CGRP is an important neurotransmitter associated with migraine attacks, and recent studies regarding migraine management, including prevention and acute treatment, are targeted at the CGRP receptor pathway. This study investigated the effect of a CGRP receptor antagonist for the acute treatment of migraine attacks by meta-analysis of five randomized controlled trials, including two CGRP receptor antagonists (ubrogepant and rimegepant). We found that small molecular receptor antagonists increased the odds of having pain freedom by 106.6% compared to the placebo. According to the prescribing information, 50 or 100 mg of ubrogepant and 75 mg of rimegepant are being prescribed for acute migraine treatment. The present study demonstrated that 50 and 100 mg of ubrogepant and 75 mg of rimegepant were more effective than the placebo for acute migraine treatment in terms of pain freedom, headache relief, and nausea freedom at 2 hours after treatment. In addition, ubrogepant 50 mg and rimegepant 75 mg proved more effective than placebo regarding the absence of most bothersome symptoms at 2 hours.
CGRP receptor antagonists can be used in migraineurs who do not sufficiently control acute headaches with triptan or in migraineurs with medication overuse headache (MOH) due to frequent use of acute treatment medication. Triptans are the first-line therapy for acute migraine. However, up to 40% of migraineurs are not responsive to oral triptans . There is insufficient evidence that CGRP receptor antagonists are superior to triptans in terms of efficacy; however, they can be used for those who have not been effectively treated with triptans. Furthermore, CGRP receptor antagonists have been suggested to reduce the risk of developing MOH in animal studies. Ubrogepant and sumatriptan showed efficacy as acute medications for bright light stress and nitric oxide donor-induced cephalic allodynia in a preclinical rat model of MOH, consistent with their clinical efficacy in the acute treatment of migraine. However, unlike sumatriptan, ubrogepant did not result in cutaneous allodynia and latent sensations, which may suggest that ubrogepant is less associated with the development of MOH than sumatriptan . In addition, comparing the risk of MOH between CGRP receptor antagonists (olcegant) and 5-H1F (LY344864) receptor antagonists showed different results. Persistent exposure of mice to the 5-HT1F agonist produced a significant reduction in the hind paw and orofacial mechanical withdrawal thresholds but not olcegant . This result also suggests that CGRP receptor antagonists have a lower risk of developing MOH than 5-H1F.
One of the most important potential adverse side effects of CGRP receptor blockade, including CGRP receptor antagonist, CGRP antibody, and CGRP receptor antibody, is a vasoconstrictor effect in cerebral and coronary arteries, whether or not it leads to ischemic events . CGRP has been shown to act as a neuroprotector by increasing blood flow during severe hypertension and cerebral ischemia in animals [30, 31]. Previous research has reported cardiovascular safety issues of CGRP receptor blockades . The development of telcagepant was stopped due to hepatotoxic concerns and was not included in the present study; telcagepant was well tolerated in those with stable angina . A monoclonal antibody against the CGRP receptor (erenumab) demonstrated a cardiovascular safety profile in patients with stable angina. This study suggests that CGRP receptor blockers do not worsen myocardial ischemia . However, there is a debate that this study has limitations in the study design considering the participants, pharmacokinetics, and pharmacodynamics . The study found that about 78% of participants were male, and it was difficult to reflect the characteristics of migraine, which is more prevalent in women. Participants in the study were those with stable angina, and there were limitations in evaluating the distal section of the coronary bed, in which CGRP highly affects the vasodilator. In addition, the effect of the block of the CGRP receptor on the coronary artery was also evaluated at an early time when considering the pharmacodynamics of erenumab. Although CGRP receptor blockades have recently been approved and can be used for prevention and acute treatment of migraine, cardiovascular adverse side effects have not been disclosed with these drugs, the results for migraineurs regarding the safety of vasoconstriction issues are not sufficient .
To the best of our knowledge, this is the first meta-analysis to evaluate only the available CGRP receptor antagonist in a practical clinical setting for acute migraine treatment. However, this study has some limitations. First, a relatively small number of studies were included in the analysis. The International Headache Society has recommended evidence-based guidelines for the quality of clinical trials for the treatment of headache disorders. The evaluation of the most bothersome symptoms is suggested as a co-primary endpoint in the guidelines . However, the results of 100 mg of ubrogepant for the most bothersome symptoms were found in only one article, and a meta-analysis could not be conducted. Second, as studies were restricted to English-language publications, there was language bias. Third, records were searched on only two major databases: MEDLINE and EMBASE.