DOUBLE BLIND STUDY OF PROPRANOLOL FOR MIGRAINE PROPHYLAXIS Seymour Diamond, M.D. * *
Department of Neurology, The Chicago Medical School, Diamond Headache Clinic, Ltd., Chicago, Illinois.
Jose L. Medina, M.D. ** **
Neurology Service, Hines Veterans Administration Hospital, Diamond Headache Clinic, Ltd., and Rush Medical College.
Submitted for publication-10/10/75; Accepted 1/2/76. SYNOPSIS Eighty-three migraine patients were admitted to a double-blind, single cross-over, propranolol vs. placebo study. Sixty-two patients completed the trial. The daily dosage was either 80 or 160 mg. propranolol, or an equivalent number of placebo capsules, for 4 to 8 weeks for the first medication and 8 weeks for the second one. At the end of the trial, 32 patients preferred propranolol and 18 placebo. Those who preferred propranolol had greater reduction in severity and frequency of headaches and less consumption of analgesics and ergotamine than patients who preferred placebo. Side effects were benign. Propranolol is safe and effective for the prophylaxis of migraine if patients are carefully selected. CHANCE MAY have led to the discovery of a safe and valuable drug in the prophylaxis of migraine: Rabkin, et all observed disappearance of coexistent migraine headaches in a cardiac patient treated with propranolol. Several studies2,3,4 have confirmed the value of propranolol in the prevention of migraine. The number of patients studied has ranged from 19 to 29, and the effectiveness of propranolol has varied from 55.2% to 81%. To evaluate propranolol in the prophylaxis of migraine, we have conducted a double-blind, single crossover study in 62 patients. SUBJECTS AND METHODS Eighty-three patients were admitted to the trial, all had classic or common migraine.5 None had asthma, cardiac disease, diabetes mellitus or any physical or neurologic abnormalities. In all, informed written consent was obtained. There were 67 women and 16 men. Their ages ranged from 21 to 62 years (average 38.1 years). The patients were randomly given either propranolol or placebo. All took both medications. Each trial period of propranolol or placebo was for at least 4 weeks. At the end of the fourth week of each period patients could choose to stop the drug or to continue for up to 6 or 8 weeks. Therefore, the duration of the trial varied between a minimum of 8 weeks and a maximum of 16 weeks. The initial divided dosage was 80 mg. of propranolol or a corresponding number of placebo capsules. At the end of the second, fourth or sixth weeks of each period, the patients could choose to double the amount of medication or placebo or to remain on the same dosage. Their decisions were based on subjective amelioration or lack of improvement of headaches. All patients were instructed to grade headaches into: (1) Severe-Incapacitation unable to perform their duties; (2) Moderate-annoying headache with difficulties to carry out activities; and (3) Mild-bothersome headache which permit fulfillment of obligations with minimal or no difficulties. During the trial, patients were allowed to take common analgesics, narcotics or ergot medications for the relief of migraine attacks, but no other prophylactic drugs were allowed. They kept a record of drugs used. At the end of the trial, the patient's preference for one or other medication was considered the decision for or against propranolol. Table I shows the measurements used in this study. The incidence of adverse reactions and their relationship to the trial was assessed and recorded. Twenty-one patients dropped out; 7 due to side effects and 14 for reasons unrelated to the trial medication. In one case, side effects occurred while on placebo and in 6 on propranolol. Sixty-two patients completed the trial. Fifty took propranolol for 8 weeks, six for 6 weeks and six for 4 weeks. Forty patients received placebo for 8 weeks, ten for 6 weeks and twelve for 4
Severe Headache 3 H.U. Moderate Headache 2 H. U. Mild Headache 1 H.U. Total of H.U. H.I. = -------------------------------------Number of Days Observed Placebo Period H.I. H.I.R. = --------------------------------- = change Propranolol Period H.I. > 1, better on Propranolol
1, better on Propranolol
< 1, better on Placebo
H .U. = Headache Units R.M.U. = Relief Medication Units H.I.= Headache Index R.M.I. = Relief Medication Index H.I.R. = Headache Index Ratio R.M.I.R. = Relief Medication Index Ratio weeks. Forty-nine doubled the dosages of both medications, thirteen patients did not. Ten did not increase propranolol and three did not double the dose of placebo. Fifty-seven patients had common and five classic migraine. RESULTS Thirty-four of 62 patients (54.8%) were propranolol responders because they preferred propranolol. Seventeen patients were placebo responders because they chose placebo as the active medication. In 27 of 34 patients the preference for propranolol was supported by H.I.R. and R.M.I.R. This indicated that the patient's preference for propranolol did not occur by chance alone. In 10 of 17 placebo responders, both H.I.R. and R.M.I.R. corroborated the preference of the patients. The H.I.R. and R.M.I.R. of propranolol and placebo responders were compared (Table II). The differences of the ratios between both groups were statistically significant (p