-blockers, Outcome 2 Responders (parallel-group and pooled
crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Analysis 3.3. Comparison 3 Propranolol versus other beta-blockers, Outcome 3 Responders (vs. nadolol; parallel-group and
pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Analysis 3.4. Comparison 3 Propranolol versus other beta-blockers, Outcome 4 Responders (vs. metoprolol; parallel-group
and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
iPropranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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). . . . . . . . . . . . . . . . . . 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). . . . . . . . . . . . . . . . . . . . . . . . 95
Analysis 3.7. Comparison 3 Propranolol versus other beta-blockers, Outcome 7 Number of patients with adverse events
(parallel-group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . 95
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). . . . . . . . . . . . . . . . . . . . . . . . 97
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). . . . . . . . . . . . . . . . . . . . . . . . . 98
Analysis 4.1. Comparison 4 Propranolol versus other drugs, Outcome 1 Responders (parallel-group and 1st period crossover
data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Analysis 4.2. Comparison 4 Propranolol versus other drugs, Outcome 2 Responders (parallel-group and pooled crossover
data [one 1st period]). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Analysis 4.3. Comparison 4 Propranolol versus other drugs, Outcome 3 Attack frequency measures (parallel-group and 1st
period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis 4.4. Comparison 4 Propranolol versus other drugs, Outcome 4 Attack frequency measures (parallel-group and
pooled crossover data [two 1st period]). . . . . . . . . . . . . . . . . . . . . . . . . . 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). . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse events (parallel-
group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to adverse events (parallel-
group; no 1st period crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to adverse events (parallel-
group and pooled crossover data). . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
109ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iiPropranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Propranolol for migraine prophylaxis
Klaus Linde1, Karin Rossnagel2
1Centre for Complementary Medicine Research, Department of Internal Medicine II, Technical University Munich, Munich, Germany.2Institute of Social Medicine & Epidemiology, Charité 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. [email protected].
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.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
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.
1Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
P L A I N L A N G U A G E S U M M A R Y
Propranolol for migraine prophylaxis
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.
B A C K G R O U N D
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. Popula-
tion-based studies from the US and elsewhere suggest that six to
seven per cent of men and 15% to 18% of women experience mi-
graine headaches (Lipton 2001; Stewart 1994). Preventive drugs
are used by a small proportion of migraineurs. Available guide-
lines 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 at-
tacks, 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 test-
ing newer agents for migraine prophylaxis (Gray 1999; Holroyd
1991). While propranolol is well-tolerated in general, it is associ-
ated with a variety of adverse effects (such as bradycardia, hypoten-
sion, bronchospasm, gastrointestinal complaints, vertigo, hypo-
glycaemia, etc).
O B J E C T I V E S
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:
1. more effective than placebo;
2. as effective as other pharmacological agents.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised and quasi-randomised (using methods such as alter-
nation) 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 ran-
domised.
Types of participants
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). Tri-
als 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
2Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
were included only if results for the subgroup of migraine sufferers
were presented separately.
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 compar-
ing 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 re-
porting 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 iden-
tified and excluded all citations that were clearly ineligible (e.g.,
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.
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 addi-
tional point is given), double-blinding (statement that the study
was double-blind = 1 point; additional point if a credible descrip-
tion of how blinding was achieved was given), and dropouts and
withdrawals (a point was given if the number and reasons for drop-
outs and withdrawals were presented for each group separately).
3Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The Delphi list has nine questions, which concern randomisation;
concealment of randomisation; baseline comparability; specifica-
tion 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 ques-
tion 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 meth-
ods, 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 respon-
ders, number of patients with adverse events, and number of drop-
outs due to adverse events for individual trials. As the measure
for headache frequency we used, if available, the number of mi-
graine 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 fre-
quency 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 in-
cluded studies’ table, we indicate which measures were actually
used for each trial. As denominators we used the number of pa-
tients included in the analysis for responder ratios and the rela-
tive 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 exam-
ple, 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 inter-
vals. We tried to calculate effect sizes for single trials as often as
possible despite these uncertainties. Therefore, the effect size esti-
mates 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 quan-
titative 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 pro-
vided 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-block-
ers. We calculated both fixed-effect and random-effects estimates,
but only fixed-effect estimates (which give more weight to larger
4Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
trials) are presented in the ’Results’ section. Due to the hetero-
geneity 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 avail-
able, results were summarized for the following outcomes: re-
sponse, headache frequency, analgesic use, headache indices, ad-
verse 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 fol-
lowing scale: + = propranolol significantly better than control (pri-
mary or most clinically relevant outcome measures statistically sig-
nificantly better with propranolol than with control); (+) = pro-
pranolol 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. Dis-
agreements were resolved by discussion and consensus was reached
on each study.
R E S U L T S
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 cri-
teria (see table on the ’Characteristics of included studies’). One
publication presented separate data on patients suffering from mi-
graine 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 arti-
cles (Amery 1988; Anonymous 1979; Montastruc 1992; Raveau-
Landon 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 observa-
tion 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 ’Character-
istics 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 propra-
nolol alone versus propranolol in combination with another drug,
one a comparison with another propranolol dose, and one a com-
parison with d-propranolol. There were 15 comparisons with cal-
cium antagonists (10 flunarizine, three nifedipine, one nimodip-
ine, 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-hydroxytryp-
tophan, 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 propor-
tion 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 Society’s criteria (IHS 1988) for con-
firming the diagnosis, 20 the Ad Hoc Committee’s 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 (me-
dian 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
5Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of dropouts and withdrawals. Twenty-five studies reported num-
bers 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 de-
scribed 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 trans-
parent 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 me-
dian 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 sta-
tistically significant. The overall relative risk of response to treat-
ment (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 (I² = 50.1%) in the
set of four trials, but not in the set of nine trials (I² = 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 stan-
dardized 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 pro-
pranolol 160 mg may be slightly more effective than 120 mg, but
the results from the four trials using 160 mg were highly hetero-
geneous (I² = 60.8%).
Data on headache intensity were reported inconsistently, but ef-
fects 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, re-
ported 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 re-
porting 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 [Com-
parison No. 01 06]).
For three, respectively 13, trials the number of patients dropping
out due to adverse events was reported. Patients receiving pro-
pranolol 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 sta-
tistically 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 pro-
pranolol 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 (flu-
narizine in seven cases), and the trial comparing propranolol alone
6Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
with a combination of propranolol and flunarizine reported the
number of patients experiencing adverse events. These were simi-
lar 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 (Com-
parison No. 02 05). The overall relative risk for trials compar-
ing 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 (I² = 53.5% for the four-
and 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 anal-
yses for comparisons with nadolol (Comparison No. 03 03) and
metoprolol (Comparison No. 03 04). In the three trials compar-
ing 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 (I² = 68.8%). The three trials compar-
ing propranolol and metoprolol had more consistent results (I²
= 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 propra-
nolol and amitriptyline. We did not perform quantitative meta-
analyses 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 (Com-
parisons No. 04 01 and No. 04 02). None found a significant
difference. Both trials comparing propranolol 160 mg and femox-
etine 400 mg reported a possibly relevant trend in favour of pro-
pranolol (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 compar-
ing it with tolfenamic acid 300 mg (Kjaersgard 1994) and to 5-
hydroxytryptophan 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 re-
porting 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 drop-
ping 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.
D I S C U S S I O N
7Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Despite the methodological limitations of the majority of the avail-
able trials, there is clear and consistent evidence that propranolol
is superior to placebo in the interval treatment of patients suffer-
ing from migraine. Based on the available trials, it is not possible
to draw reliable conclusions on whether different doses of pro-
pranolol 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 reli-
able meta-analysis of the available studies.
The major problem encountered in this review was the highly vari-
able and often insufficient reporting of the complex outcome data.
Migraine prophylaxis trials typically use headache diaries to mon-
itor the course of the disease. From these headache diaries a variety
of outcomes can be extracted (headache days, migraine days, mi-
graine attacks, days with a defined headache intensity, attack inten-
sity, 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 er-
rors, confidence intervals, or often no measure of variance; me-
dians 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 ma-
jority of the trials were performed at a time when intention-to-
treat analyses were not mandatory. Therefore, dropouts and with-
drawals 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 cau-
tion. 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 un-
certainty 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 per-
spective is the lack of adequate follow up after stopping treatment.
The few studies that had such a follow up reported very high with-
drawal 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).
A U T H O R S ’ C O N C L U S I O N S
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. How-
ever, 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 Interna-
tional Headache Society’s 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 appli-
cable to migraine treatment in primary care. Major topics for fu-
ture 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.
A C K N O W L E D G E M E N T S
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.
8Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
R E F E R E N C E S
References to studies included in this review
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Headache 1989;29(4):215–8.
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G, D’Alessandro R, Baruzzi A, et al.Propranolol and
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one month of treatment with propranolol in migraineurs.
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H, et al.Cyclandelate in the prophylaxis of migraine: a
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propranolol in the prophylactic treatment of migraine.
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Forssman 1976 {published data only}
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Lundin H. Propranolol for migraine prophylaxis. Headache
1976;16(5):238–45.
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comparable to propranolol in the prophylaxis of migraine
with and without aura. Cephalalgia 1991;11 Suppl 11:156.∗ Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS.
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propranolol in the prophylaxis of migraine. CanadianJournal of Neurological Sciences 1992;19(3):340–5.
Gerber 1995 {published data only}∗ Gerber WD, Schellenberg R, Thom M, Haufe C, Bölsche
F, Wedekind W, et al.Cyclandelate versus propranolol in the
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cyclandelate and propranolol in migraine after stopping a
four-month drug prophylaxis [Zur Langzeitwirkung von
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Deutsche Medizinische Wochenschrift 1987;112(45):1740–3.
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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):475–8.
Holdorff 1977 {published data only}
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Johnson 1986 {published data only}
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prophylaxis. Acta Neurologica Scandinavica 1986;73(5):
490–2.
Kangasniemi 1983 {published data only}
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- a new 5-HT uptake inhibitor - and propranolol in the
prophylactic treatment of migraine. Acta NeurologicaScandinavica 1983;68(4):262–7.
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Kjaersgard 1994 {published data only}
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Klapper 1994 {published data only}
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Kuritzky A, Hering R. Prophylactic treatment of migraine
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Lücking 1988a {published data only}∗ Lücking CH, Oestreich W, Schmidt R, Soyka D.
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Soyka D, Oestreich W. Flunarizine versus propranolol
in migraine prophylaxis - A multicenter double-blind
study in 12 hospitals [Flunarizin versus Propranolol in der
Intervallprophylaxe der Migräne – eine multizentrische
Doppelblindstudie in 12 Kliniken]. Nervenheilkunde 1987;
6:177–83.
Lücking 1988b {published data only}∗ Lücking CH, Oestreich W, Schmidt R, Soyka D.
Flunarizine vs. propranolol in the prophylaxis of migraine:
two double-blind comparative studies in more than 400
patients. Cephalalgia 1988;8 Suppl 8:22–6.
Soyka D, Oestreich W. Flunarizine versus propranolol
in the interval treatment of migraine [Flunarizin versus
Propranolol in der Intervallbehandlung der Migräne –
multizentrische Doppelblindsudie bei niedergelassenen
Allgemeinärzten und Internisten]. Nervenheilkunde 1990;9:
45–51.
Soyka D, Oestreich W. Therapeutic effectiveness of
flunarizine and propranolol in the interval therapy of
migraine. Cephalalgia 1987;7 Suppl 6:467–8.
Ludin 1989 {published data only}
Ludin HP. Flunarizine and propranolol in the treatment of
migraine. Headache 1989;29(4):219–24.
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
5–Hydroxytrypthophan und von Propranolol in der
Intervalltherapie der Migräne]. Schweizerische Medizinische
Wochenschrift. Journal Suisse de Medecine 1991;121(43):
1585–90.
Malvea 1973 {published data only}
Malvea BP, Gwon N, Graham JR. Propranolol prophylaxis
of migraine. Headache 1973;12(4):163–7.
Mathew 1981-Study 1 {published data only}
Mathew NT. Prophylaxis of migraine and mixed headache.
A randomized controlled study. Headache 1981;21(3):105-
9. [Study 1 included patients with migraine only].
Mathew 1981-Study 2 {published data only}
Mathew NT. Prophylaxis of migraine and mixed headache.
A randomized controlled study. Headache 1981;21(3):
10Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
105-9 [Study 2 included patients with migraine + interval
headaches].
Micieli 2001 {published data only}
Micieli G, Cavallini A, Marcheselli S, Mailland F, Ambrosoli
L, Nappi G. Alpha-dihydroergocryptine and predictive
factors in migraine prophylaxis. Int J Clin Pharmacol Ther2001;39:155–151.
Mikkelsen 1986 {published data only}
Mikkelsen B, Pedersen KK, Christiansen LV. Prophylactic
treatment of migraine with tolfenamic acid, propanolol and
placebo. Acta Neurologica Scandinavica 1986;73(4):423–7.
Nadelmann 1986 {published data only}
Nadelmann JW, Phil M, Stevens J, Saper JR. Propranolol in
the prophylaxis of migraine. Headache 1986;26(4):175–82.
Nicolodi 1997 {published data only}
Nicolodi M, Del Bianco PL, Sicuteri F. The way to
serotonergic use and abuse in migraine. InternationalJournal of Clinical Pharmacology Research 1997;17(2-3):
79–84.
Olerud 1986 {published data only}
Olerud B, Gustavsson CL, Furberg B. Nadolol and
propranolol in migraine management. Headache 1986;26
(10):490–3.
Olsson 1984 {published data only}
Olsson JE, Behring HC, Forssman B, Hedman C, Hedman
G, Johansson F, et al.Metoprolol and propranolol in
migraine prophylaxis: a double-blind multicentre study.
Acta Neurologica Scandinavica 1984;70(3):160–8.
Palferman 1983 {published data only}
Palferman TG, Gibberd FB, Simmonds JP. Prophylactic
propranolol in the treatment of headache. British Journal of
Clinical Practice 1983;37(1):28–9.
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):273–8.
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 [Beta–bloquants
et migraine. Efficacité, contre placebo, du propranolol a
libération prolongée]. Thérapie 1990;45(5):441–5.
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.
Cephalalgia 1989;9 Suppl 10:367–8.∗ 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):247–53.
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):1156–9.
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):
320–4.
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, 1987:139–45.
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):75–7.
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):229–32.
Stensrud 1980 {published data only}∗ Stensrud P, Sjaastad O. Comparative trial of Tenormin
(atenol) and Inderal (propranolol) in migraine. Headache
1980;20(4):204–7.
Stensrud P, Sjaastad O. Comparative trial of Tenormin
(atenolol) and Inderal (propranolol) in migraine. UpsalaJournal of Medical Sciences - Supplement 1980;31:37–40.
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):
421–6.
Tfelt-Hansen 1984 {published data only}
Standnes B. The prophylactic effect of timolol versus
propranolol and placebo in common migraine: beta-
blockers in migraine. Cephalalgia 1982;2(3):165–70.∗ 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. ActaNeurologica Scandinavica 1984;69(1):1–8.
Weber 1972 {published data only}
Weber RB, Reinmuth OM. The treatment of migraine with
propranolol. Neurology 1972;22(4):366–9.
Wideroe 1974 {published data only}
Wideroe TE, Vigander T. Propranolol in the treatment of
migraine. BMJ 1974;2(921):699–701.
Ziegler 1987 {published data only}∗ Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz
HA, Preskorn SH, Manson J. Migraine prophylaxis. A
11Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
comparison of propranolol and amitriptyline. Archives of
Neurology 1987;44(5):486–9.
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):825–30.
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 8:11–3.
Anonymous 1979 {published data only}
Anonymous. Propranolol for prevention of migraine
headaches. Medical Letter on Drugs & Therapeutics 1979;21
(19):77–8.
Banerjee 1991 {published data only}
Banerjee M, Findley L. Propranolol in the treatment of
acute migraine attacks. Cephalalgia 1991;11(4):193–6.
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):
101–5.
Cortelli 1985 {published data only}
Cortelli P, Sacquegna T, Albani F, Baldrati A, D’Alessandro
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):46–8.
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):269–74.
Diamond 1987 {published data only}
Diamond S, Solomon GD, Freitag FG, Mehta ND. Long-
acting propranolol in the prophylaxis of migraine. Headache
1987;27(2):70–2.
Fuller 1990 {published data only}
Fuller GN, Guiloff RJ. Propranolol in acute migraine: a
controlled study. Cephalalgia 1990;10(5):229–33.
Havanka-Kann. 1988 {published data only}
Havanka-Kanniainen H, Hokkanen E, Myllylä VV.
Long acting propranolol in the prophylaxis of migraine.
Comparison of the daily doses of 80 mg and 160 mg.
Headache 1988;28(9):607–11.
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 Psychology1995;63(2):327–30.
Julien 1976 {published data only}
Julien J, Vallat JM, Lagueny A, Darriet M. Preventive
treatment of migraine with propranolol (letter) [Le
traitement prophylactique des migraines par le propranolol].
Nouvelle Presse Médicale 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):381–8.
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):1805–9.
Rosen 1983 {published data only}
Rosen JA. Observations on the efficacy of propranolol for
the prophylaxis of migraine. Annals of Neurology 1983;13
(1):92–3.
Schmidt 1991 {published data only}
Schmidt R, Oestreich W. Flunarizine in migraine
prophylaxis: the clinical experience. Journal of
Cardiovascular Pharmacology 1991;18 Suppl 8:S21–6.
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):89–92.
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. ActaNeurologica 1982;4(3):196–204.
Tfelt-Hansen 1986 {published data only}
Tfelt-Hansen P. Efficancy of beta-blockers in migraine. A
critical review. Cephalalgia 1986;6 Suppl 5:15–24.
Turner 1984 {published data only}
Turner P. Beta-blocking drugs in migraine. Postgraduate
Medical Journal 1984;60 Suppl 2:51–5.
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):328–36.
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):
15–22.
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):336–8.
12Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Wober 1991 {published data only}
Wober C, Wober-Bingel C, Koch G, Wessely P. Long-term
results of migraine prophylaxis with flunarizine and beta-
blockers. Cephalalgia 1991;11(6):251–6.
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 duplo–cego comparando propranolol a um
analgesico (acetaminofen) e placebo]. Folha médica (Rio de
Janeiro) 1978;77(4):501–8.
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):223–6.
Additional references
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):717–8.
Clarke 2003
Clarke M, Oxman AD, editors. Optimal search strategy for
RCTs. Cochrane Reviewers’ Handbook 4.1.6 [updated January2003]; Appendix 5c. In: The Cochrane Library, Issue 1, 2003.
Oxford: Update Software.
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):333–40.
IHS 1988
Headache Classification Committee of the International
Headache Society. Classification and diagnostic criteria
for headache disorders, cranial neuralgias and facial pain.
Cephalalgia 1988;8 Suppl 7:1–96.
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):1–12.
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):646–57.
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):1273–87.
Ramadan 1997
Ramadan NM, Schultz LL, Gilkey SJ. Migraine prophylactic
drugs: proof of efficacy, utilization and cost. Cephalalgia
1997;17(2):73–80.
Stewart 1994
Stewart WF, Shechter A, Rasmussen BK. Migraine
prevalence. A review of population-based studies. Neurology
1994;44(6 Suppl 4):S17–S23.
Tfelt-Hansen 2000
Tfelt-Hansen P, Block G, Dahlöf C, Diener HC, Ferrari
MD, Goadsby PJ, et al.Guidelines for controlled trials of
drugs for migraine: second edition. Cephalalgia 2000;20
(9):765–86.
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):1235–41.∗ Indicates the major publication for the study
13Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
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
14Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Dropouts-AEs: not reported
V: 0
Notes High dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
15Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 Support for judgement
Allocation concealment (selection bias) 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)
16Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Andersson 1981 (Continued)
Dropouts-AEs: 2/49 vs. 2/49
V: (+)
Notes Baseline data for 28 patients only
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
Dropouts-AEs: 2/18 vs. 3/18
V: 0
Notes Small trial with relatively high dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
17Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Behan 1980
Methods D: crossover
C: unclear
B: double
WD: 20/56
J: 0-1-0
DU: -/2x3m (1m)/-
Participants N: 56/36
D: 12 migraine with, 44 without aura
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
Dropouts-AEs: 0/56 vs. 3/56
V: (+)
Notes High dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: all migraine without aura
C: IHS
F: 68%
A: 20-45 years
DU: unclear
18Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 Support for judgement
Allocation concealment (selection bias) 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
D: all migraine without aura
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)
19Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bordini 1997 (Continued)
V: 0 vs. C1, (-) vs. C2
Notes Small groups, low propranolol dose
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 15 migraine with, 15 without aura
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
Dropouts-AEs: 0/45 vs. 2/45
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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
20Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dahlöf 1987
Methods D: crossover
C: unclear
B: double
WD: none
J: 1-1-1
DU: 4w/2x1m/2x5m (5m washout)
Participants N: 28/28
D: 20 migraine with, 8 without aura
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
Dropouts-AEs: not reported
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 Support for judgement
Allocation concealment (selection bias) 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
21Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Dropouts-AEs: 6/83 vs. 1/83
V: +
Notes High dropout rate, unclear presentation
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
Dropouts-AEs: not reported
V: not interpretable
22Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Diamond 1982 (Continued)
Notes Trial meets the inclusion criteria, but primarily investigates long-term treatment with pro-
pranolol and includes only a 4-week RCT, whose results, however, are not presented in
detail
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 4 migraine with, 54 without aura
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
Dropouts-AEs: not reported
V: (-) vs. C1, (+) vs. C2
Notes Rigorous study
Dropout rates not fully clear
Risk of bias
Bias Authors’ judgement Support for judgement
23Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Diener 1989 (Continued)
Allocation concealment (selection bias) 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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
24Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
C1: Flunarizine 10 mg
C2: Flunarizine 5 mg
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
Dropouts-AEs: 18/270 vs. 19/275 vs. 21/263
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 Support for judgement
Allocation concealment (selection bias) 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
25Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Dropouts-AEs: 2/10 vs. 1/12
V: 0
Notes Small study focusing on endocrinological effects
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
Dropouts-AEs: 2/40 vs. 2/40
26Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Forssman 1976 (Continued)
V: +
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
C: World Federation of Neurology Research Group
F: 90%
A: mean 36 years
DU: mean 17 years
S: 4 Canadian centers
Interventions P: 160 mg
C: Flunarizine 10 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
Dropouts-AEs: 5/45 vs. 3/44
V: (-)
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
27Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
AU: similar in both groups
AEs: 6/42 vs. 4/42
Dropouts-AEs: not reported
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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Grotemeyer 1987
Methods D: crossover
C: unclear
B: double
WD: 6/30
J: 0-1-0
DU: -/2x12w (no washout)/-
Participants N: 30/24
D: migraine without aura
C: Ad Hoc and other
F: 73%
A: 36 (sd 11) years
28Propranolol for migraine prophylaxis (Review)
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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
Dropouts-AEs: not reported
V: (+)
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
C: World Federation of Neurology Research Group
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
Dropouts-AEs: not reported
V: uninterpretable
29Propranolol for migraine prophylaxis (Review)
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Hedman 1986 (Continued)
Notes Small study focusing on laboratory parameters
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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 R: 8/13 vs. 7/14 (at least 50% index reduction)
F: not reported
AU: not reported
HI: no difference
AEs: not reported
Dropouts-AEs: not reported
V: 0
Notes Very high dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
30Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
D: 10 migraine with, 19 without aura
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
Dropouts-AEs: 1/29 vs. 1/29 vs. 1/29
V: + vs. C1; 0 vs. C2
Notes High dropout rate; otherwise rigorous crossover trial
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 4 migraine with, 25 without aura
C: unclear
F: 86%
31Propranolol for migraine prophylaxis (Review)
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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
Dropouts-AEs: 3/29 vs. 0/29
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 Support for judgement
Allocation concealment (selection bias) 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
D: 6 migraine with, 30 without aura
C: World Federation of Neurology Research Group
F: 89%
A: 18-51 years
DU: mean 16 years
S: unclear
Interventions P: 160 mg
C: Metoprolol 200 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
32Propranolol for migraine prophylaxis (Review)
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Kangasniemi 1984 (Continued)
AEs: similar in both groups
Dropouts-AEs: 2/36 vs. 0/36
V: 0
Notes Well-reported crossover study with low dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: all migraine without aura
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
Dropouts-AEs: 1/37 vs. 4/37
V: 0
Notes Pragmatic crossover study with some reporting shortcomings
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
33Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kass 1980
Methods D: crossover
C: unclear
B: double
WD: 2/23
J: 1-1-0
DU: 4w/2x16w (no washout)/-
Participants N: 23/21
D: 6 migraine with, 17 without aura
C: World Federation of Neurology Research Group
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
Dropouts-AEs: 0/23 vs. 0/23
V: (+)
Notes Small crossover trial with interesting outcome measures and data presentation
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 14 migraine with, 62 without aura
C: IHS
F: 79%
A: 19-65 years
34Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Dropouts-AEs: 9/76 vs. 5/76
V: 0
Notes High dropout rate
Unclear statistics
No significant carryover effect detected
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
35Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Klapper 1994 (Continued)
HI: not reported
AEs: not reported
Dropouts-AEs: 3/24 vs. 9/24
V: uninterpretable
Notes Extremely high dropout rate, insufficient reporting
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 7 migraine with, 24 without aura
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
Dropouts-AEs: not reported
V: +
Notes Available only as an abstract
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
36Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
D: 15 migraine with, 44 without aura
C: unclear
F: 71%
A: mean 34 years
DU: not reported
S: 15 neurological practices in Switzerland
Interventions P: 120 mg
C: Flunarizine 10 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
Dropouts-AEs: 3/32 vs. 2/27
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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Lücking 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%
37Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lücking 1988a (Continued)
A: mean 42 years
DU: not reported
S: 12 hospital outpatient departments (probably in Germany)
Interventions P: 120 mg
C: Flunarizine 10 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
Dropouts-AEs: not reported
V: 0
Notes Relevant dropout; no intent-to-treat analysis
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Lücking 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
C: Flunarizine 10 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
38Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lücking 1988b (Continued)
Dropouts-AEs: not reported
V: 0
Notes Large study with high dropout rate; no intent-to-treat analysis
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 8 migraine with, 31 without aura
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
Dropouts-AEs: 2/20 vs. 0/19
V: 0
Notes Relevant baseline differences, high attack frequency
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
39Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
D: all migraine without aura
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
AU: similar in both groups
HI: 18.6 vs. 23.3
AEs: listed only for propranolol
Dropouts-AEs: not reported
V: +
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
40Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 Support for judgement
Allocation concealment (selection bias) 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
41Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mathew 1981-Study 2 (Continued)
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 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 Support for judgement
Allocation concealment (selection bias) 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
42Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Mikkelsen 1986
Methods D: crossover
C: unclear
B: double
WD: 8/39
J: 1-2-1
DU: -/3x12w (no washout)/-
Participants N: 39/31
D: 10 migraine with, 21 without aura
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
Dropouts-AEs: 2/39 vs. 0/39 vs. 2/39
V: + vs. C1, (-) vs. C2
43Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mikkelsen 1986 (Continued)
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
44Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Dropouts-AEs: not reported
V: 0
Notes Large trial, reported briefly with other studies in one publication
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 2 migraine with, 26 without aura
C: Ad Hoc
F: 79%
A: 17-61 years
DU: 2-45 years
45Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
Dropouts-AEs: 0/15 vs. 1/13
V: 0
Notes Small, rigorous trial with relevant baseline imbalances
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 22 migraine with, 34 without aura
C: World Federation of Neurology Research Group
F: 73%
A: 19-59 years
DU: 5-43 years
S: 6 neurology clinics in Sweden
Interventions P: 80 mg
C: Metoprolol 100 mg
Outcomes R: 16/53 vs. 21/56 (at least 50% index reduction)
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
AEs: similar in both groups
Dropouts-AEs: 0/56 vs. 0/56
V: 0
46Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Olsson 1984 (Continued)
Notes Well-reported crossover study
Strong deterioration during washout phase between the two treatment phases
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
Dropouts-AEs: not reported
V: (+)
Notes Small study with high dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
47Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Pita 1977
Methods D: crossover
C: unclear
B: double
WD: 1/9
J: 1-1-1
DU: -/2x2m (no washout)/-
Participants N: 9/8
D: 4 migraine with, 5 without aura
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
Dropouts-AEs: 1/9 vs. 0/9
V: +
Notes Extremely small trial with very positive results
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
48Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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
AEs: similar in both groups
Dropouts-AEs: 0/40 vs. 1/34
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 Support for judgement
Allocation concealment (selection bias) 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
49Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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 Support for judgement
Allocation concealment (selection bias) 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
Dropouts-AEs: not reported
V: (+) vs. C1, 0 vs. C2
Notes Insufficient reporting
Results seem partly contradictory
Small effects
Risk of bias
50Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sargent 1985 (Continued)
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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)
D: 9 migraine with, 74 without aura
C: unclear
F: 77%
A: mean 40 years
DU: mean 19 years
S: unclear, Germany
Interventions P: 160 mg
C1: Metoprolol 200 mg
C2: Flunarizine 10 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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
51Propranolol for migraine prophylaxis (Review)
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Shimell 1990
Methods D: parallel
C: unclear
B: double
WD: 10 /58
J: 1-2-1
DU: -/4m/-
Participants N: 58/57
D: 27 migraine with, 30 without aura
D: IHS
F: 70%
A: 16-61 years
DU: mean 27 years
S: neurology outpatient clinic in Johannesburg, South Africa
Interventions P: 180 mg
C: Flunarizine 10 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
AEs: similar in both groups
Dropouts-AEs: 3/29 vs. 2/29
V: 0
Notes No headache diary
Possibly intent-to-treat analysis
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
52Propranolol for migraine prophylaxis (Review)
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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
Dropouts-AEs: not reported
V: + vs. C1, 0 vs. C2
Notes Small crossover study, available only as an abstract
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 3 migraine with, 17 without aura
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
53Propranolol for migraine prophylaxis (Review)
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Stensrud 1976 (Continued)
AEs: not reported
Dropouts-AEs: 1/20 vs. 0/20 vs. 0/20
V: + vs. C1, (+) vs. C2
Notes No headache diary
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
D: 6 migraine with, 29 without aura
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
Dropouts-AEs: 1/35 vs. 0/35 vs. 0/35
V: (+) vs. C1, 0 vs. C2
Notes Results reported insufficiently
Risk of bias
Bias Authors’ judgement Support for judgement
54Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Stensrud 1980 (Continued)
Allocation concealment (selection bias) 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
Dropouts-AEs: 4/44 vs. 2/49 vs. 2/47
V: 0 vs. C1, - vs. C2
Notes High dropout rate
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
55Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tfelt-Hansen 1984
Methods D: crossover
C: unclear
B: double
WD: 16/96
J: 1-2-0
DU: 4w/3x12w (no washout)/-
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
Dropouts-AEs: 6/89 vs. 2/90 vs. 9/89
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 Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Weber 1972
Methods D: crossover
C: unclear
B: double
WD: 6/25
J: 1-1-0
DU: -/2x3m (no washout)/-
Participants N: 25/19
D: 6 migraine with, 13 without aura
C: Ad Hoc
F: 52%
A: 19-61 years
56Propranolol for migraine prophylaxis (Review)
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Weber 1972 (Continued)
DU: not reported
S: unclear, USA
Interventions P: 80 mg
C: Placebo
Outcomes R: 1st period: 5/8 vs. 0/11; pooled: 15/19 vs. 2/19
F: not reported
AU: not reported
HI: not reported
AEs: unclear
Dropouts-AEs: 0/25 vs. 0/25
V: +
Notes Small crossover trial with extremely positive results
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) Unclear risk B - Unclear
Wideroe 1974
Methods D: crossover
C: unclear
B: double
WD: 4/30
J: 1-1-0
DU: -/2x3m (no washout)/-
Participants N: 30/26
D: 6 migraine with, 24 without aura
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 R: 1st period: 12/12 vs. 5/14; pooled: 25/26 vs. 10/26
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
Dropouts-AEs: not reported
57Propranolol for migraine prophylaxis (Review)
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Wideroe 1974 (Continued)
V: +
Notes Included only patients who had responded to propranolol before
Risk of bias
Bias Authors’ judgement Support for judgement
Allocation concealment (selection bias) 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
C2: Amitriptyline 50-150 mg
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
Dropouts-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 Support for judgement
58Propranolol for migraine prophylaxis (Review)
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Ziegler 1987 (Continued)
Allocation concealment (selection bias) 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 No original data - review
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 Not randomised or quasi-randomised clinical study
Diamond 1987 Not randomised or quasi-randomised clinical study
Fuller 1990 Study on treatment of acute migraine attacks
Havanka-Kann. 1988 Did not include a comparison with placebo or another drug
Holroyd 1995 Did not include a comparison with placebo or another drug
59Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Julien 1976 Not randomised or quasi-randomised clinical study
Montastruc 1992 No original data - review
Penzien 1990 Did not include a comparison with placebo or another drug
Raveau-Landon 1988 No original data - review
Rosen 1983 Not randomised or quasi-randomised clinical study
Schmidt 1991 Not randomised or quasi-randomised clinical study
Sovak 1981 Did not include a comparison with placebo or another drug
Steardo 1982 Open trial with unclear method of allocation
Tfelt-Hansen 1986 No original data - review
Turner 1984 No original data - review
Verspeelt 1996a Not randomised or quasi-randomised clinical study
Verspeelt 1996b Not randomised or quasi-randomised clinical study
Winther 1990 Observation period less than 4 weeks
Wober 1991 Not randomised or quasi-randomised clinical study
60Propranolol for migraine prophylaxis (Review)
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D A T A A N D A N A L Y S E S
Comparison 1. Propranolol versus placebo
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Responders (parallel-group and
1st period crossover data)
4 205 Risk Ratio (M-H, Fixed, 95% CI) 1.72 [1.23, 2.40]
1.1 Propranolol 160 mg 1 26 Risk Ratio (M-H, Fixed, 95% CI) 2.62 [1.34, 5.14]
1.2 Propranolol 120 mg 1 133 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.85, 2.20]
1.3 Propranolol 80-120 mg 1 27 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.63, 2.42]
1.4 Propranolol 80 mg 1 19 Risk Ratio (M-H, Fixed, 95% CI) 14.67 [0.93, 232.44]
2 Responders (parallel-group and
pooled crossover data)
9 668 Risk Ratio (M-H, Fixed, 95% CI) 1.94 [1.61, 2.35]
2.1 Propranolol 160 mg 3 228 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [1.59, 2.87]
2.2 Propranolol 80-160 mg 1 124 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [1.26, 3.18]
2.3 Propranolol 120 mg 2 193 Risk Ratio (M-H, Fixed, 95% CI) 1.43 [0.97, 2.10]
2.4 Propranolol 80-120 mg 1 27 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.63, 2.42]
2.5 Propranolol 80 mg 1 38 Risk Ratio (M-H, Fixed, 95% CI) 7.5 [1.98, 28.40]
2.6 Propranolol, dose unclear 1 58 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [1.02, 3.93]
3 Attack frequency measures
(parallel-group and 1st period
crossover data)
4 172 Std. Mean Difference (IV, Fixed, 95% CI) -0.45 [-0.75, -0.14]
3.1 Propranolol 160 mg 2 67 Std. Mean Difference (IV, Fixed, 95% CI) -0.77 [-1.27, -0.27]
3.2 Propranolol 120 mg 2 105 Std. Mean Difference (IV, Fixed, 95% CI) -0.26 [-0.64, 0.13]
4 Attack frequency measures
(parallel-group and pooled
crossover data)
10 634 Std. Mean Difference (IV, Fixed, 95% CI) -0.40 [-0.56, -0.24]
4.1 Propranolol 240 mg 1 34 Std. Mean Difference (IV, Fixed, 95% CI) -0.40 [-1.08, 0.28]
4.2 Propranolol 160 mg 4 291 Std. Mean Difference (IV, Fixed, 95% CI) -0.49 [-0.72, -0.25]
4.3 Propranolol 120 mg 5 309 Std. Mean Difference (IV, Fixed, 95% CI) -0.32 [-0.55, -0.10]
5 Number of patients with adverse
events (parallel-group; no 1st
period crossover data)
2 220 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.97, 1.82]
5.1 Propranolol 120 mg 2 220 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.97, 1.82]
6 Number of patients with adverse
events (parallel-group and
pooled crossover data)
6 619 Risk Ratio (M-H, Fixed, 95% CI) 1.43 [1.12, 1.81]
6.1 Propranolol 240 mg 1 47 Risk Ratio (M-H, Fixed, 95% CI) 2.09 [0.20, 21.48]
6.2 Propranolol 160 mg 1 166 Risk Ratio (M-H, Fixed, 95% CI) 1.52 [0.99, 2.34]
6.3 Propranolol 80-160 mg 1 124 Risk Ratio (M-H, Fixed, 95% CI) 1.6 [0.79, 3.25]
6.4 Propranolol 120 mg 3 282 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [0.95, 1.77]
7 Number of dropouts due to
adverse events (parallel-group
and 1st period crossover data)
3 264 Risk Ratio (M-H, Fixed, 95% CI) 1.90 [0.36, 10.14]
7.1 Propranolol 80-320 mg 1 57 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.2 Propranolol 160 mg 1 74 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.01, 6.77]
7.3 Propranolol 120 mg 1 133 Risk Ratio (M-H, Fixed, 95% CI) 6.38 [0.35, 116.13]
61Propranolol for migraine prophylaxis (Review)
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8 Number of dropouts due to
adverse events (parallel-group
and pooled crossover data)
13 1150 Risk Ratio (M-H, Fixed, 95% CI) 2.11 [1.09, 4.08]
8.1 Propranolol 80-320 mg 1 114 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.2 Propranolol 240 mg 2 138 Risk Ratio (M-H, Fixed, 95% CI) 1.0 [0.21, 4.78]
8.3 Propranolol 160 mg 5 381 Risk Ratio (M-H, Fixed, 95% CI) 2.15 [0.77, 6.01]
8.4 Propranolol 80-160 mg 1 166 Risk Ratio (M-H, Fixed, 95% CI) 6.0 [0.74, 48.75]
8.5 Propranolol 120 mg 3 301 Risk Ratio (M-H, Fixed, 95% CI) 1.88 [0.51, 6.91]
8.6 Propranolol 80 mg 1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
Comparison 2. Propranolol versus calcium antagonists
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Responders (all trials
parallel-group)
10 1794 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.93, 1.09]
1.1 Propranolol 180 mg vs.
flunarizine 10 mg
1 57 Risk Ratio (M-H, Fixed, 95% CI) 1.30 [1.01, 1.68]
1.2 Propranolol 160 mg vs.
flunarizine 10 mg
2 598 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.76, 1.03]
1.3 Propranolol 160 mg vs.
flunarizine 5 mg
1 517 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.89, 1.28]
1.4 Propranolol 120 mg vs.
flunarizine 10 mg
3 464 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.87, 1.15]
1.5 Propranolol 80 mg vs.
flunarizine 10 mg
1 42 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.73, 1.38]
1.6 Propranolol 60 mg vs.
flunarizine 10 mg
1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.89, 1.28]
1.7 Propranolol 120-180 mg
vs. nifedipine 60-90 mg
1 20 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.77, 1.51]
1.8 Propranolol 80-160 mg
vs. nifedipine 20-40 mg
1 36 Risk Ratio (M-H, Fixed, 95% CI) 5.37 [0.72, 40.20]
1.9 Propranolol 60 mg
vs. propranolol 60 mg +
flunarizine 10 mg
1 30 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.89, 1.28]
2 Attack frequency measures (all
trials parallel-group)
6 1543 Std. Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.12, 0.08]
2.1 Propranolol 160 mg vs.
flunarizine 10 mg
1 524 Std. Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.11, 0.23]
2.2 Propranolol 160 mg vs.
flunarizine 5 mg
1 518 Std. Mean Difference (IV, Fixed, 95% CI) -0.07 [-0.24, 0.10]
2.3 Propranolol 120 mg vs.
flunarizine 10 mg
3 462 Std. Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.24, 0.13]
2.4 Propranolol 120-180 mg
vs. nifedipine 60-90 mg
1 20 Std. Mean Difference (IV, Fixed, 95% CI) 0.19 [-0.73, 1.11]
2.5 Propranolol 120 mg vs.
nimodipine 120 mg
1 19 Std. Mean Difference (IV, Fixed, 95% CI) -0.18 [-1.09, 0.74]
62Propranolol for migraine prophylaxis (Review)
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3 Number of patients with adverse
events (all trials parallel-group)
8 1753 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.91, 1.15]
3.1 Propranolol 160 mg vs.
flunarizine 10 mg
2 634 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.86, 1.24]
3.2 Propranolol 160 mg vs.
flunarizine 5 mg
1 533 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.76, 1.24]
3.3 Propranolol 120 mg vs.
flunarizine 10 mg
3 464 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.97, 1.52]
3.4 Propranolol 60 mg vs.
flunarizine 10 mg
1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.13, 3.44]
3.5 Propranolol 120-180 mg
vs. nifedipine 60-90 mg
1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.58, 0.98]
3.6 Propranolol 120 mg vs.
nimodipine 120 mg
1 22 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.38, 1.12]
3.7 Propranolol 60 mg vs.
propanolol 60 mg + flunarizine
10 mg
1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.11, 2.33]
4 Number of patients with adverse
events (vs. flunarizine; all trials
parallel-group)
6 1661 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.94, 1.20]
4.1 Propranolol 160 mg vs.
flunarizine 10 mg
2 634 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.86, 1.24]
4.2 Propranolol 160 mg vs.
flunarizine 5 mg
1 533 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.76, 1.24]
4.3 Propranolol 120 mg vs.
flunarizine 10 mg
3 464 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.97, 1.52]
4.4 Propranolol 60 mg vs.
flunarizine 10 mg
1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.13, 3.44]
5 Number of dropouts due
to adverse events (all trials
parallel-group)
9 1533 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.59, 1.13]
5.1 Propranolol 180 mg vs.
flunarizine 10 mg
1 58 Risk Ratio (M-H, Fixed, 95% CI) 1.5 [0.27, 8.32]
5.2 Propranolol 160 mg vs.
flunarizine 10 mg
3 665 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.61, 1.78]
5.3 Propranolol 160 mg vs.
flunarizine 5 mg
1 533 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.46, 1.53]
5.4 Propranolol 120 mg vs.
flunarizine 10 mg
1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.23, 7.03]
5.5 Propranolol 80 mg vs.
flunarizine 10 mg
1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5.6 Propranolol 60 mg vs.
flunarizine 10 mg
1 35 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5.7 Propranolol 120 mg vs.
nimodipine 120 mg
1 22 Risk Ratio (M-H, Fixed, 95% CI) 2.4 [0.25, 22.75]
5.8 Propranolol 160 mg vs.
nifedipine 40 mg
1 36 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.11, 1.06]
5.9 Propranolol 120-180 mg
vs. nifedipine 60-90 mg
1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.17, 0.88]
63Propranolol for migraine prophylaxis (Review)
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5.10 Propranolol 60 mg
vs. propranolol 60 mg +
flunarizine 10 mg
1 35 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6 Number of dropouts due to
adverse events (vs. flunarizine;
all trials parallel-group)
7 1400 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.67, 1.44]
6.1 Propranolol 180 mg vs.
flunarizine 10 mg
1 58 Risk Ratio (M-H, Fixed, 95% CI) 1.5 [0.27, 8.32]
6.2 Propranolol 160 mg vs.
flunarizine 10 mg
3 665 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.61, 1.78]
6.3 Propranolol 160 mg vs.
flunarizine 5 mg
1 533 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.46, 1.53]
6.4 Propranolol 120 mg vs.
flunarizine 10 mg
1 59 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.23, 7.03]
6.5 Propranolol 80 mg vs.
flunarizine 10 mg
1 50 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.6 Propranolol 60 mg vs.
flunarizine 10 mg
1 35 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Number of dropouts due to
adverse events (vs. nifedipine;
all trials parallel-group)
2 76 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.19, 0.72]
7.1 Propranolol 160 mg vs.
nifedipine 40 mg
1 36 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.11, 1.06]
7.2 Propranolol 120-180 mg
vs. nifedipine 60-90 mg
1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.38 [0.17, 0.88]
Comparison 3. Propranolol versus other beta-blockers
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Responders (parallel-group; no
1st period crossover data)
3 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
1.1 Propranolol 160 mg vs.
nadolol 160 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Propranolol 160 mg vs.
nadolol 80 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Propranolol 80-160 mg
vs. metoprolol 100-200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Responders (parallel-group and
pooled crossover data)
6 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
2.1 Propranolol 160 mg vs.
nadolol 160 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Propranolol 160 mg vs.
nadolol 80 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
64Propranolol for migraine prophylaxis (Review)
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2.3 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.4 Propranolol 160 mg vs.
metoprolol 200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.5 Propranolol 80-160 mg
vs. metoprolol 100-200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.6 Propranolol 80 mg vs.
metoprolol 100 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.7 Propranolol 160 mg vs.
timolol 20 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Responders (vs. nadolol;
parallel-group and pooled
crossover data)
2 147 Risk Ratio (M-H, Fixed, 95% CI) 0.60 [0.37, 0.97]
3.1 Propranolol 160 mg vs.
nadolol 160 mg
1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.15, 0.79]
3.2 Propranolol 160 mg vs.
nadolol 80 mg
1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.56 [0.22, 1.40]
3.3 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 27 Risk Ratio (M-H, Fixed, 95% CI) 1.49 [0.65, 3.39]
4 Responders (vs. metoprolol;
parallel-group and pooled
crossover data)
3 216 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.56, 1.09]
4.1 Propranolol 160 mg vs.
metoprolol 200 mg
1 66 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.54, 1.45]
4.2 Propranolol 80-160 mg
vs. metoprolol 100-200 mg
1 41 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.27, 1.24]
4.3 Propranolol 80 mg vs.
metoprolol 100 mg
1 109 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.47, 1.37]
5 Attack frequency measures
(pooled crossover only; no
parallel-group or 1st period
crossover data)
4 290 Std. Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.24, 0.22]
5.1 Propranolol 160 mg vs.
metoprolol 200 mg
1 68 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [-0.48, 0.48]
5.2 Propranolol 80 mg vs.
metoprolol 100 mg
1 24 Std. Mean Difference (IV, Fixed, 95% CI) -0.43 [-1.24, 0.38]
5.3 Propranolol 160 mg vs.
timolol 20 mg
1 160 Std. Mean Difference (IV, Fixed, 95% CI) 0.10 [-0.21, 0.41]
5.4 Propranolol 160 mg vs.
d-propranolol 160 mg
1 38 Std. Mean Difference (IV, Fixed, 95% CI) -0.27 [-0.91, 0.37]
6 Number of patients with adverse
events (parallel-group; no 1st
period crossover data)
1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
6.1 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Number of patients with adverse
events (parallel-group and
pooled crossover data)
3 217 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.65, 1.24]
7.1 Propranolol 160 mg vs.
timolol 20 mg
1 166 Risk Ratio (M-H, Fixed, 95% CI) 0.92 [0.65, 1.30]
65Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7.2 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 27 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.31, 1.93]
7.3 Propranolol 80 mg vs.
metoprolol 100 mg
1 24 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8 Number of dropouts due to
adverse events (parallel-group;
no 1st period crossover data)
4 317 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.48, 2.10]
8.1 Propranolol 160 mg vs.
nadolol 160 mg
1 91 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [0.41, 11.09]
8.2 Propranolol 160 mg vs.
nadolol 80 mg
1 93 Risk Ratio (M-H, Fixed, 95% CI) 2.23 [0.43, 11.57]
8.3 Propranolol 120 mg vs.
nadolol 160 mg
1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.4 Propranolol 120 mg vs.
nadolol 80 mg
1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.62]
8.5 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 28 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.01, 6.60]
8.6 Propranolol 160 mg vs.
metoprolol 200 mg
1 41 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.17, 2.01]
9 Number of dropouts due to
adverse events (parallel-group
and pooled crossover data)
9 789 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.61, 1.80]
9.1 Propranolol 160 mg vs.
nadolol 160 mg
1 91 Risk Ratio (M-H, Fixed, 95% CI) 2.14 [0.41, 11.09]
9.2 Propranolol 160 mg vs.
nadolol 80 mg
1 93 Risk Ratio (M-H, Fixed, 95% CI) 2.23 [0.43, 11.57]
9.3 Propranolol 120 mg vs.
nadolol 160 mg
1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
9.4 Propranolol 120 mg vs.
nadolol 80 mg
1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.62]
9.5 Propranolol 80-160 mg
vs. nadolol 40-160 mg
1 28 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.01, 6.60]
9.6 Propranolol 160 mg vs.
metoprolol 200 mg
2 113 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.33, 2.72]
9.7 Propranolol 80 mg vs.
metoprolol 100 mg
1 112 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
9.8 Propranolol 160 mg vs.
atenolol 100 mg
1 70 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.13, 71.22]
9.9 Propranolol 160 mg vs.
timolol 20 mg
1 178 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.25, 1.79]
9.10 Propranolol 160 mg vs.
d-propranolol 160 mg
1 40 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.13, 69.52]
66Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 4. Propranolol versus other drugs
Outcome or subgroup titleNo. of
studies
No. of
participants Statistical method Effect size
1 Responders (parallel-group and
1st period crossover data)
5 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
1.1 Propranolol 160 mg vs.
femoxetine 400 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.2 Propranolol 120-160 mg
vs. cyclandelate 1200-1600 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.3 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.4 Propranolol 60-240 mg vs.
divalproex sodium 1000-2000
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
1.5 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Responders (parallel-group and
pooled crossover data [one 1st
period])
10 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
2.1 Propranolol 160 mg vs.
femoxetine 400 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.2 Propranolol 120-160 mg
vs. cyclandelate 1200-1600 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.3 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.4 Propranolol 60-240 mg vs.
divalproex sodium 1000-2000
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.5 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.6 Propranolol 120 mg vs.
methysergide 3 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.7 Propranolol 160 mg vs.
clonidine 100 mcg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.8 Propranolol 80-240 mg
vs. amitriptyline 50-150 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2.9 Propranolol 1.8 mg/kg vs.
ASA 13.5 mg/kg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Attack frequency measures
(parallel-group and 1st period
crossover data)
8 Std. Mean Difference (IV, Fixed, 95% CI) Totals not selected
3.1 Propranolol 160 mg vs.
femoxetine 400 mg
2 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.2 Propranolol 120 mg vs.
tolfenamic acid 300 mg
2 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.3 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
67Propranolol for migraine prophylaxis (Review)
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3.4 Propranolol 120 mg vs.
naproxen 1100 mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.5 Propranolol 1230 mcg/kg
vs. methysergide 30.8 mcg/kg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
3.6 Propranolol 80 mg vs.
alpha-dihydroergocryptine 20
mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4 Attack frequency measures
(parallel-group and pooled
crossover data [two 1st period])
10 Std. Mean Difference (IV, Fixed, 95% CI) Totals not selected
4.1 Propranolol 160 mg vs.
femoxetine 400 mg
2 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.2 Propranolol 120 mg vs.
tolfenamic acid 300 mg
2 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.3 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.4 Propranolol 120 mg vs.
naproxen 1100 mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.5 Propranolol 1230 mcg/kg
vs. methysergide 30.8 mcg/kg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.6 Propranolol 240 mg vs.
mefenamic acid 1500 mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.7 Propranolol 160 mg vs.
clonidine 100 mcg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
4.8 Propranolol 80 mg vs.
alpha-dihydroergocryptine 20
mg
1 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]
5 Number of patients with adverse
events (parallel-group; no 1st
period crossover data)
4 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
5.1 Propranolol 120-160 mg
vs. cyclandelate 1200-1600 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5.2 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5.3 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
5.4 Propranolol 120 mg vs.
naproxen 1100 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6 Number of patients with adverse
events (parallel-group and
pooled crossover data)
10 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
6.1 Propranolol 120-160 mg
vs. cyclandelate 1200-1600 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.2 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.3 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.4 Propranolol 120 mg vs.
naproxen 1100 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.5 Propranolol 120 mg vs.
tolfenamic acid 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
68Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
6.6 Propranolol 120 mg vs.
methysergide 3 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.7 Propranolol 160 mg vs.
clonidine 100 mcg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.8 Propranolol 60-240 mg vs.
divalproex sodium 1000-2000
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.9 Propranolol 1.8 mg/kg vs.
ASA 13.5 mg/kg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.10 Propranolol 240 mg vs.
mefenamic acid 1500 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Number of dropouts due to
adverse events (parallel-group;
no 1st period crossover data)
5 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
7.1 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.2 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.3 Propranolol 160 mg vs.
dihydroergotamine 10 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.4 Propranolol 120-160 mg
vs. amitriptyline 50-75 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7.5 Propranolol 120-160 mg
vs. amitriptyline 50-75 mg +
propranolol 120-160 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8 Number of dropouts due to
adverse events (parallel-group
and pooled crossover data)
16 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected
8.1 Propranolol 160 mg vs.
femoxetine 400 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.2 Propranolol 120 mg vs.
cyclandelate 1200 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.3 Propranolol 80-240 mg vs.
divalproex sodium 750-1500
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.4 Propranolol 60-240 mg vs.
divalproex sodium 1000-2000
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.5 Propranolol 120 mg vs.
5-hydroxytryptophan 300 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.6 Propranolol 240 mg vs.
mefenamic acid 1500 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.7 Propranolol 120 mg vs.
tolfenamic acid 300 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.8 Propranolol 120 mg vs.
methysergide 3 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.9 Propranolol 160 mg vs.
dihydroergotamine 10 mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.10 Propranolol 80 mg vs.
alpha-dihydroergocryptine 20
mg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
69Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
8.11 Propranolol 160 mg vs.
clonidine 100 mcg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.12 Propranolol 1.8 mg/kg
vs. ASA 13.5 mg/kg
1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.13 Propranolol 120-160 mg
vs. amitriptyline 50-75 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
8.14 Propranolol 120-160 mg
vs. amitriptyline 50-75 mg +
propranolol 120-160 mg
2 Risk Ratio (M-H, Fixed, 95% CI) 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: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 1 Responders (parallel-group and 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg
Wideroe 1974 12/12 5/14 15.9 % 2.62 [ 1.34, 5.14 ]
Subtotal (95% CI) 12 14 15.9 % 2.62 [ 1.34, 5.14 ]
Total events: 12 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.80 (P = 0.0050)
2 Propranolol 120 mg
Diener 1996 33/78 17/55 61.9 % 1.37 [ 0.85, 2.20 ]
Subtotal (95% CI) 78 55 61.9 % 1.37 [ 0.85, 2.20 ]
Total events: 33 (Treatment), 17 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.30 (P = 0.19)
3 Propranolol 80-120 mg
Holdorff 1977 8/13 7/14 20.9 % 1.23 [ 0.63, 2.42 ]
Subtotal (95% CI) 13 14 20.9 % 1.23 [ 0.63, 2.42 ]
Total events: 8 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.60 (P = 0.55)
4 Propranolol 80 mg
Weber 1972 5/8 0/11 1.3 % 14.67 [ 0.93, 232.44 ]
Subtotal (95% CI) 8 11 1.3 % 14.67 [ 0.93, 232.44 ]
Total events: 5 (Treatment), 0 (Control)
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
(Continued . . . )
70Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Heterogeneity: not applicable
Test for overall effect: Z = 1.91 (P = 0.057)
Total (95% CI) 111 94 100.0 % 1.72 [ 1.23, 2.40 ]
Total events: 58 (Treatment), 29 (Control)
Heterogeneity: Chi2 = 5.64, df = 3 (P = 0.13); I2 =47%
Test for overall effect: Z = 3.17 (P = 0.0015)
Test for subgroup differences: Chi2 = 5.52, df = 3 (P = 0.14), I2 =46%
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Responders (parallel-group and pooled
crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 2 Responders (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg
Pita 1977 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 ]
Subtotal (95% CI) 114 114 36.5 % 2.14 [ 1.59, 2.87 ]
Total events: 77 (Treatment), 36 (Control)
Heterogeneity: Chi2 = 0.52, df = 2 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 5.04 (P < 0.00001)
2 Propranolol 80-160 mg
Diamond 1976 34/62 17/62 17.2 % 2.00 [ 1.26, 3.18 ]
Subtotal (95% CI) 62 62 17.2 % 2.00 [ 1.26, 3.18 ]
Total events: 34 (Treatment), 17 (Control)
Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
(Continued . . . )
71Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Test for overall effect: Z = 2.93 (P = 0.0034)
3 Propranolol 120 mg
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 ]
Subtotal (95% CI) 108 85 29.3 % 1.43 [ 0.97, 2.10 ]
Total events: 47 (Treatment), 26 (Control)
Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 1.81 (P = 0.071)
4 Propranolol 80-120 mg
Holdorff 1977 8/13 7/14 6.8 % 1.23 [ 0.63, 2.42 ]
Subtotal (95% CI) 13 14 6.8 % 1.23 [ 0.63, 2.42 ]
Total events: 8 (Treatment), 7 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.60 (P = 0.55)
5 Propranolol 80 mg
Weber 1972 15/19 2/19 2.0 % 7.50 [ 1.98, 28.40 ]
Subtotal (95% CI) 19 19 2.0 % 7.50 [ 1.98, 28.40 ]
Total events: 15 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.97 (P = 0.0030)
6 Propranolol, dose unclear
Malvea 1973 16/29 8/29 8.1 % 2.00 [ 1.02, 3.93 ]
Subtotal (95% CI) 29 29 8.1 % 2.00 [ 1.02, 3.93 ]
Total events: 16 (Treatment), 8 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.01 (P = 0.044)
Total (95% CI) 345 323 100.0 % 1.94 [ 1.61, 2.35 ]
Total events: 197 (Treatment), 96 (Control)
Heterogeneity: Chi2 = 9.28, df = 8 (P = 0.32); I2 =14%
Test for overall effect: Z = 6.85 (P < 0.00001)
Test for subgroup differences: Chi2 = 8.45, df = 5 (P = 0.13), I2 =41%
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
72Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.3. Comparison 1 Propranolol versus placebo, Outcome 3 Attack frequency measures (parallel-
group and 1st period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 3 Attack frequency measures (parallel-group and 1st period crossover data)
Study or subgroup Treatment Control
Std.Mean
Difference Weight
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 160 mg
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 ]
Subtotal (95% CI) 34 33 36.9 % -0.77 [ -1.27, -0.27 ]
Heterogeneity: Chi2 = 1.17, df = 1 (P = 0.28); I2 =14%
Test for overall effect: Z = 3.00 (P = 0.0027)
2 Propranolol 120 mg
Mikkelsen 1986 9 6.4 (4.1) 9 7.6 (6.1) 10.8 % -0.22 [ -1.15, 0.71 ]
Sargent 1985 44 -0.21 (1.86) 43 0.25 (1.57) 52.3 % -0.26 [ -0.69, 0.16 ]
Subtotal (95% CI) 53 52 63.1 % -0.26 [ -0.64, 0.13 ]
Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.93); I2 =0.0%
Test for overall effect: Z = 1.31 (P = 0.19)
Total (95% CI) 87 85 100.0 % -0.45 [ -0.75, -0.14 ]
Heterogeneity: Chi2 = 3.68, df = 3 (P = 0.30); I2 =19%
Test for overall effect: Z = 2.86 (P = 0.0042)
Test for subgroup differences: Chi2 = 2.51, df = 1 (P = 0.11), I2 =60%
-4 -2 0 2 4
Favours treatment Favours control
73Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.4. Comparison 1 Propranolol versus placebo, Outcome 4 Attack frequency measures (parallel-
group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data)
Study or subgroup Treatment Control
Std.Mean
Difference Weight
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 240 mg
Johnson 1986 17 13.8 (12) 17 20.1 (18) 5.4 % -0.40 [ -1.08, 0.28 ]
Subtotal (95% CI) 17 17 5.4 % -0.40 [ -1.08, 0.28 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.16 (P = 0.25)
2 Propranolol 160 mg
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 ]
Subtotal (95% CI) 147 144 45.2 % -0.49 [ -0.72, -0.25 ]
Heterogeneity: Chi2 = 7.65, df = 3 (P = 0.05); I2 =61%
Test for overall effect: Z = 4.06 (P = 0.000050)
3 Propranolol 120 mg
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 ]
Subtotal (95% CI) 155 154 49.4 % -0.32 [ -0.55, -0.10 ]
Heterogeneity: Chi2 = 1.13, df = 4 (P = 0.89); I2 =0.0%
Test for overall effect: Z = 2.82 (P = 0.0048)
Total (95% CI) 319 315 100.0 % -0.40 [ -0.56, -0.24 ]
Heterogeneity: Chi2 = 9.75, df = 9 (P = 0.37); I2 =8%
Test for overall effect: Z = 4.98 (P < 0.00001)
Test for subgroup differences: Chi2 = 0.97, df = 2 (P = 0.62), I2 =0.0%
-4 -2 0 2 4
Favours treatment Favours control
74Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.5. Comparison 1 Propranolol versus placebo, Outcome 5 Number of patients with adverse
events (parallel-group; no 1st period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 5 Number of patients with adverse events (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 120 mg
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 ]
Total events: 49 (Treatment), 33 (Control)
Heterogeneity: Chi2 = 4.66, df = 1 (P = 0.03); I2 =79%
Test for overall effect: Z = 1.77 (P = 0.077)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
75Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.6. Comparison 1 Propranolol versus placebo, Outcome 6 Number of patients with adverse
events (parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 6 Number of patients with adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 240 mg
Johnson 1986 2/23 1/24 1.4 % 2.09 [ 0.20, 21.48 ]
Subtotal (95% CI) 23 24 1.4 % 2.09 [ 0.20, 21.48 ]
Total events: 2 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.62 (P = 0.54)
2 Propranolol 160 mg
Tfelt-Hansen 1984 35/83 23/83 32.3 % 1.52 [ 0.99, 2.34 ]
Subtotal (95% CI) 83 83 32.3 % 1.52 [ 0.99, 2.34 ]
Total events: 35 (Treatment), 23 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.92 (P = 0.055)
3 Propranolol 80-160 mg
Diamond 1976 16/62 10/62 14.1 % 1.60 [ 0.79, 3.25 ]
Subtotal (95% CI) 62 62 14.1 % 1.60 [ 0.79, 3.25 ]
Total events: 16 (Treatment), 10 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.30 (P = 0.19)
4 Propranolol 120 mg
Diener 1996 19/78 5/55 8.2 % 2.68 [ 1.06, 6.74 ]
Mikkelsen 1986 3/31 3/31 4.2 % 1.00 [ 0.22, 4.58 ]
Sargent 1985 30/44 28/43 39.8 % 1.05 [ 0.78, 1.41 ]
Subtotal (95% CI) 153 129 52.3 % 1.30 [ 0.95, 1.77 ]
Total events: 52 (Treatment), 36 (Control)
Heterogeneity: Chi2 = 4.51, df = 2 (P = 0.10); I2 =56%
Test for overall effect: Z = 1.66 (P = 0.097)
Total (95% CI) 321 298 100.0 % 1.43 [ 1.12, 1.81 ]
Total events: 105 (Treatment), 70 (Control)
Heterogeneity: Chi2 = 6.42, df = 5 (P = 0.27); I2 =22%
Test for overall effect: Z = 2.90 (P = 0.0037)
Test for subgroup differences: Chi2 = 0.61, df = 3 (P = 0.89), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
76Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 7 Number of dropouts due to adverse events (parallel-group and 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 80-320 mg
Nadelmann 1986 0/28 0/29 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 28 29 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
2 Propranolol 160 mg
Pradalier 1989 0/40 1/34 0.28 [ 0.01, 6.77 ]
Subtotal (95% CI) 40 34 0.28 [ 0.01, 6.77 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.78 (P = 0.44)
3 Propranolol 120 mg
Diener 1996 4/78 0/55 6.38 [ 0.35, 116.13 ]
Subtotal (95% CI) 78 55 6.38 [ 0.35, 116.13 ]
Total events: 4 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.25 (P = 0.21)
Total (95% CI) 146 118 1.90 [ 0.36, 10.14 ]
Total events: 4 (Treatment), 1 (Control)
Heterogeneity: Chi2 = 2.05, df = 1 (P = 0.15); I2 =51%
Test for overall effect: Z = 0.75 (P = 0.45)
Test for subgroup differences: Chi2 = 2.01, df = 1 (P = 0.16), I2 =50%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
77Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.8. Comparison 1 Propranolol versus placebo, Outcome 8 Number of dropouts due to adverse
events (parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 1 Propranolol versus placebo
Outcome: 8 Number of dropouts due to adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 80-320 mg
Nadelmann 1986 0/57 0/57 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 57 57 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
2 Propranolol 240 mg
Forssman 1976 2/40 2/40 1.00 [ 0.15, 6.76 ]
Johnson 1986 1/29 1/29 1.00 [ 0.07, 15.24 ]
Subtotal (95% CI) 69 69 1.00 [ 0.21, 4.78 ]
Total events: 3 (Treatment), 3 (Control)
Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0%
Test for overall effect: Z = 0.0 (P = 1.0)
3 Propranolol 160 mg
Pita 1977 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 ]
Total events: 9 (Treatment), 3 (Control)
Heterogeneity: Chi2 = 1.88, df = 4 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 1.46 (P = 0.14)
4 Propranolol 80-160 mg
Diamond 1976 6/83 1/83 6.00 [ 0.74, 48.75 ]
Subtotal (95% CI) 83 83 6.00 [ 0.74, 48.75 ]
Total events: 6 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.68 (P = 0.094)
5 Propranolol 120 mg
Borgesen 1974 0/45 2/45 0.20 [ 0.01, 4.05 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
78Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Diener 1996 4/78 0/55 6.38 [ 0.35, 116.13 ]
Mikkelsen 1986 2/39 0/39 5.00 [ 0.25, 100.89 ]
Subtotal (95% CI) 162 139 1.88 [ 0.51, 6.91 ]
Total events: 6 (Treatment), 2 (Control)
Heterogeneity: Chi2 = 3.22, df = 2 (P = 0.20); I2 =38%
Test for overall effect: Z = 0.95 (P = 0.34)
6 Propranolol 80 mg
Weber 1972 0/25 0/25 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 25 25 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI) 589 561 2.11 [ 1.09, 4.08 ]
Total events: 24 (Treatment), 9 (Control)
Heterogeneity: Chi2 = 6.95, df = 10 (P = 0.73); I2 =0.0%
Test for overall effect: Z = 2.21 (P = 0.027)
Test for subgroup differences: Chi2 = 1.84, df = 3 (P = 0.61), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
79Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Propranolol versus calcium antagonists, Outcome 1 Responders (all trials
parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 1 Responders (all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI 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 ]
Subtotal (95% CI) 29 28 4.1 % 1.30 [ 1.01, 1.68 ]
Total events: 27 (Treatment), 20 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.04 (P = 0.041)
2 Propranolol 160 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 297 301 33.0 % 0.88 [ 0.76, 1.03 ]
Total events: 145 (Treatment), 166 (Control)
Heterogeneity: Chi2 = 0.71, df = 1 (P = 0.40); I2 =0.0%
Test for overall effect: Z = 1.56 (P = 0.12)
3 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 125/258 118/259 23.5 % 1.06 [ 0.89, 1.28 ]
Subtotal (95% CI) 258 259 23.5 % 1.06 [ 0.89, 1.28 ]
Total events: 125 (Treatment), 118 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.66 (P = 0.51)
4 Propranolol 120 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 236 228 28.6 % 1.00 [ 0.87, 1.15 ]
Total events: 145 (Treatment), 141 (Control)
Heterogeneity: Chi2 = 0.08, df = 2 (P = 0.96); I2 =0.0%
Test for overall effect: Z = 0.02 (P = 0.98)
5 Propranolol 80 mg vs. flunarizine 10 mg
Bonuso 1998 15/19 18/23 3.3 % 1.01 [ 0.73, 1.38 ]
Subtotal (95% CI) 19 23 3.3 % 1.01 [ 0.73, 1.38 ]
Total events: 15 (Treatment), 18 (Control)
Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
(Continued . . . )
80Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Test for overall effect: Z = 0.05 (P = 0.96)
6 Propranolol 60 mg vs. flunarizine 10 mg
Bordini 1997 15/15 14/15 2.9 % 1.07 [ 0.89, 1.28 ]
Subtotal (95% CI) 15 15 2.9 % 1.07 [ 0.89, 1.28 ]
Total events: 15 (Treatment), 14 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.72 (P = 0.47)
7 Propranolol 120-180 mg vs. nifedipine 60-90 mg
Albers 1989 12/13 6/7 1.6 % 1.08 [ 0.77, 1.51 ]
Subtotal (95% CI) 13 7 1.6 % 1.08 [ 0.77, 1.51 ]
Total events: 12 (Treatment), 6 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.43 (P = 0.67)
8 Propranolol 80-160 mg vs. nifedipine 20-40 mg
Diener 1989 6/19 1/17 0.2 % 5.37 [ 0.72, 40.20 ]
Subtotal (95% CI) 19 17 0.2 % 5.37 [ 0.72, 40.20 ]
Total events: 6 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.64 (P = 0.10)
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 ]
Subtotal (95% CI) 15 15 2.9 % 1.07 [ 0.89, 1.28 ]
Total events: 15 (Treatment), 14 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.72 (P = 0.47)
Total (95% CI) 901 893 100.0 % 1.00 [ 0.93, 1.09 ]
Total events: 505 (Treatment), 498 (Control)
Heterogeneity: Chi2 = 11.78, df = 11 (P = 0.38); I2 =7%
Test for overall effect: Z = 0.08 (P = 0.94)
Test for subgroup differences: Chi2 = 10.34, df = 8 (P = 0.24), I2 =23%
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
81Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.2. Comparison 2 Propranolol versus calcium antagonists, Outcome 2 Attack frequency measures
(all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 2 Attack frequency measures (all trials parallel-group)
Study or subgroup Treatment Control
Std.Mean
Difference Weight
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 160 mg vs. flunarizine 10 mg
Diener 2002 259 1.7 (1.6) 265 1.6 (1.6) 34.0 % 0.06 [ -0.11, 0.23 ]
Subtotal (95% CI) 259 265 34.0 % 0.06 [ -0.11, 0.23 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.71 (P = 0.48)
2 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 259 1.7 (1.6) 259 1.8 (1.2) 33.6 % -0.07 [ -0.24, 0.10 ]
Subtotal (95% CI) 259 259 33.6 % -0.07 [ -0.24, 0.10 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.80 (P = 0.42)
3 Propranolol 120 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 234 228 29.9 % -0.05 [ -0.24, 0.13 ]
Heterogeneity: Chi2 = 0.94, df = 2 (P = 0.63); I2 =0.0%
Test for overall effect: Z = 0.59 (P = 0.56)
4 Propranolol 120-180 mg vs. nifedipine 60-90 mg
Albers 1989 13 2.2 (3.24) 7 1.5 (3.97) 1.2 % 0.19 [ -0.73, 1.11 ]
Subtotal (95% CI) 13 7 1.2 % 0.19 [ -0.73, 1.11 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.41 (P = 0.68)
5 Propranolol 120 mg vs. nimodipine 120 mg
Formisano 1991 8 2.6 (1.5) 11 2.9 (1.7) 1.2 % -0.18 [ -1.09, 0.74 ]
Subtotal (95% CI) 8 11 1.2 % -0.18 [ -1.09, 0.74 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.38 (P = 0.70)
Total (95% CI) 773 770 100.0 % -0.02 [ -0.12, 0.08 ]
Heterogeneity: Chi2 = 2.61, df = 6 (P = 0.86); I2 =0.0%
Test for overall effect: Z = 0.37 (P = 0.71)
Test for subgroup differences: Chi2 = 1.68, df = 4 (P = 0.80), I2 =0.0%
-4 -2 0 2 4
Favours treatment Favours control
82Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.3. Comparison 2 Propranolol versus calcium antagonists, Outcome 3 Number of patients with
adverse events (all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 3 Number of patients with adverse events (all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 315 319 36.6 % 1.03 [ 0.86, 1.24 ]
Total events: 124 (Treatment), 121 (Control)
Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 0.33 (P = 0.74)
2 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 88/270 88/263 27.0 % 0.97 [ 0.76, 1.24 ]
Subtotal (95% CI) 270 263 27.0 % 0.97 [ 0.76, 1.24 ]
Total events: 88 (Treatment), 88 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.21 (P = 0.83)
3 Propranolol 120 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 236 228 25.0 % 1.22 [ 0.97, 1.52 ]
Total events: 102 (Treatment), 81 (Control)
Heterogeneity: Chi2 = 0.89, df = 2 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 1.70 (P = 0.090)
4 Propranolol 60 mg vs. flunarizine 10 mg
Bordini 1997 2/15 3/15 0.9 % 0.67 [ 0.13, 3.44 ]
Subtotal (95% CI) 15 15 0.9 % 0.67 [ 0.13, 3.44 ]
Total events: 2 (Treatment), 3 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.48 (P = 0.63)
5 Propranolol 120-180 mg vs. nifedipine 60-90 mg
Albers 1989 15/20 20/20 6.2 % 0.76 [ 0.58, 0.98 ]
Subtotal (95% CI) 20 20 6.2 % 0.76 [ 0.58, 0.98 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
83Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Total events: 15 (Treatment), 20 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.08 (P = 0.037)
6 Propranolol 120 mg vs. nimodipine 120 mg
Formisano 1991 6/10 11/12 3.0 % 0.65 [ 0.38, 1.12 ]
Subtotal (95% CI) 10 12 3.0 % 0.65 [ 0.38, 1.12 ]
Total events: 6 (Treatment), 11 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.56 (P = 0.12)
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 ]
Subtotal (95% CI) 15 15 1.2 % 0.50 [ 0.11, 2.33 ]
Total events: 2 (Treatment), 4 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.88 (P = 0.38)
Total (95% CI) 881 872 100.0 % 1.02 [ 0.91, 1.15 ]
Total events: 339 (Treatment), 328 (Control)
Heterogeneity: Chi2 = 12.30, df = 9 (P = 0.20); I2 =27%
Test for overall effect: Z = 0.40 (P = 0.69)
Test for subgroup differences: Chi2 = 10.67, df = 6 (P = 0.10), I2 =44%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
84Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.4. Comparison 2 Propranolol versus calcium antagonists, Outcome 4 Number of patients with
adverse events (vs. flunarizine; all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 4 Number of patients with adverse events (vs. flunarizine; all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 315 319 40.8 % 1.03 [ 0.86, 1.24 ]
Total events: 124 (Treatment), 121 (Control)
Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 0.33 (P = 0.74)
2 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 88/270 88/263 30.2 % 0.97 [ 0.76, 1.24 ]
Subtotal (95% CI) 270 263 30.2 % 0.97 [ 0.76, 1.24 ]
Total events: 88 (Treatment), 88 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.21 (P = 0.83)
3 Propranolol 120 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 236 228 27.9 % 1.22 [ 0.97, 1.52 ]
Total events: 102 (Treatment), 81 (Control)
Heterogeneity: Chi2 = 0.89, df = 2 (P = 0.64); I2 =0.0%
Test for overall effect: Z = 1.70 (P = 0.090)
4 Propranolol 60 mg vs. flunarizine 10 mg
Bordini 1997 2/15 3/15 1.0 % 0.67 [ 0.13, 3.44 ]
Subtotal (95% CI) 15 15 1.0 % 0.67 [ 0.13, 3.44 ]
Total events: 2 (Treatment), 3 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.48 (P = 0.63)
Total (95% CI) 836 825 100.0 % 1.06 [ 0.94, 1.20 ]
Total events: 316 (Treatment), 293 (Control)
Heterogeneity: Chi2 = 3.19, df = 6 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 0.96 (P = 0.34)
Test for subgroup differences: Chi2 = 2.27, df = 3 (P = 0.52), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
85Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.5. Comparison 2 Propranolol versus calcium antagonists, Outcome 5 Number of dropouts due to
adverse events (all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 5 Number of dropouts due to adverse events (all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 180 mg vs. flunarizine 10 mg
Shimell 1990 3/29 2/29 1.50 [ 0.27, 8.32 ]
Subtotal (95% CI) 29 29 1.50 [ 0.27, 8.32 ]
Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.46 (P = 0.64)
2 Propranolol 160 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 334 331 1.05 [ 0.61, 1.78 ]
Total events: 26 (Treatment), 24 (Control)
Heterogeneity: Chi2 = 0.48, df = 2 (P = 0.79); I2 =0.0%
Test for overall effect: Z = 0.17 (P = 0.87)
3 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 18/270 21/263 0.83 [ 0.46, 1.53 ]
Subtotal (95% CI) 270 263 0.83 [ 0.46, 1.53 ]
Total events: 18 (Treatment), 21 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
4 Propranolol 120 mg vs. flunarizine 10 mg
Ludin 1989 3/32 2/27 1.27 [ 0.23, 7.03 ]
Subtotal (95% CI) 32 27 1.27 [ 0.23, 7.03 ]
Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.27 (P = 0.79)
5 Propranolol 80 mg vs. flunarizine 10 mg
Bonuso 1998 0/25 0/25 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 25 25 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
86Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
6 Propranolol 60 mg vs. flunarizine 10 mg
Bordini 1997 0/18 0/17 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 18 17 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
7 Propranolol 120 mg vs. nimodipine 120 mg
Formisano 1991 2/10 1/12 2.40 [ 0.25, 22.75 ]
Subtotal (95% CI) 10 12 2.40 [ 0.25, 22.75 ]
Total events: 2 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.76 (P = 0.45)
8 Propranolol 160 mg vs. nifedipine 40 mg
Scholz 1987 3/19 8/17 0.34 [ 0.11, 1.06 ]
Subtotal (95% CI) 19 17 0.34 [ 0.11, 1.06 ]
Total events: 3 (Treatment), 8 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.85 (P = 0.064)
9 Propranolol 120-180 mg vs. nifedipine 60-90 mg
Albers 1989 5/20 13/20 0.38 [ 0.17, 0.88 ]
Subtotal (95% CI) 20 20 0.38 [ 0.17, 0.88 ]
Total events: 5 (Treatment), 13 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.27 (P = 0.023)
10 Propranolol 60 mg vs. propranolol 60 mg + flunarizine 10 mg
Bordini 1997 0/18 0/17 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 18 17 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI) 775 758 0.82 [ 0.59, 1.13 ]
Total events: 60 (Treatment), 71 (Control)
Heterogeneity: Chi2 = 8.40, df = 8 (P = 0.40); I2 =5%
Test for overall effect: Z = 1.23 (P = 0.22)
Test for subgroup differences: Chi2 = 7.90, df = 6 (P = 0.25), I2 =24%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
87Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.6. Comparison 2 Propranolol versus calcium antagonists, Outcome 6 Number of dropouts due to
adverse events (vs. flunarizine; all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 6 Number of dropouts due to adverse events (vs. flunarizine; all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 180 mg vs. flunarizine 10 mg
Shimell 1990 3/29 2/29 1.50 [ 0.27, 8.32 ]
Subtotal (95% CI) 29 29 1.50 [ 0.27, 8.32 ]
Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.46 (P = 0.64)
2 Propranolol 160 mg vs. flunarizine 10 mg
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 ]
Subtotal (95% CI) 334 331 1.05 [ 0.61, 1.78 ]
Total events: 26 (Treatment), 24 (Control)
Heterogeneity: Chi2 = 0.48, df = 2 (P = 0.79); I2 =0.0%
Test for overall effect: Z = 0.17 (P = 0.87)
3 Propranolol 160 mg vs. flunarizine 5 mg
Diener 2002 18/270 21/263 0.83 [ 0.46, 1.53 ]
Subtotal (95% CI) 270 263 0.83 [ 0.46, 1.53 ]
Total events: 18 (Treatment), 21 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.58 (P = 0.56)
4 Propranolol 120 mg vs. flunarizine 10 mg
Ludin 1989 3/32 2/27 1.27 [ 0.23, 7.03 ]
Subtotal (95% CI) 32 27 1.27 [ 0.23, 7.03 ]
Total events: 3 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.27 (P = 0.79)
5 Propranolol 80 mg vs. flunarizine 10 mg
Bonuso 1998 0/25 0/25 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 25 25 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
88Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
6 Propranolol 60 mg vs. flunarizine 10 mg
Bordini 1997 0/18 0/17 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 18 17 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI) 708 692 0.98 [ 0.67, 1.44 ]
Total events: 50 (Treatment), 49 (Control)
Heterogeneity: Chi2 = 1.12, df = 5 (P = 0.95); I2 =0.0%
Test for overall effect: Z = 0.09 (P = 0.93)
Test for subgroup differences: Chi2 = 0.65, df = 3 (P = 0.89), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Analysis 2.7. Comparison 2 Propranolol versus calcium antagonists, Outcome 7 Number of dropouts due to
adverse events (vs. nifedipine; all trials parallel-group).
Review: Propranolol for migraine prophylaxis
Comparison: 2 Propranolol versus calcium antagonists
Outcome: 7 Number of dropouts due to adverse events (vs. nifedipine; all trials parallel-group)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nifedipine 40 mg
Scholz 1987 3/19 8/17 39.4 % 0.34 [ 0.11, 1.06 ]
Subtotal (95% CI) 19 17 39.4 % 0.34 [ 0.11, 1.06 ]
Total events: 3 (Treatment), 8 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.85 (P = 0.064)
2 Propranolol 120-180 mg vs. nifedipine 60-90 mg
Albers 1989 5/20 13/20 60.6 % 0.38 [ 0.17, 0.88 ]
Subtotal (95% CI) 20 20 60.6 % 0.38 [ 0.17, 0.88 ]
Total events: 5 (Treatment), 13 (Control)
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
89Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Heterogeneity: not applicable
Test for overall effect: Z = 2.27 (P = 0.023)
Total (95% CI) 39 37 100.0 % 0.37 [ 0.19, 0.72 ]
Total events: 8 (Treatment), 21 (Control)
Heterogeneity: Chi2 = 0.04, df = 1 (P = 0.85); I2 =0.0%
Test for overall effect: Z = 2.93 (P = 0.0034)
Test for subgroup differences: Chi2 = 0.04, df = 1 (P = 0.85), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
Analysis 3.1. Comparison 3 Propranolol versus other beta-blockers, Outcome 1 Responders (parallel-
group; no 1st period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 1 Responders (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg
Sudilovsky 1987 5/27 18/33 0.34 [ 0.15, 0.79 ]
2 Propranolol 160 mg vs. nadolol 80 mg
Sudilovsky 1987 5/27 11/33 0.56 [ 0.22, 1.40 ]
3 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 8/14 5/13 1.49 [ 0.65, 3.39 ]
4 Propranolol 80-160 mg vs. metoprolol 100-200 mg
Diener 1989 6/19 12/22 0.58 [ 0.27, 1.24 ]
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
90Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.2. Comparison 3 Propranolol versus other beta-blockers, Outcome 2 Responders (parallel-group
and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 2 Responders (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg
Sudilovsky 1987 5/27 18/33 0.34 [ 0.15, 0.79 ]
2 Propranolol 160 mg vs. nadolol 80 mg
Sudilovsky 1987 5/27 11/33 0.56 [ 0.22, 1.40 ]
3 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 8/14 5/13 1.49 [ 0.65, 3.39 ]
4 Propranolol 160 mg vs. metoprolol 200 mg
Kangasniemi 1984 15/33 17/33 0.88 [ 0.54, 1.45 ]
5 Propranolol 80-160 mg vs. metoprolol 100-200 mg
Diener 1989 6/19 12/22 0.58 [ 0.27, 1.24 ]
6 Propranolol 80 mg vs. metoprolol 100 mg
Olsson 1984 16/53 21/56 0.81 [ 0.47, 1.37 ]
7 Propranolol 160 mg vs. timolol 20 mg
Tfelt-Hansen 1984 48/80 44/80 1.09 [ 0.84, 1.42 ]
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
91Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.3. Comparison 3 Propranolol versus other beta-blockers, Outcome 3 Responders (vs. nadolol;
parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 3 Responders (vs. nadolol; parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg
Sudilovsky 1987 5/27 18/33 51.8 % 0.34 [ 0.15, 0.79 ]
Subtotal (95% CI) 27 33 51.8 % 0.34 [ 0.15, 0.79 ]
Total events: 5 (Treatment), 18 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 2.49 (P = 0.013)
2 Propranolol 160 mg vs. nadolol 80 mg
Sudilovsky 1987 5/27 11/33 31.6 % 0.56 [ 0.22, 1.40 ]
Subtotal (95% CI) 27 33 31.6 % 0.56 [ 0.22, 1.40 ]
Total events: 5 (Treatment), 11 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.24 (P = 0.21)
3 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 8/14 5/13 16.6 % 1.49 [ 0.65, 3.39 ]
Subtotal (95% CI) 14 13 16.6 % 1.49 [ 0.65, 3.39 ]
Total events: 8 (Treatment), 5 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.94 (P = 0.35)
Total (95% CI) 68 79 100.0 % 0.60 [ 0.37, 0.97 ]
Total events: 18 (Treatment), 34 (Control)
Heterogeneity: Chi2 = 6.42, df = 2 (P = 0.04); I2 =69%
Test for overall effect: Z = 2.07 (P = 0.038)
Test for subgroup differences: Chi2 = 6.20, df = 2 (P = 0.05), I2 =68%
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
92Propranolol for migraine prophylaxis (Review)
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Analysis 3.4. Comparison 3 Propranolol versus other beta-blockers, Outcome 4 Responders (vs.
metoprolol; parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 4 Responders (vs. metoprolol; parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. metoprolol 200 mg
Kangasniemi 1984 15/33 17/33 35.0 % 0.88 [ 0.54, 1.45 ]
Subtotal (95% CI) 33 33 35.0 % 0.88 [ 0.54, 1.45 ]
Total events: 15 (Treatment), 17 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.49 (P = 0.62)
2 Propranolol 80-160 mg vs. metoprolol 100-200 mg
Diener 1989 6/19 12/22 22.9 % 0.58 [ 0.27, 1.24 ]
Subtotal (95% CI) 19 22 22.9 % 0.58 [ 0.27, 1.24 ]
Total events: 6 (Treatment), 12 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 1.40 (P = 0.16)
3 Propranolol 80 mg vs. metoprolol 100 mg
Olsson 1984 16/53 21/56 42.1 % 0.81 [ 0.47, 1.37 ]
Subtotal (95% CI) 53 56 42.1 % 0.81 [ 0.47, 1.37 ]
Total events: 16 (Treatment), 21 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.80 (P = 0.42)
Total (95% CI) 105 111 100.0 % 0.78 [ 0.56, 1.09 ]
Total events: 37 (Treatment), 50 (Control)
Heterogeneity: Chi2 = 0.83, df = 2 (P = 0.66); I2 =0.0%
Test for overall effect: Z = 1.47 (P = 0.14)
Test for subgroup differences: Chi2 = 0.83, df = 2 (P = 0.66), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
93Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 5 Attack frequency measures (pooled crossover only; no parallel-group or 1st period crossover data)
Study or subgroup Treatment Control
Std.Mean
Difference Weight
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 160 mg vs. metoprolol 200 mg
Kangasniemi 1984 34 3 (1.9) 34 3 (1.8) 23.5 % 0.0 [ -0.48, 0.48 ]
Subtotal (95% CI) 34 34 23.5 % 0.0 [ -0.48, 0.48 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P = 1.0)
2 Propranolol 80 mg vs. metoprolol 100 mg
Hedman 1986 12 2.4 (1) 12 3.1 (2) 8.1 % -0.43 [ -1.24, 0.38 ]
Subtotal (95% CI) 12 12 8.1 % -0.43 [ -1.24, 0.38 ]
Heterogeneity: not applicable
Test for overall effect: Z = 1.03 (P = 0.30)
3 Propranolol 160 mg vs. timolol 20 mg
Tfelt-Hansen 1984 80 3.69 (3.44) 80 3.35 (3.13) 55.3 % 0.10 [ -0.21, 0.41 ]
Subtotal (95% CI) 80 80 55.3 % 0.10 [ -0.21, 0.41 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.65 (P = 0.52)
4 Propranolol 160 mg vs. d-propranolol 160 mg
Stensrud 1976 19 5 (3.7) 19 6.16 (4.6) 13.0 % -0.27 [ -0.91, 0.37 ]
Subtotal (95% CI) 19 19 13.0 % -0.27 [ -0.91, 0.37 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.83 (P = 0.40)
Total (95% CI) 145 145 100.0 % -0.01 [ -0.24, 0.22 ]
Heterogeneity: Chi2 = 2.17, df = 3 (P = 0.54); I2 =0.0%
Test for overall effect: Z = 0.11 (P = 0.91)
Test for subgroup differences: Chi2 = 2.17, df = 3 (P = 0.54), I2 =0.0%
-4 -2 0 2 4
Favours treatment Favours control
94Propranolol for migraine prophylaxis (Review)
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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: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 6 Number of patients with adverse events (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 5/14 6/13 0.77 [ 0.31, 1.93 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment 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: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 7 Number of patients with adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. timolol 20 mg
Tfelt-Hansen 1984 35/83 38/83 0.92 [ 0.65, 1.30 ]
Subtotal (95% CI) 83 83 0.92 [ 0.65, 1.30 ]
Total events: 35 (Treatment), 38 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.47 (P = 0.64)
2 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 5/14 6/13 0.77 [ 0.31, 1.93 ]
Subtotal (95% CI) 14 13 0.77 [ 0.31, 1.93 ]
Total events: 5 (Treatment), 6 (Control)
Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
95Propranolol for migraine prophylaxis (Review)
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(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Test for overall effect: Z = 0.55 (P = 0.58)
3 Propranolol 80 mg vs. metoprolol 100 mg
Hedman 1986 0/12 0/12 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 12 12 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI) 109 108 0.90 [ 0.65, 1.24 ]
Total events: 40 (Treatment), 44 (Control)
Heterogeneity: Chi2 = 0.12, df = 1 (P = 0.73); I2 =0.0%
Test for overall effect: Z = 0.64 (P = 0.52)
Test for subgroup differences: Chi2 = 0.12, df = 1 (P = 0.73), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
96Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 8 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg
Sudilovsky 1987 4/44 2/47 2.14 [ 0.41, 11.09 ]
Subtotal (95% CI) 44 47 2.14 [ 0.41, 11.09 ]
Total events: 4 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.90 (P = 0.37)
2 Propranolol 160 mg vs. nadolol 80 mg
Sudilovsky 1987 4/44 2/49 2.23 [ 0.43, 11.57 ]
Subtotal (95% CI) 44 49 2.23 [ 0.43, 11.57 ]
Total events: 4 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.95 (P = 0.34)
3 Propranolol 120 mg vs. nadolol 160 mg
Ryan 1984 0/16 0/16 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 16 16 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
4 Propranolol 120 mg vs. nadolol 80 mg
Ryan 1984 0/16 1/16 0.33 [ 0.01, 7.62 ]
Subtotal (95% CI) 16 16 0.33 [ 0.01, 7.62 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
5 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 0/15 1/13 0.29 [ 0.01, 6.60 ]
Subtotal (95% CI) 15 13 0.29 [ 0.01, 6.60 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.77 (P = 0.44)
6 Propranolol 160 mg vs. metoprolol 200 mg
Scholz 1987 3/19 6/22 0.58 [ 0.17, 2.01 ]
Subtotal (95% CI) 19 22 0.58 [ 0.17, 2.01 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
97Propranolol for migraine prophylaxis (Review)
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(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Total events: 3 (Treatment), 6 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.86 (P = 0.39)
Total (95% CI) 154 163 1.00 [ 0.48, 2.10 ]
Total events: 11 (Treatment), 12 (Control)
Heterogeneity: Chi2 = 3.54, df = 4 (P = 0.47); I2 =0.0%
Test for overall effect: Z = 0.01 (P = 0.99)
Test for subgroup differences: Chi2 = 3.54, df = 4 (P = 0.47), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
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).
Review: Propranolol for migraine prophylaxis
Comparison: 3 Propranolol versus other beta-blockers
Outcome: 9 Number of dropouts due to adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. nadolol 160 mg
Sudilovsky 1987 4/44 2/47 2.14 [ 0.41, 11.09 ]
Subtotal (95% CI) 44 47 2.14 [ 0.41, 11.09 ]
Total events: 4 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.90 (P = 0.37)
2 Propranolol 160 mg vs. nadolol 80 mg
Sudilovsky 1987 4/44 2/49 2.23 [ 0.43, 11.57 ]
Subtotal (95% CI) 44 49 2.23 [ 0.43, 11.57 ]
Total events: 4 (Treatment), 2 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.95 (P = 0.34)
3 Propranolol 120 mg vs. nadolol 160 mg
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
98Propranolol for migraine prophylaxis (Review)
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(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Ryan 1984 0/16 0/16 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 16 16 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
4 Propranolol 120 mg vs. nadolol 80 mg
Ryan 1984 0/16 1/16 0.33 [ 0.01, 7.62 ]
Subtotal (95% CI) 16 16 0.33 [ 0.01, 7.62 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
5 Propranolol 80-160 mg vs. nadolol 40-160 mg
Olerud 1986 0/15 1/13 0.29 [ 0.01, 6.60 ]
Subtotal (95% CI) 15 13 0.29 [ 0.01, 6.60 ]
Total events: 0 (Treatment), 1 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.77 (P = 0.44)
6 Propranolol 160 mg vs. metoprolol 200 mg
Kangasniemi 1984 2/36 0/36 5.00 [ 0.25, 100.63 ]
Scholz 1987 3/19 6/22 0.58 [ 0.17, 2.01 ]
Subtotal (95% CI) 55 58 0.94 [ 0.33, 2.72 ]
Total events: 5 (Treatment), 6 (Control)
Heterogeneity: Chi2 = 1.78, df = 1 (P = 0.18); I2 =44%
Test for overall effect: Z = 0.11 (P = 0.91)
7 Propranolol 80 mg vs. metoprolol 100 mg
Olsson 1984 0/56 0/56 0.0 [ 0.0, 0.0 ]
Subtotal (95% CI) 56 56 0.0 [ 0.0, 0.0 ]
Total events: 0 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
8 Propranolol 160 mg vs. atenolol 100 mg
Stensrud 1980 1/35 0/35 3.00 [ 0.13, 71.22 ]
Subtotal (95% CI) 35 35 3.00 [ 0.13, 71.22 ]
Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.68 (P = 0.50)
9 Propranolol 160 mg vs. timolol 20 mg
Tfelt-Hansen 1984 6/89 9/89 0.67 [ 0.25, 1.79 ]
Subtotal (95% CI) 89 89 0.67 [ 0.25, 1.79 ]
Total events: 6 (Treatment), 9 (Control)
Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
(Continued . . . )
99Propranolol for migraine prophylaxis (Review)
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(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Test for overall effect: Z = 0.80 (P = 0.42)
10 Propranolol 160 mg vs. d-propranolol 160 mg
Stensrud 1976 1/20 0/20 3.00 [ 0.13, 69.52 ]
Subtotal (95% CI) 20 20 3.00 [ 0.13, 69.52 ]
Total events: 1 (Treatment), 0 (Control)
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
Total (95% CI) 390 399 1.05 [ 0.61, 1.80 ]
Total events: 21 (Treatment), 21 (Control)
Heterogeneity: Chi2 = 6.25, df = 8 (P = 0.62); I2 =0.0%
Test for overall effect: Z = 0.16 (P = 0.87)
Test for subgroup differences: Chi2 = 4.37, df = 7 (P = 0.74), I2 =0.0%
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
100Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.1. Comparison 4 Propranolol versus other drugs, Outcome 1 Responders (parallel-group and 1st
period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 1 Responders (parallel-group and 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg
Kangasniemi 1983 3/11 1/11 3.00 [ 0.37, 24.58 ]
2 Propranolol 120-160 mg vs. cyclandelate 1200-1600 mg
Gerber 1995 18/34 20/28 0.74 [ 0.50, 1.10 ]
3 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 33/78 30/81 1.14 [ 0.78, 1.68 ]
4 Propranolol 60-240 mg vs. divalproex sodium 1000-2000 mg
Kaniecki 1997 12/17 9/15 1.18 [ 0.70, 1.97 ]
5 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 7/20 8/19 0.83 [ 0.37, 1.84 ]
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
101Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.2. Comparison 4 Propranolol versus other drugs, Outcome 2 Responders (parallel-group and
pooled crossover data [one 1st period]).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 2 Responders (parallel-group and pooled crossover data [one 1st period])
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg
Andersson 1981 11/28 4/28 2.75 [ 0.99, 7.61 ]
Kangasniemi 1983 3/11 1/11 3.00 [ 0.37, 24.58 ]
2 Propranolol 120-160 mg vs. cyclandelate 1200-1600 mg
Gerber 1995 18/34 20/28 0.74 [ 0.50, 1.10 ]
3 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 33/78 30/81 1.14 [ 0.78, 1.68 ]
4 Propranolol 60-240 mg vs. divalproex sodium 1000-2000 mg
Kaniecki 1997 20/32 21/32 0.95 [ 0.66, 1.38 ]
5 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 7/20 8/19 0.83 [ 0.37, 1.84 ]
6 Propranolol 120 mg vs. methysergide 3 mg
Behan 1980 19/36 13/36 1.46 [ 0.86, 2.49 ]
7 Propranolol 160 mg vs. clonidine 100 mcg
Kass 1980 13/21 8/21 1.63 [ 0.86, 3.08 ]
8 Propranolol 80-240 mg vs. amitriptyline 50-150 mg
Ziegler 1987 12/30 10/30 1.20 [ 0.61, 2.34 ]
9 Propranolol 1.8 mg/kg vs. ASA 13.5 mg/kg
Baldrati 1983 9/12 9/12 1.00 [ 0.63, 1.59 ]
0.1 0.2 0.5 1 2 5 10
Favours control Favours treatment
102Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.3. Comparison 4 Propranolol versus other drugs, Outcome 3 Attack frequency measures
(parallel-group and 1st period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 3 Attack frequency measures (parallel-group and 1st period crossover data)
Study or subgroup Treatment Control
Std.Mean
Difference
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg
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 9 6.4 (4.1) 13 10.2 (6.8) -0.62 [ -1.50, 0.25 ]
3 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 19 4.4 (4) 19 7.3 (7.4) -0.48 [ -1.12, 0.17 ]
4 Propranolol 120 mg vs. naproxen 1100 mg
Sargent 1985 44 -0.21 (1.86) 42 0.48 (2.02) -0.35 [ -0.78, 0.07 ]
5 Propranolol 1230 mcg/kg vs. methysergide 30.8 mcg/kg
Nicolodi 1997 128 3.1 (1.4) 128 3.06 (1.4) 0.03 [ -0.22, 0.27 ]
6 Propranolol 80 mg vs. alpha-dihydroergocryptine 20 mg
Micieli 2001 15 1.3 (1.2) 15 1.3 (1.2) 0.0 [ -0.72, 0.72 ]
-4 -2 0 2 4
Favours treatment Favours control
103Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.4. Comparison 4 Propranolol versus other drugs, Outcome 4 Attack frequency measures
(parallel-group and pooled crossover data [two 1st period]).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data [two 1st period])
Study or subgroup Treatment Control
Std.Mean
Difference
Std.Mean
Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg
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 ]
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 31 6.6 (4.9) 31 6.9 (6.1) -0.05 [ -0.55, 0.44 ]
3 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 19 4.4 (4) 19 7.3 (7.4) -0.48 [ -1.12, 0.17 ]
4 Propranolol 120 mg vs. naproxen 1100 mg
Sargent 1985 44 -0.21 (1.86) 42 0.48 (2.02) -0.35 [ -0.78, 0.07 ]
5 Propranolol 1230 mcg/kg vs. methysergide 30.8 mcg/kg
Nicolodi 1997 128 3.1 (1.4) 128 3.06 (1.4) 0.03 [ -0.22, 0.27 ]
6 Propranolol 240 mg vs. mefenamic acid 1500 mg
Johnson 1986 17 13.8 (12) 17 12.9 (10.8) 0.08 [ -0.60, 0.75 ]
7 Propranolol 160 mg vs. clonidine 100 mcg
Kass 1980 21 12.67 (11.15) 21 13 (11.65) -0.03 [ -0.63, 0.58 ]
8 Propranolol 80 mg vs. alpha-dihydroergocryptine 20 mg
Micieli 2001 15 1.3 (1.2) 15 1.3 (1.2) 0.0 [ -0.72, 0.72 ]
-4 -2 0 2 4
Favours treatment Favours control
104Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 5 Number of patients with adverse events (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 120-160 mg vs. cyclandelate 1200-1600 mg
Gerber 1995 6/42 4/42 1.50 [ 0.46, 4.93 ]
2 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 19/78 13/81 1.52 [ 0.81, 2.86 ]
3 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 7/20 7/19 0.95 [ 0.41, 2.20 ]
4 Propranolol 120 mg vs. naproxen 1100 mg
Sargent 1985 30/44 38/42 0.75 [ 0.60, 0.94 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
105Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse
events (parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 6 Number of patients with adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 120-160 mg vs. cyclandelate 1200-1600 mg
Gerber 1995 6/42 4/42 1.50 [ 0.46, 4.93 ]
2 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 19/78 13/81 1.52 [ 0.81, 2.86 ]
3 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 7/20 7/19 0.95 [ 0.41, 2.20 ]
4 Propranolol 120 mg vs. naproxen 1100 mg
Sargent 1985 30/44 38/42 0.75 [ 0.60, 0.94 ]
5 Propranolol 120 mg vs. tolfenamic acid 300 mg
Mikkelsen 1986 3/31 2/31 1.50 [ 0.27, 8.36 ]
6 Propranolol 120 mg vs. methysergide 3 mg
Behan 1980 12/36 16/36 0.75 [ 0.42, 1.35 ]
7 Propranolol 160 mg vs. clonidine 100 mcg
Kass 1980 11/21 11/21 1.00 [ 0.56, 1.78 ]
8 Propranolol 60-240 mg vs. divalproex sodium 1000-2000 mg
Kaniecki 1997 11/32 16/32 0.69 [ 0.38, 1.24 ]
9 Propranolol 1.8 mg/kg vs. ASA 13.5 mg/kg
Baldrati 1983 6/12 6/12 1.00 [ 0.45, 2.23 ]
10 Propranolol 240 mg vs. mefenamic acid 1500 mg
Johnson 1986 2/23 2/22 0.96 [ 0.15, 6.21 ]
0.1 0.2 0.5 1 2 5 10
Favours treatment Favours control
106Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to
adverse events (parallel-group; no 1st period crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 7 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 4/78 5/81 0.83 [ 0.23, 2.98 ]
2 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 2/20 0/19 4.76 [ 0.24, 93.19 ]
3 Propranolol 160 mg vs. dihydroergotamine 10 mg
Scholz 1987 3/19 0/13 4.90 [ 0.27, 87.59 ]
4 Propranolol 120-160 mg vs. amitriptyline 50-75 mg
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 1 2 5 10
Favours treatment Favours control
107Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to
adverse events (parallel-group and pooled crossover data).
Review: Propranolol for migraine prophylaxis
Comparison: 4 Propranolol versus other drugs
Outcome: 8 Number of dropouts due to adverse events (parallel-group and pooled crossover data)
Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Propranolol 160 mg vs. femoxetine 400 mg
Andersson 1981 2/49 2/49 1.00 [ 0.15, 6.82 ]
Kangasniemi 1983 3/29 0/29 7.00 [ 0.38, 129.74 ]
2 Propranolol 120 mg vs. cyclandelate 1200 mg
Diener 1996 4/78 5/81 0.83 [ 0.23, 2.98 ]
3 Propranolol 80-240 mg vs. divalproex sodium 750-1500 mg
Klapper 1994 3/24 9/24 0.33 [ 0.10, 1.08 ]
4 Propranolol 60-240 mg vs. divalproex sodium 1000-2000 mg
Kaniecki 1997 1/37 4/37 0.25 [ 0.03, 2.13 ]
5 Propranolol 120 mg vs. 5-hydroxytryptophan 300 mg
Maissen 1991 2/20 0/19 4.76 [ 0.24, 93.19 ]
6 Propranolol 240 mg vs. mefenamic acid 1500 mg
Johnson 1986 1/29 1/29 1.00 [ 0.07, 15.24 ]
7 Propranolol 120 mg vs. tolfenamic acid 300 mg
Kjaersgard 1994 9/76 5/76 1.80 [ 0.63, 5.12 ]
Mikkelsen 1986 2/39 2/39 1.00 [ 0.15, 6.75 ]
8 Propranolol 120 mg vs. methysergide 3 mg
Behan 1980 0/56 3/56 0.14 [ 0.01, 2.70 ]
9 Propranolol 160 mg vs. dihydroergotamine 10 mg
Scholz 1987 3/19 0/13 4.90 [ 0.27, 87.59 ]
10 Propranolol 80 mg vs. alpha-dihydroergocryptine 20 mg
Micieli 2001 5/40 4/40 1.25 [ 0.36, 4.32 ]
11 Propranolol 160 mg vs. clonidine 100 mcg
Kass 1980 0/23 0/23 0.0 [ 0.0, 0.0 ]
12 Propranolol 1.8 mg/kg vs. ASA 13.5 mg/kg
Baldrati 1983 2/18 3/18 0.67 [ 0.13, 3.53 ]
13 Propranolol 120-160 mg vs. amitriptyline 50-75 mg
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 1 2 5 10
Favours treatment Favours control
(Continued . . . )
108Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI 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 1 2 5 10
Favours treatment Favours control
A D D I T I O N A L T A B L E S
Table 1. Methodological quality - Delphi list
Study Randomi-
sation
Conceal-
ment
Base-
line com-
parab.
Inclusion
criteria
Blind
evaluators
Blind care
providers
Blind pa-
tients
Reporting
of results
Intent-to-
treat
Ahuja
1985
1 ? ? 0 1 1 1 1 ?
Al-Qassab
1993
1 ? ? 0 1 1 1 1 ?
Albers
1989
1 ? ? 1 0 0 0 1 0
Andresson
1981
1 ? ? 1 1 1 1 1 0
Baldrati
1983
1 ? ? ? 1 1 1 0 0
Behan
1980
? ? ? 0 1 1 1 0 0
Bonuso
1998
1 ? ? 0 ? ? ? 0 0
Bordini
1997
1 ? ? 1 1 1 1 0 0
Borgesen
1974
1 ? ? 1 1 1 1 1 0
109Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Methodological quality - Delphi list (Continued)
Dahlöf
1987
1 ? ? 1 1 1 1 0 1
Diamond
1976
1 ? ? 0 1 1 1 0 0
Diamond
1982
1 ? ? 0 1 1 1 0 0
Diener
1996
1 ? 1 1 1 1 1 1 1
Diener
2002
1 1 1 1 1 1 1 1 1
Diener
1989
1 ? 1 1 1 1 1 1 ?
Formisano
1991
1 ? 0 0 0 0 1 1 0
Forssman
1976
1 ? ? 1 1 1 1 1 0
Gawel
1991
? 1 1 1 1 1 1 0 0
Gerber
1995
1 ? 1 1 1 1 1 1 0
Grote-
meyer
1987
? ? ? ? 1 1 1 1 0
Hedman
1986
1 ? ? 0 1 1 1 1 0
Holdorff
1977
1 ? 0 1 1 1 1 0 0
Johnson
1986
1 1 ? ? 1 1 1 1 0
Kangas-
niemi
1983
1 ? ? 1 1 1 1 1 0
Kangas-
niemi
1984
1 ? 0 1 1 1 1 1 0
110Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Methodological quality - Delphi list (Continued)
Kaniecki
1997
1 ? ? 1 ? ? ? 0 0
Kass 1980 1 ? ? 1 1 1 1 1 0
Kjaesgard-
Rasmussen
1994
1 ? 1 1 1 1 1 1 ?
Klapper
1994
1 ? 1 0 0 0 0 0 0
Kuritzky
1987
1 ? ? ? ? ? ? 0 0
Lücking
1988a
1 ? ? 1 1 1 1 1 0
Lücking
1998b
1 ? ? 1 1 1 1 1 0
Ludin
1989
1 ? ? 1 1 1 1 1 0
Maissen
1985
? ? 0 1 1 1 1 1 ?
Malvea
1973
1 ? ? 1 1 1 1 0 0
Mathew
1981-
Study 1
1 ? ? 0 0 0 0 1 0
Mathew
1981-
Study 2
1 ? ? 0 0 0 0 1 0
Micieli
2001
1 ? 0 1 1 1 1 1 0
Mikkelsen
1986
1 ? ? 1 1 1 1 1 0
Nadel-
mann
1986
1 ? ? 1 1 1 1 1 0
111Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Methodological quality - Delphi list (Continued)
Nicolodi
1997
1 ? ? ? 1 1 1 1 ?
Olerud
1986
1 ? 0 0 1 1 1 1 0
Olsson
1984
1 ? ? 1 1 1 1 1 0
Palferman
1983
1 ? ? 1 1 1 1 0 0
Pita 1977 1 ? ? 1 1 1 1 1 0
Pradalier
1989
1 ? 1 1 1 1 1 1 ?
Ryan 1984 1 ? ? 1 1 1 1 0 0
Sargent
1985
1 ? ? 1 1 1 1 1 0
Scholz
1987
1 ? ? ? 0 1 1 1 0
Shimell
1990
1 ? 1 1 1 1 1 0 ?
Solomon
1986
? ? ? 0 1 1 1 0 0
Stensrud
1976
1 ? ? 0 1 1 1 1 0
Stensrud
1980
1 ? ? 0 1 1 1 0 0
Sudilovski
1987
1 ? 1 0 1 1 1 1 0
Tfelt-
Hasen
1984
1 ? ? 1 1 1 1 1 0
Weber
1972
1 ? ? ? 1 1 1 1 0
Wideroe
1976
1 ? ? 0 1 1 1 1 0
112Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 1. Methodological quality - Delphi list (Continued)
Ziegler
1987
1 ? ? 1 1 1 1 0 0
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 0 1 0 0 0
Al-Qassab 1993 0 1 1 1 0
Albers 1989 0 1 1 0 1
Andersson 1981 0 0 0 0 0
Baldrati 1983 0 1 1 1 0
Behan 1980 0 0 0 0 0
Bonuso 1998 0 1 0 0 0
Bordini 1997 0 1 0 0 0
Borgesen 1974 1 1 1 1 0
Dahlöf 1987 0 1 0 1 0
Diamond 1976 0 0 0 0 0
Diamond 1982 0 1 0 1 0
Diener 1996 0 1 1 1 1
Diener 2002 1 1 1 1 1
Diener 1989 0 1 1 1 0
Formisano 1991 0 1 0 1 0
Forssman 1976 0 0 1 1 1
Gawel 1992 0 1 1 1 0
Gerber 1995 0 1 1 1 0
Grotemeyer 1987 0 1 0 0 0
113Propranolol for migraine prophylaxis (Review)
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Table 2. Adequacy of observation and reporting of key clinical issues (questions 1-5) (Continued)
Hedman 1986 0 1 0 0 1
Holdroff 1977 0 1 0 0 0
Johnson 1986 0 0 0 1 0
Kangasniemi 1983 0 0 0 1 0
Kangasniemi 1984 0 1 1 1 0
Kaniecki 1997 1 1 0 1 0
Kass 1980 0 1 0 1 1
Kjaesgard-
Rasmussen 1994
0 1 1 1 1
Klapper 1994 0 0 0 0 0
Kuritzky 1987 0 0 0 0 0
Lücking 1988a 0 0 0 0 0
Lücking 1988b 0 0 0 0 0
Ludin 1989 0 1 0 1 0
Maissen 1985 0 1 0 1 0
Malvea 1973 1 0 0 1 0
Mathew 1981-
study 1
0 0 0 1 0
Mathew 1981-
study 2
0 0 0 1 0
Micieli 2001 0 1 1 1 1
Mikkelsen 1986 0 1 0 0 0
Nadelmann 1986 0 1 1 1 0
Nicolodi 1997 0 0 0 1 0
Olerud 1986 0 1 0 1 0
Olsson 1984 1 1 1 1 1
114Propranolol for migraine prophylaxis (Review)
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Table 2. Adequacy of observation and reporting of key clinical issues (questions 1-5) (Continued)
Palferman 1983 0 0 0 0 0
Pita 1977 1 1 1 0 0
Pradlier 1989 0 1 1 1 0
Ryan 1984 0 0 0 1 0
Sargent 1985 0 0 0 0 0
Scholz 1987 0 0 0 1 0
Shimell 1990 1 1 1 0 0
Solomon 1986 0 0 0 0 0
Stensrud 1976 0 1 0 0 0
Stensrud 1980 0 1 0 0 0
Sudilovsky 1987 0 1 0 1 0
Tfelt-Hansen 1984 1 1 1 1 0
Weber 1972 0 1 0 0 0
Wideroe 1976 1 1 0 0 0
Ziegler 1987 0 0 0 1 0
Table 3. Adequacy of observation and reporting of key clinical issues (questions 6-10)
Study Diary used Frequency data Intensity data 2-month follow up 6-month follow up
Ahuja 1985 0 1 0 0 0
Al-Qassab 1993 1 1 1 0 0
Albers 1989 1 1 0 0 0
Andersson 1981 1 1 1 0 0
Baldrati 1983 1 0 0 0 0
Behan 1980 1 0 0 0 0
Bonuso 1998 0 0 0 0 1
115Propranolol for migraine prophylaxis (Review)
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Table 3. Adequacy of observation and reporting of key clinical issues (questions 6-10) (Continued)
Bordini 1997 1 0 0 0 0
Borgesen 1974 1 1 0 0 0
Dahlöf 1974 1 0 0 1 1
Diamond 1976 0 0 0 0 0
Diamond 1982 1 0 0 0 0
Diener 1996 1 0 0 1 0
Diener 2002 1 1 1 1 0
Diener 1989 1 0 0 0 0
Formisano 1991 1 1 0 0 0
Forssman 1976 1 0 0 0 0
Gawel 1992 1 0 1 1 0
Gerber 1995 1 0 0 0 0
Grotemeyer 1987 0 1 0 0 0
Hedman 1986 0 1 0 0 0
Holdorff 1977 0 0 0 0 0
Johnson 1986 1 1 0 0 0
Kangasniemi 1983 1 1 0 0 0
Kangasniemi 1984 1 1 0 1 0
Kaniecki 1997 1 0 0 0 0
Kass 1980 1 1 0 1 0
Kjaesgard-
Rasmussen 1994
0 1 1 0 0
Klapper 1994 1 0 0 0 0
Kuritzky 1987 1 0 0 0 0
Lücking 1988a 1 1 1 0 0
116Propranolol for migraine prophylaxis (Review)
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Table 3. Adequacy of observation and reporting of key clinical issues (questions 6-10) (Continued)
Lücking 1988b 1 1 1 0 0
Ludin 1989 1 1 1 0 0
Maissen 1985 1 1 1 1 0
Malvea 1973 1 0 0 0 0
Mathew 1981-
study 1
1 0 0 0 0
Mathew 1981-
study 2
1 0 0 0 0
Micieli 2001 1 1 0 0 0
Mikkelsen 1986 1 1 1 0 0
Nadelmann 1986 1 0 0 0 0
Olerud 1986 1 1 1 1 0
Olsson 1984 1 1 0 1 0
Palferman 1983 1 0 0 0 0
Pita 1977 0 1 1 0 0
Pradalier 1989 1 1 0 0 0
Ryan 1984 1 0 0 1 0
Sargent 1985 1 1 1 0 0
Scholz 1987 1 0 0 0 0
Shimell 1990 0 0 0 1 0
Solomon 1986 1 0 0 0 0
Stensrud 1976 0 1 0 0 0
Stensrud 1980 1 0 0 0 0
Sudilovsky 1987 1 1 1 0 0
Tfelt-Hansen 1984 1 1 1 0 0
Weber 1972 0 0 0 0 0
117Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 3. Adequacy of observation and reporting of key clinical issues (questions 6-10) (Continued)
Wideroe 1976 1 1 0 0 0
Ziegler 1987 1 0 0 0 0
Nicolodi 1997 1 1 0 0 0
W H A T ’ S N E W
Last assessed as up-to-date: 15 May 2003.
Date Event Description
1 October 2012 Amended Contact details updated.
H I S T O R Y
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 Contact details updated.
29 January 2009 Amended Contact details updated.
26 August 2008 Amended Converted to new review format.
C O N T R I B U T I O N S O F A U T H O R S
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.
118Propranolol for migraine prophylaxis (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D E C L A R A T I O N S O F I N T E R E S T
None known.
S O U R C E S O F S U P P O R T
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.
N O T E S
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’).
I N D E X T E R M S
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
119Propranolol for migraine prophylaxis (Review)
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