Oxytocin receptor antagonism in migraine: a randomized, double-blind, placebo-controlled provocation study.

BACKGROUND AND OBJECTIVES: Oxytocin has been implicated in migraine pathophysiology through its roles in pain modulation and vascular regulation. Its receptors are present in migraine-related brain regions and cerebral vessels and interact with key migraine mediators such as calcitonin gene-related peptide (CGRP). Declining oxytocin levels coincide with increased migraine frequency, but a causal role in humans remains unclear. This study examined whether acute oxytocin receptor blockade provokes migraine attacks or alters cerebrovascular function. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, women with episodic migraine (WM), healthy women (HC), and men with episodic migraine (MM) aged 18-45 years received the oxytocin receptor antagonist atosiban (6.75 mg bolus followed by 54 mg over 3 h) or placebo on two separate visits. Women used continuous hormonal contraception to ensure stable hormone levels. The primary endpoint was the incidence of migraine-like attacks in WM within 12 h post-infusion. Secondary endpoints included the incidence and intensity of any headache and vascular responses. RESULTS: A total of 20 WM (27.1 ± 5.6 years), 20 HC (25.7 ± 6.8 years) and 20 MM (29.3 ± 6.1 years) completed both provocations visits. During the 12-hour observation period, the incidence of migraine-like attacks in WM did not differ between atosiban and placebo (atosiban: 6 (30%) vs. placebo: 4 (20%; p = 0.75)). Headache of any kind were reported in 15 (75%) vs. 11 (55%) (p = 0.34). HC did not experience migraine-like attacks, though nine (45%) participants reported headache of any kind after atosiban vs. six (30%) after placebo (p = 0.25). Among MM, migraine attacks occurred in two (10%) participants after atosiban vs. three (15%) after placebo (p > 0.999). While HC showed significantly increased temporal artery diameter and middle cerebral artery flow velocity during atosiban administration, no significant vascular changes were observed in participants with migraine. DISCUSSION: Short-acting oxytocin receptor antagonism did not trigger migraine attacks, suggesting that acute suppression of oxytocin signaling alone is unlikely to trigger migraine under stable hormonal conditions. Instead, oxytocin may act as a modulatory factor within neurovascular networks. Future studies using longer-lasting or brain-penetrant antagonists are needed to further clarify oxytocin's role in migraine susceptibility. TRIAL REGISTRATION INFORMATION: DRKS - Deutsches Register Klinischer Studien: DRKS00033341. Registered: 08.01.2024. First patient enrolled: 08.07.2024.