Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses

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

CEPHALALGIA Carroll Reidy M, Savundra PA, Cleave N, McAinsh J. Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses. Cephalalgia 1990;10:101-5. Oslo. ISSN 0333-1024 A randomized double-blind, cross-over study using treatment periods of 12 weeks with a 2-week washout, comparing two long-acting formulations of propranolol ('Inderal'* LA 160 mg daily and Half-'Inderal' LA 80 mg daily) was performed after a placebo run-in of 4 weeks on 51 patients. The study indicated that both long-acting formulations were significantly better than placebo in reducing the frequency of migraine attacks (p < 0.01). After 12 weeks there was a significantly lower (p = 0.03) frequency of migraine attacks in patients on the higher dose formulation than in those on the lower dose formulation. There was no significant difference in the frequency of side effects produced by the two formulations.

JD Carroll, M Reidy, PA Savundra, Regional Neurological Unit, Royal Surrey County Hospital, Guildford, Surrey, UK; N Cleave, Centre of Mathematical Software Research, University of Liverpool, Liverpool, UK; J McAinsh, ICI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK; Correspondence to JD Carroll; Accepted 31 October 1989 In recent years propranolol has become a drug of choice in the prevention of migraine headache because of its efficacy, safety and lack of rebound headaches. The effectiveness of propranolol in different controlled studies has ranged from 55 to 81% of the patients (1). Because of its short plasma half-life, most of the studies with propranolol have been conducted with the drug being administered 2-4 times daily. Furthermore, prophylactic therapy for migraine patients is long term and compliance is a problem. A sustained release form of propranolol was therefore developed to provide a convenient preparation that could be given once daily and produce both a steady propranolol blood level and a prolonged degree of beta-blockade (2,3). Two strengths of the sustained release propranolol formulation are available. They contain 160 mg propranolol hydrochloride ('Inderal' LA) and 80 mg propranolol hydrochloride (Half-'Inderal' LA), respectively. The sustained release propranolol formulation comprises a hard gelatine capsule filled with small spheroids. Each spheroid contains approximately 600 mg of propranolol hydrochloride and is individually coated with an ultrathin, semi-permeable membrane which allows diffusion controlled release of the drug into the gastrointestinal tract. In vitro dissolution data show that 50% of the dose is dissolved in about 4 h from the sustained release formulation compared with about 5 min from a conventional propranolol tablet (2). An accurate picture of the pharmacokinetic behaviour of any sustained release formulation can be obtained by comparing its blood level profile following a single oral dose with that following the same dose of a conventional tablet. Such comparisons have been made (3-10). In each of these studies the conventional 'Inderal' tablet produced a blood profile of propranolol with a high initial peak followed by a rapid fall, such that the peak to 24 h blood level varied between 20- and 90-fold. By comparison, 'Inderal' LA showed prolonged absorption, lower peak levels, produced a less rapid fall in systemic levels and gave a statistically significantly higher 24 h blood level. The net result was a sustained blood profile with peak to 24 h blood levels varying only 2- to 6-fold. This difference in profiles is consistent with the

dissolution characteristics of the formulations. The half-life following dosing with 'Inderal' LA has been reported to be between 10 and 20 h, i.e. two to three times that of the conventional tablet formulation. A similar pharmacokinetic profile has been established in man for 'Inderal' LA-80 (9). The propranolol bioavailability from 'Inderal' LA is approximately 50% of that from conventional tablets. This apparent difference in systemic bioavailability of propranolol is believed to result from the slower rate of absorption of propranolol from 'Inderal' LA, and the effect of this slower rate on the saturable first pass metabolism of propranolol in the liver (11). This paper reports the results of a clinical trial comparing the efficacy and tolerability of these two strengths of 'Inderal' LA in the prophylaxis of migraine. Patients and methods

Fifty-one patients (35F and 16M) selected by the Ad hoc committee classification (12) of headache to have either classical or common migraine were recruited and gave their informed consent. The patients had a mean age of 39 years (range 17 to 62 years) and a history of migraine with a median duration of 14 years (range 2 to 50 years). The median frequency of attacks was eight per month (range 0.9 to 20) and the median duration of an attack was 24 h (range 3 to 96 h). The protocol for the study was approved by the local ethics committee. After a four-week run-in period during which they received placebo (single-blind), patients were randomized to receive long-acting propranolol 160 mg ('Inderal' LA) once-daily or long-acting propranolol 80 mg (Half-'Inderal' LA) once-daily in a double-blind cross-over study with 12 week treatment periods. The order of treatments was subject to balanced double-blind randomization and the active treatment periods were separated by a two-week washout period in which the patients received placebo. The patients were assessed at entry, at the end of the run-in and washout periods, and at four-weekly intervals during each treatment period. At entry, demographic and historic details were recorded, together with relevant clinical history and resting blood pressure and heart rate. At subsequent visits blood pressure and heart rate and any side effects volunteered by or by general direct question from the patient were recorded and the patient submitted diary cards giving details of their migraine attacks since the last visit. The migraine data on the patients' diary cards consisted of the date of attack; time of onset; time of relief (headache or nausea); headache severity and details of escape medication such as the type of migraine relief tablet; time of consumption and quantity of tablets taken. In particular, headache severity was made from patients' self-assessment cards graded as follows: slight = 1, moderate = 2, severe = 3 and incapacitating = 4. Statistical analysis

The analysis of treatment efficacy centred on the frequencies of migraine attacks. A non-parametric test for the equality of residual (carry-over) effects was conducted using the Wilcoxon statistic. In the absence of carryover effects, the equality of period effects and direct treatment effects was tested, again with the Wilcoxon statistic. The evaluation variables, duration of migraine and headache severity, were compared during the placebo and active treatments using the Wilcoxon matched pairs, signed ranks test (two-tailed). All available information was used for the tests. Thus, if a patient who withdrew from the study was present for the run-in and all or part of one treatment period, his or her results were included in the analysis. Comparisons were also made between 'Inderal' LA and Half-'Inderal' LA attack frequencies at week 12 of the treatment period, and between frequencies at weeks 4 and 8, weeks 8 and 12 and weeks 4 and 12, within treatments. Most patients took a variety of migraine relief tablets during the trial. Thus the num-

Table 1. Results for efficacy parameters. Placebo Variables (run-in) 'Inderal' LA Half-'Inderal' LA Frequency (per month) 6.1 3.4 3.9 (0-26) (0-16) (0-28) No. 6 44 42 Duration (h) 6.9 6.9 7.3 (2-13) (2-18) (1-19) No. 42 34 36 Severity 1.5 1.9 1.9 (1-4) (1-4) (1-4) No. 48 43 42 The figures quoted are the medians and ranges of the evaluation variable.

Table 2. Median frequencies for patients present throughout the study. Placebo Variables (run-in) 'Inderal' LA Half-'Inderal' LA Frequency 6, 10 3.40 3.70 (0-24) (0-16) (0-17) No. 37 37 37 The figures quoted are the medians and ranges of the evaluation variable. ber of migraine relief tablets consumed was not analysed as an efficacy variable. Only the proportion of attacks during which escape medication was taken was considered, and compared between treatments with the sign test. The proportions of patients with side effects for each treatment were compared using McNemar's test, and the number of different side effects for each treatment with the sign test. Results

Efficacy The median results for the evaluation variables are given in Table 1. Fourteen patients withdrew from the study at some stage. The medians and ranges of the frequency of migraine attack for those present for the whole study are given in Table 2. The frequencies of attack during the 'Inderal' LA and Half-'Inderal' LA treatment periods were significantly lower than Table 3. Efficacy results at week 12. Variables 'Inderal' LA Half-'Inderal' LA Frequency 3.2 4.0 (0-16) (0-18) No. 38 35 The figures quoted are the medians and ranges of the evaluation variable. that during the placebo run-in (p < 0.01 in both cases). There is no statistically significant difference between the frequencies of attack under 'Inderal' LA and under Half-'Inderal' LA (p = 0.26). However, a comparison of the two treatment periods at week 12 (Table 3) shows the attack frequency after treatment with 'Inderal' LA to be significantly lower than that after Half-'Inderal' LA (p = 0.03). There were no significant differences between the mean migraine attack durations for placebo and active treatment, or the two active treatments. The same was true for mean headache severity. The proportion of

Table 4. Number of patients experiencing side effects. Treatment Placebo Placebo 'Inderal' Half-'Inderal' run-in washout LA LA 8 8* 27† 18‡ *

Includes one patient who was withdrawn; includes three patients who were withdrawn; ‡ includes one patient who was withdrawn. †

attacks for which migraine relief tablets were taken was not significantly different between placebo and active treatment, or between the two active treatments. There is no evidence of unequal carryover. There is a slight indication of a period effect, with the frequencies of attacks being lower in the second period (0.05 < p < 0.10). Tolerability Of those withdrawn because of side effects three patients did so while on treatment with 'Inderal' LA (dizziness, visual disturbance, insomnia and depression), one patient on treatment with Half-'Inderal' LA (nausea, drowsiness) and one patient withdrew during the washout period (tiredness). Of the remaining withdrawals one patient had poor attendance, three patients were non-responders to the trial medication and five patients did so for unspecified reasons. The number of patients volunteering side effects is given in Table 4. The proportions of patients with side effects were significantly higher for each of the two active treatment periods than for the placebo run-in (p < 0.01). There was, however, no significant difference between the proportions of patients with volunteered (p = 0.45) or elicited (p = 0.58) side effects for 'Inderal' LA and Half-'Inderal' LA. The most common side effect was tiredness (11 patients on Half-'Inderal' LA, 9 patients on 'Inderal' LA, 4 patients on placebo). The mean blood pressure dropped by about 12/9 mmHg during active treatment and was accompanied by a fall in mean heart rate of about 15 beats min-1. The reduction in blood pressure was slightly less with the lower dose treatment. These decreases in blood pressure with a beta-adrenergic blocking drug in normotensive patients concur with other studies and are of little clinical importance. Discussion

This study has demonstrated that the sustained release formulation of propranolol given once-daily at two dose strengths significantly reduces the number of headaches per patient compared with placebo. The difference in efficacy between the two strengths of the formulation was not statistically significant. This finding is in agreement with preliminary reports of related studies with sustained release propranolol in 42 patients with classic or common migraine (13, 14). In the study by Havanka-Kanniainen et al. (13) the sustained release formulation significantly reduced the migraine attack rate in both classical and common migraine. Furthermore, Kuritzky and Hering (14) reported that in 31 patients with classical or common migraine 160 mg 'Deralin' SR once daily reduced the number of migraine attacks from 5.56 on placebo to 3.23 (p < 0.02). Contrary to the present study both the severity of attacks and the duration of headache were significantly reduced by the sustained release propranolol formulation (p < 0.002). Both of these studies and the present report therefore confirm the clinical efficacy of propranolol in migraine obtained from previously published anecdotal reports, uncontrolled trials (15, 16) and controlled trials (17-29) and support the use of once-daily treatment. This study has also shown that both 'Inderal' LA and Half-'Inderal' LA are well tolerated medications in patients with migraine since few severe side effects were reported. Only five patients (10%) withdrew due to side effects but the frequency of side effects in the remaining patients was higher with propranolol based therapy than placebo. These observations confirm those previously published (13, 14).


The results of this randomized, double-blind trial in 51 patients with migraine confirm that 'Inderal' LA and Half-'Inderal' LA once-daily are well tolerated and effective treatments of classical and common migraine. The treatments reduced the frequency of migraine attacks at the end of each trial period. These data suggest that the degree of improvement increases with duration of treatment. Furthermore, for the majority of patients Half-'Inderal' LA appears, from this study, to be adequate prophylactic therapy for migraine and may be better tolerated than 'Inderal' LA, which appears to offer no additional benefit. References


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Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses.

A randomized double-blind, cross-over study using treatment periods of 12 weeks with a 2-week washout, comparing two long-acting formulations of propr...
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