Migraine prophylactic drugs: proof of efficacy, utilization and cost

In order to understand the pattern of utilization of migraine prophylactic drugs by US physicians, we reviewed the scientific rigor of published trials of anti-migraine medications, assessed their cost, and tested the correlation, if any, between utilization, scientific rigor and cost.

Scientific rigor of published reports. We identified all placebo-controlled, randomized, double-blind trials of migraine prophylactic agents through Medline search, major Headache textbooks and proceedings of major scientific meetings where headache-related topics are discussed. We excluded trials that did not include placebo treatment during the active phase of the study. The trials were reviewed and rated for scientific rigor using a 5-point scale (scientific score [ss]; 1 = low, 5 = good), blinded to the physicians' utilization data and cost of the drugs. Studies that did not show benefit of the active drug over placebo were scored -1 to -5, thus allowing for the reverse logic of negative studies. US physicians utilization. Neurologists and primary care physicians (PCP) completed phone-mail-phone questionnaires which inquired about first and second choices of migraine prophylaxis. These choices were averaged to obtain a weighted average percent usage of each drug. Cost. The average wholesale price (AWP) of each drug was obtained from data published by Adelman and Von Seggern, and from the Amerisource (7/9/96) catalog.

Spearman's correlation coefficient was used to assess the relationship between the average ss, physician use, and cost of each drug.

Propranolol (ss = 1.44), amitriptyline (ss = 2.33) and verapamil (ss = 1.00) were the three preferred migraine prophylactic drugs by both neurologists and PCPs. Approximately 10% of neurologists said that divalproex (ss = 3.75) would be their first or second choice. The selective serotonin reuptake blockers were favored by 13.21% of PCPs. All other prophylactic drugs were felt to be first or second line of treatment by less than 10% of either neurologists or PCPs. Except for one study (ss = 1) that showed that propranolol reduced the migraine frequency by 76% over placebo, trials of the three most preferred medications failed to demonstrate that the active drug is > 50% better than placebo, i.e. the difference in headache frequency when on placebo vs active drug is > 50%. Of the drugs available in the United States, flurbiprofen and metoprolol achieved the best ss (5.00 and 4.33, respectively) but their efficacy over placebo (23% and 14-33%, respectively) and cost ($67.2 and $65.6) were unfavorable. Neurologists and PCPs chose migraine prophylaxis on the basis of scientific merit (r = 0.644, p = 0.018; r = 0.576, p = 0.05, respectively) but not cost (r = -0.254, p = 0.45; r = -0.255, p = 0.455).

The three most commonly chosen migraine prophylactic agents have not been shown irrefutably to prevent migraine. Furthermore, their benefit, if any, does not exceed 50% over placebo. The well-conducted recent trials that demonstrated the efficacy of divalproex in migraine prevention are steps in the right direction of finding the "ideal migraine preventative agent". Until that drug is discovered, it is difficult to argue that one migraine prophylactic medication is superior to another and accordingly should be used as a first line of treatment.