What's in the pipeline for pediatric headache treatment?

When the Childhood and Adolescent Migraine Prevention (CHAMP) trial was published in 2017,1 it was as if a shadow fell over the landscape of pediatric headache. “Nothing works in kids!” rang the lament. In all three treatment arms (topiramate vs. amitriptyline vs. placebo), approximately two-thirds achieved a ≥50% reduction in headache days. In truth, rather than showing that “nothing works” in children, CHAMP demonstrated that all three of these treatments worked for kids—at least for the two-thirds who got better. No doubt some of the improvement was due to placebo response. However, there were also careful co-interventions in CHAMP that likely contributed to participants' improvement: (1) giving a clear diagnosis of migraine; (2) providing evidence-based acute treatments (non-steroidal anti-inflammatory drugs [NSAIDs] and triptans); (3) regular counseling about sleep, exercise, hydration, and meals2; and (4) counseling about the avoidance of medication overuse.3 Thus, CHAMP participants in all arms were actually given a number of interventions, which worked for many of them. None of the CHAMP participants received no treatment; therefore, providing no treatment is neither an evidence-based nor clinically acceptable approach to migraine prevention in children. It is also important to remember that one-third of CHAMP participants did not improve. In addition, many of the patients who attend pediatric headache and neurology clinics would never have qualified for the CHAMP study in the first place. Exclusion criteria included many things commonly present in patients attending these clinics: presence of continuous headache, medication overuse, already having had an adequate trial of one or both of the commonly used trial medications, having a particularly high Pediatric Migraine Disability Assessment (PedMIDAS) score, and/or the presence of significant psychiatric or medical comorbidities.3 Nevertheless, in the wake of CHAMP, a pall hung over the field for almost a decade. Topiramate had received a United States Food and Drug Administration (FDA) label for migraine prevention in 2014 for 12- to 17-year-olds, becoming the first labeled treatment in this age group. Yet enthusiasm was muted by the CHAMP results. Furthermore, when the joint American Academy of Neurology/ American Headache Society (AAN/AHS) guidelines4 for pharmacologic migraine prevention in children were published in 2019, they emphasized that if prescribing topiramate to patients of childbearing potential, clinicians must counsel about its teratogenicity and potential to reduce efficacy of oral combined hormonal contraceptives at higher doses. The guidelines recommend clinicians should discuss the evidence “for amitriptyline combined with CBT for migraine prevention,” but also inform patients about amitriptyline's side effects, “including risk of suicide”. Propranolol is noted in the guidelines to be “possibly more likely” than placebo to bring about ≥50% reduction in headache attacks, based on one Class III study5 with wide confidence intervals: relative risk [RR] 5.20 (95% confidence interval [CI] 1.59–17.00).4 Overall, the guidelines emphasized counseling about lifestyle factors as well as shared decision-making with patients and caregivers regarding medications, given the potential side effects and limited evidence of benefit over placebo. Beyond the pharmacologic guidelines, several neuromodulation devices have gained FDA clearance for use in children and adolescents. However, the bar for device clearance is generally lower than it is for medication gaining an FDA labeled indication, so insurance coverage for neuromodulation devices, and thus use in clinical practice, has been limited in many cases. Finally, in 2025, the landscape brightened. A randomized, placebo-controlled trial of fremanezumab demonstrated safety and efficacy for migraine prevention in 6- to 17-year-olds with episodic migraine.6 In August 2025, fremanezumab became FDA labeled for episodic migraine prevention in 6- to 17-year-olds, making it the only migraine preventive therapy FDA labeled down to age six.7 Unfortunately, a few months later, we learned that the chronic migraine trial did not demonstrate superiority of fremanezumab over placebo.8 Just as with CHAMP and so many other migraine trials in youth, both groups saw improvement. Fundamentally, this is still good news. Looking forward, there is a tremendous amount of promise on the horizon for both acute and preventive migraine treatment in youth. Results of additional studies might be available as soon as 2026. See Table 1 for insight into how much more there is to come. In the end, all of the above boils down to: What should we do right now in clinical practice to help our patients? For first-line management, the basics of the CHAMP study still apply. We should offer multidisciplinary care2, 4 and access to evidence-based acute medications (NSAIDs and triptans). For those needing preventive therapy—first line options are those that have some evidence for efficacy in migraine prevention, and a side-effect profile similar to placebo (which is distinct from saying no side effects). Supplements, such as riboflavin, and neuromodulation devices for headache likely fall into this category. So too does using the lowest effective doses of prescription preventives with well understood long-term safety profiles, in appropriately selected patients. For example, propranolol, noted above to have some evidence for efficacy for migraine prevention in children and adolescents, has been in clinical use since the 1960s and has been used safely even in infants, where it has demonstrated efficacy for treatment of infantile hemangioma.9 While what we know so far about long term risks of CGRP monoclonal antibodies seems reassuring, there's nothing like 60-plus years of clinical use of a medication to reassure parents and clinicians that nothing is going to surprise us down the line. The majority of children and adolescents will benefit from the above treatments. For the rest, particularly those children and adolescents who have significant headache-related disability, escalating therapy to newer and traditionally “second line” agents is entirely reasonable. In our practice, as long as there are safety data, we will continue to treat aggressively with both medication and non-medication approaches, not restricting to what is “on label.” For what's next in pediatric migraine treatment, keep your eye on the horizon. Amy A. Gelfand: Conceptualization; writing – original draft; writing – review and editing. Christina L. Szperka: Writing – review and editing; conceptualization. The authors have nothing to report. In the past 24 months, Amy A. Gelfand has received royalties from UpToDate (for authorship), and honoraria from Elsevier (for authorship), the American Academy of Neurology (for editing) and the Weill Cornell Neurology Department, Kobenhavns Unversitet, and the College Board (for speaking). She receives a stipend from the American Headache Society for her role as Editor of Headache. She receives grant support from PCORI as a member of the Steering Committee for the REACH study and from the UCSF Resource Allocation Program as an investigator. She is also supported by a generous philanthropic donation made by Nathalie and Nicolas Giauque to the UCSF Child & Adolescent Headache Program. Christina L. Szperka's institution has received compensation for her work as a consultant for AbbVie, Lundbeck, and Teva. She has received personal compensation for serving on data safety monitoring boards for Eli Lilly and Upsher-Smith. She has also received research support from the PCORIs as a member of the Steering Committee for the REACH study.