Triggering migraine attacks using PACAP: a systematic review of human provocation studies

To synthesize evidence from experimental studies evaluating migraine induction, clinical features, vascular responses, and induced neuroimaging changes following intravenous infusion (IV) of pituitary adenylate cyclase-activating polypeptide (PACAP) in persons with migraine. A systematic literature search was conducted in PubMed and Embase to identify experimental studies involving IV PACAP-38 or PACAP-27 infusion in adults with migraine. Eligible studies included double-blind, placebo-controlled crossover trials, blinded head-to-head comparisons with IV vasoactive intestinal polypeptide (VIP), and open-label provocation studies reporting clinical and/or vascular outcomes. The primary outcome was the incidence of migraine attacks induced by IV PACAP infusion in adults with migraine. Secondary outcomes included headache characteristics, associated symptoms, vascular responses, and induced neuroimaging changes. Owing to substantial heterogeneity across studies, quantitative meta-analysis was not feasible; therefore, a structured narrative synthesis was performed. Eleven studies from eight unique study populations were included. IV PACAP induced migraine attacks in approximately 50–75% of persons with migraine, whereas placebo resulted in substantially lower rates (0–10%). Migraine attacks typically developed with a delayed onset, most commonly 3–6 hours after infusion start. PACAP-38 and PACAP-27 produced comparable migraine induction rates. Familial aggregation studies showed no strong influence of familial migraine load on migraine induction. Magnetic resonance angiography demonstrated sustained dilation of the middle meningeal artery, lasting several hours after PACAP infusion. Pre-treatment with a monoclonal antibody directed against calcitonin gene-related peptide (CGRP) did not prevent PACAP-induced migraine, whereas early administration of sumatriptan reduced migraine induction. Pre-treatment with an antihistamine reduced migraine induction numerically but did not reach statistical significance. IV PACAP infusion induces migraine attacks in persons with migraine and is associated with sustained meningeal arterial dilation. These findings support PACAP provocation as a robust experimental model for studying migraine attack initiation and inform ongoing investigation of PACAP-targeted treatments.