OnabotulinumtoxinA Appears to be Safe and Effective in Pediatric Chronic Migraine, With More Controlled Studies Needed

Serena Orr, MD, MSc, FRCPC

A recently published systematic review and meta-analyses indicated that onabotulinumtoxinA is a safe treatment option for children and adolescents with chronic migraine (CM), with promising efficacy supported by available pediatric data and pivotal adult trials. However, the pediatric data carried a high risk of bias and did not conclusively determine whether onabotulinumtoxinA offers additional therapeutic benefits over placebo injections in this population.¹

After screening 634 studies, the analysis included 14 studies comprising 491 children and adolescents aged less than 18 years with a diagnosis of migraine who were treated with at least 50 units of onabotulinumtoxinA and had outcomes assessed at least 4 weeks after 1 or more injection cycle. Of the studies, 2 were randomized controlled trials (RCTs), 12 were observational uncontrolled studies (5 of which were pooled in meta-analyses), and all but 1 included only youth with CM.

Led by Serena Orr, MD, MSc, FRCPC, an assistant professor of neurology at the University of Calgary, data from the 5 Class IV studies included in the meta-analyses showed that treatment with onabotulinumtoxinA resulted in decreased headache frequency in this patient population, with a large effect size estimate (Hedge’s g = 0.97; 95% CI, 0.58-1.35; P <.0001). In the meta-regression model, neither the number of cycles of onabotulinumtoxinA (ß = –0.49; 95% CI, –2.57 to 1.58; P = .639) nor the use of the PREEMPT protocol (ß = 0.59; 95% CI, –0.61 to 1.78; P = .334) had a significant influence on the effect estimate. For context, 4 of these studies followed the PREEMPT protocol.

Using the same studies, the pooled effect estimate demonstrated that pain severity decreased significantly after treatment with onabotulinumtoxinA (Hedge’s g = 1.24; 95% CI, 0.55-1.94; P = .0005). There was a moderate level of heterogeneity between studies (r2 = 0.56). Similar to the previous analysis, the number of cycles of onabotulinumtoxinA (ß = –0.95; 95% CI, –1.94 to 0.34; P = .058) nor the use of the PREEMPT protocol (ß = 0.69; 95% CI, –0.64 to 2.01; P = .0310) were significant in the meta-regression model.

"Our work highlights the need for an adequately powered RCT comparing onabotulinumtoxinA to placebo injection cycles in children and adolescents with CM,” Orr et al wrote.¹ "More broadly, the inclusion of children and adolescents in pivotal trials that are typically almost always limited to adult participants (such as the PREEMPT trials)12 would increase access to therapies proven to be effective in adults for children and adolescents. Uncontrolled studies, which currently dominate the pediatric onabotulinumtoxinA literature (12/14 included studies), are incapable of establishing intervention efficacy due to high placebo response rates among children and adolescents with migraine."

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There were several studies not included in the meta-analyses, including one Class I study and a Class IV study. In the Class I study, which tested the efficacy of onabotulinumtoxinA in adolescents with CM, all treatment groups, including placebo, showed reductions in headache days; however, no statistically significant differences were observed. Adverse events were mild, such as neck pain and musculoskeletal discomfort, and no severe events were reported. The study’s limitations, including its single injection cycle and underpowered design, highlighted the challenges of demonstrating therapeutic gains over a strong placebo effect in pediatric migraine research.²

A smaller Class IV crossover study further investigated onabotulinumtoxinA in adolescents with CM. This study found significant reductions in headache frequency, pain severity, and migraine-related disability compared to placebo. Despite these promising findings, limitations such as potential patient unblinding, unclear baseline group differences, and early outcome measurement suggest that further research is needed to confirm long-term efficacy and better understand the benefits of repeated treatment cycles in this population.³

Continuing on with the excluded studies, open-label trials, both prospective and retrospective, suggested that onabotulinumtoxinA may reduce headache frequency and severity in adolescents with CM, though the strong placebo effect and selection bias limit conclusions. Prospective studies showed significant reductions in headache frequency and severity, but small sample sizes and uncontrolled designs tempered their findings. Retrospective studies, including those using higher doses or multiple injection cycles, generally reported improvements in headache metrics and responder rates, but results were often biased by dropouts or selective reporting. AEs were typically mild, including local pain and muscle weakness, though one study noted serious migraine-related symptoms. While promising, these studies underscore the need for controlled trials to confirm efficacy and safety over repeated treatment cycles.

REFERENCES
1. Lindsay R, Kalifa A, Kuziek J, et al. The safety and efficacy of onabotulinumtoxinA injections for children and adolescents with chronic migraine: A systematic review and meta-analysis. Headache. 2024;64(10):1200-1216. doi:10.1111/head.14798
2. Winner PK, Kabbouche M, Yonker M, Wangsadipura V, Lum A, Brin MF. A randomized trial to evaluate onabotulinumtoxinA for prevention of headaches in adolescents with chronic migraine. Headache. 2020; 60(3): 564-575.
3. Shah S, Calderon MD, Crain N, Pham J, Rinehart J. Effectiveness of onabotulinumtoxinA (BOTOX) in pediatric patients experiencing migraines: a randomized, double-blinded, placebo-controlled crossover study in the pediatric pain population. Reg Anesth Pain Med. 2021; 46(1): 41-48.