Plasma Levels of CGRP During a 2-h Infusion of VIP in Healthy Volunteers and Patients With Migraine: An Exploratory Study

Lanfranco Pellesi, Mohammad Al-Mahdi Al-Karagholi, Roberto De Icco, Basit Ali Chaudhry, Cristina Lopez Lopez, Josefin Snellman, Jens Hannibal, Faisal Mohammad Amin, Messoud Ashina, Lanfranco Pellesi, Mohammad Al-Mahdi Al-Karagholi, Roberto De Icco, Basit Ali Chaudhry, Cristina Lopez Lopez, Josefin Snellman, Jens Hannibal, Faisal Mohammad Amin, Messoud Ashina

Abstract

Introduction: The activation of perivascular fibers and the consequent release of vasoactive peptides, including the vasoactive intestinal polypeptide (VIP), play a role in migraine pathogenesis. A 2-h infusion of VIP provoked migraine, but the mechanisms remain unknown. We investigated whether 2-h infusion of VIP caused alterations in plasma levels of the calcitonin gene-related peptide (CGRP) and whether any changes might be related to the induced migraine attacks.

Materials and methods: We enrolled individuals with episodic migraine without aura and healthy participants to randomly receive a 2-h infusion of either VIP (8 pmol/kg/min) or placebo (sterile saline) in two randomized, placebo-controlled crossover trials. We collected clinical data and measured plasma levels of VIP and CGRP at fixed time points: at baseline (T0) and every 30 min until 180 min (T180) after the start of the infusion.

Results: Blood samples were collected from patients with migraine (n = 19) and healthy individuals (n = 12). During VIP infusion, mixed effects analysis revealed a significant increase in plasma CGRP (p = 0.027) at T30 (vs. T180, adjusted p-value = 0.039) and T60 (vs. T180, adjusted p-value = 0.027) in patients with migraine. We found no increase in plasma CGRP during VIP-induced migraine attacks (p = 0.219). In healthy individuals, there was no increase in plasma CGRP during VIP (p = 0.205) or placebo (p = 0.428) days.

Discussion: Plasma CGRP was elevated in patients with migraine during a prolonged infusion of VIP, but these alterations were not associated with VIP-induced migraine attacks. Given the exploratory design of our study, further investigations are needed to clarify the role of CGRP in VIP-induced migraine.

Clinical trial registration: ClinicalTrials.gov, identifier: NCT03989817 and NCT04260035.

Keywords: PACAP38; autonomic; headache; pain; parasympathetic system.

Conflict of interest statement

MA reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva Pharmaceuticals during the conduct of the study. MA reported serving as Associate Editor of Cephalalgia, The Journal of Headache and Pain and Brain. FA is principal investigator for a phase IV trial for Teva. FA has received personal fees for lecturing and/or participating in advisory boards for Teva, Novartis, Eli Lilly and Lundbeck. CL reported being full employee at Roche Holding AG and shareholder of Novartis International AG. JS reported being full-time employee and shareholder of Novartis International AG. MA-K reported being an invited speaker for Novartis and receiving fees from ElectroCore. JH reported receiving fees from the Danish Biotechnology Center for Cellular Communication. CL and JS were employed by Novartis Pharma AG. This study received funding from Novartis Pharma AG. The funder had the following involvement with the study: support for study design and critical revision of the manuscript.

Copyright © 2022 Pellesi, Al-Karagholi, De Icco, Chaudhry, Lopez, Snellman, Hannibal, Amin and Ashina.

Figures

Figure 1
Figure 1
Changes in plasma concentration of vasoactive intestinal polypeptide (VIP) during and after 2-h infusion of placebo (p = 0.240) or VIP (p < 0.001) in patients with migraine. The light blue area represents placebo infusion, while the red area represents VIP infusion. Dotted lines represent individual values, while thick lines show mean concentrations.
Figure 2
Figure 2
Linear regression lines of plasma calcitonin gene-related peptide (CGRP) during VIP (red) and placebo days (blue) in patients with migraine (A) and healthy individuals (B). Dotted lines represent the 99% confidence bands of the best fit-line. In (A), T30 (adjusted p-value = 0.039) and T60 (adjusted p-value = 0.027) were significantly different from T180 during VIP days.
Figure 3
Figure 3
Changes in plasma concentration of vasoactive intestinal polypeptide (VIP) during and after 2-h infusion of placebo (p = 0.599) or VIP (p < 0.001) in healthy individuals. The light blue area represents placebo infusion, while the red area represents VIP infusion. Dotted lines represent individual values, while thick lines show mean concentrations.
Figure 4
Figure 4
Mean plasma concentration of CGRP at the baseline in healthy individuals and patients with migraine (p = 0.232).

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