Migraine-inducing effects of pitolisant in women with migraine without aura: Protocol for a randomized, double-blind, placebo-controlled crossover trial

Background Histamine and migraine have long been associated, with evidence showing that histamine infusion can trigger migraine-like attacks and that plasma histamine levels are often elevated in migraine patients, both during and between attacks. However, the precise mechanisms underlying this relationship remain unclear. The aim of this study is to examine whether pitolisant, a selective H 3 receptor inverse agonist, can induce migraine-like attacks in women diagnosed with migraine without aura. Methods A cohort of 14 female participants with migraine without aura will be enrolled in a randomized, double-blind, placebo-controlled crossover study. The women will be monitored for headache occurrence, related symptoms and migraine-like episodes for 12 h after pitolisant administration. The primary outcome is the difference in the occurrence of migraine-like attacks between women with migraine without aura receiving pitolisant compared with placebo, and the co-primary outcome is the difference in headache intensities over time between the two treatments. The main secondary outcome is the difference in the incidence of any headache, regardless of whether migraine criteria are met, following pitolisant and placebo administration. Conclusion This study will provide novel insights into the involvement of the H 3 receptor in migraine pathophysiology and clarify whether selective modulation of this receptor is sufficient to provoke migraine-like attacks. The findings may inform the development of more targeted and better-tolerated therapeutic strategies.