Rapid development of tolerance to dipyridamole-associated headaches

In the Second European Stroke Prevention Study headaches associated with dipyridamole frequently (8% of patients taking dipyridamole or dipyridamole plus acetylsalicylic acid (ASA) vs 2% of patients taking ASA or placebo) led to discontinuation of therapy. We have now used data from a recent trial comparing the bioequivalence of two formulations of the fixed combination of 200 mg dipyridamole in an extended release formulation and 25 mg ASA to explore predicting factors for headaches associated with this drug combination.

The bioequivalence trial employed a two-way crossover, randomised, open design. Trial medication was given for two periods of five days separated by a 72 h washout period. Statistical methods were employed to explore the prevalence, the time course, and the relation to individual pharmacokinetic parameters of treatment associated headaches.

Headache episodes, being mostly mild and transient, rapidly declined from 67% of the volunteers on the first day of treatment to 3% on the final days of treatment (days 4-5 of the second period). During the first days the prevalence of the headaches peaked 2-3 h after the morning administration, which coincided with the peak of the plasma concentrations of dipyridamole. The occurrence of headaches was not related to interindividual differences of the pharmacokinetic parameters.

The rapid decrease in the incidence of headaches over time implies that most patients quickly develop tolerance to dipyridamole-associated headaches. Appropriate information given to the patient when prescribing and dispensing dipyridamole/ASA may reduce early withdrawals from treatment and increase compliance.