Pituitary adenylate cyclase-activating polypeptide (PACAP), namely the PACAP27 isoform, is a trigger for migraine without aura, a small study in Cephalalgia suggests.

The crossover study recruited a total of 20 patients with migraine without aura (mean age, 29 years) who had ≥2 migraine without aura attacks per month. On 2 different experiment days, patients were randomly assigned to receive either an infusion of 10 pmol/kg/minute PACAP27 or saline placebo over the course of 20 minutes.

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A standard questionnaire was used to record headache- and migraine-associated symptoms, and a numerical rating scale from 0 to 10 was used to record pain intensity. A laser speckle contrast device was used to measure blood flow intensity and fluctuation in facial skin.

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More than half (55%) of patients reported migraine like attacks after treatment infusion with PACAP27 vs only 10% of patients who received placebo (P =.022). Median times for start of migraine like attacks and headache onset was 3 hours (range, 30 minutes-7 hours) and 10 minutes (range, 10 minutes-3 hours), respectively. Patients who received PACAP27 had a larger headache intensity score area under the curve of 0 to 13 hours compared with patients who received placebo (P =.003).

PACAP27 was also associated with a greater incidence of migraine-associated symptoms, including nausea (P =.016), photophobia (P =.039), and fatigue (P =.008). Treatment with PACAP27 was also associated with increased facial skin blood flow (P =.001). A greater proportion of patients who received PACAP27 experienced fatigue compared with patients who received saline placebo (45% vs 5%, respectively; P =.008).

Limitations of the study include its crossover design and small sample size, as well as the strict inclusion of only patients who had migraine without aura.

The researchers suggest their “data reinforce PACAP and its receptors’ role in migraine pathogenesis and the therapeutic potential of targeting PACAP or its receptors for novel migraine treatment.”

Disclosure: Several of the study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Ghanizada H, Al-Karagholi MA, Arngrim N, Olesen J, Ashina M. PACAP27 induces migraine-like attacks in migraine patients [published online July 12, 2019]. Cephalalgia. doi:10.1177/0333102419864507