Propranolol in acute migraine: a controlled study
GN Fuller, RJ Guiloff
CEPHALALGIA Fuller GN, Guiloff RJ. Propranolol in acute migraine: a controlled study. Cephalalgia 1990;10:229-33. Oslo. ISSN 0333-1024 Propranolol is an established agent in migraine prophylaxis. Uncontrolled studies have suggested an action in the acute attack. We present the first double-blind placebo controlled study of propranolol in 27 unselected patients with common (migraine without aura) and classical (migraine with aura) migraine. There were 23 pairs of headaches in the 14 patients who completed the study. No difference was found, when the data were analysed by headache pair or by patient, in severity duration and subjective assessment of efficacy between those treated in an attack with propranolol 40 mg and placebo. • Acute migraine, controlled study, propranolol GN Fuller, RJ Guiloff, Department of Neurology, Charing Cross and Westminster Medical School, Westminster Hospital, 17 Page Street, London SW1P 2AP, UK; Accepted 23 July 1990 Propranolol is well established as an agent effective in migraine prophylaxis with between 50 and 80% of those treated responding (1-4). Many patients have infrequent headaches and do not want to take prophylaxis. There have been a number of case reports of patients given propranolol as prophylaxis for common (migraine without aura) and classical (migraine with aura) migraine who have found that it can be used to abort acute attacks (5), an observation we have also made. There has been one open study (6) in which a single dose of between 40 and 80 mg of propranolol was given to 30 patients with common or classical migraine. A good or excellent response was found in 16 (53%) within 2h. There is a single reported case of propranolol aborting an attack of cluster headache (7). In placebo controlled studies of other agents in acute migraine the response to placebo can be as high as 50% (8). We present the results of the first double-blind controlled study of propranolol in acute migraine. Methods
Patients Consecutive patients that met inclusion criteria were recruited from a general neurology clinic. The inclusion criteria were (1) common or classical migraine as defined by the Ad Hoc Committee (9) and revised by Tfelt-Hansen (10) and (2) the migraine must be of one year's duration, with attacks occurring between once a week and once every four months, and (3) age between 16 and 65. Exclusion criteria were (1) contraindications to propranolol or paracetamol or (2) pre-existing migraine prophylaxis or beta-blocker therapy for other indications, (3) non-migrainous headaches that are not clearly distinguishable from migraine. Patients gave a full written informed consent. Drugs and randomization Each patient treated four attacks with trial medication: two attacks were treated with 40 mg propranolol and two with placebo. The order of drug and placebo was randomized by the pharmacy in two pairs ensuring patients had had both propranolol and placebo after two attacks. The randomization code was kept by the pharmacist and broken at the end of the study. The doctor and patient were blinded at all times. The patients were also given a punch out pack of paracetamol 0.5 g tablets which they were instructed to take as required two hours after the test. medication. Attack record cards Patients were given four attack record
cards with four postage paid addressed envelopes. The following information could be recorded on the cards: The delay between the start of the attack and taking the capsule; the severity, graded out of ten, of the headache and of other symptoms, such as sickness, at the time the capsule was taken (T0) and two hours later (T1); the duration of the attack; an assessment of the effect of the capsule graded as no effect (0), poor (1), fair (2), good (3) and excellent (4); the number of paracetamol tablets taken during the attack; the overall severity of the migraine; any adverse effects noted. Statistical methods and end points The comparability of propranolol and placebo treated headaches was assessed by: (a) delay in taking the test medication and (b) the severity of the headache at T0. The following end points were compared: (a) assessment of effect of capsule; (b) the difference in severity of headache at T0 and T1; (c) the difference in severity of other symptoms at T0 and T1; (d) the duration of headache; (e) the overall severity of the migraine. Data were analysed in two ways. Firstly, considering the headache as the event, and comparing each actively treated headache with its matched placebo control. Secondly, by considering the response by patient, when the mean result for each patient was analysed. The former analysis assumes the independence of each headache pair but does not try to combine ordinal data. The latter requires nominal ordinal data to be combined. This was done by taking the mean numerical score attributed to the data for both active treatments or placebo treatments. The validity of such a mean is questionable for all parameters except duration of headache and can be taken only as an approximation. Ordinal data were compared within each headache pair using Wilcoxon ranked pairs test. The proportions of responders within each group were compared with Chi squared. Confidence intervals when given are at 95% (95% CI). The study was approved by the local Ethical Committee. Results
Twenty-seven patients were recruited. Twenty-three pairs of headaches from 14 patients were eligible for analysis; of the remaining 13 patients, 10 did not reply and 3 returned only one form. The headaches available for study came from 9 patients with common and 5 with classical migraine aged between 16 and 52 (median 31 years). There were 11 women and three men, 11 had lateralized headaches and 7 had a family history, 6 did not and one was adopted. Of those who were ineligible there were 5 men and 8 women, aged between 16 and 51 (median 27 years), 11 with common and 2 with classical migraine. Record cards The capsules were most frequently taken within 30 min of the start of the headache (propranolol 14; placebo 10); in 16 attacks tablets were taken between 30 min and 2 h after the start of the headache (propranolol 4, placebo 12); and in 6 attacks (5 propranolol and 1 placebo) tablets were taken between 2 and 3 h after the headache started. There was no statistical difference between delay in taking propranolol and taking placebo using Wilcoxon ranked pairs test (p = 0.79). The severity of the headache at T0 did not differ between the propranolol (median 5.5, range 2-10) and placebo (median 5, range 1-10) treated headaches (p = 0.39). The parameters described below were not completed in all record cards and the totals may be less than 23 attacks. The response, change between the rating of headache severity at the time the capsule was taken (T0) and 2 h later (T1) and duration of headache are summarized by headache pair in Table 1 and by patient in Table 2. No significant differences were found between propranolol and placebo when these data were analysed either by headache pair or by patient. Five out of 23 headache pairs (22%, 95% C15-39%) had a good or excellent response after propranolol compared to 4 (17%, 95% CI 2-33%) on placebo. Two out of 14 patients had a mean good or excellent
Table 1. Response to treatment: analysis by headache. Assessment No effect Poor Fair Propranolol 9 4 5 Placebo 11 5 3
Propranolol Placebo
Good 3 3
Difference in score of headache seventy between T0 and T1 Deterioration Improvement -3 -2 -1 0 +1 +2 +3 +4 1 1 1 9 1 2 2 1 2 2 1 9 3 1 2 0
0-30 2 3
Propranolol Placebo
31-60 4 3
Excellent 2 1
+5 1 2
Duration of headache (min) 61-120 121-240 3 4 1 3
+6 2 0
241+ 5 8
The cells contain number of headache attacks.
Table 2. Summary of response to treatment: analysis by patient. Assessment No effect Poor Fair Propranolol 3 4 5 Placebo 6 3 4
Propranolol Placebo
Propranolol Placebo
-3 0 1
Good 2 1
Excellent 0 0
Difference in score of headache severity between T0 and T1 Deterioration Improvement -2 -1 0 +1 +2 +3 +4 +5 0 1 7 1 1 0 2 1 1 2 4 3 0 2 1 0
0-30 0 0
31-60 3 2
Duration of headache (min) 6 1- 120 121-240 3 3 5
+6 l 0
241 + 3 4
The cells contain number of patients. response (14.3%) compared to one (7.2%) with placebo. The severity of symptoms other than headache improved between T0 and T1 with placebo in 6 of 18 and with propranolol in 9 of 19, was unchanged in 10/ 18 and 8/19 and worsened in 2/18 and 2/19 respectively. When analysed by patient, 6/14 propranolol and 6/14 placebo showed improvement, 7/14 propranolol and 4 placebo were unchanged and 1/14 propranolol and 4/14 placebo deteriorated. In seven out of the nine attacks where good or excellent responses were reported the capsules were taken within 70 min of the onset of headache; three had taken placebo and four propranolol. The number of paracetamol tablets taken during each type of attack did not differ (propranolol mean 2.0, range 0-8; placebo mean 2.4, range 0-10). The durations were similar for both propranolol and placebo when analysed by
headache pair (propranolol: median 140 min interquartile range (IQR) 52-300 min; placebo: median 144 IQR 45-385 min) and longer, but not significantly so, for placebo when analysed by patient (propranolol: median 135 min IQR 60-240; placebo: median 207 IQR 85-270). Patients with classical migraine rated effectiveness of propranolol as better than placebo in 5, the same in 2 and worse in one of the 8 headaches. This compares with common migraine, where propranolol was rated higher than placebo in 4, the same in 4 and worse than placebo in 7 out of the 15 headaches. These differences do not achieve statistical significance. Seven episodes of adverse effects were reported. Light-headedness and stomach pains in one patient and sleepiness in another were reported following propranolol. Following placebo two patients reported sleepiness, one associated with worsening headache, two reported nausea one with dizziness and one reported worsening headache alone. Discussion
This double-blind controlled trial has found no benefit of 40 mg propranolol in acute migraine over placebo when analysed by headache pair or by patient. There was a high default rate (49%). However, as each patient acted as his own control there is no reason to believe that this distorted the nature of the population studied, though it clearly substantially reduced the power. The small sample also prevents useful statistical comparisons between subgroups. The placebo rate found in this study was lower than in some previously reported (8). The placebo rate depends in part on what level of improvement is taken as a positive response. In this study only those described as good or excellent were included. Had "fair" responses been included the placebo rate would have been 30.4% (95% CI 14-47%) and the response to propranolol 43.4% (95% CI 26-61%). The dose we used was similar to that reported in the previous case reports (5, 6) and in the open study (7). The pharmacokinetics of propranolol are very variable (11) and the dose may have been inappropriate. The timing of the medication may be critically important. In this study the patients were instructed to take the tablets as soon as possible and the delays that were seen are therefore likely to be representative of those that would be encountered if this therapy was used in clinical practice. If a more immediate administration were shown to be required this is unlikely to be achieved. The lack of demonstrable response to propranolol could be explained in several ways. Firstly, there may be no response. Secondly, the dose that was used was inappropriate. Thirdly, there may be a slight response that would require a more powerful study to detect. The rate of 53% found in the open study (7) lies well outside the 95% confidence intervals (5-39%) for the good or excellent response to propranolol found in this study. Fourthly, only certain migraine patients might respond; for example there appear to be some differences between the five classical and the nine common migraine sufferers seen in this study, but the two groups are too small for statistical comparison. This study has shown that in an unselected group of consecutive common and classical migraine sufferers propranolol, at a dose of 40 mg, is not clinically useful in the treatment of acute attacks. Acknowledgement.-We thank Janet Clabour and the Riverside Health Authority Pharmacy staff for their help with this project. References
1.
Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1972;22:366-9
2.
Wideroe T-E, Vigander T. Propranolol in the treatment of migraine. Br Med J 1974;2:699-701
3.
Diamond S, Medina JL. Double blind study of propranolol for migraine prophylaxis. Headache 1976;16:24-7
4.
Forssman B, Henriksson K-G, Johannsson V, Lindvall L, Lundin H. Propranolol for migraine prophylaxis. Headache 1976;16:238-45
5.
Featherstone HJ. Low dose propranolol therapy for
aborting acute migraine. West J Med 1983;138:416-17 6.
Tokola R, Hokkanan E. Propranolol for acute migraine. Br Med J 1978;2:1089
7.
Fogelholm R. Propranolol and cluster headache. Br Med J 1972;4:110
8.
Waters WE. Controlled clinical trial of ergotamine tartrate. Br Med J 1970;2:325-7
9.
d Hoc Committee on Classification of Headache. Classification of headache. JAMA 1962;179:717-18
10.
Tfelt-Hansen P, Olesen J. Methodological aspects of drug trials in migraine. Neuroepidemiol 1985;4:204-26
11.
Cortelli P, Sacquegna T, Albani F et al. Propranolol plasma levels and relief of migraine. Arch Neurol 1985;42:46-8
GN Fuller, RJ Guiloff
CEPHALALGIA Fuller GN, Guiloff RJ. Propranolol in acute migraine: a controlled study. Cephalalgia 1990;10:229-33. Oslo. ISSN 0333-1024 Propranolol is an established agent in migraine prophylaxis. Uncontrolled studies have suggested an action in the acute attack. We present the first double-blind placebo controlled study of propranolol in 27 unselected patients with common (migraine without aura) and classical (migraine with aura) migraine. There were 23 pairs of headaches in the 14 patients who completed the study. No difference was found, when the data were analysed by headache pair or by patient, in severity duration and subjective assessment of efficacy between those treated in an attack with propranolol 40 mg and placebo. • Acute migraine, controlled study, propranolol GN Fuller, RJ Guiloff, Department of Neurology, Charing Cross and Westminster Medical School, Westminster Hospital, 17 Page Street, London SW1P 2AP, UK; Accepted 23 July 1990 Propranolol is well established as an agent effective in migraine prophylaxis with between 50 and 80% of those treated responding (1-4). Many patients have infrequent headaches and do not want to take prophylaxis. There have been a number of case reports of patients given propranolol as prophylaxis for common (migraine without aura) and classical (migraine with aura) migraine who have found that it can be used to abort acute attacks (5), an observation we have also made. There has been one open study (6) in which a single dose of between 40 and 80 mg of propranolol was given to 30 patients with common or classical migraine. A good or excellent response was found in 16 (53%) within 2h. There is a single reported case of propranolol aborting an attack of cluster headache (7). In placebo controlled studies of other agents in acute migraine the response to placebo can be as high as 50% (8). We present the results of the first double-blind controlled study of propranolol in acute migraine. Methods
Patients Consecutive patients that met inclusion criteria were recruited from a general neurology clinic. The inclusion criteria were (1) common or classical migraine as defined by the Ad Hoc Committee (9) and revised by Tfelt-Hansen (10) and (2) the migraine must be of one year's duration, with attacks occurring between once a week and once every four months, and (3) age between 16 and 65. Exclusion criteria were (1) contraindications to propranolol or paracetamol or (2) pre-existing migraine prophylaxis or beta-blocker therapy for other indications, (3) non-migrainous headaches that are not clearly distinguishable from migraine. Patients gave a full written informed consent. Drugs and randomization Each patient treated four attacks with trial medication: two attacks were treated with 40 mg propranolol and two with placebo. The order of drug and placebo was randomized by the pharmacy in two pairs ensuring patients had had both propranolol and placebo after two attacks. The randomization code was kept by the pharmacist and broken at the end of the study. The doctor and patient were blinded at all times. The patients were also given a punch out pack of paracetamol 0.5 g tablets which they were instructed to take as required two hours after the test. medication. Attack record cards Patients were given four attack record
cards with four postage paid addressed envelopes. The following information could be recorded on the cards: The delay between the start of the attack and taking the capsule; the severity, graded out of ten, of the headache and of other symptoms, such as sickness, at the time the capsule was taken (T0) and two hours later (T1); the duration of the attack; an assessment of the effect of the capsule graded as no effect (0), poor (1), fair (2), good (3) and excellent (4); the number of paracetamol tablets taken during the attack; the overall severity of the migraine; any adverse effects noted. Statistical methods and end points The comparability of propranolol and placebo treated headaches was assessed by: (a) delay in taking the test medication and (b) the severity of the headache at T0. The following end points were compared: (a) assessment of effect of capsule; (b) the difference in severity of headache at T0 and T1; (c) the difference in severity of other symptoms at T0 and T1; (d) the duration of headache; (e) the overall severity of the migraine. Data were analysed in two ways. Firstly, considering the headache as the event, and comparing each actively treated headache with its matched placebo control. Secondly, by considering the response by patient, when the mean result for each patient was analysed. The former analysis assumes the independence of each headache pair but does not try to combine ordinal data. The latter requires nominal ordinal data to be combined. This was done by taking the mean numerical score attributed to the data for both active treatments or placebo treatments. The validity of such a mean is questionable for all parameters except duration of headache and can be taken only as an approximation. Ordinal data were compared within each headache pair using Wilcoxon ranked pairs test. The proportions of responders within each group were compared with Chi squared. Confidence intervals when given are at 95% (95% CI). The study was approved by the local Ethical Committee. Results
Twenty-seven patients were recruited. Twenty-three pairs of headaches from 14 patients were eligible for analysis; of the remaining 13 patients, 10 did not reply and 3 returned only one form. The headaches available for study came from 9 patients with common and 5 with classical migraine aged between 16 and 52 (median 31 years). There were 11 women and three men, 11 had lateralized headaches and 7 had a family history, 6 did not and one was adopted. Of those who were ineligible there were 5 men and 8 women, aged between 16 and 51 (median 27 years), 11 with common and 2 with classical migraine. Record cards The capsules were most frequently taken within 30 min of the start of the headache (propranolol 14; placebo 10); in 16 attacks tablets were taken between 30 min and 2 h after the start of the headache (propranolol 4, placebo 12); and in 6 attacks (5 propranolol and 1 placebo) tablets were taken between 2 and 3 h after the headache started. There was no statistical difference between delay in taking propranolol and taking placebo using Wilcoxon ranked pairs test (p = 0.79). The severity of the headache at T0 did not differ between the propranolol (median 5.5, range 2-10) and placebo (median 5, range 1-10) treated headaches (p = 0.39). The parameters described below were not completed in all record cards and the totals may be less than 23 attacks. The response, change between the rating of headache severity at the time the capsule was taken (T0) and 2 h later (T1) and duration of headache are summarized by headache pair in Table 1 and by patient in Table 2. No significant differences were found between propranolol and placebo when these data were analysed either by headache pair or by patient. Five out of 23 headache pairs (22%, 95% C15-39%) had a good or excellent response after propranolol compared to 4 (17%, 95% CI 2-33%) on placebo. Two out of 14 patients had a mean good or excellent
Table 1. Response to treatment: analysis by headache. Assessment No effect Poor Fair Propranolol 9 4 5 Placebo 11 5 3
Propranolol Placebo
Good 3 3
Difference in score of headache seventy between T0 and T1 Deterioration Improvement -3 -2 -1 0 +1 +2 +3 +4 1 1 1 9 1 2 2 1 2 2 1 9 3 1 2 0
0-30 2 3
Propranolol Placebo
31-60 4 3
Excellent 2 1
+5 1 2
Duration of headache (min) 61-120 121-240 3 4 1 3
+6 2 0
241+ 5 8
The cells contain number of headache attacks.
Table 2. Summary of response to treatment: analysis by patient. Assessment No effect Poor Fair Propranolol 3 4 5 Placebo 6 3 4
Propranolol Placebo
Propranolol Placebo
-3 0 1
Good 2 1
Excellent 0 0
Difference in score of headache severity between T0 and T1 Deterioration Improvement -2 -1 0 +1 +2 +3 +4 +5 0 1 7 1 1 0 2 1 1 2 4 3 0 2 1 0
0-30 0 0
31-60 3 2
Duration of headache (min) 6 1- 120 121-240 3 3 5
+6 l 0
241 + 3 4
The cells contain number of patients. response (14.3%) compared to one (7.2%) with placebo. The severity of symptoms other than headache improved between T0 and T1 with placebo in 6 of 18 and with propranolol in 9 of 19, was unchanged in 10/ 18 and 8/19 and worsened in 2/18 and 2/19 respectively. When analysed by patient, 6/14 propranolol and 6/14 placebo showed improvement, 7/14 propranolol and 4 placebo were unchanged and 1/14 propranolol and 4/14 placebo deteriorated. In seven out of the nine attacks where good or excellent responses were reported the capsules were taken within 70 min of the onset of headache; three had taken placebo and four propranolol. The number of paracetamol tablets taken during each type of attack did not differ (propranolol mean 2.0, range 0-8; placebo mean 2.4, range 0-10). The durations were similar for both propranolol and placebo when analysed by
headache pair (propranolol: median 140 min interquartile range (IQR) 52-300 min; placebo: median 144 IQR 45-385 min) and longer, but not significantly so, for placebo when analysed by patient (propranolol: median 135 min IQR 60-240; placebo: median 207 IQR 85-270). Patients with classical migraine rated effectiveness of propranolol as better than placebo in 5, the same in 2 and worse in one of the 8 headaches. This compares with common migraine, where propranolol was rated higher than placebo in 4, the same in 4 and worse than placebo in 7 out of the 15 headaches. These differences do not achieve statistical significance. Seven episodes of adverse effects were reported. Light-headedness and stomach pains in one patient and sleepiness in another were reported following propranolol. Following placebo two patients reported sleepiness, one associated with worsening headache, two reported nausea one with dizziness and one reported worsening headache alone. Discussion
This double-blind controlled trial has found no benefit of 40 mg propranolol in acute migraine over placebo when analysed by headache pair or by patient. There was a high default rate (49%). However, as each patient acted as his own control there is no reason to believe that this distorted the nature of the population studied, though it clearly substantially reduced the power. The small sample also prevents useful statistical comparisons between subgroups. The placebo rate found in this study was lower than in some previously reported (8). The placebo rate depends in part on what level of improvement is taken as a positive response. In this study only those described as good or excellent were included. Had "fair" responses been included the placebo rate would have been 30.4% (95% CI 14-47%) and the response to propranolol 43.4% (95% CI 26-61%). The dose we used was similar to that reported in the previous case reports (5, 6) and in the open study (7). The pharmacokinetics of propranolol are very variable (11) and the dose may have been inappropriate. The timing of the medication may be critically important. In this study the patients were instructed to take the tablets as soon as possible and the delays that were seen are therefore likely to be representative of those that would be encountered if this therapy was used in clinical practice. If a more immediate administration were shown to be required this is unlikely to be achieved. The lack of demonstrable response to propranolol could be explained in several ways. Firstly, there may be no response. Secondly, the dose that was used was inappropriate. Thirdly, there may be a slight response that would require a more powerful study to detect. The rate of 53% found in the open study (7) lies well outside the 95% confidence intervals (5-39%) for the good or excellent response to propranolol found in this study. Fourthly, only certain migraine patients might respond; for example there appear to be some differences between the five classical and the nine common migraine sufferers seen in this study, but the two groups are too small for statistical comparison. This study has shown that in an unselected group of consecutive common and classical migraine sufferers propranolol, at a dose of 40 mg, is not clinically useful in the treatment of acute attacks. Acknowledgement.-We thank Janet Clabour and the Riverside Health Authority Pharmacy staff for their help with this project. References
1.
Weber RB, Reinmuth OM. The treatment of migraine with propranolol. Neurology 1972;22:366-9
2.
Wideroe T-E, Vigander T. Propranolol in the treatment of migraine. Br Med J 1974;2:699-701
3.
Diamond S, Medina JL. Double blind study of propranolol for migraine prophylaxis. Headache 1976;16:24-7
4.
Forssman B, Henriksson K-G, Johannsson V, Lindvall L, Lundin H. Propranolol for migraine prophylaxis. Headache 1976;16:238-45
5.
Featherstone HJ. Low dose propranolol therapy for
aborting acute migraine. West J Med 1983;138:416-17 6.
Tokola R, Hokkanan E. Propranolol for acute migraine. Br Med J 1978;2:1089
7.
Fogelholm R. Propranolol and cluster headache. Br Med J 1972;4:110
8.
Waters WE. Controlled clinical trial of ergotamine tartrate. Br Med J 1970;2:325-7
9.
d Hoc Committee on Classification of Headache. Classification of headache. JAMA 1962;179:717-18
10.
Tfelt-Hansen P, Olesen J. Methodological aspects of drug trials in migraine. Neuroepidemiol 1985;4:204-26
11.
Cortelli P, Sacquegna T, Albani F et al. Propranolol plasma levels and relief of migraine. Arch Neurol 1985;42:46-8
