Recently, a fixed combination of

sumatriptan 85 mg and naproxen 500 mg (32% pain-free [PF]) was superior to placebo (10% PF) and sumatriptan 85 mg (24% PF) in 2 very large RCTs (n = 1461 and n = 1495) and sustained PF for 24 hours was 24%, 8% and 15%, respectively.143 From a clinical perspective it is the evaluation that despite highly statistically significant results in very large RCTs, the majority of the migraine patients are not treated satisfactorily with triptans, with 30-40% PF response at 2 hours with most triptans142 Migraine and Calcitonin Gene-Related Peptide (CGRP) (1990).— In 1983, a novel neuropeptide, CGRP, was demonstrated in neural tissue144 and its presence in perivascular nerves of cerebral arteries was demonstrated with immunocytochemistry ABT-263 purchase and radioimmunoassay.145 CGRP was LEE011 price found to be a potent vasodilator of cerebral vessels.146,147 Stimulation of the human trigeminal ganglion in the treatment of trigeminal neuralgia resulted in flushing and the release of vasoactive peptides, substance P, and CGRP, in the external jugular vein (EJV).148 In 1990 it was shown that CGRP, but not neuropeptide Y, vasoactive intestinal peptide, and substance P, was considerably increased in the EJV during migraine attacks both in migraine with and without aura.17 Three years later, the effect of trigeminal

ganglion stimulation on CBF and jugular vein peptides in cats was studied before and after administration of sumatriptan and dihydroergotamine.149 The increase of CBF and release of CGRP

Diflunisal in EJV in cats was reduced by both drugs. Treatment of migraine patients with sumatriptan also led to a decrease of elevated CGRP in the EJV and relief of headache in most cases.149 The finding of increased CGRP in the EJV led to the development of new migraine drugs based on CGRP receptor blockade.150 However, in a Danish study (n = 17) with intra-patient comparison, in which blood samples from the EJV were taken in the patients’ home, there was no tendency for an increase of CGRP during an attack of migraine without aura.151 In a later study, also with intra-patient comparisons, 8 migraine patients were investigated in the laboratory during, and outside, attacks of migraine without aura. No increase of CGRP in EJV was found.152,153 Furthermore, in one nitroglycerin-induced migraine attack study, CGRP in EJV was not increased.153 In contrast, saliva CGRP was increased during migraine attacks in patients responding to rizatriptan154 whereas there was a nonattack-related increase in CGRP in saliva in migraine in another study.155 The important role of CGRP in migraine pathophysiology is shown by 2 sets of facts. First, infusion of CGRP induced delayed migraine attacks in migraine patients.156 Second, CGRP receptor antagonists were effective in the treatment of migraine attacks.