Vasoactive Intestinal Polypeptide Infusion Can Induce Migraines in People with Migraine without Aura

June 2022

Vasoactive peptides, including vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase–activating polypeptides (PACAPs), are released from nerve fibers when the trigeminovascular system is activated, and these events may be involved in initiating migraine attacks. PACAPs are vasoactive peptides that have been shown to induce migraines in people who have migraine without aura after infusion for only 20 minutes. Vasodilation of the superficial temporal artery and the middle meningeal artery can last for 4 hours after PACAP-induced migraine attacks.

In contrast, a 20-minute infusion of the related peptide, VIP, rarely induces migraine attacks, and the duration of vasodilation after infusion is short compared with that caused by PACAPs. It is unclear whether the lack of migraines with VIP infusion is due to its shorter duration of vasodilation and whether VIP plays a role in inducing naturally occurring migraines.

A prior study by Pellesi and colleagues showed that infusing VIP for 2 hours increased the duration of vasodilation and induced headaches in healthy participants who do not have migraines. In a follow-on study, investigators used this protocol in participants with migraine without aura to test whether VIP provoked migraines and whether these induced migraines have features of naturally occurring migraines.

In this double-blind crossover trial, participants were aged 18 to 40 years and had received a diagnosis of migraine without aura with 1 to 6 attacks per month. Participants were randomly assigned to receive VIP or placebo infusion for 2 hours. At least 2 weeks later, they subsequently received a second infusion of the opposite treatment. According to the inclusion criteria, participants could not have a headache the day of the infusion; pain medication in the previous 48 hours; or caffeinated beverages, tobacco, or alcohol in the previous 8 hours. The primary end point was the incidence of migraine attacks within 12 hours of treatment.

A total of 15 of 21 patients had a migraine attack within 12 hours of VIP infusion, and 1 patient experienced an attack after placebo infusion. The median time to the onset of a migraine attack was 1 hour 40 minutes, and the median time to peak intensity was 1 hour 50 minutes following infusion. The localization of the provoked headache pain was similar to that of spontaneous migraines.

The diameter of the superficial temporal artery was significantly greater after VIP infusion compared with placebo, demonstrating that VIP does cause vasodilation in the superficial temporal artery if infused for a long enough time. Heart rate was also significantly greater after VIP infusion compared with placebo.

Adverse events with VIP infusion were seen at similar frequencies as noted in the previous study with healthy participants, indicating that they are adverse events of VIP dosing rather than of migraines. These included flushing, changes in temperature sensation, and heart palpitations, which occurred in almost all participants during or after VIP infusion. In contrast, only up to 3 participants with migraines reported one of these adverse effects when infused with the placebo.

Photophobia and nausea, however, were more common in participants who had migraine without aura when they received VIP infusion than they were in the previous study with healthy volunteers. The investigators concluded from these observations that photophobia and nausea were related to migraine attacks and were not adverse events of VIP infusion.

The investigators suggested that VIP infusion may have caused migraine attacks by protracted dilation of the superficial temporal artery. They also speculated that their findings may be relevant to naturally occurring migraine attacks: “Collectively, the present study implicates [VIP receptors] in the pathogenesis of migraine, and selective antagonists might be of future interest for the treatment of migraine.”


Pellesi L, Al-Karagholi MA, De Ice R, et al. Effect of vasoactive intestinal polypeptide on development of migraine headaches: a randomized clinical trial. JAMA Netw Open. 2021;4(8):e2118543.

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