Three new acute migraine treatments—lasmiditan, a 5-hydroxytryptamine1F (5-HT1F) receptor agonist, and the calcitonin gene-related peptide (CGRP) antagonists (gepants) rimegepant and ubrogepant—were less efficacious than most triptans on 2-hour pain freedom or pain relief, a systematic review and network meta-analysis found.
Most triptans were associated with higher odds ratios (ORs) for pain freedom at 2 hours compared with lasmiditan (OR range 1.72-3.40), rimegepant (OR range 1.58-3.13), and ubrogepant (OR range 1.54-3.05), reported Kuo-Tung Tang, MD, MPH, PhD, of Taichung Veterans General Hospital, Taiwan, and Shuu-Jiun Wang, MD, of Taipei Veterans General Hospital, Taiwan, and co-authors.
Most triptans were also associated with higher ORs for some pain relief at 2 hours than lasmiditan (OR range 1.46-3.31), rimegepant (OR range 1.33-3.01), and ubrogepant (OR range 1.38-3.13), they noted in JAMA Network Open.
“For pain freedom or pain relief at 2 hours after the dose, lasmiditan, rimegepant, and ubrogepant were associated with higher ORs compared with placebo, but lower ORs compared with most triptans,” Tang and colleagues wrote. “However, the lack of cardiovascular risks for these new classes of migraine-specific treatments may offer an alternative to triptans.”
Triptans are contraindicated in migraine patients with vascular disease, noted Hans-Christoph Diener, MD, PhD, of the University Duisburg-Essen in Germany, a researcher in stroke and headache who was not involved with the meta-analysis.
“What are the potential advantages of the new drugs for the treatment of migraine attacks?” Diener wrote in an email to BreakingMED.
“They could be more effective than triptans—which they are not,” he pointed out. “They could be effective in patients who do not respond to triptans, but this was not investigated.”
“They also could be used in patients who have contraindications for triptans,” Diener added. “Triptans are extremely safe and patients with real contraindications are rare.”
In their analysis, Tang and colleagues searched Cochrane Register of Controlled Trials, Embase, and PubMed to March 2020 for double-blind randomized clinical trials of migraine-specific acute treatments. They included 64 randomized clinical trials with 46,442 participants (74%-87% women; age range 36-43). Most (92%) studies did not allow concomitant use of migraine prevention drugs.
Doses were restricted to those in widespread clinical use for dihydroergotamine, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan, lasmiditan, rimegepant, and ubrogepant. The primary outcome was the OR for freedom from pain 2 hours after the dose, with secondary outcomes of OR for any pain relief at 2 hours and any adverse events.
“Our study showed that dihydroergotamine, 2-mg nasal spray, was associated with the best therapeutic efficacy in terms of pain relief at 2 hours; however, the acute and long-term adverse events of ergot derivatives have resulted in their being replaced by triptans and not recommended for routine use,” the researchers wrote, noting that “eletriptan, 40 mg, was associated with the best therapeutic efficacy in pain freedom at 2 hours.”
“The ability of eletriptan to cross the blood-brain barrier also explained its better efficacy and faster and more consistent absorption than sumatriptan and other triptans,” they added.
Most adverse events were mild to moderate and “the percentages of serious adverse events were low (0.0%-2.1%),” Tang and coauthors noted. “Chest symptoms, including chest pain, tightness, heaviness, and pressure, accounted for 0% to 20% of the adverse events for each specific treatment.”
Lasmiditan 100 mg had the highest likelihood of any adverse event (95.1%). Dihydroergotamine, almotriptan, rimegepant, and ubrogepant were not associated with a higher OR for adverse events compared with placebo.
Three triptans also were associated with a higher OR for any adverse event than the CGRP antagonists: rizatriptan (OR 1.96, 95% CI 1.14-3.35), sumatriptan (OR 1.83, 95% CI 1.09-3.09), and zolmitriptan (OR 2.34, 95% CI 1.39-3.95).
“Our findings provide some reference for clinical applications in the acute treatment of migraine,” the researchers suggested. “First, although the 5-HT1F receptor agonist lasmiditan and the CGRP antagonists rimegepant and ubrogepant have enriched the therapies available for acute migraine treatment, most triptans are associated with higher ORs for pain freedom or pain relief at 2 hours compared with these two new classes of anti-migraine drugs, which may imply that triptans will remain the current mainstay of specific acute migraine treatment.”
“Second, although these two new classes of anti-migraine drugs may not be as efficacious as triptans, these novel abortive agents without cardiovascular risks might offer an alternative to current specific migraine treatments for patients at risk of cardiovascular disease,” they added. “Third, successful treatment with the 5-HT1F receptor agonist and the CGRP antagonists compared with placebo reveals that vasoconstriction is not essential for anti-migraine therapy, which suggests a direction for future pharmaceutical development of specific acute migraine treatment.”
Lasmiditan was approved by the FDA in 2019 for treatment of acute adult migraine with or without aura. Results in the present study were consistent with a prior meta-analysis showing a relatively high incidence of adverse events including dizziness, nausea, and fatigue considered central-nervous system related, though mostly tolerable.
Ubrogepant was approved for acute migraine treatment in December 2019 and rimegepant in February 2020. Though effective versus placebo at 2 hours, lower efficacy versus triptans at 2 hours is an issue “widely discussed, and some investigators noted a late benefit, in the 3-hour to 8-hour post-dose period, for ubrogepant and rimegepant because of their relatively long half-lives (5-7 hours and 10-12 hours, respectively), which could not be demonstrated in these included studies,” Tang and co-authors pointed out.
“Triptans appeared to be associated with higher risks of any adverse events than rimegepant and ubrogepant,” they observed. “Therefore, future studies are encouraged to compare gepants with triptans in efficacy at a later point, as well as tolerability.”
Limitations include the study’s focus on short-term response and adverse effects; issues of longer term efficacy and safety remain unclear. Studies in the meta-analysis also varied in their inclusion or exclusion of migraine aura and use of preventive medications.
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Three new acute migraine treatments—lasmiditan, rimegepant, and ubrogepant—were less efficacious than most triptans on 2-hour pain freedom or pain relief, a systematic review and network meta-analysis found.
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The newer drugs may be an alternative for migraine patients at risk of cardiovascular disease.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This research was supported in part by grants from the Ministry of Science and Technology and Ministry of Education in Taiwan.
Wang reported receiving personal fees from Eli Lilly, Daiichi-Sankyo, Norvatis Taiwan, Biogen, Pfizer, and Bayer; and grants from AbbVie, Norvatis, Eli Lilly, Taiwan Ministry of Technology and Science, Brain Research Center, National Yang Ming Chiao Tung University, and Taipei Veterans General Hospital outside the submitted work.
Cat ID: 35
Topic ID: 82,35,730,35,192,925
