Preventive Medications in Pediatric Migraine: A Network Meta-Analysis

Abstract

Importance: Pediatric migraine substantially impacts quality of life and academic performance among children and adolescents. Understanding the efficacy and safety of pharmacological interventions for migraine prophylaxis in this population is crucial for developing effective treatment strategies.

Objective: To conduct a comprehensive network meta-analysis to evaluate the efficacy and safety associated with pharmacological treatments for pediatric migraine prophylaxis among pediatric patients with a migraine diagnosis and assess interventions involving various oral pharmacological interventions compared with each other and placebo.

Data sources: PubMed, Embase, and SCOPUS were searched for publications up to September 2023. Search terms and indexing were chosen to encompass relevant studies, focusing on randomized clinical trials in pediatric migraine prophylaxis.

Study selection: Inclusion criteria targeted randomized clinical trials involving pediatric patients with migraine. Studies were selected based on their examination of oral pharmacological interventions. The search yielded an initial 9162 citations.

Data extraction and synthesis: Data extraction adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Five investigators independently extracted study data into a spreadsheet in duplicate. Study-level estimates were calculated, employing a random-effects model for primary and secondary outcomes due to identified heterogeneity. Data analysis was conducted from December 2023 to March 2024.

Main outcomes and measures: The primary outcome was migraine frequency (number of attacks per month). Secondary outcomes included a 50% or greater responder rate, headache duration, headache intensity, and disability (assessed by pediatrics migraine-specific disability tool). Adverse events were also evaluated.

Results: The analysis incorporated 45 trials with 3771 participants. Compared with placebo, pregabalin (ratio of means [RoM], 0.38; 95% CI, 0.18-0.79) and topiramate with vitamin D3 (RoM, 0.44; 95% CI, 0.30-0.65) were associated with reduction in migraine frequency. 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), and amitriptyline (RoM, 0.73; 95% CI, 0.54-0.97) were also associated with reduction in migraine frequency, but these findings were drawn from individual studies. For the 50% or greater responder rate, flunarizine and α-lipoic acid (risk ratio [RR], 8.73; 95% CI, 2.44-31.20), flunarizine (RR, 4.00; 95% CI, 1.38-11.55), pregabalin (RR, 1.88; 95% CI, 1.13-3.14), and cinnarizine (RR, 1.46; 95% CI, 1.04-2.05) were associated with significantly greater effectiveness than placebo. 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), and cinnarizine (RoM, 0.64; 95% CI, 0.54-0.76) were significantly associated with reduction in headache intensity. However, no treatments were associated with significant improvements in quality of life or reduction of the duration of migraine attacks. Adverse events were higher with 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) compared with placebo.

Conclusions and relevance: In this network meta-analysis of randomized clinical trials, topiramate and pregabalin were associated with reduction in headache frequency and intensity. Although there were also other drugs that showed statistically significant results (flunarizine, riboflavin, amitriptyline, and cinnarizine), more studies were required for a robust conclusion. None of the drugs were associated with improved quality of life or attack duration, underscoring the need for further research to develop more comprehensive treatment strategies and explore the potential of combination therapies, especially those involving vitamins. Future studies should focus on validating these findings and expanding the treatment landscape for pediatric migraine management.

Figure 1.. Association of Treatment With Headache Frequency

Forest plot (A) and network graph (B) displaying the comparative efficacy of various treatments in reducing the frequency of migraine attacks in pediatric patients. The data includes the ratio of means (RoM) for each treatment compared with placebo, calculated using a random-effects model due to heterogeneity (I² = 67.6%). Significant reductions were observed with pregabalin, topiramate with vitamin d3, flunarizine, levetiracetam, riboflavin, cinnarizine, and amitriptyline. The analysis was based on 37 studies^{,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,} with 2617 patients. Visual inspection of funnel plots and Begg test confirmed no significant publication bias. 5-HTP indicates 5-hydroxytryptophan.

Figure 2.. Association of Treatment With 50% or Greater Responder Rate

Forest plot (A) and network graph (B) displaying treatments achieving at least a 50% reduction in headache frequency, defined as the number of patients with at least 50% headache frequency reduction after treatment compared with baseline. Risk ratios (RRs) were calculated using a random-effects model due to significant heterogeneity (I² = 70.2%). Flunarizine with α-lipoic acid (ALA), flunarizine alone, pregabalin, and cinnarizine showed significant efficacy compared with placebo. Data were derived from 29 studies^{,,,,,,,,,,,,,,,,,,,,,,,,,,,,} involving 2801 patients. No significant publication bias was detected through funnel plot analysis and Begg test.

Figure 3.. Association of Treatment With Headache Intensity

Forest plot (A) and network graph (B) displaying treatments that were associated with a significant reduction of the self-reported intensity of headaches. Ratio of means (RoM) values were calculated using a random-effects model (I² = 43.5%). Effective treatments included propranolol with cinnarizine, pregabalin, valproate, levetiracetam, and cinnarizine. The analysis incorporated 19 studies.^{,,,,,,,,,,,,,,,,,,} Visual inspection of funnel plots and Begg test indicated no significant publication bias.

Figure 4.. Association of Treatment With Quality of Life

Forest plot (A) and network graph (B) displaying the association of various treatments with quality of life, measured using the Pediatric Migraine Disability Assessment tool. Despite evaluating multiple treatments across 13 studies,^,,,,,,,,,,,, none showed significant improvements in quality of life compared with placebo. The analysis faced limitations due to the small number of studies per treatment. RoM indicates ratio of means.

Figure 5.. Association of Treatment With Headache Duration

Forest plot (A) and network graph (B) displaying the effect of treatments on the duration of migraine attacks. Data from 17 studies^{,,,,,,,,,,,,,,,,} covering 15 different treatments showed no significant reduction in headache duration for any of the treatments compared with placebo. Funnel plot analysis and Begg test confirmed no significant publication bias. RoM indicates ratio of means.