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.