TY - JOUR

T1 - Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache

AU - Ghanizada, Hashmat

AU - Al-Karagholi, Mohammad Al Mahdi

AU - Arngrim, Nanna

AU - Mørch-Rasmussen, Mette

AU - Metcalf-Clausen, Matias

AU - Larsson, Henrik Bo Wiberg

AU - Amin, Faisal Mohammad

AU - Ashina, Messoud

PY - 2020

Y1 - 2020

N2 - Background: Pituitary 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. Methods: Thirty-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. Results: We 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). Conclusions: Post-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 registration: Clinicaltrials.gov (NCT03585894).

AB - Background: Pituitary 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. Methods: Thirty-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. Results: We 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). Conclusions: Post-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 registration: Clinicaltrials.gov (NCT03585894).

KW - Arterial dilation

KW - Headache

KW - Mast cell degranulation

KW - MRA

KW - Neuroinflammation

KW - NSAIDs

KW - PACAP38

KW - Pain

KW - Plasma protein extravasation

U2 - 10.1186/s10194-020-01089-3

DO - 10.1186/s10194-020-01089-3

M3 - Journal article

C2 - 32093617

AN - SCOPUS:85080944584

VL - 21

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

SN - 1129-2369

IS - 1

M1 - 19

ER -