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Use of Topiramate in Preventing Pediatric Migraine

Use of Topiramate in Preventing Pediatric Migraine

Clinical Experience

Since 2002, over two dozen studies have been published describing the use of topiramate in children with migraines. These include observational and retrospective studies, as well as randomized, blinded placebo-controlled, dose-ranging, and comparison trials. A 2008 meta-analysis of pediatric migraine prophylaxis studies identified topiramate as one of only two drugs with adequate evidence to demonstrate its efficacy in the pediatric population.

Three placebo-controlled studies have shown the benefit of topiramate in reducing migraine frequency. In 2005, Winner and colleagues randomized 162 children, ages 6–15 years, with migraines to receive topiramate or placebo. Topiramate was initiated at 15 mg once daily and titrated to a final dose of 2–3 mg/kg/day over 8 weeks (maximum dose 200 mg/day). The final dose was then maintained for another 12 weeks. Migraine frequency decreased by a similar degree in the two groups, with a mean reduction of 2.6 migraines/month in the topiramate group and 2.0 in the placebo group (p = 0.061). There was a significant difference, however, in the percentage of patients experiencing a reduction in migraines of 75% or greater (32% of the topiramate patients versus 14% of controls, p = 0.02). There was no difference between the groups in the discontinuation rate due to lack of efficacy or adverse effects.

A second placebo-controlled topiramate trial enrolled 44 children with migraines between the ages of 8 and 14 years. Children in the topiramate group received an initial dose of 25 mg, with weekly titration by 25 mg-increments as needed to a maximum of 100 mg/day (given as 50 mg twice daily). This was followed by a 12-week maintenance phase. The mean reduction in migraine frequency in the topiramate group (from 16.14 + 9.35 events per month at baseline to 4.27 + 1.95 at completion) was significantly greater than that in the placebo group (13.38 + 7.78 to 7.48 + 5.94, p = 0.025). The number of patients with a 50% or greater reduction in migraine frequency was also significantly higher in the treatment group (95.2% compared to 52.4% of controls, p = 0.002). There were no differences in migraine severity or duration, or in the number of rescue medications needed.

Impact on quality of life, as assessed by the Pediatric Migraine Disability Assessment Scale (PedMIDAS) was reduced by topiramate use. Children in the treatment group had a mean reduction in PedMIDAS score from 50.7 + 32.1 to 10.4 + 6.4 by the end of 4 months, while the placebo group decreased from 42.7 + 27.5 to 23.7 + 19.1 in the controls. School absenteeism was also significantly improved in the topiramate group, falling from 4.04 days/month at baseline to 0.38 days/month at 4 months, compared to the placebo group, where the baseline rate of 0.04 days/month had increased slightly to 0.38 days/month at 4 months (p = 0.002).

In 2009, Lewis and colleagues reported the results of a placebo-controlled topiramate study in 103 adolescents (12–17 years of age) with migraines. The patients were randomized to receive topiramate, at a dose of 50 mg or 100 mg, or placebo for 16 weeks. The number of patients achieving a 50% or greater reduction in migraine frequency was 83% in the 100 mg/day group, 46% in the 50 mg/day group, and 45% in the placebo group (p = 0.002 for the 100 mg/day group and p = 0.957 for the 50 mg/day group). The patients receiving 100 mg/day had a significantly greater percent reduction in monthly migraine rate compared to placebo (median 72.2% versus 44.4%, p = 0.016). In addition, more than half of patients in the 100 mg/day group were migraine-free during the last 4 weeks of the study. None of the other outcome measures for the 50 mg/day group were significantly different from placebo. Six subjects withdrew because of adverse effects, including fatigue in two patients, and nervousness, emotional lability/depression, renal stones, and hypokalemia each in one patient. The mean weight change from baseline was 1.7 + 3.8%, -0.1 + 3.0%, and -0.6 + 5.2% for the placebo, 50 mg/day, and 100 mg/day groups, respectively. No patient had a weight change of more than 10% from baseline.

In all three trials, one or more outcome measurements related to migraine frequency showed a significant improvement from baseline in the patients who received a placebo. This high rate of placebo response has also been observed in studies of acute migraine treatments, particularly in those conducted in children and adolescents. A meta-analysis of 13 pediatric acute migraine studies found a pooled placebo response rate of 46%.

Topiramate has been compared to amitriptyline, sodium valproate, and flunarizine, a calcium channel blocker with histamine (H) blocking properties available in other countries but classified as an orphan drug in the United States. In each of the three comparison studies, topiramate was found to produce a reduction in headache or migraine frequency equivalent to the comparator.

In 2013, Sezer and colleagues conducted a pilot study comparing topiramate to amitriptyline in children with chronic daily headaches. The authors randomized 57 children between 9 and 16 years of age to receive either amitriptyline 0.5 mg/kg/day or topiramate 25 mg/day initially, with titration up to 100 mg/day. After 4 months, 55% of the children given amitriptyline and 61% of those given topiramate had achieved a 50% or greater reduction in headache frequency. The number of children who were headache-free (defined as having no events in one month or more) was also similar between the groups: 28% and 31%, respectively. Adverse effects were mild, 10% of patients receiving amitriptyline and 7% of those receiving topiramate reported drowsiness, nervousness, or dizziness. No patients withdrew because of adverse effects. The mean weight change was +1.8 kg with amitriptyline and –1.1 kg with topiramate.

A multicenter study is currently underway to compare the effectiveness of topiramate, amitriptyline, and placebo in children and adolescents with migraine. The CHAMP study, sponsored by the National Institute of Neurological Disorders and Stroke and National Institutes of Health, will enroll 675 children between 8 and 17 years of age at 40 centers throughout the United States. The drugs will be titrated over an 8-week period to a target dose of 2 mg/kg/day for topiramate and 1 mg/kg/day for amitriptyline, then continued for a total of 24 weeks. The primary outcome measures will be the percentage of patients with a 50% or greater reduction in migraine frequency between the end of titration and the final 28 days of treatment and the mean change in PedMIDAS scores.

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