Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals

Abstract

Background A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation of any model. The hypothesis of the present study was that sumatriptan is effective in 5-ISMN-induced headache in healthy individuals. Methods In a double-blind, randomised, crossover design, 30 healthy volunteers of both sexes received 5-ISMN 60 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results 5-ISMN induced a reproducible headache in all 30 participants. The headache had several migraine-like features in all participants and 20 individuals developed a migraine-like attack. Median peak headache score was 5 on both experimental days ( p = 1.00). There was no reduction, but instead an increase in headache intensity 2 hours after sumatriptan ( p = 0.003). Difference in area under the headache score curve (AUC) 0-4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future drug testing.

Sumatriptan Does Not Antagonize CGRP‐Induced Symptoms in Healthy Volunteers

“…We expected that a longer lasting infusion would induce more headache. This was a reasonable idea since previous long‐term provocation studies with nitric oxide donors induced more headache than short‐term provocations . For reasons of feasibility, we studied healthy volunteers rather than migraine patients.…”

“…It has previously been attempted to develop a human model for testing new anti‐migraine drugs, using cilostazol (a phosphodiesterase 3 inhibitor) and a long‐lasting nitric oxide donor; isosorbide‐5‐mononitrate (5‐ISMN) . Cilostazol induced a headache with migraine‐like features in healthy volunteers and migraine‐like attacks in migraine without aura patients.…”

Effects of systemic inhibitors of acid‐sensing ion channels 1 (ASIC1) against acute and chronic mechanical allodynia in a rodent model of migraine

“…Preclinical migraine models in rodents are based on human observations. NO donors such as nitroglycerin (NTG) (Ashina et al ., ) and nitrate‐based drugs with slower pharmacokinetics like isosorbide dinitrate (ISDN) used in the treatment of cardiovascular disease (Iversen et al ., ; Olesen and Ashina, ; Hansen and Olesen, ) trigger a delayed‐migraine attack associated with cutaneous facial and extra‐facial allodynia (Thomsen et al ., ). In rodents, NO donors evoke elevated CGRP blood levels, meningeal inflammation, photo and phonophobia, sensitization of central neurons of the trigeminal nucleus caudalis (TNC), cephalic and extra‐cephalic allodynia, as well as spontaneous facial pain.…”

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

“…However, our results should be interpreted with caution because sumatriptan infusion caused immediate but short exacerbation of PACAP38-induced headache. The sumatriptan-induced headache was previously observed after infusion of calcitonin gene-related peptide (CGRP), levcromakalim, isosorbide-5-mononitrate (NO donor) and cilostazol in healthy volunteers [2,9,23,24]. It is also a well-known side effect of sumatriptan treatment in migraine patients [15,39].…”