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

J Headache Pain. 2020 Feb 24;21(1):19. doi: 10.1186/s10194-020-01089-3.

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.

Keywords: Arterial dilation; Headache; MRA; Mast cell degranulation; NSAIDs; Neuroinflammation; PACAP38; Pain; Plasma protein extravasation.

Publication types

  • Randomized Controlled Trial

MeSH terms

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

Substances

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

Associated data

  • ClinicalTrials.gov/NCT03585894