Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial

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  • Lanfranco Pellesi
  • Mohammad Al Mahdi Al-Karagholi
  • Roberto De Icco
  • Hande Coskun
  • Fatima Azzahra Elbahi
  • Cristina Lopez-Lopez
  • Josefin Snellman
  • Hannibal, Jens
  • Faisal Mohammad Amin
  • dlt446, dlt446

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP. Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month. Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days. Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo. Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P <.001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P =.003; AUC0-180min, P <.001). Conclusions and Relevance: A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs. Trial Registration: ClinicalTrials.gov Identifier: NCT04260035.

Original languageEnglish
Article numbere2118543
JournalJAMA network open
Issue number8
Number of pages13
Publication statusPublished - 4 Aug 2021

Bibliographical note

Funding Information:
Acquisition, analysis, or interpretation of data: Pellesi, Al-Karagholi, De Icco, Coskun, Elbahi, Hannibal, Amin, Ashina. Drafting of the manuscript: Pellesi, Al-Karagholi, De Icco, Ashina. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Pellesi, Al-Karagholi, Amin, Ashina. Obtained funding: Al-Karagholi, Lopez-Lopez, Snellman, Ashina. Administrative, technical, or material support: Al-Karagholi, Coskun, Elbahi, Snellman, Amin, Ashina. Supervision: Al-Karagholi, De Icco, Snellman, Amin, Ashina. Conflict of Interest Disclosures: Dr Ashina reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva Pharmaceuticals during the conduct of the study. Dr Ashina reported serving as the associate editor of Cephalalgia and the associate editor of The Journal of Headache and Pain and being the current president of the International Headache Society. Dr Amin reported receiving a grant from the American Brain Foundation and personal fees from Novartis, Eli Lilly, Teva Pharmaceuticals, and Lundbeck outside of the submitted work. Dr Lopez-Lopez and Dr Snellman reported being full-time employees and shareholders of Novartis International AG. Dr Al-Karagholi reported being an invited speaker for Novartis and receiving fees from ElectroCore. Dr Hannibal reported receiving fees from the Danish Biotechnology Center for Cellular Communication. No other disclosures were reported.

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