Induction of cGMP-mediated migraine attacks is independent of CGRP receptor activation

• Published in: Cephalalgia 2024-06, Vol.44 (6), p.3331024241259489
• Main Authors: Raffaelli, Bianca, Do, Thien Phu, Ashina, Håkan, Snellman, Josefin, Maio-Twofoot, Tina, Ashina, Messoud
• Format: Article
• Language: English
• Subjects: Adult; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Calcitonin Gene-Related Peptide Receptor Antagonists; Cross-Over Studies; Cyclic GMP - metabolism; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders - chemically induced; Migraine Disorders - metabolism; Phosphodiesterase 5 Inhibitors - pharmacology; Receptors, Calcitonin Gene-Related Peptide - metabolism; Sildenafil Citrate - pharmacology; Young Adult
• ISSN: 0333-1024; 1468-2982; 1468-2982
• DOI: 10.1177/03331024241259489

Background The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. Methods In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. Results In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p