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Study Suggests Vasoactive Intestinal Polypeptide May Induce Migraine


New research published in JAMA Network Open highlights one potential cause of migraine.

Results of a randomized, double-blind, placebo-controlled study suggest the role of vasoactive intestinal polypeptide (VIP) or a prolonged dilation of cranial arteries may be critical in migraine pathophysiology. Findings were published in JAMA Network Open. 

Although the exact underlying mechanisms of migraine remain unknown, research has revealed the condition is “a neurovascular disorder with biological underpinnings that involve a complex interplay of the trigeminovascular system and deep brain structure,” authors explained.

Once the trigeminovascular system is activated, afferent and efferent nerve fibers release various VIPs, which stimulate G-protein coupled receptors (GPCRs). Previous studies also found provoked migraine attacks were accompanied by a 4-hour lasting dilation of the superficial temporal artery and middle meningeal artery.

However, “to date, it remains unclear whether the limited migraine-inducing property of VIP can be attributed to its equally limited vasodilatory response,” researchers said.

To better understand the effects of VIP on migraine, investigators conducted a randomized 2-way crossover study among patients with migraine without aura (n = 21).

Individuals aged between 18 and 40 were recruited from a Danish headache center and had a migraine frequency of 1 to 6 attacks per month. Participants were also informed VIP infusion may induce headaches, but timing and characteristic details were not discussed prior to the trial.

“Patients were randomly allocated to receive VIP (8 pmol/kg/min) or placebo (sterile saline) over 2 hours on 2 different study days that were separated by at least 2 weeks,” authors wrote, while all participants arrived headache free at each study day.

Researchers measured patients’ headache intensity-associated symptoms and vital signs 10 minutes before baseline, at baseline, and every 10 minutes after the start of infusion until 3 hours and 20 minutes.

Of the patients included, 17 were women and 4 were men with a mean age of around 26 years.

Analyses revealed:

  • 15 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
  • Median time to onset of migraine-like attacks was 1 hour 40 minutes (Interquartile range [IQR], 1 hour to 1 hour 50 minutes)
  • 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)
  • After VIP more patients reported nausea and photophobia but not phonophobia compared with the placebo (nausea: 18 [86%] vs 1 [5%]; P < .001; photophobia: 12 [57%] vs 0; P =  .02; phonophobia: 9 [43%] vs 0; P  =  .08)

“Collectively, the present study implicates vasoactive intestinal polypeptide 1 (VPAC1) and vasoactive intestinal polypeptide 2 (VPAC2) receptors in the pathogenesis of migraine,” authors explained.

Additional studies in different cohorts are needing to confirm the findings. “We suggest that selective antagonists of VIP and its receptors could be potential targets for novel drugs for migraine,” researchers concluded.


Pellesi L, Al-Karagholi MA, De Icco R, et al. Effect of vasoactive intestinal polypeptide on development of migraine headaches: a randomized clinical trial. JAMA Netw Open. Published online August 6, 2021. doi:10.1001/jamanetworkopen.2021.18543

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