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

Abstract

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/.

Fig 1

Study selection process. *See supplementary appendix table S2 for full list

Fig 2

Network plots of eligible direct comparisons for primary and secondary efficacy outcomes and any serious adverse events. Line width is proportional to the number of trials comparing each pair of treatments. Node size is proportional to the number of randomised participants

Fig 3

Network plots of eligible direct comparisons for six specific non-serious adverse events considered most important by clinician and patient representative panels. Line width is proportional to the number of trials comparing each pair of treatments. Node size is proportional to the number of randomised participants. See supplementary appendix 5 for network plots of the remaining specific adverse events

Fig 4

Network meta-analysis for efficacy of drugs (in alphabetical order) for the acute treatment of migraine (freedom from pain, sustained pain freedom, pain relief, and use of rescue drugs). Comparisons should be read from left to right. Comparative estimates (reported as odds ratios with corresponding 95% confidence intervals) are located at the intersection between the treatment defined by the column and the treatment defined by the row. Bottom left rectangle: For pain freedom and sustained pain freedom from two to 24 hours, estimates >1 favour the treatment defined by the column. Top right rectangle: for pain relief, estimates >1 favour the treatment defined by the row. For use of rescue drugs, estimates <1 favour the treatment defined by the row. Emboldened numbers represent estimates where the confidence interval is either >1 or <1. Certainty of the evidence (according to confidence in network meta-analysis (CINeMA)) for the two primary outcomes is presented: *=high certainty of evidence; †=moderate certainty of evidence; ‡=low certainty of evidence; §=very low certainty of evidence. ASA=acetylsalicylic acid; ALM=almotriptan; CEL=celecoxib; DIC=diclofenac potassium; ELE=eletriptan; FRO=frovatriptan; IBU=ibuprofen; LAS=lasmiditan; NAP=naproxen sodium; NAR=naratriptan; PAR=paracetamol; PHE=phenazone; RIM=rimegepant; RIZ=rizatriptan; SUM=sumatriptan; UBR=ubrogepant; ZOL=zolmitriptan

Fig 5

Network meta-analysis for adverse events (dizziness, fatigue, nausea, and sedation) associated with drugs (in alphabetical order) for the acute treatment of migraine. Comparisons should be read from left to right. Comparative estimates are located at the intersection between the treatment defined by the column and the treatment defined by the row. Data are presented as odds ratio with corresponding 95% confidence intervals. Bottom left rectangle: for dizziness and nausea, estimates <1 favour the treatment defined by the column. Top right rectangle: for sedation and fatigue, estimates <1 favour the treatment defined by the row. Emboldened numbers represent estimates where the confidence interval of the comparative estimate is either >1 or <1. ASA=acetylsalicylic acid; ALM=almotriptan; CEL=celecoxib; DIC=diclofenac potassium; ELE=eletriptan; FRO=frovatriptan; IBU=ibuprofen; LAS=lasmiditan; NAP=naproxen sodium; NAR=naratriptan; PAR=paracetamol; PHE=phenazone; RIM=rimegepant; RIZ=rizatriptan; SUM=sumatriptan; UBR=ubrogepant; ZOL=zolmitriptan

Fig 6

Vitruvian plots of each active intervention (in alphabetical order) compared with sumatriptan (reference drug) across key outcomes. Efficacy is reported in the bottom wedges by four outcomes: freedom from pain at two hours, sustained pain freedom from two to 24 hours, pain relief at two hours, and use of rescue drugs from two to 24 hours. Tolerability is reported in the lateral and top wedges by the specific adverse events of chest pain or discomfort, dizziness, fatigue, nausea, paraesthesia, and sedation. Colour indicates the relative performance of the intervention of interest and the precision of the estimate in comparison with sumatriptan (reference drug), from green (the intervention is better than sumatriptan), to yellow (unclear whether the drug performs better or worse than sumatriptan), and to red (the intervention is worse than sumatriptan). The more precise the estimate is, the more intense the colours. Estimated event rates are expressed as absolute percentages. The wedge titles are coloured to indicate availability of data for the analyses (if no data are available for the analyses, the wedge titles are white (ie, without any colour)). Supplementary appendix 10 provides further details, including vitruvian plots with ibuprofen or placebo as the reference intervention

Fig 7

Continued: Vitruvian plots of each active intervention (in alphabetical order) compared with sumatriptan (reference drug) across key outcomes. Efficacy is reported in the bottom wedges by four outcomes: freedom from pain at two hours, sustained pain freedom from two to 24 hours, pain relief at two hours, and use of rescue drugs from two to 24 hours. Tolerability is reported in the lateral and top wedges by the specific adverse events of chest pain or discomfort, dizziness, fatigue, nausea, paraesthesia, and sedation. Colour indicates the relative performance of the intervention of interest and the precision of the estimate in comparison with sumatriptan (reference drug, blue), from green (the intervention is better than sumatriptan), to yellow (unclear whether the drug performs better or worse than sumatriptan), and to red (the intervention is worse than sumatriptan). The more precise the estimate is, the more intense the colours. Estimated event rates are expressed as absolute percentages. The wedge titles are coloured to indicate availability of data for the analyses (if no data are available for the analyses, the wedge titles are white (ie, without any colour)). Supplementary appendix 10 provides further details, including vitruvian plots with ibuprofen or placebo as the reference intervention