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

Abstract

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). Registered 13 July 2018.

• Authors: Hashmat Ghanizada, Mohammad Al-Mahdi Al-Karagholi, Nanna Arngrim, Mette Mørch-Rasmussen, Matias Metcalf-Clausen, Henrik Bo Wiberg Larsson, Faisal Mohammad Amin, Messoud Ashina
• Journal: The journal of headache and pain (J Headache Pain) Vol. 21 Issue 1 Pg. 19 (Feb 24 2020) ISSN: 1129-2377 [Electronic] England
• PMID: 32093617 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Serotonin 5-HT1 Receptor Agonists
• Vasodilator Agents
• Sumatriptan
• Ketorolac

Topics

• Adult
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage)
• Cross-Over Studies
• Double-Blind Method
• Female
• Headache (chemically induced, diagnosis, drug therapy)
• Humans
• Infusions, Intravenous
• Ketorolac (administration & dosage)
• Magnetic Resonance Angiography
• Male
• Models, Theoretical
• Pain Measurement (drug effects, methods)
• Pituitary Adenylate Cyclase-Activating Polypeptide (administration & dosage, adverse effects)
• Serotonin 5-HT1 Receptor Agonists (administration & dosage)
• Sumatriptan (administration & dosage)
• Vasodilator Agents (administration & dosage, adverse effects)