Acute Migraine Headache Treatment for Adults: Lasmiditan vs CGRP-Antagonists

Rimegepant and ubrogepant, both calcitonin gene-related peptide (CGRP)-antagonists, demonstrate favorably efficacy and safety for the treatment of acute migraine in adults. Although lasmiditan shows notable efficacy, it may increase the risk for adverse events (AEs). These are the findings of a study published in The Journal of Headache and Pain.

Effective treatment for acute-stage migraine remains challenging. Many patients experience insufficient symptom control using standard-of-care triptans. Furthermore, these drugs are contraindicated in people with cardiovascular disease.

In 2019, lasmiditan, a 5-hydroxytryptamine 1F (5-HT1F) receptor agonist, received US Food and Drug Administration (FDA) approval for acute migraine treatment. In the same year, ubrogepant became the first CGRP antagonist medication to be approved for this indication,³ followed by rimegepant and zavegepant.

As yet, no randomized controlled trial (RCT) has compared these newer medications head-to-head. For the study, researchers designed a network meta-analysis to perform an indirect, statistical comparison among lasmiditan, rimegepant, ubrogepant, and zavegepant for the treatment of acute migraine.

The registered protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research team analyzed 18 previous multicenter RCTs, performed in countries worldwide between 2014 and 2023, that tested the efficacy and safety of any of these 4 drugs to treat acute migraine attack. Sixteen of those trials were double-blind, while 2 were open-label; 13 were phase 3 and the rest were phase 2 studies.

In total, these studies included 22,429 patients (mean age, 36.0-45.7; 79% women) with a minimum 1-year history of migraine. The authors assessed risk of bias for each study, as well as certainty of evidence for each comparison of therapeutic or safety outcome across the studied drugs.

Each drug, at various dosages, was more likely than placebo to reduce head pain within 2 hours. Only the lowest dose (5 mg) of zavegepant was equivalent to placebo.

However, lasmiditan at 100 mg and 200 mg doses, in particular, was the drug most likely to reduce head pain within 2 hours (surface under the cumulative ranking curve [SUCRA] scores = .94 and .91, respectively, out of a possible score of 1).,

Ubrogepant at 100 mg had the highest SUCRA for quick pain freedom at 2 hours (0.79) and sustained pain freedom for over 24 hours (0.74). Rimegepant at 75 mg had the highest SUCRA for providing freedom from photophobia within 2 hours (0.96).

Among AEs, at any dose, compared with placebo, lasmiditan carried a higher risk for dizziness, insomnia, somnolence, and fatigue than any of the CGRP antagonists. Ubrogepant was more strongly associated than placebo with nasopharyngitis, and zavegepant with dysgeusia. By contrast, rimegepant (75 mg) demonstrated AE risks similar to those of placebo.

Study limitations included a high risk of bias in 3 studies, and large heterogeneity among the studies overall. This led to an overall low certainty of evidence for many comparisons: certainty of evidence was rated as either low or very low for 40% of comparisons with placebo, and 70% of pairwise comparisons between drugs.

“These results warrant circumspect evaluation, primarily attributable to the intrinsic constraints inherent in indirect comparative analyses. It is crucial for future research to encompass larger, well-designed RCTs to validate our findings and ascertain the optimal dosage and long-term safety of these medications for patients receiving migraine treatment,” the researchers concluded.

A planned 2-year follow-up study will update these results.