Comparative effects of different drugs for the acute management of migraine episodes in adults: systematic review and network meta-analysis

Data sources: Until 24 June 2023, the Cochrane Register of Controlled Trials, Medline, Embase, ClinicalTrials.gov, the EU Clinical Trials Register, the WHO International Clinical Trials Registration System, and the websites of regulatory agencies and pharmaceutical companies without language restriction.

Methods: Selection, data extraction, coding and assessment of risk of bias were performed independently and in duplicate. Random-effects network meta-analyses were performed for primary analyses. Primary outcomes were the proportion of participants who were pain-free 2 hours after dosing and the proportion of participants who were pain-free between 2 and 24 hours after dosing, in both cases without the use of rescue medication. Certainty of evidence was assessed using the online tool CINeMA (confidence in network meta-analysis). Vitruvian diagrams were used to summarise the results. An international panel of clinicians and people with experience of migraine were involved in designing the study and interpreting the results.

Eligibility criteria for study selection: Randomised, double-blind trials in adults (≥18 years) with a diagnosis of migraine according to the International Classification of Headache Disorders.

Results: 137 randomised controlled trials involving 89,445 participants allocated to one of the 17 compounds or placebo were included. All compounds showed superior efficacy to placebo for pain relief at 2 hours (odds ratios ranging from 1.73 (95% confidence interval [CI] 1.27 to 2.34) for naratriptan to 5.19 (4, 25 to 6.33) for eletriptan), and most of them also for maintaining pain relief after 24 hours (odds ratios from 1.71 (1.07 to 2.74) for celecoxib to 7.58 (2.58 to 22.27) for ibuprofen). In direct comparisons between active molecules, eletriptan was the most effective drug in relieving pain after two hours (odds ratios from 1.46 (1.18 to 1.81) to 3.01 (2.13 to 4.25)), followed by rizatrix (2.13 to 4.25) and ibuprofen. 25)), followed by rizatriptan (1.59 (1.18 to 2.17) to 2.44 (1.75 to 3.45)), sumatriptan (1.35 (1.03 to 1.75) to 2.04 (1.49 to 2.86)) and zolmitriptan (1.47 (1.04 to 2.08) to 1.96 (1.39 to 2.86)). For lasting pain relief, the most effective molecules were eletriptan and ibuprofen (odds ratios from 1.41 (1.02 to 1.93) to 4.82 (1.31 to 17.67)). Confidence in CINeMA ranged from high to very low. Sensitivity analyses looking only at Food and Drug Administration-approved doses, high versus low doses, risk of bias, and moderate to severe headache at baseline confirmed the main findings for the primary and secondary endpoints.

Conclusions: Overall, eletriptan, rizatriptan, sumatriptan and zolmitriptan had the best profiles and were more effective than the recently marketed drugs lasmiditan, rimegepant and ubrogepant. Although cost-effectiveness analyses are warranted and particular attention should be paid to patients with a high-risk cardiovascular profile, the most effective triptans should be considered the preferred acute treatment for migraine and included in the WHO essential medicines list to promote global accessibility and uniform standards of care.