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

Hashmat Ghanizada, Mohammad Al-Mahdi Al-Karagholi, Nanna Arngrim, Mette Mørch-Rasmussen, Matias Metcalf-Clausen, Henrik Bo Wiberg Larsson, Faisal Mohammad Amin, Messoud Ashina, Hashmat Ghanizada, Mohammad Al-Mahdi Al-Karagholi, Nanna Arngrim, Mette Mørch-Rasmussen, Matias Metcalf-Clausen, Henrik Bo Wiberg Larsson, Faisal Mohammad Amin, Messoud Ashina

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.

Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Messoud Ashina is a consultant, speaker or scientific advisor for Allergan, Amgen, Alder, ATI, Eli Lilly, Novartis, and Teva, primary investigator for Alder, Amgen, ElectroCore, Novartis and Teva trials. MA has no ownership interest and does not own stocks of any pharmaceutical company. MA serves as associated editor of Cephalalgia, Headache, and co-editor of the Journal of Headache and Pain. MA is the President of the International Headache Society. Mohammad Al-Mahdi Al-Karagholi has acted as an invited speaker for Novartis and received travel grant from ElectroCore, Hashmat Ghanizada, Nanna Arngrim, Faisal Mohammad Amin, Mette Mørch-Rasmussen, Matias Metcalf-Clausen and Henrik Bo Wiberg Larsson declare they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
a Pre-treatment study design. b Post-treatment study design. c Recruitment flow chart. All participants took part in each group in two experimental days separated by one week
Fig. 2
Fig. 2
Headache intensity of individual volunteers (black lines) and the median headache intensity (red line) after PACAP38 and pre-treatment with ketorolac /sumatriptan (n = 17) and post-treatment with ketorolac /sumatriptan (n = 17)
Fig. 3
Fig. 3
Effect of pre-treatment (solid line) and post-treatment (dotted line) on extra-intracerebral arteries dilated with PACAP38. Middle meningeal artery (MMA), superficial temporal artery (STA) and middle cerebral artery (MCA)
Fig. 4
Fig. 4
Percentage change from baseline for mean arterial pressure (MAP) and heart rate (HR) after PACAP38 and pre-treatment and post-treatment with ketorolac and sumatriptan

References

    1. Akerman S, Goadsby PJ. Neuronal PAC1 receptors mediate delayed activation and sensitization of trigeminocervical neurons: Relevance to migraine. Sci Transl Med. 2015;7:308ra157. doi: 10.1126/scitranslmed.aaa7557.
    1. Al-Karagholi MA-M, Ghanizada H, Hansen JM, Skovgaard LT, Olesen J, Larsson HBW, Ashina M (2019) Levcromakalim, an adenosine triphosphate-sensitive Potassium Channel opener, dilates Extracerebral but not arteries, cerebral. Headache:1468–1480
    1. Amin F, Lundholm E, Hougaard A, Arngrim N, Wiinberg L, de Koning PJ, Larsson HB, Ashina M. Measurement precision and biological variation of cranial arteries using automated analysis of 3 T magnetic resonance angiography. J Headache Pain. 2014;15:25. doi: 10.1186/1129-2377-15-25.
    1. Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, De Koning PJH, Andersen MR, Larsson HBW, Fahrenkrug J, Olesen J, Ashina M. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137:779–794. doi: 10.1093/brain/awt369.
    1. Amin FM, Asghar MS, Guo S, Hougaard A, Hansen AE, Schytz HW, van der Geest RJ, de Koning PJ, Larsson HB, Olesen J, Ashina M. Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. Cephalalgia. 2012;32:140–149. doi: 10.1177/0333102411431333.
    1. Amin FM, Asghar MS, Ravneberg JW, De Koning PJ, Larsson HB, Olesen J, Ashina M. The effect of sumatriptan on cephalic arteries: a 3T MR-angiography study in healthy volunteers. Cephalalgia. 2013;33:1009–1016. doi: 10.1177/0333102413483374.
    1. Anzai M, Suzuki Y, Takayasu M, Kajita Y, Mori Y, Seki Y, Saito K, Shibuya M. Vasorelaxant effect of PACAP-27 on canine cerebral arteries and rat intracerebral arterioles. Eur J Pharmacol. 1995;285:173–179. doi: 10.1016/0014-2999(95)00404-9.
    1. Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaards MB, Hougaard A, Wolfram F, de Koning PJH, Olsen KS, Secher NH, Larsson HBW, Olesen J, Ashina M (2015) Migraine induced by hypoxia: a MRI spectrocopy and angiography study. Brain:723–737
    1. Asghar MS, Becerra L, Larsson HBW, Borsook D. Calcitonin Gene-Related Peptide Modulates Heat Nociception in the Human Brain - An fMRI Study in Healthy Volunteers 2016:1–20
    1. Asghar MS, Hansen AE, Kapijimpanga T, Van Der Geest RJ, Van Der Koning P, Larsson HBW, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010;75:1520–1526. doi: 10.1212/WNL.0b013e3181f9626a.
    1. Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Van Der Koning P, Larsson HBW, Olesen J, Ashina M. Evidence for a vascular factor in migraine. Ann Neurol. 2011;69:635–645. doi: 10.1002/ana.22292.
    1. Baun M, Pedersen MHF, Olesen J, Jansen-Olesen I. Dural mast cell degranulation is a putative mechanism for headache induced by PACAP-38. Cephalalgia. 2012;32:337–345. doi: 10.1177/0333102412439354.
    1. Birk S, Sitarz JT, Petersen KA, Oturai PS, Kruuse C, Fahrenkrug J, Olesen J. The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers. Regul Pept. 2007;140:185–191. doi: 10.1016/j.regpep.2006.12.010.
    1. Burstein R, Jakubowski M. Analgesic Triptan action in an animal model of intracranial pain: a race against the development of central sensitization. Ann Neurol. 2004;55:27–36. doi: 10.1002/ana.10785.
    1. Burstein R, Jakubowski M, Levy D. Anti-migraine action of triptans is preceded by transient aggravation of headache caused by activation of meningeal nociceptors. Pain. 2005;115:21–28. doi: 10.1016/j.pain.2005.01.027.
    1. Buzzi MG, Dimitriadou V, Theoharides TC, Moskowitz MA. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Res. 1992;583:137–149. doi: 10.1016/S0006-8993(10)80017-4.
    1. Buzzi MG, Moskowitz MA. The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater. Br J Pharmacol. 1990;99:202–206. doi: 10.1111/j.1476-5381.1990.tb14679.x.
    1. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet (London, England) 1988;1:1309–1311. doi: 10.1016/S0140-6736(88)92122-8.
    1. Falkenberg K, Olesen J (2018) Pre-treatment with sumatriptan for cilostazol induced headache in healthy volunteers. J Headache Pain 19(1):71. 10.1186/s10194-018-0890-y
    1. Ghanizada H, Al-Mahdi Al-Karagholi M, Arngrim N, Ghanizada M, Wiberg Larsson HB, Amin FM, Ashina M. Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: a 3T MRI study. Peptides. 2019;121:170134. doi: 10.1016/j.peptides.2019.170134.
    1. Ghanizada Hashmat, Al-Karagholi Mohammad Al-Mahdi, Arngrim Nanna, Olesen Jes, Ashina Messoud. PACAP27 induces migraine-like attacks in migraine patients. Cephalalgia. 2019;40(1):57–67. doi: 10.1177/0333102419864507.
    1. Green DP, Limjunyawong N, Gour N, Pundir P, Dong X. A Mast-Cell-Specific Receptor Mediates Neurogenic Inflammation and Pain. Neuron. 2019;101:412–420. doi: 10.1016/j.neuron.2019.01.012.
    1. Hansen EK, Guo S, Ashina M, Olesen J. Toward a pragmatic migraine model for drug testing: 1. Cilostazol in healthy volunteers. Cephalalgia. 2016;36:172–178. doi: 10.1177/0333102415583986.
    1. Hansen EK, Olesen J. Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals. Cephalalgia. 2017;37:11–19. doi: 10.1177/0333102416636095.
    1. Héron A, Dubayle D. A focus on mast cells and pain. J Neuroimmunol. 2013;264:1–7. doi: 10.1016/j.jneuroim.2013.09.018.
    1. Hoskin KL, Kaube H, Goadsby PJ. Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain. 1996;119:1419–1428. doi: 10.1093/brain/119.5.1419.
    1. Humphrey PP, Feniuk W, Marriott AS, Tanner RJ, Jackson MR, Tucker ML. Preclinical studies on the anti-migraine drug, sumatriptan. Eur Neurol. 1991;31:282–290. doi: 10.1159/000116755.
    1. Iversen H, Olesen J. Headache induced by a nitric oxide donor (nitroglycerin) responds to Sumatriptan. A human model for development of migraine drugs. Cephalalgia. 1996;16:412–418. doi: 10.1046/j.1468-2982.1996.1606412.x.
    1. Jakubowski M, Levy D, Goor-Aryeh I, Collins B, Bajwa Z, Burstein R. Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors. Headache. 2005;45:850–861. doi: 10.1111/j.1526-4610.2005.05153.x.
    1. Jansen-Olesen I, Hougaard Pedersen S. PACAP and its receptors in cranial arteries and mast cells. J Headache Pain 2018;19
    1. Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain. 2007;130:166–176. doi: 10.1016/j.pain.2007.03.012.
    1. Levy D, Jakubowski M, Burstein R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists. Proc Natl Acad Sci U S A. 2004;101:4274–4279. doi: 10.1073/pnas.0306147101.
    1. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun. 1989;164:567–574. doi: 10.1016/0006-291X(89)91757-9.
    1. Miyata A, Jiang L, Dahl RD, Kitada C, Kubo K, Fujino M, Minamino N, Arimura A. Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) Biochem Biophys Res Commun. 1990;170:643–648. doi: 10.1016/0006-291X(90)92140-U.
    1. Moller K, Zhang YZ, Hakanson R, Luts A, Sjolund B, Uddman R, Sundler F. Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: immunocytochemical and immunochemical evidence. Neuroscience. 1993;57:725–732. doi: 10.1016/0306-4522(93)90018-B.
    1. Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology. 1993;43:S16–S20.
    1. Pardutz A, Schoenen J. NSAIDs in the acute treatment of migraine: a review of clinical and experimental data. Pharmaceuticals. 2010;3:1966–1987. doi: 10.3390/ph3061966.
    1. Pedersen SH, la Cour SH, Calloe K, Hauser F, Olesen J, Klaerke DA, Jansen-Olesen I. PACAP-38 and PACAP (6–38) Degranulate rat meningeal mast cells via the orphan MrgB3-receptor. Front Cell Neurosci. 2019;13:1–11. doi: 10.3389/fncel.2019.00114.
    1. Peroutka SJ, McCarthy BG. Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. Eur J Pharmacol. 1989;163:133–136. doi: 10.1016/0014-2999(89)90406-8.
    1. Reuter U. Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain. 2001;124:2490–2502. doi: 10.1093/brain/124.12.2490.
    1. Rice ASC, Lloyd J, Bullingham RES, O’Sullivan G. Ketorolac penetration into the cerebrospinal fluid of humans. J Clin Anesth. 1993;5:459–462. doi: 10.1016/0952-8180(93)90061-I.
    1. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132:16–25. doi: 10.1093/brain/awn307.
    1. Silberstein SD, Stirpe JC. COX inhibitors for the treatment of migraine. Expert Opin Pharmacother. 2014;15:1863–1874. doi: 10.1517/14656566.2014.937704.
    1. Sinha V, Kumar R, Singh G. Ketorolac tromethamine formulations: an overview. Expert Opin Drug Deliv. 2009;6:961–975. doi: 10.1517/17425240903116006.
    1. Theoharides TC, Donelan J, Kandere-Grzybowska K, Konstantinidou A. The role of mast cells in migraine pathophysiology. Brain Res Rev. 2005;49:65–76. doi: 10.1016/j.brainresrev.2004.11.006.
    1. Tvedskov JF, Iversen HK, Olesen J, Tfelt-Hansen P. Nitroglycerin provocation in normal subjects is not a useful human migraine model? Cephalalgia. 2010;30:928–932. doi: 10.1111/j.1468-2982.2009.02014.x.
    1. Valledor AF, Comalada M, Santamaría-Babi LF, Lloberas J, Celada A. Macrophage Proinflammatory activation and deactivation. Quest Balance Adv Immunol. 2010;108:1–20. doi: 10.1016/B978-0-12-380995-7.00001-X.
    1. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104:2S–8S. doi: 10.1016/S0002-9343(97)00203-9.
    1. Vaudry D, Falluel-morel A, Bourgault S, Basille M, Burel D, Wurtz O, Fournier A, Chow BKC, Hashimoto H, Galas L, Vaudry H, National I, Sante D. Pituitary Adenylate Cyclase-activating polypeptide and its receptors : 20 years after the discovery. Pept Res. 2009;61:283–357. doi: 10.1124/pr.109.001370.283.
    1. Zhang XC, Kainz V, Burstein R, Levy D. Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain. 2011;152:140–149. doi: 10.1016/j.pain.2010.10.002.
    1. Zhang XC, Strassman AM, Burstein R, Levy D. Sensitization and activation of intracranial meningeal nociceptors by mast cell mediators. J Pharmacol Exp Ther. 2007;322:806–812. doi: 10.1124/jpet.107.123745.
    1. Zhang YZ, Sjo B, Moller K, Håkanson R, Sundler F. Pituitary adenylate cyclase activating peptide produces a marked and long-lasting depression of a C-fibre-evoked flexion reflex. Neuroscience. 1993;57:733–737. doi: 10.1016/0306-4522(93)90019-C.
    1. Ødum L, Petersen LJ, Skov PS, Ebskov LB. Pituitary adenylate cyclase activating polypeptide (PACAP) is localized in human dermal neurons and causes histamine release from skin mast cells. Inflamm Res. 1998;47:488–492. doi: 10.1007/s000110050363.

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