Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis.

Objective: To compare all licensed drug interventions as oral monotherapy for the acute treatment of migraine episodes in adults.
Design: Systematic review and network meta-analysis.
Data Sources: Cochrane Central Register of Controlled Trials, Medline, Embase, ClinicalTrials.gov, EU Clinical Trials Register, WHO International Clinical Trials Registry Platform, as well as websites of regulatory agencies and pharmaceutical companies without language restrictions until 24 June 2023.
Methods: Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Random effects network meta-analyses were conducted for the primary analyses. The primary outcomes were the proportion of participants who were pain-free at two hours post-dose and the proportion of participants with sustained pain freedom from two to 24 hours post-dose, both without the use of rescue drugs. Certainty of the evidence was graded using the confidence in network meta-analysis (CINeMA) online tool. Vitruvian plots were used to summarise findings. An international panel of clinicians and people with lived experience of migraine co-designed the study and interpreted the findings.
Eligibility Criteria for Selecting Studies: Double blind randomised trials of adults (≥18 years) with a diagnosis of migraine according to the International Classification of Headache Disorders.
Results: 137 randomised controlled trials comprising 89 445 participants allocated to one of 17 active interventions or placebo were included. All active interventions showed superior efficacy compared with placebo for pain freedom at two hours (odds ratios 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 sustained pain freedom to 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 head-to-head comparisons between active interventions, eletriptan was the most effective drug for pain freedom at two hours (odds ratios from 1.46 (1.18 to 1.81) to 3.01 (2.13 to 4.25)), 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 sustained pain freedom, the most efficacious interventions were eletriptan and ibuprofen (odds ratios from 1.41 (1.02 to 1.93) to 4.82 (1.31 to 17.67)). Confidence in accordance with CINeMA ranged from high to very low. Sensitivity analyses on Food and Drug Administration licensed doses only, high versus low doses, risk of bias, and moderate to severe headache at baseline confirmed the main findings for both primary and secondary outcomes.
Conclusions: Overall, eletriptan, rizatriptan, sumatriptan, and zolmitriptan had the best profiles and they were more efficacious than the recently marketed drugs lasmiditan, rimegepant, and ubrogepant. Although cost effectiveness analyses are warranted and careful consideration should be given to patients with a high risk cardiovascular profile, the most effective triptans should be considered as preferred acute treatment for migraine and included in the WHO List of Essential Medicines to promote global accessibility and uniform standards of care.
Systematic Review Registration: Open Science Framework https://osf.io/kq3ys/.
Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: WKK has received an educational fee from Pfizer outside of the submitted work. EGO is supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre (NIHR203316) and the Lundbeck Foundation Applied Research Collaboration Oxford and Thames Valley at Oxford Health National Health Service Foundation Trust, by the NIHR Oxford Cognitive Health Clinical Research Facility, by the NIHR Oxford Health Biomedical Research Centre, by the Brasenose College Senior Hulme Scholarship, and has also received research and consultancy fees from Angelini Pharma. ZAZ has received a scholarship grant from Rigshospitalet. LK has received a research grant from the Lundbeck Foundation (R155–2014–171). RHC has received support for travel from the Augustinus Foundation. HMA have received an educational fee from Pfizer outside of the submitted work. CID has received an International Headache Society research fellowship grant, a Hellenic Neurology Society scholarship, support for travel from Merck Serono, and is a member of the European Headache Federation. AT has received research and consultancy fees from Angelini Pharma, INCiPiT (Italian Network for Paediatric Trials), and Takeda; and has also acted as a Clinical Advisor to Akrivia Health. HA reports personal fees from Lundbeck, Pfizer, and Teva outside of the submitted work. ERT is the current executive director and the past president of the European Migraine and Headache Alliance. HCD received honorariums for participation in clinical trials, contribution to advisory boards or oral presentations from: AbbVie, Lilly, Lundbeck, Novartis, Pfizer, Teva, Weber & Weber, and WebMD. The German Research Council (DFG) and the German Ministry of Education and Research (BMBF) support headache research by HCD. HCD serves on the editorial boards of Cephalalgia, Lancet Neurology, and Drugs. AC is supported by the NIHR Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration, by the NIHR Oxford Health Biomedical Research Centre (grant NIHR203316), and by the Wellcome Trust (GALENOS Project); AC has also received research, educational, and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation, Lundbeck, and Angelini Pharma. MA is a consultant, speaker, or scientific advisor for AbbVie, Amgen, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, Pfizer, and Teva; a primary investigator for ongoing AbbVie and Pfizer trials; and is the past president of the International Headache Society; MA is supported through the Lundbeck Foundation professor grant (R310-2018-3711) and serves as associate editor of the Journal of Headache and Pain, and associate editor of Brain.
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