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.

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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118WHATS 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 ComplementaryMedicine Research,Department of InternalMedicine II, Technical UniversityMunich,Munich,Germany.2Institute of Social Medicine & Epidemiology, Charit University Hospital, Berlin, Germany

Contact address: Anna Hobson, Cochrane Pain, Palliative & Supportive Care Group, Pain Research Unit, The Churchill Hospital,

Old Road, Oxford, OX3 7LE, UK. [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)


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 reviewidentified 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 themany 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 allocationmethod, 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 parameterswere 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).



TheDelphi 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 4weeks); descriptionof 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,

andmethods for outcomemeasurements), 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 belowmust be interpretedwith 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 frommi-

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, onemefenamic

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 Societys criteria (IHS 1988) for con-

firming the diagnosis, 20 the Ad Hoc Committees criteria (Ad

Hoc 1962), and nine other criteria; in 17 trials, the diagnostic

criteria used were not reported. Propranolol doses ranged from 60

to 320 mg per day. Baseline periods varied from 0 to 10 weeks

(median 4 weeks), and treatment phases from 4 to 30 weeks (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 (I = 50.1%) in the

set of four trials, but not in the set of nine trials (I = 13.8%).

Responder ratios tended to be higher in trials with higher dosages

of propranolol, but the trial with the lowest dosage (80 mg) had

the most positive result (Weber 1972).

Four trials, or 10 if pooled crossover trials are included, reported

sufficient data on headache frequency. Here, too, all 10 trials

showed at least a trend in favour of propranolol. The overall 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 (I = 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 included13 trialswith 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 onewith a trend in favour

of the combination of propranolol and flunarizine.

Comparisons with other beta-blockers

This category included 10 trials with 12 comparisons, plus one

trial comparing propranolol with d-propranolol.

Responder data were reported for four comparisons (Comparison

No. 03 01), or seven when including crossover trials with pooled

data (Comparison No. 03 02). In one trial, nadolol 160 mg was

significantly superior to propranolol 160 mg (Sudilovsky 1987);

the other six trials did not yield significant differences. As trial

results were statistically heterogeneous (I = 53.5% for the 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 (I = 68.8%). The three trials compar-

ing propranolol and metoprolol had more consistent results (I

= 0%), but did not show significant differences (responder ratio

0.78, 95% CI 0.56 to 1.09).

Only four trials, all crossover in design, reported attack frequency

data, all pooled, and none reported significant differences; the

overall standardized mean difference was -0.01 (95% CI -0.24

to 0.22; Comparison No. 03 05). There were also no clearcut

differences in the number of patients with adverse events (one,

respectively three, trials; Comparisons No. 03 06 and No. 03 07)

or the number of patients dropping out due to adverse events (six,

respectively 11, comparisons; Comparisons No. 03 08 and No. 03

09).

The vote count results were as follows: seven comparisons showing

nodifference, threewith 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

alonewith a combinationof 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

combinationwith 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 themethodological limitations of themajority 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.

Themajor 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 reviewondrug

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 Societys guidelines for controlled trials of drugs

for migraine (Tfelt-Hansen 2000), so that future studies will be

conducted according to a high methodological standard and will

more readily permit quantitative meta-analysis. However, as these

guidelines recommend quite narrow inclusion criteria, it seems

unclear whether the findings of such trials will be directly 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 OW 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;82:2635.

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):2158.

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):12831.

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):2808.

Baldrati 1983 {published data only}

Baldrati A, Cortelli P, Procaccianti G, Gamberini

G, DAlessandro R, Baruzzi A, et al.Propranolol and

acetylsalicylic acid in migraine prophylaxis. Double-blind

crossover study. Acta Neurologica Scandinavica 1983;67(3):1816.

Behan 1980 {published data only}

Behan PO, Reid M. Propranolol in the treatment of

migraine. Practitioner 1980;224(1340):2013.

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):14758.

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):53641.

Borgesen 1974 {published data only}

Borgesen SE. Treatment of migraine with propranolol.

Postgraduate Medical Journal 1976;52 Suppl 4(0):1635. Borgesen SE, Nielsen JL, Moller CE. Prophylactic

treatment of migraine with propranolol. A clinical trial.

Acta Neurologica Scandinavica 1974;50(5):6516.Borgesen SE, Nielsen JL, Moller CE. Propranolol in

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

Dahlf 1987 {published data only}

Dahlf C. No clearcut longterm prophylactic effect of

one month of treatment with propranolol in migraineurs.

Cephalalgia 1987;7 Suppl 6:45960.

Diamond 1976 {published data only}

Diamond S, Medina JL. Double blind study of propranolol

for migraine prophylaxis. Headache 1976;16(1):247.


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

study of propanolol in the treatment of migraine. Headache1982;22(6):26871.

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

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

prophylaxis evaluated by visual evoked potentials. Annals of

Neurology 1989;25(2):12530.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):3745.

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):

4417.

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

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Cephalalgia 2002;22(3):20921.

Formisano 1991 {published data only}

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

DUrso R, et al.Nimodipine in migraine: clinical efficacy

and endocrinological effects. European Journal of ClinicalPharmacology 1991;41(1):6971.

Forssman 1976 {published data only}

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

Lundin H. Propranolol for migraine prophylaxis. Headache

1976;16(5):23845.

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):3405.

Gerber 1995 {published data only} Gerber WD, Schellenberg R, Thom M, Haufe C, Blsche

F, Wedekind W, et al.Cyclandelate versus propranolol in the

prophylaxis of migraine - a double-blind placebo-controlled

study. Functional Neurology 1995;10(1):2735.Schellenberg R, Schwarz A, Niederberger U, Blsche 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

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einer viermonatigen medikamentsen Prophylaxe].

Nervenheilkunde 1997;16:1837.

Grotemeyer 1987 {published data only}

Grotemeyer KH, Husstedt IW, Schlake HP. Betablocker vs

placebo in vasomotor headache. A double-blind crossover

study [Betablocker vs Placebo bei vasomotorischem

Kopfschmerz. Eine doppelblinde CrossoverStudie].

Deutsche Medizinische Wochenschrift 1987;112(45):17403.

Hedman 1986 {published data only}

Hedman C, Winther K, Knudsen JB. The difference

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

their effect on platelet function in migraine patients. Acta

Neurologica Scandinavica 1986;74(6):4758.

Holdorff 1977 {published data only}

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

prophylaxis: a double-blind study [Propranolol in der

Migrneprophylaxe. Eine Doppelblindstudie]. Medizinische

Klinik 1977;72(25):11158.

Johnson 1986 {published data only}

Johnson RH, Hornabrook RW, Lambie DG. Comparison of

mefenamic acid and propranolol with placebo in migraine

prophylaxis. Acta Neurologica Scandinavica 1986;73(5):4902.

Kangasniemi 1983 {published data only}

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

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

prophylactic treatment of migraine. Acta NeurologicaScandinavica 1983;68(4):2627.

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

in the prophylactic treatment of classical and common

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

916.

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):914.

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):11415.

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):3516.

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):44650.

Klapper 1994 {published data only}

Klapper JA. An open label cross-over comparison of

divalproex sodium and propranolol HCl in the prevention

of migraine headaches. Headache Quarterly 1994;5(1):503.

Kuritzky 1987 {published data only}

Kuritzky A, Hering R. Prophylactic treatment of migraine

with long acting propranolol - a comparison with placebo.


Lcking 1988a {published data only} Lcking 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):216.

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 Migrne eine multizentrische

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Lcking 1988b {published data only} Lcking 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 8:226.Soyka D, Oestreich W. Flunarizine versus propranolol

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Soyka D, Oestreich W. Therapeutic effectiveness of

flunarizine and propranolol in the interval therapy of

migraine. Cephalalgia 1987;7 Suppl 6:4678.

Ludin 1989 {published data only}

Ludin HP. Flunarizine and propranolol in the treatment of

migraine. Headache 1989;29(4):21924.

Maissen 1991 {published data only}

Maissen CP, Ludin HP. Comparative efficacy of

5-hydroxytryptophan and propranolol in interval

treatment of migraine [Vergleich der Wirksamkeit von

5Hydroxytrypthophan und von Propranolol in der

Intervalltherapie der Migrne]. Schweizerische Medizinische

Wochenschrift. Journal Suisse de Medecine 1991;121(43):158590.

Malvea 1973 {published data only}

Malvea BP, Gwon N, Graham JR. Propranolol prophylaxis

of migraine. Headache 1973;12(4):1637.

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;39:155151.

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):4237.

Nadelmann 1986 {published data only}

Nadelmann JW, Phil M, Stevens J, Saper JR. Propranolol in

the prophylaxis of migraine. Headache 1986;26(4):17582.

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):

7984.

Olerud 1986 {published data only}

Olerud B, Gustavsson CL, Furberg B. Nadolol and

propranolol in migraine management. Headache 1986;26(10):4903.

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):1608.

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):289.

Pita 1977 {published data only}

Pita E, Higueras A, Bolanos J, Perez N, Mundo A.

Propranolol and migraine. A clinical trial. Archivos de

Farmacologia y Toxicologia 1977;3(3):2738.

Pradalier 1989 {published data only}

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

Masson M, et al.Beta-blockers and migraine. Efficacy of

time-release propranolol versus placebo [Betabloquants

et migraine. Efficacit, contre placebo, du propranolol a

libration prolonge]. Thrapie 1990;45(5):4415.Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J,

Masson M, et al.Double-blind placebo controlled study of

the use of long-acting propranolol in migraine prophylaxis.

Cephalalgia 1989;9 Suppl 10:3678. Pradalier A, Serratrice G, Collard M, Hirsch E, Feve

J, Masson M, et al.Long-acting propranolol in migraine

prophylaxis: results of a double-blind, placebo-controlled

study. Cephalalgia 1989;9(4):24753.

Ryan 1984 {published data only}

Ryan RE Sr. Comparative study of nadolol and propranolol

in prophylactic treatment of migraine. American Heart

Journal 1984;108(4 Pt 2):11569.

Sargent 1985 {published data only}

Sargent J, Solbach P, Damasio H, Baumel B, Corbett

J, Eisner L, et al.A comparison of naproxen sodium to

propranolol hydrochloride and a placebo control for the

prophylaxis of migraine headache. Headache 1985;25(6):

3204.

Scholz 1987 {published data only}

Scholz E, Gerber WD, Diener HC, Langohr HD, Reinecke

M. Dihydroergotamine vs flunarizine vs nifidepine vs

metoprolol vs propranolol in migraine prophylaxis: a

comparative study based on time series analysis. In: Rose

CF editor(s). Advances in headache research: proceedings of

the 6th International Migraine Symposium. London: JohnLibbey, 1987:13945.

Shimell 1990 {published data only}

Shimell CJ, Fritz VU, Levien SL. A comparative trial of

flunarizine and propranolol in the prevention of migraine.

South African Medical Journal 1990;77(2):757.

Solomon 1986 {published data only}

Solomon GD, Scott AFB. Verapamil and propranolol in

migraine prophylaxis: a double-blind, crossover study.

Headache 1986;26(6):325.

Stensrud 1976 {published data only}

Stensrud P, Sjaastad O. Short-term clinical trial of

propranolol in racemic form (Inderal), D-propranolol and

placebo in migraine. Acta Neurologica Scandinavica 1976;53(3):22932.

Stensrud 1980 {published data only} Stensrud P, Sjaastad O. Comparative trial of Tenormin

(atenol) and Inderal (propranolol) in migraine. Headache

1980;20(4):2047.

Stensrud P, Sjaastad O. Comparative trial of Tenormin

(atenolol) and Inderal (propranolol) in migraine. UpsalaJournal of Medical Sciences - Supplement 1980;31:3740.

Sudilovsky 1987 {published data only}

Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA,

Meyer JH. Comparative efficacy of nadolol and propranolol

in the management of migraine. Headache 1987;27(8):

4216.

Tfelt-Hansen 1984 {published data only}

Standnes B. The prophylactic effect of timolol versus

propranolol and placebo in common migraine: beta-

blockers in migraine. Cephalalgia 1982;2(3):16570. Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen

H, Olesen J. Timolol vs propranolol vs placebo in common

migraine prophylaxis: a double-blind multicenter trial. ActaNeurologica Scandinavica 1984;69(1):18.

Weber 1972 {published data only}

Weber RB, Reinmuth OM. The treatment of migraine with

propranolol. Neurology 1972;22(4):3669.

Wideroe 1974 {published data only}

Wideroe TE, Vigander T. Propranolol in the treatment of

migraine. BMJ 1974;2(921):699701.

Ziegler 1987 {published data only} Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz

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



comparison of propranolol and amitriptyline. Archives of

Neurology 1987;44(5):4869.Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, Seim

J. Propranolol and amitriptyline in the prophylaxis of

migraine. Pharmacokinetic and therapeutic effects. Archives

of Neurology 1993;50(8):82530.

References to studies excluded from this review

Amery 1988 {published data only}

Amery WK. Onset of action of various migraine

prophylactics. Cephalalgia 1988;8 Suppl 8:113.

Anonymous 1979 {published data only}

Anonymous. Propranolol for prevention of migraine

headaches. Medical Letter on Drugs & Therapeutics 1979;21(19):778.

Banerjee 1991 {published data only}

Banerjee M, Findley L. Propranolol in the treatment of

acute migraine attacks. Cephalalgia 1991;11(4):1936.

Carroll 1990 {published data only}

Carroll JD, Reidy M, Savundra PA, Cleave N, McAinsh J.

Long-acting propranolol in the prophylaxis of migraine: a

comparative study of two doses. Cephalalgia 1990;10(2):1015.

Cortelli 1985 {published data only}

Cortelli P, Sacquegna T, Albani F, Baldrati A, DAlessandro

R, Baruzzi A, et al.Propranolol plasma levels and relief of

migraine. Relationship between plasma propranolol and

4-hydroxypropranolol concentrations and clinical effects.

Archives of Neurology 1985;42(1):468.

de Bock 1997 {published data only}

de Bock GH, Eelhart J, van Marwijk HW, Tromp TP,

Springer MP. A postmarketing study of flunarizine in

migraine and vertigo. Pharmacy World & Science 1997;19

(6):26974.


Diamond S, Solomon GD, Freitag FG, Mehta ND. Long-

acting propranolol in the prophylaxis of migraine. Headache

1987;27(2):702.

Fuller 1990 {published data only}

Fuller GN, Guiloff RJ. Propranolol in acute migraine: a

controlled study. Cephalalgia 1990;10(5):22933.

Havanka-Kann. 1988 {published data only}

Havanka-Kanniainen H, Hokkanen E, Myllyl VV.

Long acting propranolol in the prophylaxis of migraine.

Comparison of the daily doses of 80 mg and 160 mg.

Headache 1988;28(9):60711.

Holroyd 1995 {published data only}

Holroyd KA, France JL, Cordingley GE, Rokicki LA,

Kvaal SA, Lipchik GL, et al.Enhancing the effectiveness of

relaxation-thermal biofeedback training with propranolol

hydrochloride. Journal of Consulting & Clinical Psychology1995;63(2):32730.

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 Mdicale 1976;5(10):653.

Montastruc 1992 {published data only}

Montastruc JL, Senard JM. Calcium channel blockers and

prevention of migraine [Medicaments anticalciques et

prophylaxie de la migraine]. Pathologie et Biologie 1992;40

(4):3818.

Penzien 1990 {published data only}

Penzien D, Johnson C, Carpenter D, Holroyd K. Drug vs.

behavioral treatment of migraine: long-acting propranolol

vs. home-based self-management training. Headache 1990;30(5):300.

Raveau-Landon 1988 {published data only}

Raveau-Landon C, Bousser MG.Metoprolol, a new effective

antimigraine agent [Le metoprolo, nouvel antimigraineux

de fond]. Presse Medicale 1988;17(35):18059.

Rosen 1983 {published data only}

Rosen JA. Observations on the efficacy of propranolol for

the prophylaxis of migraine. Annals of Neurology 1983;13

(1):923.

Schmidt 1991 {published data only}

Schmidt R, Oestreich W. Flunarizine in migraine

prophylaxis: the clinical experience. Journal of

Cardiovascular Pharmacology 1991;18 Suppl 8:S216.

Sovak 1981 {published data only}

Sovak M, Kunzel M, Sternbach RA, Dalessio DJ.

Mechanism of the biofeedback therapy of migraine:

volitional manipulation of the psychophysiological

background. Headache 1981;21(3):8992.

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):196204.

Tfelt-Hansen 1986 {published data only}

Tfelt-Hansen P. Efficancy of beta-blockers in migraine. A

critical review. Cephalalgia 1986;6 Suppl 5:1524.

Turner 1984 {published data only}

Turner P. Beta-blocking drugs in migraine. Postgraduate

Medical Journal 1984;60 Suppl 2:515.

Verspeelt 1996a {published data only}

Verspeelt J, De Locht P, Amery WK. Post-marketing cohort

study comparing the safety and efficacy of flunarizine and

propranolol in the prophylaxis of migraine. Cephalalgia

1996;16(5):32836.

Verspeelt 1996b {published data only}

Verspeelt J, De Locht P, Amery WK. Postmarketing study of

the use of flunarizine in vestibular vertigo and in migraine.

European Journal of Clinical Pharmacology 1996;51(1):

1522.

Winther 1990 {published data only}

Winther K, Hedman C, Flodgaard H. Platelet P1, P4-Di

(adenosine-51) tetraphosphate (AP4A) in migraine patients

before and during beta-adrenoceptor blockade. European

Journal of Clinical Investigation 1990;20(3):3368.



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):2516.

References to studies awaiting assessment

Bernik 1978 {published data only}

Bernik V, Maia E. The use of propranolol on migraine

prophylaxis: a double-blind clinical trials comparing

propranolol with an analgesic drug (acetaminophen) and

placebo [Uso do propranolol na profilaxia da enxacequa:

Estudo duplocego comparando propranolol a um

analgesico (acetaminofen) e placebo]. Folha mdica (Rio de

Janeiro) 1978;77(4):5018.

Rao 2000 {published data only}

Rao BS, Das DG, Taraknath VR, Sarma Y. A double blind

controlled study of propranolol and cyproheptadine in

migraine prophylaxis. Neurology India 2000;48(3):2236.

Additional references

Ad Hoc 1962

Ad Hoc Committee on the Classification of Headache of the

National Institute of Neurological Diseases and Blindness.

Classification of headache. JAMA 1962;179(9):7178.

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):33340.

IHS 1988

Headache Classification Committee of the International

Headache Society. Classification and diagnostic criteria

for headache disorders, cranial neuralgias and facial pain.


Jadad 1996

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds

DJ, Gavaghan DJ, et al.Assessing the quality of reports of

randomized clinical trials: is blinding necessary?. Controlled

Clinical Trials 1996;17(1):112.

Lipton 2001

Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed

M. Prevalence and burden of migraine in the United States:

data from the American Migraine Study II. Headache 2001;

41(7):64657.

Pryse-Phillips 1997

Pryse-Phillips WEM, Dodick DW, Edmeads JG, Gawel

MJ, Nelson RF, Purdy RA, et al.Guidelines for the diagnosis

and management of migraine in clinical practice [published

erratum appears in CMAJ 1997;157(10):1354]. CMAJ

1997;156(9):127387.

Ramadan 1997

Ramadan NM, Schultz LL, Gilkey SJ.Migraine prophylactic

drugs: proof of efficacy, utilization and cost. Cephalalgia

1997;17(2):7380.

Stewart 1994

Stewart WF, Shechter A, Rasmussen BK. Migraine

prevalence. A review of population-based studies. Neurology

1994;44(6 Suppl 4):S17S23.

Tfelt-Hansen 2000

Tfelt-Hansen P, Block G, Dahlf C, Diener HC, Ferrari

MD, Goadsby PJ, et al.Guidelines for controlled trials of

drugs for migraine: second edition. Cephalalgia 2000;20

(9):76586.

Verhagen 1998

Verhagen AP, de Vet HCW, de Bie RA, Kessels AG, Boers M,

Bouter LM, et al.The Delphi list: a criteria list for quality

assessment of randomized clinical trials for conducting

systematic reviews developed by Delphi consensus. Journal

of Clinical Epidemiology 1998;51(12):123541. Indicates the major publication for the study



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

Outcomes R: not reported

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

AU: similar in all 3 groups

HI: not reported

AEs: not reported

Dropouts-AEs: not reported

V: 0

Notes High dropout rate

Risk of bias



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: (+)

Notes High dropout rate

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: simi

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