By Devorah Segal, MD, PhD
Assistant Professor of Clinical Pediatrics, Division of Child Neurology, Weill Cornell Medical College
Dr. Segal reports no financial relationships relevant to this field of study.
SYNOPSIS: In a randomized, double-blind, placebo-controlled trial of migraine prophylaxis in children ages 8-17 years, treatment with neither amitriptyline nor topiramate showed significant differences in headache frequency or headache-related disability compared to placebo.
SOURCE: Powers SW, Coffey CS, Chamberlin LA, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med 2016; Oct 27 [Epub ahead of print] DOI: 10.1056/NEJMoa1610384.
Migraines are a common health problem in children, with a prevalence of about 3% in pre-school-aged children and rising to up to 23% in adolescents. Six million children in the United States suffer from migraines, with about 1% of children meeting criteria for chronic migraines. Despite these high numbers, there are currently no medications approved by the Food and Drug Administration (FDA) for prevention of migraines in children younger than 12 years of age, and there have been few high-quality studies available to guide treatment decisions. Therefore, pediatric neurologists must rely on data from trials in adults and on general consensus when treating these children.
The Childhood and Adolescent Migraine Prevention (CHAMP) trial was designed to test amitriptyline and topiramate against each other and against placebo to assess the effect of each in the preventive treatment of migraine in children. Amitriptyline and topiramate were selected based on a survey of pediatric headache specialists showing that these were the two most commonly prescribed medications used to prevent migraines in children. This was a Phase III, multicenter trial with patients enrolled at 31 sites across the United States. Subjects were assigned to one of three arms in a 2:2:1 ratio of amitriptyline, topiramate, and placebo, respectively. The study was funded by the NIH with no industry contribution. The primary endpoint was at least a 50% reduction in headache frequency in a 28-day period. Secondary endpoints were decreased disability as measured by a Pediatric Migraine Disability Assessment (PedMIDAS) score, absolute number of headache days in a 28-day period, number of trial completers, and adverse events. Interim analyses were scheduled to assess for futility.
Patients eligible for the study were 8-17 years old and carried a diagnosis of migraine with or without aura. To qualify, patients completed a baseline 28-day headache diary that showed at least four migraines during that period. They also completed a baseline PedMIDAS survey and had a score of 11-139, indicating mild to severe disability due to migraines. There were no significant differences among groups with respect to age, sex, race, baseline PedMIDAS score, or number of headache days during the baseline 28-day period. As expected, more girls than boys were recruited across all treatment arms.
Initially, medications were escalated over eight weeks to target doses of 1 mg/kg/day of amitriptyline and 2 mg/kg/day of topiramate, followed by a 16-week maintenance phase and then a two-week weaning phase. Subjects then completed a 28-day follow-up period in which they again maintained a headache diary and completed a PedMIDAS survey. During the treatment phase, adherence was measured by testing blood levels of the active medications. At the time of the interim assessment, 361 patients had been randomized, with 144 assigned to amitriptyline, 145 to topiramate, and 72 to placebo, and the majority of patients had endpoint data available. Statistical analysis at that time showed no difference among the three groups regarding the primary endpoint, with nearly two-thirds of patients in each group experiencing a 50% decrease in headache days. Secondary endpoints of headache disability (PedMIDAS score), number of headache days, and completion of trial also were not significantly different among the three groups. Adverse events were generally manageable in all three groups, with fatigue more common in the amitriptyline group and paresthesias in the topiramate group. A small number of serious adverse events (syncope and altered mood) were reported in the amitriptyline and topiramate groups. Notably, each group had patients who became headache free during the study, and most patients in each arm achieved headache disability in the mild range. All patients are being followed for 36 months, and the authors reported at the recent Child Neurology Society Annual Meeting that most patients continue to exhibit a sustained response.
COMMENTARY
This study is remarkable because of the rarity of large, double-blind, placebo-controlled studies of neurological disorders in children, particularly of headaches. Previous studies have suggested a large placebo effect in migraine treatment, and this study was designed taking that into account. The results of this trial, with no differences among the three arms, again highlights an enormous placebo effect in treating migraines in children. However, it also indirectly highlights the importance of non-pharmaceutical approaches to treating headaches. Notably, all study participants received guidance on healthy lifestyle choices (such as sleep hygiene, appropriate diet, and hydration) that have been associated with better headache control. Another study from the same group1 demonstrated that treating frequent migraines with amitriptyline together with cognitive behavioral therapy (CBT) had better results than amitriptyline plus “placebo” headache education therapy. Putting those earlier findings in the context of the current study suggests that CBT and related behavioral treatment strategies are more effective than medication in preventing migraines and their associated disability.
Rather than being disheartened by the apparent lack of efficacy of our most commonly used preventive medications, this study provides an opportunity for pediatric neurologists to emphasize to children and their parents that taking a daily pill is not sufficient or perhaps even necessary to achieve long-lasting headache control. Rather, a multi-modal and multidisciplinary approach is needed, one that helps children take control of their migraines by modifying lifestyle risk factors and learning to modulate their own responses to pain.
REFERENCE
- Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: A randomized clinical trial. JAMA 2013;310:2622-2630.
In a randomized, double-blind, placebo-controlled trial of migraine prophylaxis in children ages 8-17 years, treatment with neither amitriptyline nor topiramate showed significant differences in headache frequency or headache-related disability compared to placebo.
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