A comprehensive network meta-analysis of 45 randomized clinical trials involving 3,771 pediatric patients revealed new insights into the efficacy of preventive medications for migraine in children and adolescents.

In the study, published in JAMA Network Open, researchers found that several medications, including pregabalin and topiramate, were associated with significant reductions in migraine frequency and intensity compared with placebo.

The analysis evaluated various oral pharmacological interventions for migraine prophylaxis in patients younger than 18 years. The primary outcome of the study was migraine frequency, defined as the number of attacks per month. Secondary outcomes included a 50% or greater responder rate, headache duration, headache intensity, and disability assessed by the Pediatric Migraine Disability Assessment (PedMIDAS) tool.

Among the key findings were:

• Pregabalin was associated with a 62% reduction in migraine frequency compared with placebo (ratio of means [RoM] = 0.38, 95% confidence interval [CI] = 0.18–0.79).
• Topiramate with vitamin D3 supplementation showed a 56% reduction in migraine frequency (RoM = 0.44, 95% CI = 0.30–0.65).
• Flunarizine and α-lipoic acid demonstrated the highest 50% responder rate (risk ratio [RR] = 8.73, 95% CI = 2.44–31.20).
• Propranolol combined with cinnarizine was associated with a 55% reduction in headache intensity (RoM = 0.45, 95% CI = 0.28–0.72).

Compared with placebo, the following treatments were associated with significant reductions in migraine frequency:

• Pregabalin (RoM = 0.38, 95% CI = 0.18–0.79)
• Topiramate with vitamin D3 (RoM = 0.44, 95% CI = 0.30–0.65)
• Flunarizine (RoM = 0.46, 95% CI = 0.26–0.81)
• Levetiracetam (RoM = 0.47, 95% CI = 0.30–0.72)
• Riboflavin (RoM = 0.50, 95% CI = 0.32–0.77)
• Cinnarizine (RoM = 0.64, 95% CI = 0.46–0.88)
• Topiramate (RoM = 0.70, 95% CI = 0.55–0.89)
• Amitriptyline (RoM = 0.73, 95% CI = 0.54–0.97).

Fifty percent or Greater Responder Rate: Four medications showed significantly higher responder rates compared with placebo:

• Flunarizine and α-lipoic acid (RR = 8.73, 95% CI = 2.44–31.20)
• Flunarizine alone (RR = 4.00, 95% CI = 1.38–11.55)
• Pregabalin (RR = 1.88, 95% CI = 1.13–3.14)
• Cinnarizine (RR = 1.46, 95% CI = 1.04–2.05).

The following treatments were associated with significant reductions in headache intensity compared with placebo:

• Propranolol and cinnarizine (RoM = 0.45, 95% CI = 0.28–0.72)
• Pregabalin (RoM = 0.57, 95% CI = 0.33–0.96)
• Valproate (RoM = 0.60, 95% CI = 0.49–0.72)
• Levetiracetam (RoM = 0.62, 95% CI = 0.50–0.77)
• Cinnarizine (RoM = 0.64, 95% CI = 0.54–0.76).

None of the treatments showed significant improvements in quality of life or reduction in the duration of migraine attacks.

Amitriptyline (RR = 3.81, 95% CI = 1.41–10.32), topiramate (RR = 4.34, 95% CI = 1.60–11.75), and valproate (RR = 5.93, 95% CI = 1.93–18.23) were associated with higher risks of adverse events compared with placebo.

The study employed a comprehensive search strategy, including PubMed, Embase, SCOPUS, and ClinicalTrials.gov, for publications up to September 2023. Inclusion criteria targeted randomized clinical trials involving pediatric patients with migraine, examining oral pharmacological interventions. The initial search yielded 9,162 citations, with 45 trials ultimately included in the analysis.

Data analysis was conducted from December 2023 to March 2024 using a random-effects model because of identified heterogeneity (I2 = 67.6% for the primary outcome). The researchers also conducted a component meta-analysis to evaluate the effect of multicomponent treatments using supplements. This analysis suggested that the addition of vitamin supplementation (vitamin D3 and riboflavin) to pregabalin may elicit a superior response compared with placebo (RoM = 0.12, 95% CI = 0.04–0.30) and pregabalin alone (RoM = 0.31, 95% CI = 0.18–0.54).

Meta-regression analysis did not identify substantially distinct estimates in studies, including patients presenting with aura, using criteria other than the International Classification of Headache Disorders for migraine diagnosis, or based on mean age of participants or sex distribution.

The study had several limitations, including potential differences in baseline values of some outcomes, small sample sizes for some interventions, and substantial heterogeneity in dosages, treatment formats, and reporting methods. Additionally, Iran contributed the highest percentage of participants (42.08%), which may limit generalizability.

This network meta-analysis provided evidence supporting the efficacy of several medications, particularly pregabalin and topiramate, in reducing migraine frequency and intensity in pediatric patients. However, the lack of improvement in quality of life and attack duration highlighted the need for further research to develop more comprehensive treatment strategies. The potential benefits of combination therapies, especially those involving vitamin supplementation, warrant further investigation through larger, randomized clinical trials to confirm these findings and explore new avenues for enhancing care in pediatric migraine management.

The authors declared having no competing interests.