A human trigeminovascular biomarker for antimigraine drugs: A randomised, double-blind, placebo-controlled, crossover trial with sumatriptan

Abstract

Current antimigraine drugs are believed, besides their direct vasoconstrictive effect, to inhibit calcitonin gene-related peptide (CGRP) release from trigeminal nerve endings during migraine. Objective The objective of this report is to establish a biomarker for the CGRP-interfering effect of antimigraine drugs. Methods We quantified the effect of sumatriptan on the trigeminal nerve-mediated rise in forehead dermal blood flow (DBF), induced by capsaicin application (0.6 mg/ml) and electrical stimulation (0.2-1.0 mA), in a randomised, double-blind, placebo-controlled, crossover study in healthy male ( n = 11, age ± SD: 29 ± 8 years) and female ( n = 11, 32 ± 7 years) individuals. Results DBF responses to capsaicin were attenuated by sumatriptan (ΔDBF, mean ± SEM: 82 ± 18 AU, p = 0.0002), but not by placebo (ΔDBF: 21 ± 12 AU, p = 0.1026). Conclusion We demonstrated that sumatriptan inhibits increases in DBF, induced by the release of, most likely, CGRP. Thus, our model may be used as a biomarker to establish the trigeminovascular effects of (potential) antimigraine drugs, such as CGRP receptor antagonists or antibodies directed against CGRP or its receptor.

Current understanding of meningeal and cerebral vascular function underlying migraine headache

“…Despite the inconclusive findings of increased CGRP levels within the intracranial circulation during a migraine attack (83,112), the finding that sumatriptan normalized the elevated CGRP levels observed in the extra-jugular vein, concomitant with headache relief (109) further promoted the notion that trigeminal release of CGRP and the ensuing cranial neurogenic vasodilatation contribute to migraine headache. Moreover, a human experimental model of neurogenic vasodilation, where capsaicin is applied to a trigeminal (V1) dermatome in the human forehead to release endogenous CGRP (via activation of TRPV1 channels), confirmed that sumatriptan, most likely via 5-HT 1D/1F receptors, pre-synaptically inhibits CGRP release from trigeminal nerve endings (113). The key findings that exogenous CGRP infusions could trigger delayed migraine-like headaches accompanied by a unilateral dilatation of the middle meningeal artery, and no dilation of the middle cerebral artery (114,115) suggested a peripheral role for CGRP and its related meningeal vasodilation in migraine headache, especially since CGRP, like substance P, is unlikely to pass readily into the brain, due to its large molecular weight.…”

Evaluating rimegepant for the treatment of migraine

“…It was discovered that the triptans could reduce elevated CGRP levels during nitroglycerin-induced migraine attacks and spontaneous headaches, leading to pain relief [7,10]. Moreover, sumatriptan inhibits the increase in dermal blood flow after capsaicin application on the forehead, induced by CGRP release [11]. Another novel drug that has been approved by the FDA for the treatment of migraine is the 5-HT 1F receptor agonist lasmiditan.…”

Targeting CGRP and 5‐HT1FReceptors for the Acute Therapy of Migraine: A Literature Review

“…However, the true site or sites of action of sumatriptan is yet to be determined. Sumatriptan has been shown to reduce plasma CGRP levels in patients treated with sumatriptan for a migraine attack with concurrent improvement in pain and, in healthy individuals, inhibit capsaicin‐induced CGRP release . This suggests agonism of one or a combination of the 5‐HT 1B , 5‐HT 1D and 5‐HT 1F receptors, results in inhibition of CGRP release and therefore efficacy in pain relief in migraine.…”

“…Sumatriptan has been shown to reduce plasma CGRP levels in patients treated with sumatriptan for a migraine attack with concurrent improvement in pain 72 and, in healthy individuals, inhibit capsaicin-induced CGRP release. 73 This suggests agonism of one or a combination of the 5-HT 1B , 5-HT 1D and 5-HT 1F receptors, results in inhibition of CGRP release and therefore efficacy in pain relief in migraine. Selective 5-HT 1B agonists reduce the vasodepressor effects of CGRP, 74 although currently it is unclear at which structure or structures their action is instigated.…”