Art. Cefalea

Propranolol for migraine prophylaxis (Review)

Linde K, Rossnagel K

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 11

http://www.thecochranelibrary.com

Propranolol for migraine prophylaxis (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

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


(vs. flunarizine; all trials parallel-group). . . . . . . . . . . . . . . . . . . . . . . . . . 88


(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)


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-


Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse events (parallel-


Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to adverse events (parallel-


Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to adverse events (parallel-


109ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

119INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiPropranolol for migraine prophylaxis (Review)


[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.


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)


mailto:[email protected]

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



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).



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



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



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



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



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.



R E F E R E N C E S

References to studies included in this review

Ahuja 1985 {published data only}

Ahuja GK, Verma AK. Propranolol in prophylaxis of

migraine. Indian Journal of Medical Research 1985;82:

263–5.

Albers 1989 {published data only}

Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine

versus propranolol for the initial prophylaxis of migraine.

Headache 1989;29(4):215–8.

Al-Qassab 1993 {published data only}

Al-Qassab HK, Findley LJ. Comparison of propranolol

LA 80 mg and propranolol LA 160 mg in mirgraine

prophylaxis: a placebo controlled study. Cephalalgia 1993;

13(2):128–31.

Andersson 1981 {published data only}

Andersson PG, Petersen EN. Propranolol and femoxetine, a

5HT-uptake inhibitor, in migraine prophylaxis. A double-

blind crossover study. Acta Neurologica Scandinavica 1981;

64(4):280–8.

Baldrati 1983 {published data only}

Baldrati A, Cortelli P, Procaccianti G, Gamberini

G, D’Alessandro R, Baruzzi A, et al.Propranolol and

acetylsalicylic acid in migraine prophylaxis. Double-blind

crossover study. Acta Neurologica Scandinavica 1983;67(3):

181–6.

Behan 1980 {published data only}

Behan PO, Reid M. Propranolol in the treatment of

migraine. Practitioner 1980;224(1340):201–3.

Bonuso 1998 {published data only}

Bonuso S, Di Stasio E, Marano E, de Angelis S, Amato

D, Scellini T. Long-term outcome of migraine therapy:

predictive value of the frontotemporal nitroglycerin test.

Neurology 1998;51(5):1475–8.

Bordini 1997 {published data only}

Bordini CA, Arruda MA, Ciciarelli MC, Speciali JG.

Propranolol vs flunarizine vs flunarizine plus propranolol in

migraine without aura prophylaxis. A double-blind trial.

Arquivos de Neuro-Psiquiatria 1997;55(3B):536–41.

Borgesen 1974 {published data only}

Borgesen SE. Treatment of migraine with propranolol.

Postgraduate Medical Journal 1976;52 Suppl 4(0):163–5.∗ Borgesen SE, Nielsen JL, Moller CE. Prophylactic

treatment of migraine with propranolol. A clinical trial.

Acta Neurologica Scandinavica 1974;50(5):651–6.

Borgesen SE, Nielsen JL, Moller CE. Propranolol in

migraine. Lancet 1974;2(7871):58.

Dahlöf 1987 {published data only}

Dahlöf C. No clearcut longterm prophylactic effect of

one month of treatment with propranolol in migraineurs.

Cephalalgia 1987;7 Suppl 6:459–60.

Diamond 1976 {published data only}

Diamond S, Medina JL. Double blind study of propranolol

for migraine prophylaxis. Headache 1976;16(1):24–7.


Diamond S, Kudrow L, Stevens J, Shapiro DB. Long-term

study of propanolol in the treatment of migraine. Headache1982;22(6):268–71.

Diener 1989 {published data only}∗ Diener HC, Scholz E, Dichgans J, Gerber WD, Jäck

A, Bille A, et al.Central effects of drugs used in migraine

prophylaxis evaluated by visual evoked potentials. Annals of

Neurology 1989;25(2):125–30.

Gerber WD, Diener HC, Scholz E, Niederberger U.

Responders and non-responders to metoprolol, propanolol

and nifidepine treatment in migraine prophylaxis: a dose-

range study based on time-series analysis. Cephalalgia 1991;

11(1):37–45.

Diener 1996 {published data only}

Diener HC, Foh M, Iaccarino C, Wessely P, Isler H, Strenge

H, et al.Cyclandelate in the prophylaxis of migraine: a

randomized, parallel, double-blind study in comparison

with placebo and propanolol. Cephalalgia 1996;16(6):

441–7.

Diener 2002 {published data only}

Diener HC. Efficacy and tolerability of flunarizine and

propranolol in the prophylactic treatment of migraine.

Cephalalgia 1999;19(4):374.∗ Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath

V, Ludin HP, Nappi G, et al.Efficacy and tolerability in

migraine prophylaxis of flunarizine in reduced doses: a

comparison with propranolol 160 mg daily [published

erratum appears in Cephalalgia 2002;22(6):488].

Cephalalgia 2002;22(3):209–21.

Formisano 1991 {published data only}

Formisano R, Falaschi P, Cerbo R, Proietti A, Catarci T,

D’Urso R, et al.Nimodipine in migraine: clinical efficacy

and endocrinological effects. European Journal of ClinicalPharmacology 1991;41(1):69–71.

Forssman 1976 {published data only}

Forssman B, Henriksson KG, Johannsson V, Lindvall L,

Lundin H. Propranolol for migraine prophylaxis. Headache

1976;16(5):238–45.

Gawel 1992 {published data only}

Gawel M, Kreeft J, Nelson R, Simard D. Flunarizine is

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.

Comparison of the efficacy and safety of flunarizine to

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

prophylaxis of migraine - a double-blind placebo-controlled

study. Functional Neurology 1995;10(1):27–35.

Schellenberg R, Schwarz A, Niederberger U, Bölsche F,

Schindler M, Gerber WD, et al.On the long-term effect of



cyclandelate and propranolol in migraine after stopping a

four-month drug prophylaxis [Zur Langzeitwirkung von

Cyclandelat und Propranolol bei Migräne nach Beendigung

einer viermonatigen medikamentösen Prophylaxe].

Nervenheilkunde 1997;16:183–7.

Grotemeyer 1987 {published data only}

Grotemeyer KH, Husstedt IW, Schlake HP. Betablocker vs

placebo in vasomotor headache. A double-blind crossover

study [Betablocker vs Placebo bei vasomotorischem

Kopfschmerz. Eine doppelblinde Cross–over–Studie].

Deutsche Medizinische Wochenschrift 1987;112(45):1740–3.

Hedman 1986 {published data only}

Hedman C, Winther K, Knudsen JB. The difference

between non-selective and beta 1-selective beta-blockers in

their effect on platelet function in migraine patients. Acta

Neurologica Scandinavica 1986;74(6):475–8.

Holdorff 1977 {published data only}

Holdorff B, Sinn M, Roth G. Propranolol for migraine

prophylaxis: a double-blind study [Propranolol in der

Migräneprophylaxe. Eine Doppelblindstudie]. Medizinische

Klinik 1977;72(25):1115–8.

Johnson 1986 {published data only}

Johnson RH, Hornabrook RW, Lambie DG. Comparison of

mefenamic acid and propranolol with placebo in migraine

prophylaxis. Acta Neurologica Scandinavica 1986;73(5):

490–2.

Kangasniemi 1983 {published data only}

Kangasniemi PJ, Nyrke T, Lang AH, Petersen E. Femoxetine

- a new 5-HT uptake inhibitor - and propranolol in the

prophylactic treatment of migraine. Acta NeurologicaScandinavica 1983;68(4):262–7.

Kangasniemi 1984 {published data only}∗ Kangasniemi P, Hedman C. Metoprolol and propranolol

in the prophylactic treatment of classical and common

migraine. A double-blind study. Cephalalgia 1984;4(2):

91–6.

Nyrke T, Kangasniemi P, Lang AH, Petersen E. Steady-state

visual evoked potentials during migraine prophylaxis by

propranolol and femoxetine. Acta Neurologica Scandinavica

1984;69(1):9–14.

Kaniecki 1997 {published data only}

Kaniecki RG. A comparison of divalproex with propranolol

and placebo for the prophylaxis of migraine without aura.

Archives of Neurology 1997;54(9):1141–5.

Kass 1980 {published data only}

Kass B, Nestvold K. Propranolol (Inderal) and clonidine

(Catapressan) in the prophylactic treatment of migraine. A

comparative trial. Acta Neurologica Scandinavica 1980;61

(6):351–6.

Kjaersgard 1994 {published data only}

Kjaersgard Rasmussen MJ, Holt Larsen B, Borg L, Soelberg

Sorensen P, Hansen PE. Tolfenamic acid versus propranolol

in the prophylactic treatment of migraine. Acta Neurologica

Scandinavica 1994;89(6):446–50.

Klapper 1994 {published data only}

Klapper JA. An open label cross-over comparison of

divalproex sodium and propranolol HCl in the prevention

of migraine headaches. Headache Quarterly 1994;5(1):

50–3.

Kuritzky 1987 {published data only}

Kuritzky A, Hering R. Prophylactic treatment of migraine

with long acting propranolol - a comparison with placebo.


Lücking 1988a {published data only}∗ Lücking CH, Oestreich W, Schmidt R, Soyka D.

Flunarizine versus propranolol in the prophylaxis of

migraine: two double-blind comparative studies in more

than 400 patients. Cephalalgia 1988;8(Suppl 8):21–6.

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):



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



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 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.



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.


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



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



Al-Qassab 1993


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


F: median attack frequency 3.8 (P1) vs. 3.8 (P2) vs. 3.2 (C)

AU: similar in all 3 groups

HI: not reported

AEs: not reported


V: 0

Notes High dropout rate

Risk of bias



Albers 1989

Methods D: parallel

C: unclear

B: unblinded

WD: 20/40

J: 2-0-1

DU: -/6m/-


D: migraine

C: Ad Hoc

F: 89%

A: 23-47 years



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



Andersson 1981


C: unclear

B: double

WD: 12/49

J: 1-1-1

DU: 1m/2x3m (no washout)/-


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


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)



Andersson 1981 (Continued)


V: (+)

Notes Baseline data for 28 patients only

Risk of bias



Baldrati 1983


C: unclear

B: double

WD: 6/18

J: 1-1-1

DU: 1m/2x3m (2w)/-


D: all migraine without aura

C: Ad Hoc

F: 89%

A: 18-49 years

DU: 3-38 years

S: probably neurological university outpatient clinic in Italy

Interventions P: 1.8 mg/kg

C: Acetylsalicylic acid 13.5 mg/kg

Outcomes R: 9/12 vs. 9/12 (at least 50% index reduction)

F: not reported

AU: not reported

HI: 65% reduction in both groups

AEs: 6/12 vs. 6/12


V: 0

Notes Small trial with relatively high dropout rate

Risk of bias





Behan 1980


C: unclear

B: double

WD: 20/56

J: 0-1-0

DU: -/2x3m (1m)/-



C: unclear

F: 66%

A: 18-56 years

DU: 1-33 years

S: probably neurology clinic in Glasgow


C: Methysergide 3 mg

Outcomes R: 19/36 vs. 13/36

F: frequency lower with propranolol

AU: not reported

HI: not reported

AEs: 12/36 vs. 16/36


V: (+)


Risk of bias



Bonuso 1998

Methods D: parallel

C: unclear

B: unclear

WD: 8/50

J: 1-0-0

DU: unclear/2m/4m



C: IHS

F: 68%

A: 20-45 years

DU: unclear



Bonuso 1998 (Continued)

S: unclear, Italy


C: Flunarizine 10 mg


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



Bordini 1997

Methods D: parallel

C: unclear

B: double

WD: 7/52

J: 1-1-0

DU: 3w/17w/6w



C: IHS

F: 91%

A: 17-48 years

DU: not reported

S: outpatient department of a university hospital in Brazil


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)



Bordini 1997 (Continued)

V: 0 vs. C1, (-) vs. C2

Notes Small groups, low propranolol dose

Risk of bias



Borgesen 1974


C: unclear

B: double

WD: 15/45

J: 1-1-0

DU: 4w/2x3m/-



C: Ad Hoc

F: 83%

A: 18-59 years

DU: 1-50 years

S: neurology department in Denmark


C: Placebo


F: 1.03 (sd 1.02) vs. 1.33 (1.15) attacks per week

AU: similar in both groups

HI: not reported

AEs: not reported


V: +


Responder rates and attack frequency calculated from single patient data presented in the

publication

Risk of bias





Dahlöf 1987


C: unclear

B: double

WD: none

J: 1-1-1

DU: 4w/2x1m/2x5m (5m washout)



C: World Federation of Neurology Research Group

F: 83%

A: 18-60 years

DU: > 2 years

S: Sweden


C: Placebo


F: significantly better than placebo

AU: significantly better than placebo

HI: significantly better than placebo

AEs: more with propranolol


V: +

Notes Available only as expanded abstract

Long follow up suggesting no long-lasting benefit of 1-month treatment

Risk of bias



Diamond 1976


C: unclear

B: double

WD: 21/83

J: 1-1-0

DU-/2x4-8w (no washout)/-


D: Migraine with or without aura

C: unclear

F: 81%

A: 21-62 years



Diamond 1976 (Continued)

DU: not reported

S: neurology department in Chicago, USA


C: Placebo

Outcomes R: 34/62 preferred propranolol, 17/62 placebo

F: not reported

AU: not reported

HI: not reported

AEs: 16/62 vs. 10/62


V: +

Notes High dropout rate, unclear presentation

Risk of bias



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


D: migraine

C: Ad Hoc

F: not reported

A: not reported

DU: not reported

S: unclear, USA


C: Placebo


F: not reported

AU: not reported

HI: not reported

AEs: not reported


V: not interpretable



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



Diener 1989

Methods D: parallel

C: unclear

B: double

WD: 8/58

J: 1-1-0

DU: 2m/7m/1-2m



C: Ad Hoc

F: 81

A: mean age 43 years

DU: 1-55 years

S: unclear, Germany


C1: Metoprolol 100-200 mg

C2: Nifedipine 20-40 mg

Outcomes R: 6/19 vs. 12/22 vs. 1/17 (according to time series analysis)

F: greater reduction in metoprolol group, but relevant baseline differences

AU: no significant differences

HI: not measured

AEs: more circulatory disturbances with propanolol, more fatigue with metoprolol


V: (-) vs. C1, (+) vs. C2

Notes Rigorous study

Dropout rates not fully clear

Risk of bias




Diener 1989 (Continued)


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


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





Diener 2002

Methods D: parallel

C: adequate

B: double

WD: 144/810

J: 2-2-1

DU: 4w/16w/-

Participants N: 810/783 (in intent-to-treat analysis, 808 in safety analysis)

D: 72% migraine without aura

C: IHS

F: 81%

A: 17-66 years

DU: 0.8 to 57 years

S: 130 centres in 8 countries

Interventions P: 160 mg (slow-release)



Outcomes R: 125/258 vs. 141/264 vs. 118/259

F: 1.7 (sd 1.6) vs. 1.6 (1.6) vs. 1.8 (1.2)

AU: 0.9 vs. 1.1 vs. 1.1 migraine attacks treated symptomatically

AEs: 88/270 vs. 88/275 vs. 88/263


V: 0 vs. C1, 0 vs. C2

Notes Excellent, large, multicentre study

Standard deviations for frequency calculated from reported 95% CIs

Risk of bias


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


D: migraine with and without aura

C: IHS

F: 55%

A: mean 39 years



Formisano 1991 (Continued)

DU: mean 20 years

S: unclear, Italy


C: Nimodipine 120 mg


F: 2.6 (sd 1.5) vs. 2.9 (1.7)

AU: not reported

HI: not reported

AEs: probably 6/10 vs. 11/12 (numbers not fully clear)


V: 0

Notes Small study focusing on endocrinological effects

Risk of bias



Forssman 1976


C: unclear

B: double

WD: 8/40

J: 1-2-1

DU: 10w/2x12w (no washout)/-


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


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




Forssman 1976 (Continued)

V: +

Notes

Risk of bias



Gawel 1992

Methods D: parallel

C: unclear

B: double

WD: 18/94

J: 1-1-0

DU: 1m/4m/-

Participants N: 94/76 (89 in safety analysis)

D: 37 migraine with and 57 without aura


F: 90%

A: mean 36 years

DU: mean 17 years

S: 4 Canadian centers



Outcomes R: 20/39 vs. 25/37 (patient global assessment; threshold used to define positive response

not specified; denominators not fully clear, only percentages given)

F: slightly better reduction with flunarizine

AU: similar reduction

HI: not reported

AEs: 36/45 vs. 33/44


V: (-)

Notes

Risk of bias





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


C: Cyclandelate 1200-1600 mg


F: Slightly more reduction with propranolol


AEs: 6/42 vs. 4/42


V: 0


A second publication reports on a follow-up study, which is, however, uninterpretable due

to a very high dropout rate

Risk of bias



Grotemeyer 1987


C: unclear

B: double

WD: 6/30

J: 0-1-0



D: migraine without aura

C: Ad Hoc and other

F: 73%

A: 36 (sd 11) years



Grotemeyer 1987 (Continued)

DU: not reported

S: probably neurological university outpatient department in Germany


C: Placebo


F: 19 (sd 16) attacks during 8 weeks vs. 22 (16)

AU: not reported

HI: not reported

AEs: not reported


V: (+)

Notes

Risk of bias



Hedman 1986


C: unclear

B: double

WD: unclear

J: 1-1-0

DU: 2w/2x1m (2w)/-

Participants N: 12/12 (numbers not fully clear)

D: migraine with aura


F: 67%

A: 30-49 years

DU: unclear

S: unclear, Denmark


C: Metoprolol 100 mg


F: 2.4 (sem 0.3) vs. 3.1 (0.6)

AU: not reported

HI: not reported

AEs: 0 vs. 0


V: uninterpretable



Hedman 1986 (Continued)

Notes Small study focusing on laboratory parameters

Risk of bias



Holdorff 1977

Methods D: parallel

C: unclear

B: double

WD: 26/53

J: 1-1-0

DU: -/3m/-


D: mostly migraine without aura

C: Ad Hoc

F: unclear

A: unclear

DU: unclear

S: probably neurological university hospital outpatient department in Germany


C: Placebo


F: not reported

AU: not reported

HI: no difference

AEs: not reported


V: 0

Notes Very high dropout rate

Risk of bias





Johnson 1986


C: adequate

B: double

WD: 12/29

J: 1-2-1

DU: 1m/3x3m (no washout)/-

Participants N: 29/17 (22-24 for adverse events)


C: unclear

F: 69%

A: 22-80 years

DU: 4-50 years

S: probably university outpatient department in New Zealand


C1: Placebo

C2: Mefenamic acid 1500 mg


F: 13.8 (sd 12.0) vs. 20.1 (18.0) vs. 12.9 (10.8) attacks in 3 months

AU: not reported

HI: median migraine hours 75 vs. 138 vs. 66

AEs: 2/23 vs. 1/24 vs. 2/22


V: + vs. C1; 0 vs. C2

Notes High dropout rate; otherwise rigorous crossover trial

Risk of bias


Allocation concealment (selection bias) Low risk A - Adequate

Kangasniemi 1983


C: unclear

B: double

WD: 5/29

J: 1-1-0

DU: 4w/2x8w (4w)/-



C: unclear

F: 86%



Kangasniemi 1983 (Continued)

A: 24-47 years

DU: 4-40 years

S: private practice, Finland


C: Femoxetine 400 mg

Outcomes R: 3/11 vs. 1/11 (1st period; no pooled data)

F: 1st period: 5.00 (sem 0.71) vs. 6.81 (1.12); pooled: 4.67 (sem 0.64) vs. 6.16 (0.82)

AU: propranolol better

HI: propranolol significantly better

AEs: more side effects with propranolol


V: (+)

Notes Responder data presented only for separate phases; frequency data reported for separate

phases and for both phases pooled

Risk of bias



Kangasniemi 1984


C: unclear

B: double

WD: 3/36

J: 1-2-1

DU: 4w/2x3m (no washout)/1m (placebo)




F: 89%

A: 18-51 years

DU: mean 16 years

S: unclear



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



Kangasniemi 1984 (Continued)

AEs: similar in both groups


V: 0

Notes Well-reported crossover study with low dropout rate

Risk of bias



Kaniecki 1997


C: unclear

B: probably none

WD: 5/37

J: 1-0-1

DU: 8w/2x12w (4w)/-



C: IHS

F: 81%

A: not reported

DU: not reported

S: neurological practice, USA


C: Divalproex sodium 1000-2000 mg

Outcomes R: 1st period: 12/17 vs. 9/15; pooled: 20/32 vs. 21/32

F: similar reduction

AU: not reported

HI: not reported

AEs: 11/32 vs. 16/32


V: 0

Notes Pragmatic crossover study with some reporting shortcomings

Risk of bias





Kass 1980


C: unclear

B: double

WD: 2/23

J: 1-1-0





F: 70%

A: 22-62 years

DU: not reported

S: neurology department, Norway


C: Clonidine 100 mcg

Outcomes R: 13/21 vs. 8/21 (at least 50% headache days reduction)

F: 12.7 (sd 11.2) vs. 13.0 (11.7) headache days during last 12 treatment weeks

AU: less with propranolol

HI: not reported

AEs: 11/21 vs. 11/21


V: (+)

Notes Small crossover trial with interesting outcome measures and data presentation

Risk of bias



Kjaersgard 1994


C: unclear

B: double

WD: 20/76

J: 1-2-1

DU: 4w/2x12w (4w)/-



C: IHS

F: 79%

A: 19-65 years



Kjaersgard 1994 (Continued)

DU: 1-40 years

S: 2 outpatient neurology departments in Denmark


C: Tolfenamic acid 300 mg


F: reduction migraine days vs. baseline 1.7 (sd 1.9) vs. 0.6 (1.6) (1st period; no pooled

data)

AU: not reported

HI: not reported

AEs: 28 vs. 26 adverse effects


V: 0


Unclear statistics

No significant carryover effect detected

Risk of bias



Klapper 1994


C: unclear

B: double

WD: 12/24

J: 1-0-1

DU: -/2x2m (2w)/-


D: migraine

C: IHS

F: unclear

A: unclear

DU: unclear

S: unclear, USA


C: Divalproex sodium 750-1500 mg


F: divalproex significantly better

AU: not reported



Klapper 1994 (Continued)

HI: not reported

AEs: not reported


V: uninterpretable

Notes Extremely high dropout rate, insufficient reporting

Risk of bias



Kuritzky 1987


C: unclear

B: unclear

WD: 7/38

J: 1-0-0

DU: -/2x8w (unclear whether washout)/-



C: unclear

F: unclear

A: 17-53 years

DU: mean 14 years

S: unclear, Israel

Interventions P: 160 mg (long-acting)

C: Placebo


F: 3.23 vs. 5.56 attacks (p = 0.014; no variance data presented)

AU: not reported

HI: not reported

AEs: not reported


V: +

Notes Available only as an abstract

Risk of bias





Ludin 1989

Methods D: parallel

C: unclear

B: double

WD: 12/59

J: 1-2-1

DU: 1m/4m/-

Participants N: 59/59 (intent-to-treat analysis)


C: unclear

F: 71%

A: mean 34 years

DU: not reported

S: 15 neurological practices in Switzerland




F: 3.7 (sd 4.2) vs. 4.8 (6.2)

AU: 3.4 (sd 5.5) vs. 4.1 (6.9, number of analgesics)

HI: 67 (sd 74) vs. 93 (154)

AEs: 15/32 vs. 13/27


V: 0

Notes Well-reported study

In flunarizine group, either good response or deterioration; with propranolol, fewer strong

responders, but better on average

Risk of bias



Lücking 1988a

Methods D: parallel

C: unclear

B: double

WD: 18/87

J: 1-1-0

DU: -/4m/-


D: mainly migraine with aura

C: Ad Hoc

F: 74%



Lücking 1988a (Continued)

A: mean 42 years

DU: not reported

S: 12 hospital outpatient departments (probably in Germany)



Outcomes R: 24/34 vs. 24/35 (investigator global assessment ’very good’ or ’good’)

F: 3 (sd 5) vs. 4 (5)

AU: decreased in 16/34 vs. 18/35

HI: not reported

AEs: 21/34 vs. 16/35


V: 0

Notes Relevant dropout; no intent-to-treat analysis

Risk of bias



Lücking 1988b

Methods D: parallel

C: unclear

B: double

WD: 98/434

J: 1-1-0

DU: -/4m/-


D: mainly migraine with aura

C: Ad Hoc

F: 82%

A: mean 42 years

DU: not reported

S: 99 medical practices (probably in Germany)



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



Lücking 1988b (Continued)


V: 0

Notes Large study with high dropout rate; no intent-to-treat analysis

Risk of bias



Maissen 1991

Methods D: parallel

C: unclear

B: double

WD: 7/39

J: 0-2-1

DU: 1m/4m/3m



C: own

F: 67%

A: mean 39 years

DU: not reported

S: 7 neurologists in Switzerland


C: 5-hydroxytryptophan 300 mg


F: reduction from 7.1 (sd 5.8) vs. 9.4 (5.7) to 4.4 (4.0) vs. 7.3 (7.4)

AU: reduction from 16.3 (sd 20.1) vs. 9.1 (7.4) to 4.3 (3.4) vs. 5.0 (5.5)

HI: not reported

AEs: 7/20 vs. 7/19


V: 0

Notes Relevant baseline differences, high attack frequency

Risk of bias





Malvea 1973


C: unclear

B: double

WD: 2/31

J: 1-1-0

DU: 1m/2x6w (no washout)/-



C: unclear

F: 87%

A: 25-57 years

DU: not reported

S: headache clinic in Boston, USA

Interventions P: Dose unclear

C: Placebo

Outcomes R: 16 preferred propranolol, 8 placebo, 5 none

F: not reported


HI: 18.6 vs. 23.3

AEs: listed only for propranolol


V: +

Notes

Risk of bias



Mathew 1981-Study 1

Methods D: parallel

C: unclear

B: none

WD: 67/340

J: 1-0-1

DU: 1m/6m/-


D: migraine (no interval headaches allowed)

C: unclear

F: 90%

A: mean 35 years

DU: not reported



Mathew 1981-Study 1 (Continued)

S: unclear, USA


C1: No prophylactic therapy

C2: Amitriptyline 50-75 mg

C3: Biofeedback

C4: Propranolol + biofeedback

C5: Amitriptyline + biofeedback

C6: Amitriptyline + propranolol

C7: Propranolol + amitriptyline + biofeedback


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



Mathew 1981-Study 2

Methods D: parallel

C: unclear

B: none

WD: 94/375

J: 1-0-1

DU: 1m/6m/-


D: migraine + interval headaches

C: unclear

F: 95%

A: mean 40 years

DU: not reported

S: unclear, USA



Mathew 1981-Study 2 (Continued)


C1: No prophylactic therapy


C3: Biofeedback

C4: Propranolol + biofeedback

C5: Amitriptyline + biofeedback

C6: Amitriptyline + propranolol

C7: Propranolol + amitriptyline + biofeedback


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



Micieli 2001


C: unclear

B: double

WD: 10/40

J: 1-1-1

DU: 1m/2x3m (1m)/3m


D: migraine without aura

C: IHS

F: 75%

A: 35 (sd 10) years

DU: 18 years

S: unclear, Italy


C: Alpha-dihydroergocryptine 20 mg



Micieli 2001 (Continued)


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


Significant baseline differences in duration of attacks and psychological profile

No significant carryover effect

Risk of bias



Mikkelsen 1986


C: unclear

B: double

WD: 8/39

J: 1-2-1




C: Ad Hoc

F: 84%

A: 15-65 years

DU: not reported

S: neurology outpatient department of a hospital in Denmark


C1: Placebo

C2: Tolfenamic acid 300 mg


F: 1st period: 6.4 (sd 4.1) vs. 7.6 (6.1) vs. 10.2 (6.8); pooled: 6.6 (sd 4.9) vs. 8.8 (6.9) vs.

6.9 (6.1)

AU: trend in favor of tolfenamic acid

HI: not reported

AEs: 3/31 vs. 3/31 vs. 2/31


V: + vs. C1, (-) vs. C2



Mikkelsen 1986 (Continued)

Notes

Risk of bias



Nadelmann 1986


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


C: Placebo


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





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


F: 3.1 (sd 1.4) vs. 3.1 (1.4)

AU: not reported

HI: not reported

AEs: not reported


V: 0

Notes Large trial, reported briefly with other studies in one publication

Risk of bias



Olerud 1986

Methods D: parallel

C: unclear

B: double

WD: 1/28

J: 1-1-1

DU: 4-17w/24w/-



C: Ad Hoc

F: 79%

A: 17-61 years

DU: 2-45 years



Olerud 1986 (Continued)

S: unclear, Sweden

Interventions P: 80-160 ng

C: Nadolol 40-160 mg


F: reduction from 3.6 to 1.9 vs. 5.6 to 2.7 (sd not reported)

AU: reduction from 11.5 to 4.1 vs. 17.1 to 9.2

HI: not reported

AEs: 5/14 vs. 6/13


V: 0

Notes Small, rigorous trial with relevant baseline imbalances

Risk of bias



Olsson 1984


C: unclear

B: double

WD: 3/56

J: 1-2-1

DU: 4w/2x8w (4w)/-




F: 73%

A: 19-59 years

DU: 5-43 years

S: 6 neurology clinics in Sweden




F: reduction from 5.4 to 4.2 in both groups (sd not reported)

AU: reduction from 9.1 to 5.7 vs. 7.6 tablets/4 weeks

HI: reduction from 12.4 to 8.7 vs. 9.7



V: 0



Olsson 1984 (Continued)

Notes Well-reported crossover study

Strong deterioration during washout phase between the two treatment phases

Risk of bias



Palferman 1983


C: unclear

B: double

WD: 6/16

J: 1-1-0

DU: -/2x8 (no washout)/-


D: migraine

C: unclear

F: 80%

A: mean 41 years

DU: mean 17 years

S: outpatient department, UK


C: Placebo


F: 21 vs. 24 headache days in 56 days (sd not reported)

AU: not reported

HI: 47 vs. 52

AEs: not reported


V: (+)

Notes Small study with high dropout rate

Risk of bias





Pita 1977


C: unclear

B: double

WD: 1/9

J: 1-1-1

DU: -/2x2m (no washout)/-

Participants N: 9/8


C: Ad Hoc

F: 78%

A: 23-39 years

DU: 1-27 years

S: clinical pharmacology department in Granada, Spain


C: Placebo

Outcomes R: 4/8 vs. 2/8; 7 preferred propranolol, 1 no preference

F: significantly fewer attacks with propranolol

AU: not reported

HI: not reported

AEs: unclear


V: +

Notes Extremely small trial with very positive results

Risk of bias



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/-


D: 8 migraine with, 61 without, 5 both

C: IHS

F: 76%

A: mean 37 years

DU: mean 17 years



Pradalier 1989 (Continued)

S: muliple centers in France

Interventions P: 160 mg (long-acting)

C: Placebo


F: 3.15 (sem 0.77) vs. 6.4 (1.70)

AU: not reported

HI: not reported



V: +

Notes Uncommon design with randomisation before baseline

High dropout rate

Intent-to-treat analysis unclear

No placebo effect

Risk of bias



Ryan 1984

Methods D: parallel

C: unclear

B: double

WD: 3/48

J: 1-1-1

DU: 4w/12w/-


D: migraine

C: unclear

F: 73%

A: 21-60 years

DU: not reported

S: unclear, USA


C1: Nadolol 80 mg

C2: Nadolol 160 mg


F: reduction 2.88 vs. 3.39 vs. 2.63 (sd not reported)

AU: not reported



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



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/-


D: migraine with and without aura

C: unclear

F: 79%

A: 18-62 years

DU: mean 20 years

S: unclear, USA


C1: Placebo

C2: Naproxen 1100 mg

Outcomes R: patient rating (1 = poor to 4 = excellent) 2.80 vs. 2.38 vs. 2.86

F: Decrease in headache days per week 0.21 (sd 1.86) vs. -0.25 (1.57) vs. -0.48 (2.02)

AU: not reported

HI: not reported

AEs: 30/44 vs. 28/43 vs. 38/42


V: (+) vs. C1, 0 vs. C2

Notes Insufficient reporting

Results seem partly contradictory

Small effects

Risk of bias



Sargent 1985 (Continued)



Scholz 1987

Methods D: parallel

C: unclear

B: double

WD: 45/109

J: 1-1-0

DU: 8w/24w/3m

Participants N: 83/83? (109 patients entered the study, 26 dropped out in the baseline period, 19

stopped treatment early - not clear whether fully analyzed)


C: unclear

F: 77%

A: mean 40 years

DU: mean 19 years

S: unclear, Germany


C1: Metoprolol 200 mg


C3: Nifedipine 40 mg

C4: Dihydroergotamine 10 mg

Outcomes R: 33% vs. 60% vs. 17% vs. 31% vs. 8% (single case statistics)

F: reduction of headache days by 30% vs. 54% vs. 11% vs. 5% vs. 37%

AU: reduction by 40% vs. 40% vs. 41% vs. 45% vs. 33%

HI: not reported

AEs: not reported

Dropouts-AEs: 3/19 vs. 6/22 vs. 2/12 vs. 8/17 vs. 0/13

V: (-) vs. C1, 0 vs. C2, 0 vs. C3, (+) vs. C4

Notes Complex five-armed trial

Dropout reporting difficult to follow

Risk of bias





Shimell 1990

Methods D: parallel

C: unclear

B: double

WD: 10 /58

J: 1-2-1

DU: -/4m/-



D: IHS

F: 70%

A: 16-61 years

DU: mean 27 years

S: neurology outpatient clinic in Johannesburg, South Africa



Outcomes R: 94% vs. 70% (patient global rating excellent/good)

F: reduction from 5.7 to 1.2 vs. 4.6 to 1.4 (sd not presented)

AU: not reported

HI: not reported



V: 0

Notes No headache diary

Possibly intent-to-treat analysis

Risk of bias



Solomon 1986


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



Solomon 1986 (Continued)

DU: unclear

S: unclear


C1: Placebo

C2: Verapamil 240 mg


F: 4.5 vs. 5.0 vs. 4.5 (sd not presented)

AU: not reported

HI: not reported

AEs: unclear


V: + vs. C1, 0 vs. C2

Notes Small crossover study, available only as an abstract

Risk of bias



Stensrud 1976


C: unclear

B: double

WD: 1/20

J: 1-1-1

DU: -/3x4w (1w)/-



C: Ad Hoc

F: 70%

A: 15-60 years

DU: not reported

S: unclear, Norway


C1: Placebo

C2: d-propranolol 160 mg


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



Stensrud 1976 (Continued)

AEs: not reported


V: + vs. C1, (+) vs. C2

Notes No headache diary

Risk of bias



Stensrud 1980


C: unclear

B: double

WD: 7/35

J: 1-2-0

DU: -/2x6w (1w)/-



C: Ad Hoc

F: 69%

A: 25-60 years

DU: not reported

S: unclear, Norway


C1: Placebo

C2: Atenolol 100 mg


F: 9.2 vs. 10.3 vs. 8.8 (headache days; sd not reported)

AU: not reported

HI: not reported

AEs: more with propranolol


V: (+) vs. C1, 0 vs. C2

Notes Results reported insufficiently

Risk of bias




Stensrud 1980 (Continued)


Sudilovsky 1987

Methods D: parallel

C: unclear

B: double

WD: 42/140

J: 1-2-0

DU: 4-8w/12w/-


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


C1: Nadolol 80 mg

C2: Nadolol 160 mg

Outcomes R: 5/27 vs. 11/33 vs. 18/33

F: not reported

AU: at least 50% reduction in 11/26 vs. 10/33 vs. 16/32

HI: 1.31 vs. 1.24 vs. 2.22 (higher values indicate better response)

AEs: not reported


V: 0 vs. C1, - vs. C2


Risk of bias





Tfelt-Hansen 1984


C: unclear

B: double

WD: 16/96

J: 1-2-0


Participants N: 96/80 (83 for adverse events; 90 started placebo and 89 both active treatments)

D: migraine

C: Ad Hoc

F: 74%

A: mean 40 years

DU: mean 21 years


C1: Placebo

C2: Timolol 20 mg

Outcomes R: 48/80 vs. 24/80 vs. 44/80

F: 3.69 (sd 3.44) vs. 4.84 (3.85) vs. 3.35 (3.13)

AU: not reported

HI: 6.66 (sd 5.87) vs. 9.03 (7.28) vs. 5.71 (5.14)

AEs: 35/83 vs. 23/83 vs. 38/83


V: + vs. C1, 0 vs. C2

Notes Rigorous, well-reported crossover trial

Probably subgroup analysis in publication by Standnes (see references)

Risk of bias



Weber 1972


C: unclear

B: double

WD: 6/25

J: 1-1-0




C: Ad Hoc

F: 52%

A: 19-61 years



Weber 1972 (Continued)

DU: not reported

S: unclear, USA


C: Placebo


F: not reported

AU: not reported

HI: not reported

AEs: unclear


V: +

Notes Small crossover trial with extremely positive results

Risk of bias



Wideroe 1974


C: unclear

B: double

WD: 4/30

J: 1-1-0




C: Ad Hoc

F: 87%

A: 18-55 years

DU: not reported

S: neurology outpatient department in Trondheim, Norway


C: Placebo


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




Wideroe 1974 (Continued)

V: +

Notes Included only patients who had responded to propranolol before

Risk of bias



Ziegler 1987


C: unclear

B: double

WD: 24/54

J: 1-1-0

DU: 4-8w/3x8w (4w)/-


D: migraine

C: Ad Hoc

F: 73%

A: 22-57 years

DU: not reported

S: unclear, USA


C1: Placebo


Outcomes R: 12/30 vs. unclear vs. 10/30 (at least 50% index reduction)

F: not reported

AU: not reported

HI: 405 vs. 511 vs. 429

AEs: not reported


V: + vs. C1, 0 vs. C2


Insufficient presentation of results

Complex design

Risk of bias




Ziegler 1987 (Continued)


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



(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



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]


1.3 Propranolol 80-120 mg 1 27 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.63, 2.42]



pooled crossover data)







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]


(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]



5 Number of patients with adverse

events (parallel-group; no 1st

period crossover data)




events (parallel-group and







7 Number of dropouts due to

adverse events (parallel-group

and 1st period crossover data)









and pooled crossover data)








Comparison 2. Propranolol versus calcium antagonists


studies

No. of


1 Responders (all trials

parallel-group)


1.1 Propranolol 180 mg vs.

flunarizine 10 mg



flunarizine 10 mg



flunarizine 5 mg



flunarizine 10 mg



flunarizine 10 mg



flunarizine 10 mg


1.7 Propranolol 120-180 mg

vs. nifedipine 60-90 mg





1.9 Propranolol 60 mg

vs. propranolol 60 mg +

flunarizine 10 mg


2 Attack frequency measures (all

trials parallel-group)

6 1543 Std. Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.12, 0.08]


flunarizine 10 mg

1 524 Std. Mean Difference (IV, Fixed, 95% CI) 0.06 [-0.11, 0.23]


flunarizine 5 mg



flunarizine 10 mg






nimodipine 120 mg





events (all trials parallel-group)



flunarizine 10 mg



flunarizine 5 mg



flunarizine 10 mg



flunarizine 10 mg






nimodipine 120 mg



propanolol 60 mg + flunarizine

10 mg



events (vs. flunarizine; all trials

parallel-group)



flunarizine 10 mg



flunarizine 5 mg



flunarizine 10 mg



flunarizine 10 mg


5 Number of dropouts due

to adverse events (all trials

parallel-group)



flunarizine 10 mg



flunarizine 10 mg



flunarizine 5 mg



flunarizine 10 mg



flunarizine 10 mg



flunarizine 10 mg



nimodipine 120 mg



nifedipine 40 mg







5.10 Propranolol 60 mg

vs. propranolol 60 mg +

flunarizine 10 mg



adverse events (vs. flunarizine;

all trials parallel-group)



flunarizine 10 mg



flunarizine 10 mg



flunarizine 5 mg



flunarizine 10 mg



flunarizine 10 mg



flunarizine 10 mg



adverse events (vs. nifedipine;

all trials parallel-group)



nifedipine 40 mg





Comparison 3. Propranolol versus other beta-blockers


studies

No. of


1 Responders (parallel-group; no


3 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected


nadolol 160 mg

1 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]


nadolol 80 mg



vs. nadolol 40-160 mg



vs. metoprolol 100-200 mg






nadolol 160 mg



nadolol 80 mg








metoprolol 200 mg






metoprolol 100 mg



timolol 20 mg


3 Responders (vs. nadolol;

parallel-group and pooled

crossover data)



nadolol 160 mg



nadolol 80 mg





4 Responders (vs. metoprolol;

parallel-group and pooled

crossover data)



metoprolol 200 mg






metoprolol 100 mg



(pooled crossover only; no

parallel-group or 1st period

crossover data)



metoprolol 200 mg



metoprolol 100 mg



timolol 20 mg



d-propranolol 160 mg














timolol 20 mg








metoprolol 100 mg



adverse events (parallel-group;

no 1st period crossover data)



nadolol 160 mg



nadolol 80 mg



nadolol 160 mg



nadolol 80 mg






metoprolol 200 mg







nadolol 160 mg



nadolol 80 mg



nadolol 160 mg



nadolol 80 mg






metoprolol 200 mg



metoprolol 100 mg



atenolol 100 mg



timolol 20 mg



d-propranolol 160 mg




Comparison 4. Propranolol versus other drugs


studies

No. of






femoxetine 400 mg



vs. cyclandelate 1200-1600 mg



cyclandelate 1200 mg


1.4 Propranolol 60-240 mg vs.

divalproex sodium 1000-2000

mg



5-hydroxytryptophan 300 mg



pooled crossover data [one 1st

period])



femoxetine 400 mg










mg






methysergide 3 mg



clonidine 100 mcg



vs. amitriptyline 50-150 mg


2.9 Propranolol 1.8 mg/kg vs.

ASA 13.5 mg/kg



(parallel-group and 1st period

crossover data)

8 Std. Mean Difference (IV, Fixed, 95% CI) Totals not selected


femoxetine 400 mg

2 Std. Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]


tolfenamic acid 300 mg








naproxen 1100 mg


3.5 Propranolol 1230 mcg/kg

vs. methysergide 30.8 mcg/kg



alpha-dihydroergocryptine 20

mg



(parallel-group and pooled

crossover data [two 1st period])

10 Std. Mean Difference (IV, Fixed, 95% CI) Totals not selected


femoxetine 400 mg









naproxen 1100 mg


4.5 Propranolol 1230 mcg/kg

vs. methysergide 30.8 mcg/kg



mefenamic acid 1500 mg



clonidine 100 mcg




mg
















naproxen 1100 mg
















naproxen 1100 mg








methysergide 3 mg



clonidine 100 mcg




mg


6.9 Propranolol 1.8 mg/kg vs.

ASA 13.5 mg/kg






adverse events (parallel-group;

no 1st period crossover data)









dihydroergotamine 10 mg






vs. amitriptyline 50-75 mg +

propranolol 120-160 mg







femoxetine 400 mg







mg




mg












methysergide 3 mg



dihydroergotamine 10 mg




mg





clonidine 100 mcg


8.12 Propranolol 1.8 mg/kg

vs. ASA 13.5 mg/kg






vs. amitriptyline 50-75 mg +

propranolol 120-160 mg


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)


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 ]




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 ]




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 ]


0.1 0.2 0.5 1 2 5 10

Favours control Favours treatment

(Continued . . . )



(. . . Continued)Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio




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


Heterogeneity: Chi2 = 5.64, df = 3 (P = 0.13); I2 =47%


Test for subgroup differences: Chi2 = 5.52, df = 3 (P = 0.14), I2 =46%

0.1 0.2 0.5 1 2 5 10


Analysis 1.2. Comparison 1 Propranolol versus placebo, Outcome 2 Responders (parallel-group and pooled

crossover data).



Outcome: 2 Responders (parallel-group and pooled crossover data)




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 ]


Heterogeneity: Chi2 = 0.52, df = 2 (P = 0.77); I2 =0.0%

Test for overall effect: Z = 5.04 (P < 0.00001)


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 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )







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 ]





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 ]




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 ]




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 (95% CI) 345 323 100.0 % 1.94 [ 1.61, 2.35 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.3. Comparison 1 Propranolol versus placebo, Outcome 3 Attack frequency measures (parallel-

group and 1st period crossover data).



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


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 ]




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 ]



Total (95% CI) 87 85 100.0 % -0.45 [ -0.75, -0.14 ]




-4 -2 0 2 4

Favours treatment Favours control



Analysis 1.4. Comparison 1 Propranolol versus placebo, Outcome 4 Attack frequency measures (parallel-

group and pooled crossover data).



Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data)


Std.Mean

Difference Weight

Std.Mean

Difference



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 ]




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 ]




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 ]



Total (95% CI) 319 315 100.0 % -0.40 [ -0.56, -0.24 ]



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

-4 -2 0 2 4




Analysis 1.5. Comparison 1 Propranolol versus placebo, Outcome 5 Number of patients with adverse

events (parallel-group; no 1st period crossover data).



Outcome: 5 Number of patients with adverse events (parallel-group; no 1st period crossover data)




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 ]




Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 Propranolol versus placebo, Outcome 6 Number of patients with adverse

events (parallel-group and pooled crossover data).



Outcome: 6 Number of patients with adverse events (parallel-group and pooled crossover data)




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 ]





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 ]





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 ]





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 (95% CI) 321 298 100.0 % 1.43 [ 1.12, 1.81 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.7. Comparison 1 Propranolol versus placebo, Outcome 7 Number of dropouts due to adverse

events (parallel-group and 1st period crossover data).



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



Nadelmann 1986 0/28 0/29 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 28 29 0.0 [ 0.0, 0.0 ]





Pradalier 1989 0/40 1/34 0.28 [ 0.01, 6.77 ]

Subtotal (95% CI) 40 34 0.28 [ 0.01, 6.77 ]





Diener 1996 4/78 0/55 6.38 [ 0.35, 116.13 ]

Subtotal (95% CI) 78 55 6.38 [ 0.35, 116.13 ]




Total (95% CI) 146 118 1.90 [ 0.36, 10.14 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.8. Comparison 1 Propranolol versus placebo, Outcome 8 Number of dropouts due to adverse




Outcome: 8 Number of dropouts due to adverse events (parallel-group and pooled crossover data)




Nadelmann 1986 0/57 0/57 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 57 57 0.0 [ 0.0, 0.0 ]





Forssman 1976 2/40 2/40 1.00 [ 0.15, 6.76 ]

Johnson 1986 1/29 1/29 1.00 [ 0.07, 15.24 ]

Subtotal (95% CI) 69 69 1.00 [ 0.21, 4.78 ]





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 ]





Diamond 1976 6/83 1/83 6.00 [ 0.74, 48.75 ]

Subtotal (95% CI) 83 83 6.00 [ 0.74, 48.75 ]





Borgesen 1974 0/45 2/45 0.20 [ 0.01, 4.05 ]

0.1 0.2 0.5 1 2 5 10


(Continued . . . )



(. . . Continued)Study or subgroup Treatment Control Risk Ratio Risk Ratio


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 ]




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 (95% CI) 589 561 2.11 [ 1.09, 4.08 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.1. Comparison 2 Propranolol versus calcium antagonists, Outcome 1 Responders (all trials

parallel-group).


Comparison: 2 Propranolol versus calcium antagonists

Outcome: 1 Responders (all trials parallel-group)



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 ]





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 ]





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 ]





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 ]





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 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )







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 ]




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 ]





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 ]




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 (95% CI) 901 893 100.0 % 1.00 [ 0.93, 1.09 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.2. Comparison 2 Propranolol versus calcium antagonists, Outcome 2 Attack frequency measures

(all trials parallel-group).



Outcome: 2 Attack frequency measures (all trials parallel-group)


Std.Mean

Difference Weight

Std.Mean

Difference



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 ]




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 ]




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 ]




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 ]



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 ]



Total (95% CI) 773 770 100.0 % -0.02 [ -0.12, 0.08 ]




-4 -2 0 2 4




Analysis 2.3. Comparison 2 Propranolol versus calcium antagonists, Outcome 3 Number of patients with

adverse events (all trials parallel-group).



Outcome: 3 Number of patients with adverse events (all trials parallel-group)




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 ]





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 ]





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 ]





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 ]





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


(Continued . . . )









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 ]




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 (95% CI) 881 872 100.0 % 1.02 [ 0.91, 1.15 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.4. Comparison 2 Propranolol versus calcium antagonists, Outcome 4 Number of patients with

adverse events (vs. flunarizine; all trials parallel-group).



Outcome: 4 Number of patients with adverse events (vs. flunarizine; all trials parallel-group)




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 ]





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 ]





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 ]





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 (95% CI) 836 825 100.0 % 1.06 [ 0.94, 1.20 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.5. Comparison 2 Propranolol versus calcium antagonists, Outcome 5 Number of dropouts due to

adverse events (all trials parallel-group).



Outcome: 5 Number of dropouts due to adverse events (all trials parallel-group)




Shimell 1990 3/29 2/29 1.50 [ 0.27, 8.32 ]

Subtotal (95% CI) 29 29 1.50 [ 0.27, 8.32 ]





Diener 2002 18/270 19/275 0.96 [ 0.52, 1.80 ]

Gawel 1992 5/45 3/44 1.63 [ 0.41, 6.41 ]

Scholz 1987 3/19 2/12 0.95 [ 0.18, 4.87 ]

Subtotal (95% CI) 334 331 1.05 [ 0.61, 1.78 ]





Diener 2002 18/270 21/263 0.83 [ 0.46, 1.53 ]

Subtotal (95% CI) 270 263 0.83 [ 0.46, 1.53 ]





Ludin 1989 3/32 2/27 1.27 [ 0.23, 7.03 ]

Subtotal (95% CI) 32 27 1.27 [ 0.23, 7.03 ]





Bonuso 1998 0/25 0/25 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 25 25 0.0 [ 0.0, 0.0 ]




0.1 0.2 0.5 1 2 5 10


(Continued . . . )






Bordini 1997 0/18 0/17 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 18 17 0.0 [ 0.0, 0.0 ]





Formisano 1991 2/10 1/12 2.40 [ 0.25, 22.75 ]

Subtotal (95% CI) 10 12 2.40 [ 0.25, 22.75 ]




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 ]





Albers 1989 5/20 13/20 0.38 [ 0.17, 0.88 ]

Subtotal (95% CI) 20 20 0.38 [ 0.17, 0.88 ]




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 (95% CI) 775 758 0.82 [ 0.59, 1.13 ]





0.1 0.2 0.5 1 2 5 10





adverse events (vs. flunarizine; all trials parallel-group).



Outcome: 6 Number of dropouts due to adverse events (vs. flunarizine; all trials parallel-group)




Shimell 1990 3/29 2/29 1.50 [ 0.27, 8.32 ]

Subtotal (95% CI) 29 29 1.50 [ 0.27, 8.32 ]





Diener 2002 18/270 19/275 0.96 [ 0.52, 1.80 ]

Gawel 1992 5/45 3/44 1.63 [ 0.41, 6.41 ]

Scholz 1987 3/19 2/12 0.95 [ 0.18, 4.87 ]

Subtotal (95% CI) 334 331 1.05 [ 0.61, 1.78 ]





Diener 2002 18/270 21/263 0.83 [ 0.46, 1.53 ]

Subtotal (95% CI) 270 263 0.83 [ 0.46, 1.53 ]





Ludin 1989 3/32 2/27 1.27 [ 0.23, 7.03 ]

Subtotal (95% CI) 32 27 1.27 [ 0.23, 7.03 ]





Bonuso 1998 0/25 0/25 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 25 25 0.0 [ 0.0, 0.0 ]




0.1 0.2 0.5 1 2 5 10


(Continued . . . )






Bordini 1997 0/18 0/17 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 18 17 0.0 [ 0.0, 0.0 ]




Total (95% CI) 708 692 0.98 [ 0.67, 1.44 ]





0.1 0.2 0.5 1 2 5 10



adverse events (vs. nifedipine; all trials parallel-group).



Outcome: 7 Number of dropouts due to adverse events (vs. nifedipine; all trials parallel-group)



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 ]





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 ]


0.1 0.2 0.5 1 2 5 10


(Continued . . . )







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





0.1 0.2 0.5 1 2 5 10


Analysis 3.1. Comparison 3 Propranolol versus other beta-blockers, Outcome 1 Responders (parallel-

group; no 1st period crossover data).


Comparison: 3 Propranolol versus other beta-blockers

Outcome: 1 Responders (parallel-group; no 1st period crossover data)



1 Propranolol 160 mg vs. nadolol 160 mg

Sudilovsky 1987 5/27 18/33 0.34 [ 0.15, 0.79 ]


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




Analysis 3.2. Comparison 3 Propranolol versus other beta-blockers, Outcome 2 Responders (parallel-group

and pooled crossover data).



Outcome: 2 Responders (parallel-group and pooled crossover data)




Sudilovsky 1987 5/27 18/33 0.34 [ 0.15, 0.79 ]


Sudilovsky 1987 5/27 11/33 0.56 [ 0.22, 1.40 ]


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 ]


Diener 1989 6/19 12/22 0.58 [ 0.27, 1.24 ]


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




Analysis 3.3. Comparison 3 Propranolol versus other beta-blockers, Outcome 3 Responders (vs. nadolol;

parallel-group and pooled crossover data).



Outcome: 3 Responders (vs. nadolol; parallel-group and pooled crossover data)




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 ]





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 ]





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 (95% CI) 68 79 100.0 % 0.60 [ 0.37, 0.97 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.4. Comparison 3 Propranolol versus other beta-blockers, Outcome 4 Responders (vs.

metoprolol; parallel-group and pooled crossover data).



Outcome: 4 Responders (vs. metoprolol; parallel-group and pooled crossover data)




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 ]





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 ]





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 (95% CI) 105 111 100.0 % 0.78 [ 0.56, 1.09 ]





0.1 0.2 0.5 1 2 5 10




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).



Outcome: 5 Attack frequency measures (pooled crossover only; no parallel-group or 1st period crossover data)


Std.Mean

Difference Weight

Std.Mean

Difference



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 ]




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 ]




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 ]



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 ]



Total (95% CI) 145 145 100.0 % -0.01 [ -0.24, 0.22 ]




-4 -2 0 2 4




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).







Olerud 1986 5/14 6/13 0.77 [ 0.31, 1.93 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.7. Comparison 3 Propranolol versus other beta-blockers, Outcome 7 Number of patients with

adverse events (parallel-group and pooled crossover data).







Tfelt-Hansen 1984 35/83 38/83 0.92 [ 0.65, 1.30 ]

Subtotal (95% CI) 83 83 0.92 [ 0.65, 1.30 ]





Olerud 1986 5/14 6/13 0.77 [ 0.31, 1.93 ]

Subtotal (95% CI) 14 13 0.77 [ 0.31, 1.93 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )







Hedman 1986 0/12 0/12 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 12 12 0.0 [ 0.0, 0.0 ]




Total (95% CI) 109 108 0.90 [ 0.65, 1.24 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.8. Comparison 3 Propranolol versus other beta-blockers, Outcome 8 Number of dropouts due to




Outcome: 8 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)




Sudilovsky 1987 4/44 2/47 2.14 [ 0.41, 11.09 ]

Subtotal (95% CI) 44 47 2.14 [ 0.41, 11.09 ]





Sudilovsky 1987 4/44 2/49 2.23 [ 0.43, 11.57 ]

Subtotal (95% CI) 44 49 2.23 [ 0.43, 11.57 ]





Ryan 1984 0/16 0/16 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 16 16 0.0 [ 0.0, 0.0 ]





Ryan 1984 0/16 1/16 0.33 [ 0.01, 7.62 ]

Subtotal (95% CI) 16 16 0.33 [ 0.01, 7.62 ]





Olerud 1986 0/15 1/13 0.29 [ 0.01, 6.60 ]

Subtotal (95% CI) 15 13 0.29 [ 0.01, 6.60 ]





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


(Continued . . . )








Total (95% CI) 154 163 1.00 [ 0.48, 2.10 ]





0.1 0.2 0.5 1 2 5 10


Analysis 3.9. Comparison 3 Propranolol versus other beta-blockers, Outcome 9 Number of dropouts due to








Sudilovsky 1987 4/44 2/47 2.14 [ 0.41, 11.09 ]

Subtotal (95% CI) 44 47 2.14 [ 0.41, 11.09 ]





Sudilovsky 1987 4/44 2/49 2.23 [ 0.43, 11.57 ]

Subtotal (95% CI) 44 49 2.23 [ 0.43, 11.57 ]





0.1 0.2 0.5 1 2 5 10


(Continued . . . )





Ryan 1984 0/16 0/16 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 16 16 0.0 [ 0.0, 0.0 ]





Ryan 1984 0/16 1/16 0.33 [ 0.01, 7.62 ]

Subtotal (95% CI) 16 16 0.33 [ 0.01, 7.62 ]





Olerud 1986 0/15 1/13 0.29 [ 0.01, 6.60 ]

Subtotal (95% CI) 15 13 0.29 [ 0.01, 6.60 ]





Kangasniemi 1984 2/36 0/36 5.00 [ 0.25, 100.63 ]

Scholz 1987 3/19 6/22 0.58 [ 0.17, 2.01 ]

Subtotal (95% CI) 55 58 0.94 [ 0.33, 2.72 ]





Olsson 1984 0/56 0/56 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 56 56 0.0 [ 0.0, 0.0 ]




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 ]





Tfelt-Hansen 1984 6/89 9/89 0.67 [ 0.25, 1.79 ]

Subtotal (95% CI) 89 89 0.67 [ 0.25, 1.79 ]



0.1 0.2 0.5 1 2 5 10


(Continued . . . )






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 (95% CI) 390 399 1.05 [ 0.61, 1.80 ]





0.1 0.2 0.5 1 2 5 10




Analysis 4.1. Comparison 4 Propranolol versus other drugs, Outcome 1 Responders (parallel-group and 1st

period crossover data).


Comparison: 4 Propranolol versus other drugs

Outcome: 1 Responders (parallel-group and 1st period crossover data)



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




Analysis 4.2. Comparison 4 Propranolol versus other drugs, Outcome 2 Responders (parallel-group and

pooled crossover data [one 1st period]).



Outcome: 2 Responders (parallel-group and pooled crossover data [one 1st period])




Andersson 1981 11/28 4/28 2.75 [ 0.99, 7.61 ]

Kangasniemi 1983 3/11 1/11 3.00 [ 0.37, 24.58 ]


Gerber 1995 18/34 20/28 0.74 [ 0.50, 1.10 ]


Diener 1996 33/78 30/81 1.14 [ 0.78, 1.68 ]


Kaniecki 1997 20/32 21/32 0.95 [ 0.66, 1.38 ]


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




Analysis 4.3. Comparison 4 Propranolol versus other drugs, Outcome 3 Attack frequency measures

(parallel-group and 1st period crossover data).



Outcome: 3 Attack frequency measures (parallel-group and 1st period crossover data)


Std.Mean

Difference

Std.Mean

Difference



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 ]


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




Analysis 4.4. Comparison 4 Propranolol versus other drugs, Outcome 4 Attack frequency measures

(parallel-group and pooled crossover data [two 1st period]).



Outcome: 4 Attack frequency measures (parallel-group and pooled crossover data [two 1st period])


Std.Mean

Difference

Std.Mean

Difference



Andersson 1981 37 3.4 (1.8) 37 4.1 (1.8) -0.38 [ -0.84, 0.08 ]

Kangasniemi 1983 24 4.67 (2.31) 24 6.16 (4.02) -0.45 [ -1.02, 0.13 ]


Kjaersgard 1994 29 -1.7 (1.9) 27 -0.6 (1.6) -0.62 [ -1.15, -0.08 ]

Mikkelsen 1986 31 6.6 (4.9) 31 6.9 (6.1) -0.05 [ -0.55, 0.44 ]


Maissen 1991 19 4.4 (4) 19 7.3 (7.4) -0.48 [ -1.12, 0.17 ]


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 ]


Kass 1980 21 12.67 (11.15) 21 13 (11.65) -0.03 [ -0.63, 0.58 ]


Micieli 2001 15 1.3 (1.2) 15 1.3 (1.2) 0.0 [ -0.72, 0.72 ]

-4 -2 0 2 4




Analysis 4.5. Comparison 4 Propranolol versus other drugs, Outcome 5 Number of patients with adverse

events (parallel-group; no 1st period crossover data).







Gerber 1995 6/42 4/42 1.50 [ 0.46, 4.93 ]


Diener 1996 19/78 13/81 1.52 [ 0.81, 2.86 ]


Maissen 1991 7/20 7/19 0.95 [ 0.41, 2.20 ]


Sargent 1985 30/44 38/42 0.75 [ 0.60, 0.94 ]

0.1 0.2 0.5 1 2 5 10




Analysis 4.6. Comparison 4 Propranolol versus other drugs, Outcome 6 Number of patients with adverse








Gerber 1995 6/42 4/42 1.50 [ 0.46, 4.93 ]


Diener 1996 19/78 13/81 1.52 [ 0.81, 2.86 ]


Maissen 1991 7/20 7/19 0.95 [ 0.41, 2.20 ]


Sargent 1985 30/44 38/42 0.75 [ 0.60, 0.94 ]


Mikkelsen 1986 3/31 2/31 1.50 [ 0.27, 8.36 ]


Behan 1980 12/36 16/36 0.75 [ 0.42, 1.35 ]


Kass 1980 11/21 11/21 1.00 [ 0.56, 1.78 ]


Kaniecki 1997 11/32 16/32 0.69 [ 0.38, 1.24 ]


Baldrati 1983 6/12 6/12 1.00 [ 0.45, 2.23 ]


Johnson 1986 2/23 2/22 0.96 [ 0.15, 6.21 ]

0.1 0.2 0.5 1 2 5 10




Analysis 4.7. Comparison 4 Propranolol versus other drugs, Outcome 7 Number of dropouts due to




Outcome: 7 Number of dropouts due to adverse events (parallel-group; no 1st period crossover data)




Diener 1996 4/78 5/81 0.83 [ 0.23, 2.98 ]


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 ]


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




Analysis 4.8. Comparison 4 Propranolol versus other drugs, Outcome 8 Number of dropouts due to








Andersson 1981 2/49 2/49 1.00 [ 0.15, 6.82 ]

Kangasniemi 1983 3/29 0/29 7.00 [ 0.38, 129.74 ]


Diener 1996 4/78 5/81 0.83 [ 0.23, 2.98 ]


Klapper 1994 3/24 9/24 0.33 [ 0.10, 1.08 ]


Kaniecki 1997 1/37 4/37 0.25 [ 0.03, 2.13 ]


Maissen 1991 2/20 0/19 4.76 [ 0.24, 93.19 ]


Johnson 1986 1/29 1/29 1.00 [ 0.07, 15.24 ]


Kjaersgard 1994 9/76 5/76 1.80 [ 0.63, 5.12 ]

Mikkelsen 1986 2/39 2/39 1.00 [ 0.15, 6.75 ]


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 ]


Micieli 2001 5/40 4/40 1.25 [ 0.36, 4.32 ]


Kass 1980 0/23 0/23 0.0 [ 0.0, 0.0 ]


Baldrati 1983 2/18 3/18 0.67 [ 0.13, 3.53 ]


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


(Continued . . . )





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


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



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




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




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




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



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


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




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




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



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




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




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.



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



Documents

Art. Cefalea