Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase

The initiating mechanisms of migraine attacks are very complex but may involve the cyclic AMP signalling pathway. It is unknown whether intracellular cyclic AMP accumulation induces migraine attacks. We investigated whether administration of cilostazol, which causes cyclic AMP accumulation, may induce migraine attacks. We included 14 migraine patients without aura in a double-blind, placebo-controlled crossover study. All participants received oral cilostazol or placebo on two separate days. We recorded migraine headache characteristics, associated symptoms and time of rescue medication intake using a questionnaire. Cilostazol induced delayed migraine-like attacks in 12 patients (86%) compared with two (14%) patients after placebo (P = 0.002). The median time to onset for migraine-like attacks was 6 h (range 3-11 h). Patients reported that the attacks mimicked their usual migraine attacks and that cilostazol-induced attacks responded to their usual migraine treatment. Median time of medication intake was 6 h (range 4-11 h). The present study suggests that intracellular cyclic AMP accumulation plays a crucial role in migraine induction. This knowledge is a further step in our understanding of the intracellular pathway of migraine initiation.