Timolol in Migraine Prophylaxis R. S. Briggs, M.B., M.R.C.P., P. A. Millac, M.D., F.R.C.P. Department of Neurology, Leicester Royal Infirmary, Leicester. LE15WW, England. Reprint requests to: P. A. Millac, Leicester Royal Infirmary, Leicester. LE15WW, England. SYNOPSIS The literature on the use of beta-blocking drugs in migraine suggests that not all such agents are effective. A double-blind crossover study of timolol in migraine prophylaxis was undertaken with fourteen patients, in order to assess the value of this drug in particular, and also to elucidate further the reason for the varied response to different beta-blockers. Timolol significantly reduced the frequency of migraine attacks, and was preferred to placebo. This supports the contention that beta-blocking drugs without intrinsic sympathomimetic activity are effective in migraine prophylaxis. (Headache 19:379-381, 1979) INTRODUCTION Beta-adrenoceptor antagonists, particularly propranolol, have been shown to reduce the frequency and severity of migraine attacks.1-4 Several mechanisms have been postulated. Vasodilation of peripheral vessels in response to circulating catecholamine may be blocked, and this has been said to be the basis of action in migraine prophylaxis.5 However, it has also been proposed that the initiation of a migraine attack is by a vasoconstrictor action of noradrenaline on vascular alpha-adrenoceptors. Prolonged treatment with beta-blockers reduces vascular resistance with a concomitant fall in blood pressure; thus with continued therapy vasodilation may be of more benefit, preventing the effects of initial alpha-mediated vasoconstriction.6 If this is the case, beta-blockers with intrinsic sympathomimetic activity would be expected to be of less value in migraine prophylaxis. Finally, it is worth noting that beta-adrenoceptor antagonists have also been shown to be competitive 5-hydroxytryptamine antagonists.7 PATIENTS AND METHODS Fourteen patients (4 male, 10 female) with frequent migraine agreed to take part in the study after routine referral to the neurology clinic. Patients gave informed consent, and the study was approved by the local Ethical Committee. Migraine was diagnosed according to the definitions of the Ad Hoc Committee;8 12 patients had "common" and 2 "classical" migraine. All had at least two attacks a month, and had been taking other drugs for prophylaxis without apparent benefit (clonidine in 9 of the 14). Patients were instructed to complete record sheets documenting the frequency, intensity and duration of every migraine attack. Episodes of migraine were treated with simple analgesics or ergotamine derivatives; each patient used the same agent consistently during the trial, and recorded the number of tablets used. During an initial 4 week period, no prophylactic treatment was given. The record sheets were examined at this stage, and all patients were found to have had at least two attacks. Patients were then randomly allocated into two groups, one group receiving placebo for six weeks followed by timolol 10 mg twice daily for six weeks, and the other group receiving treatments in the reverse order. After completing these two study periods, the patients were again randomly allocated into two groups and the treatment procedure repeated. Thus, patients completed 4 study periods lasting six weeks each, receiving active timolol during two periods and placebo during two periods. At the end of each period, record sheets were collected and compliance with treatment checked by tablet counts. After each pair of study periods (timolol and placebo), patients were asked which of the two treatments they preferred. One patient withdrew after two weeks of the third period, when she was taking placebo, complaining of constipation and fluid retention. During the first half of the trial, one patient complained of cold extremities, and another with classical migraine found that she experienced less headache during attacks but her visual disturbance was more severe; both these subjects were instructed to halve the tablets (timolol and placebo) during the third and fourth study periods. The symptoms which they had complained of on timolol 20 mg daily disappeared when the dose was reduced to 10 mg daily. RESULTS Timolol reduced the number of migraine attacks (Table 1), this effect reaching statistical significance in the second half of the trial (p < 0.01, Wilcoxon rank

Table 1 Double-blind Crossover Trial of Timolol vs. Placebo in Prophylaxis of Migraine: Headache Frequency Subject No. of Migraines in Each 6-week Period: No. 1st Placebo 1st Timolol 2nd Placebo 2nd Timolol 1 11 14 18 12 2 4 1 5 4 3 7 2 6 0 4 5 5 2 3 5* 2 3 6 12 6 8 1 7 2 5 2 1 8 9 5 9 8 9 13 9 8 1 10 5 0 3 0 11 9 5 11 5 12† 2 3 4 1 13† 12 11 6 8 14 4 5 5 3 Mean: 6.9 5.3 6.7 3.6 Probability: NS