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Reference – N Engl J Med 2016 Oct 27 early online (level 2 [mid-level] evidence)
- Several medications, including amitriptyline or topiramate, are used to prevent headaches in adults with migraine; however, evidence regarding the safety and efficacy of these agents in children and adolescents with migraine is limited.
- In an analysis of 361 children or adolescents with migraine randomized to amitriptyline, topiramate or placebo for 24 weeks, there were no significant differences in the proportion of patients with ≥ 50% reduction in headache frequency, mean reduction of headache days, or improvement in severity of migraine disability comparing each active treatment to placebo.
- Sixty-one percent of patients on placebo experienced at least a 50% reduction in headache frequency.
The American Academy of Neurology does not make any recommendations regarding the use of amitriptyline or topiramate for reducing headache frequency in children or adolescents with migraine due to limited evidence concerning their safety and efficacy in this population (Neurology 2004 Dec 28;63(12):2215). The results from two previous randomized trials have suggested a benefit with topiramate compared to placebo in reducing frequency of migraine in children and adolescents, but both of these were small (Pediatrics 2009 Mar;123(3):924, J Child Neurol 2007 Jul;22(7):829) and in a third trial, the primary efficacy outcome did not show a statistically significant favorable effect for topiramate while some other measures did (Headache 2005 Nov-Dec;45(10):1304). A possible benefit for amitriptyline has also been suggested, but this is based on two uncontrolled studies (Headache 2004 Mar;44(3):230, Headache 2000 Jul-Aug;40(7):539). In the largest trial to date to determine whether either of these medications can reduce headache frequency in the pediatric population, 361 children or adolescents with migraine (mean 11 days of headache per 28 days at baseline) were randomized to amitriptyline 1 mg/kg/day, topiramate 2 mg/kg/day, or placebo for 24 weeks in a double-blind controlled trial. Efficacy outcomes were based on differences between the last 4 weeks of treatment and the 4-week baseline period.
This trial planned to enroll 675 patients, but was terminated early when predefined criteria for futility were met. There were no significant differences in proportion of patients with a ≥ 50% reduction in headache frequency comparing each active treatment to placebo (52% with amitriptyline, 55% with topiramate, and 61% with placebo). There were also no significant differences compared to placebo in reduction in mean number of headache days per 4-week period (-6.7 with amitriptyline, -6.7 with topiramate, and -5.9 with placebo) or improvement in migraine disability scores (mean disability scores improved from moderate to mild in all groups). Serious adverse events were observed during the trial, with one suicide attempt in the topiramate group, and three patients with serious alterations in mood and one with syncope in the amitriptyline group. Adverse events which were significantly increased compared to placebo included fatigue and dry mouth in the amitriptyline group and paresthesia and weight loss in the topiramate group.
The results of this trial suggest that reduction in headache frequency in children and adolescents with migraine is similar among amitriptyline, topiramate, and placebo, and that amitriptyline and topiramate are each associated with an increased risk of adverse events. The placebo-response rate was high, as anticipated by the authors and as commonly observed in pediatric migraine trials (JAMA Pediatr 2013 Mar 1;167(3):243). Given the large placebo effect and the increased risk for adverse events associated with the active treatments, these data do not support the use of amitriptyline or topiramate for headache prevention in children or adolescents with migraine.
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