Propranolol in the treatment of acute migraine attacks

Mala Banerjee, Leslie Findley

Cephalalgia Banerjee M, Findley LJ. Propranolol in the treatment of acute migraine attacks. Cephalalgia 1991;11:193-6. Oslo. ISSN 0333-1024 The efficacy of the beta-adrenoceptor antagonist propranolol in the acute treatment of patients in attacks of either classical (migraine with aura) or common migraine (migraine without aura) headache was assessed in a double-blind placebo-controlled crossover trial with fixed doses. The trial was carried out on 25 patients. The treatment period was set at eight weeks, with the provision of shortening or lengthening it if necessary with a maximum period of seventeen weeks. A minimum of three migraine attacks were treated during each treatment period. Patients were assessed according to: the mean duration and mean severity per treatment period of migraine attacks. The secondary efficacy assessment was made on the basis of the percentage of attacks requiring escape medication per treatment period. The study, based on the t-distribution statistical model with a confidence level of 95%, showed that propranolol had no significant effect in aborting acute attacks of migraine when compared with placebo. • Mala Banerjee, Leslie Findley, Department of Neurology, Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital, Romford, Essex, England, UK; Correspondence to Mala Banerjee It is well known that beta-adrenoceptor antagonists, in particular propranolol, offer effective prophylactic treatment of recurrent migraine (1-4). These earlier investigations, based on controlled clinical trials, indicate that about 55-80 % of patients with common or classical migraine achieved benefits from pro-pranolol. The investigators also claimed that this improvement could be sustained over a long period. In contrast, it appears that there has been very little research into the use of propranolol in the acute attack of migraine. A literature survey reveals very little information (5-7). Featherstone (5) and Tokola et al. (6) reported that propranolol can be used to abort acute attacks of both classical and common migraine, whereas recently Fuller and Guiloff (7) have concluded that propranolol, in a dose of 40 mg, is not clinically useful in the treatment of acute attacks of migraine, classical or common. (Other related research, e.g. on acute relief of cluster headache, can be found in the work of Fogelheim (8).) These published results are limited in extent, contradictory and/or inconclusive. It may also be noted that available drugs for the treatment of acute migraine attacks have considerable limitations (9). Thus it would seem important to assess the efficacy of propranolol in acute migraine attacks. The present investigation was undertaken to fulfil this objective. The study was carried out from detailed data collected from the diaries of patients treated in a double-blind placebo control crossover trial with fixed doses. Patients

A total of 25 patients aged between 18 and 65 years were initially recruited (Table 1). However, seven patients withdrew from the trial (one because of presumed inefficacy of the drug, three did not attend the clinic, and three due to initial side effects of the drug [in particular, weakness]) and so were excluded from the analysis. All patients were diagnosed as having common or classical migraine. To enter the study, patients had to have either classical or common migraine as defined by the Committee of the International Headache Society (10). The patients were divided into two groups (each consisting of nine patients) for each treatment sequence (see footnotes to Table 2). All patients had had headache with any three of the following six criteria: (i) unilateral headache, (ii) throbbing or pulsating headache, (iii) GI disturbance during some or all attacks, (iv) transient neurological deficit, (v) sono/photophobia during all attacks, (vi) family history of migraine. Each headache was considered to be either moderate or severe in its intensity (disability scale). All patients were required to have had a minimum of four migraine attacks during the preceding 12 weeks Table 1. Patients' data. No.

25 (4 M, 21 F)

Age range (years)

18-65 (mean 35)

Duration of migraine since it began

1-30 years

Frequency of migraine

2-8 per month

Duration of each attack

3-72 h

Common migraine


Classical migraine


Treatment sequence 1*

12 (3 M, 9 F)

Treatment sequence 2*

13 (1 M, 12 F)


Treatment sequence 1 is propranolol/placebo. Treatment sequence 2 is placebo/propranolol.

Table 2. Results of the statistical analysis. p-values*

Mean ± standard error Treatment Treatment sequence 1** sequence 2**

Parameter Period Treatment investigated effect effect Period 1 Period 2 No. of attacks 0.46 0.71 4.6 ± 0.6 4.0 ± 0.8 Duration of attacks in h 0.03 0.23 2.6 ± 0.4 3.3 ± 0.3 Headache severity 0.65 0.95 2.3 ± 0.1 2.3 ± 0.2 Nausea severity 0.58 0.88 1.8 ± 0.4 1.7 ± 0.4 Vomiting severity 0.74 0.19 1.7 ± 0.4 2.2 ± 0.5 Aura severity 0.012 0.83 1.6 ± 0.3 1.9 ± 0.3 Escape medication (%) 0.023 0.33 42 ± 12 70 ± 11 Tablet effect 0.11 0.20 3.6 ± 0.3 3.0 ± 0.2 Comparison with other treatment 0.07 0.70 3.2 ± 0.3 2.6 ± 0.3 Side effect 0.15 0.40 3.6 ± 3.6 0.0 ± 0.0 * p > 0.05 means the effect is non-significant (p < 0.05 for significant).

Period 1 5.4 ± 1.0

Period 2 5.2 ± 1.1

2.5 ± 0.3 2.3 ± 0.1 1.7 ± 0.2 1.6 ± 0.7 1.4 ± 0.4

2.7 ± 0.2 2.3 ± 0.2 1.4 ± 0.3 0.8 ± 0.4 1.8 ± 0.3

16 ± 8 3.5 ± 0.3

28 ± 11 3.5 ± 0.2

3.5 ± 0.4 25 ± 14

3.0 ± 0.4 11 ± 11

** Treatment sequence 1: propranolol/placebo (i.e. propranolol in period 1 and placebo in period 2). Treatment sequence 2: placebo/propranolol (i.e. placebo in period 1 and propranolol in period 2). (There are 9 patients in each treatment sequence.)

without receiving any prophylactic medication during the month prior to entry into the trial. For those patients with mixed attacks of classical and common migraine, an arbitrary threshold of 50% or more was deemed to be classical. Conversely, patients with less than 50% attacks accompanied by aura were regarded as "common". All patients had normal CT brain scan. Patients who had had other types of headaches and/or evidence of renal cardiac and liver diseases were excluded. Patients with history of treatment failure with beta-adrenoreceptor antagonists or who had contra-indications for the use of these drugs were excluded. Also patients with severe nausea or vomiting at the onset of attacks, or with more than two attacks of migraine per week and having long-term medication other than oral contraceptives were excluded. Furthermore, lactating mothers, diabetics, patients with active psychiatric problems and patients who were treated prophylactically for migraine at least four weeks prior to the trial were also excluded. Methods

The investigation was based on a double-blind placebo controlled crossover trial with a fixed dosage. Each patient took a maximum of three tablets (each containing either placebo or 40 mg propranolol) for each migraine attack. A minimum of three migraine attacks were treated during each treatment period. During the trial period, which was set at eight weeks with the possibility of shortening or extending for a maximum period of 17 weeks, patients took trial medication at the earliest onset of all migraine attacks. A second dose of trial medication was taken if, in the patient's opinion, the first dose was only partially effective. The second dose was to be taken only at least two hours after the first. Again, a third dose of trial medication was taken in the event of incomplete relief perceived by the patients. The minimum time gap between the second and third doses was again set at 2 h. Patients recorded the following information on a given formatted booklet (diary) whenever an attack occurred: (a) Date and time of onset of migraine, (b) quality of migraine (aura, headache, nausea, vomiting), including severity (mild, moderate or severe with respective score of 1, 2 or 3), (c) time when trial medication was started, (d) timings and doses of subsequent trial medication or escape drugs, (e) subjective response to treatment, and (f) comments on any possible side effects of medi-cation. Prior to entering the study, a detailed history of the patient was obtained and a thorough investigation, including full blood count, blood biochemistry, heart rate and measurement of blood pressure, was carried out. All subjects had normal ECGs and all female patients underwent a pregnancy test. Patients were subsequently given a diary, a prescription for medication and also instruction on the use of the medication (trial drug at the earliest onset of migraine attack, a second dose of trial drug 2 h after the first dose if needed, and also a third dose 2 h after the second dose if still needed.) Patients who had a past history of continuing headache running into a second and third day were instructed to use escape medication irrespective of

any relief produced by the trial medication. Any attack after freedom from symptoms for 48 h was regarded as a new one and was treated as above. After treating a minimum of three attacks, patients were asked to return. The diaries were reviewed with the patients, and unused medication was collected. A new diary and medicines were issued and instruction on how to use the trial drug during acute attacks of migraine was given. Patients were told to return for the final visit (visit 4) only when a minimum of three further attacks had been treated. At visit 4, diaries and medicine were collected for final evaluation. The data contained in the patients' diaries were processed and statistically analysed using Student's t-distribution with a confidence limit of 95%. The details of the method used in the statistical analysis can be found in Hills and Armitage (11). The efficacy of the drug was assessed on the statistical variation of the following parameters: (i) No. of attacks, (ii) duration of attacks, (iii) headache severity, (iv) nausea severity, (v) vomiting severity, (vi) aura severity, (vii) escape medication, (viii) tablet effect, (ix) other treatment, and (x) side effects. For all these parameters, the mean, standard deviation, confidence limit and whether or not the statistical distribution was significant (p < 0.05 for significant), were calculated. It may be noted that for the parameter "duration of attack", the variable was log-trans-formed prior to analysis because its mean value (per patient) displayed a distribution skewed to the right. Results

Based on the statistical analyses carried out on the data, the following results on its efficacy were obtained: (i) There were no significant effects of treatment on the number of attacks compared with placebo. (ii) There were no significant effects of treatment on the duration of attacks. (However, the period effect was found to be significant for the duration of attack.) (iii) There were no significant effects of treatment on headache severity. (iv) There were no significant effects of treatment on nausea severity. (v) There were no significant effects of treatment on vomiting severity. (vi) There were no significant effects of treatment on aura severity. (However, the period effect was found to be significant for the aura severity.) (vii) The treatment period interaction and period effects were found to be significant. (It may be noted that because the treatment period interaction is significant, the treatment effect was assessed on the first period results only, which show a significant treatment effect with placebo having a lower percentage than propranolol. Because of the low number of attacks treated, the percentages can only take a few values between 0% and 100%, and so a degree of conservatism should be used when evaluating this result.) (viii) There were no significant effects of treatment on tablet effect. (ix) There were no significant effects of treatment when comparison was made with other treatments. (x) There were no significant effects of treatment on side effects. The results, including the p-values indicating significant (s) or non-significant effect (n.s.), are summarized in Table 2. As indicated in the table, propranolol does not appear to have any treatment effect on headache severity, duration of headaches, number of headaches, nausea, vomiting or aura. Also, the significant requirement of the escape medication implies that propranolol was not effective in the trial. The results in Table 2 are self-explanatory. However, an illustrative example of interpretation of Table 2 results is as follows. For example, the number of attacks abolished in treatment sequence 1 with propranolol (period 1) is 4.6, with standard error (s.e.) ±0.6. The corresponding number of attacks abolished with placebo is 4.0 (s.e. = 0.8). Likewise in treatment sequence 2, the number of attacks abolished by placebo is 5.4 (s.e. = 1.0), whereas the number of attacks abolished with propranolol in the same treatment sequence is 5.2 (s.e. ± 1.1), as evidenced from the table. In the two cases, p being more than 0.05, the treatment and period effects are both non-significant and the number of attacks mentioned in the table represents the treated number of headaches. Discussions

Beta-adrenoceptor antagonist drugs such as pro-pranolol without partial agonist activity are effective in migraine prophylaxis (12-14). It may be noted that the drug can reduce cardiac output with a compensatory increase in peripheral resistance and may also act in migraine by blocking the vasodilator influence (15). A number of properties of beta-adrenoceptor activity, including selectivity of action, intrinsic sympathomimetic activity, membrane stabilizing activity and brain penetration, may explain the action of propranolol in migraine. Another explanation for the antimigraine action of propranolol in the acute attack is probably the effective antagonistic activity at certain 5HT receptors implicated in the pain generation of the acute attack, as suggested by Fozard (16, 17). This explanation, however, has not yet been confirmed, and further insight on the efficacy can possibly be gained if the drug is used in larger doses (18, 19). Propranolol's ineffectiveness in treating acute migraine may have a number of explanations. It has been observed that during acute migraine head-

aches propranolol absorption through the stomach is reduced in comparison to the non-migraine state, and results in lower serum drug levels (20). This lower absorption of the drug may be due to gastric stasis, impaired motility or prolonged gastric emptying. There are clear advantages in the intermittent use of a drug such as propranolol, which has a number of predictable side effects (interested readers are referred to references 18, 19 and 21 for further studies). There is evidence that intermittent therapy has a proven value in the control of essential tremor (18). Thus intermittent treatment with such powerful drugs may be preferable to continued long-term administration as a general principle. A more practical point would be that the therapy with these agents could in the event of symptomatic efficacy be extended to the many patients in whom prophylactic therapy would be unjustified mainly due to side effects of the drug. The outcome of this paper concurs with the paper published recently by GN Fuller and RJ Guiloff (7), who also used similar doses of propranolol (40 mg) in their investigation. In view of these parallel investigations giving rise to similar results with identical doses, it seems plausible that a larger dose of pro-pranolol may be effective in treating the acute migraine attack (19). As we know that there may be some considerable difficulties with absorption of propranolol in acute migraine attack, a comparative pharmacokinetic study of propranolol in migraine with a control subject is thus needed. Conclusions

There is no evidence that propranolol (40 mg) can abort acute migraine attacks. Acknowledgements.-The authors are grateful to ICI, UK for providing a grant which made this work possible. The investigation was carried out at the Regional Centre for Neurology and Neurosurgery, Oldchurch Hospital, Romford, Essex, UK. Thanks are also extended to Dr A. Abbas for his assistance in the study. References


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Propranolol in the treatment of acute migraine attacks.

The efficacy of the beta-adrenoceptor antagonist propranolol in the acute treatment of patients in attacks of either classical (migraine with aura) or...
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