• Hashmat Ghanizada, Mohammad Al-Mahdi Al-Karagholi, Nanna Arngrim, Mette Mørch-Rasmussen, Matias Metcalf-Clausen, Larsson Henrik Bo Wiberg HBW Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Faculty of Health and Medical Sciences,, Amin Faisal Mohammad FM Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Val, and Messoud Ashina.
• Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansens Vej 5, DK-2600, Glostrup, Denmark.
• J Headache Pain. 2020 Feb 24; 21 (1): 19.

BackgroundPituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography.MethodsThirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries.ResultsWe found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Post-treatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min).ConclusionsPost-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects.Trial RegistrationClinicaltrials.gov (NCT03585894). Registered 13 July 2018.

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