Sildenafil provokes headache but not migraine in men with migraine without aura: a randomized, placebo-controlled crossover trial

Background: Cyclic guanosine monophosphate (cGMP)-mediated mechanisms plays a role in migraine pathophysiology. Sildenafil, a phosphodiesterase type 5 inhibitor, increases intracellular cGMP and can reliably induce migraine attacks in women. However, its migraine-inducing potential in men remains largely unknown. Methods: In this randomized, double-blind, placebo-controlled crossover trial, 12 men with migraine without aura received sildenafil (100 mg) and placebo in separate sessions ≥ 7 days apart. An open-label parallel cohort of 15 women with migraine received sildenafil (100 mg) under similar experimental conditions. The primary endpoints were (i) the incidence of migraine-like attacks after sildenafil compared with placebo in men, and (ii) the incidence of migraine-like attacks after sildenafil in men and women. Results: In men, sildenafil induced headache more frequently than placebo (83% vs. 25%, p = 0.033), whereas the incidence of migraine-like attacks did not differ between sildenafil and placebo (25% vs. 17%, p = 0.500). In women, sildenafil induced headache in all participants and migraine-like attacks in 67%, a significantly higher proportion than in men (67% vs. 25%, p = 0.038). Adverse events were more frequent after sildenafil than placebo, most commonly flushing and nasal congestion. Conclusions: Sildenafil provoked headache but not migraine in men with migraine without aura, whereas women showed a markedly greater susceptibility to migraine induction. These findings suggest that cGMP-mediated mechanisms contribute less prominently to migraine generation in men.