Vasoactive Intestinal Polypeptide Infusions May Result in Migraine Attacks

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In a randomized, placebo-controlled crossover study, researchers determined the effect of a 2-hour vasoactive intestinal polypeptide infusion on risk for migraine attacks.

Vasoactive intestinal peptide infusion may result in migraine attacks, indicating its potential role in migraine pathophysiology and as a target for novel migraine drugs, according to research results published in JAMA Network Open.

The potential limited migraine-inducing property of vasoactive intestinal peptides has been attributed to only a limited vasodilatory response.

Researchers conducted a randomized, double-blind, placebo-controlled, 2-way crossover study ( Identifier: NCT04260035) to determine if prolonged intravenous vasoactive intestinal peptide infusion could result in a migraine attack.

Patients with migraine without aura were enrolled from the Danish Headache Center or the Danish test subject website; participants were aged between 18 and 40 years and had a migraine frequency of 1 to 6 attacks per month.

Patients were randomly assigned to receive either 8 pmol/kg/min vasoactive intestinal peptides or placebo over a 2-hour period on 2 different study dates at least 2 weeks apart. Peptides were administered via 2 venous catheters in the left and right forearms. Baseline measurements were recorded at 30 minutes, and headache intensity symptoms were recorded 10 minutes before baseline, at baseline, and every 10 minutes after the infusion began through 3 hours and 20 minutes.

Headache intensity was rated on a numeric rating scale (0-10). Provoked migraine attacks had to meet 2 criteria: a headache with at least 2 clinical features, including unilateral location, pulsating quality, moderate to severe pain intensity, and aggravation or avoidance of routine physical activity, and at least 1 of the following symptoms: nausea/vomiting or photo- and phonophobia; and the migraine must mimic the usual migraine attack and be managed with a rescue medication.

Researchers measured the diameter of the frontal branch of the superficial temporal artery through a high-resolution ultrasonographic unit. Blood pressure and heart rate were measured using an autoinflatable cuff, and an electrocardiogram was recorded at baseline.

A total of 21 participants were included in the study; 81% women with a mean age of 25.9 years (range, 19-40 years). Mean weight at baseline was 69.8 kg (153.8 lb; range, 52-89 kg [114-196.2 lb]). Frequency of baseline migraine attacks ranged from 1 to 6 per month, and associated symptoms included photophobia, phonophobia, nausea, vomiting, nasal congestion, tearing, facial redness, and a sensation of fullness in the ear.

Among this cohort, 15 patients developed a migraine attack after vasoactive intestinal peptide administration, compared with 1 patient in the placebo group. Participants who experienced migraines reported that the induced attacks mimicked spontaneous migraine in all cases. Median time to migraine onset was 1 hour 40 minutes (interquartile range [IQR], 1 hour to 1 hour 50 minutes). Headache was located primarily in the frontal and temporal regions (67% and 47%, respectively).

During the 12-hour observation period, headache incidence was higher after vasoactive intestinal peptide administration vs placebo; more patients also reported nausea and photophobia, but not phonophobia. Median peak headache intensity was 3 (IQR, 2-5) and median time to peak headache was 1 hour and 50 minutes after peptide administration.

There was a noted increase in superficial temporal artery diameter and heart rate after vasoactive intestinal peptides vs placebo.

The most common adverse events included flushing, warm sensations, heart palpitations, and cold sensations. Other events included abdominal discomfort, back pain, tiredness, and diarrhea.

Study limitations included the fact that factors that may have affected the incidence of migraine-like attacks and the requirement of data validation in different cohorts.

“Our findings revisit the role of [vasoactive intestinal peptides] in migraine pathogenesis and suggest that a prolonged arterial dilation might be involved in the initiation of migraine attacks,” the researchers concluded. “We suggest that selective antagonists of [vasoactive intestinal peptides] and its receptors could be potential targets for novel drugs for migraine.”

Disclosure: This clinical trial was supported by Novartis. Please see the original reference for a full list of authors’ disclosures.


Pellesi L, Al-Karagholi MA-M, De Icco R, et al. Effect of vasoactive intestinal polypeptide on development of migraine headaches: A randomized clinical trial. JAMA Netw Open. 2021;4(8):e2118543. doi:10.1001/jamanetworkopen.2021.18543