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

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

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flowchart of the Study
Figure 1.. Flowchart of the Study
VIP indicates vasoactive intestinal polypeptide.
Figure 2.. Headache Intensity on Vasoactive Intestinal…
Figure 2.. Headache Intensity on Vasoactive Intestinal Polypeptide and Placebo Days in 21 Patients With Migraine
The abscissa refers to the time (min). (A) Median (thick, orange line) and individual (dotted lines) headache intensity on an NRS. The orange area represents the 2-hour infusion of VIP. The AUC for headache intensity was significantly greater after VIP compared with placebo (AUC0-12h, P = .003). The median time of onset for migraine-like attacks was 1 h 40 min (IQR, 1 h to 1 h 50 min). (B) Median (thick, black line) and individual (dotted lines) headache intensity on an NRS. The light blue area represents the 2-hour infusion of placebo. NRS indicates numerical rating scale.
Figure 3.. Violin Plot of the Time…
Figure 3.. Violin Plot of the Time of Appearance of Head Pain, Nausea, Migraine-Like Criteria, Phonophobia, and Photophobia
The orange dashed line represents the median, while the black dotted lines are the interquartile range. The light brown area represents the 2-hour infusion of vasoactive intestinal polypeptide. The width of the violin plot indicates the number of participants experiencing the symptom.

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