Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

Abstract

Background: Which medication, if any, to use to prevent the headache of pediatric migraine has not been established.

Methods: We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.

Results: A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.

Conclusions: There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).

Figure 1. Randomization and Follow-up

Among the patients who did not meet the inclusion criteria, the primary reasons for ineligibility included headache frequency (38 patients), score on the Pediatric Migraine Disability Assessment Scale (23 patients), and other medical conditions (15 patients). Among the patients who declined to participate, the primary reasons included concerns about side effects (4 patients), lack of time (3), and other reasons (12 patients). The trial was stopped early for futility on the recommendation of the data and safety monitoring board.

Figure 2. Patients with a_Relative_Reduction of 50% or More in the Number of Headache Days

Shown is the percentage of patients with a relative reduction of 50% or more in the number of headache days in the comparison of the 4-week baseline period with the last 4 weeks of a 24-week trial (primary end point). Results are shown for the primary analysis and two a priori sensitivity analyses to assess the effect of missing data. Sample sizes for the trial groups represent the primary analysis population. For observed data, the population is the subgroup with observed data at week 24.