Topiramate in the prevention of pediatric migraine: literature review

We found two RCTs, a post-hoc subset analysis of 51 adolescents (12–17 years) who had been enrolled in three pivotal RCTs of topiramate for migraine prophylaxis in adults and two open studies.

In a recent Class I randomized, double-blind, placebo-controlled trial [10], 44 children were randomized (in a 1:1 ratio) to receive either placebo or topiramate (titrated to 100 mg a day) for 12 weeks. Participants had a diagnosis of migraine without aura (according to 2004 International Headache Society criteria) [11] and a frequency of two or more headaches per month for 3 months before entering the study. Children with comorbid medical associations or who were already on migraine prophylaxis were excluded. Primary outcome measures were the reduction in migraine frequency and severity; secondary outcome measures included number of analgesics taken and the functional disability. Migraine monthly frequency decreased from 16.14 (±9.35) at baseline to 4.27 (±1.95) at the end of the study in the treated group as compared with a decrease from 13.38 (±7.78) to 7.48 (±5.94) in the placebo group (P = 0.025). The percentage of topiramate-treated subjects showing >50% reduction in monthly migraine days during the double-blind phase was 95.2% as opposed to 52.4% in the placebo group (P = 0.002). The Pediatric Migraine Disability Assessment Score (PedMIDAS) also decreased significantly (P = 0.003) as did school absenteeism (P = 0.002). Side effects were rated mild to moderate, did not interfere with daily activities or cause any dropouts and included weight-loss (mean loss of 0.3 kg) in 81% of patients, paresthesia (23.8%), loss of appetite (23.8%), lack of concentration (19%), sedation (19%) and abdominal pain (14.3%). This seems a well-performed trial in which the mean monthly migraine frequency reduction is clearly evident in the topiramate-treated group. Patients treated with topiramate suffered at least five episodes a month before entering the study (range 5–30); a preventive treatment was, thus, clearly indicated. The reduction in the PedMIDAS score indicates that the drug side effects (difficulties in concentrating, sedation) interfered with school, household or social activities to a lesser extent than the migraine episodes.

The other Class I, randomized, double-blind, placebo-controlled trial [12] was carried out on 162 children (age 6–15 years) who were randomized in a 2:1 ratio to receive either topiramate (which was titrated over 8 weeks to 2–3 mg/kg per day and maintained for 12 weeks) or placebo. Eligible criteria were the children with migraine with or without aura, weighing more than 20 kg, who experienced 3–10 migraine days/month for the 3 months prior to the screening and during the 4-week prospective baseline phase. Exclusion criteria included chronic migraine, analgesic overuse and previous failure of ≥2 adequately dosed migraine preventive medications. One hundred and fifty-seven subjects were included in the intention to treat (ITT) population, defined as randomized subjects who had received at least one dose of study medication and had at least one postbaseline efficacy assessment, and a total of 131 children completed the study (per-protocol population); of these, 108 were treated with topiramate. Primary outcome measure was the reduction of migraine days per month in each treatment group of the ITT population. During the double-blind-phase, relative to the 4-week prospective baseline phase, there was a reduction of 2.6 ± 2.6 migraine days per month in the topiramate group compared with a mean reduction of 2.0 ± 3.1 migraine days per month in the placebo group (P = 0.061). In the per-protocol population, the reduction in monthly migraine days (2.8 ± 2.4 as opposed to 2.2 ± 2.1 in the placebo group) reached statistical significance (P = 0.033). During the last 28 days of treatment, the mean number of monthly migraine was reduced by 3.1 ± 2.6, as opposed to 2.4 ± 2.8 in the placebo group (P = 0.023). In the treated group, 32% of patients experienced a ≥75% reduction in mean monthly migraine days compared with a 14% reduction in the placebo group (P = 0.02). The dropout rate for adverse events was 6.3% for the topiramate group and 4% for the placebo group. In the treated group, the most common adverse events were anorexia (13%); weight decrease (10.2%), with a mean loss of 1.4 ± 2.6 kg (as opposed to 0.7 ± 3.9 kg in the placebo group); abdominal pain (10.2%); paresthesia (8.3%); and somnolence (8.3%). Serious adverse events occurred in four topiramate-treated patients and included infection (n = 2), severe migraine (n = 1) and suicidal ideation (n = 1).

In this study, the mean monthly migraine frequency reduction seems less evident when compared to the previous study [10], probably because migraine frequency at baseline was lower (range 2–9 in the ITT topiramate population) and children with chronic migraine were excluded. An important aspect is that the reduction is more evident in the last 28 days of treatment, indicating that it may take a few weeks before treatment with topiramate reaches its maximum efficacy.

Winner et al. [13] performed a post-hoc subset analysis on 51 adolescents (12–17 years) who had been enrolled in three pivotal trials of topiramate for migraine prophylaxis in adults. Patients were to have had between 3 and 12 migraine attacks, and no more than 14 headache days per 28 days during the 3 months prior to the screening and during the 4-week prospective baseline phase. Also excluded were patients who overused analgesics or who had failed to respond to two or more adequate prophylactic treatments. Topiramate was administered at the dosages of 50, 100 or 200 mg a day for 26 weeks. When compared to baseline, there was a mean monthly migraine frequency reduction of 46, 63 and 65%, respectively, as opposed to a mean 16% reduction in the placebo group (P = 0.07, P = 0.02, P = 0.04, respectively). The most common adverse events (in the group treated with 100 mg a day) were as follows: paresthesia (38%), upper respiratory tract infections (23%), weight decrease (15%), abdominal pain (15%), anorexia (8%) and somnolence (8%). There were no dropouts in the group treated with topiramate. The incidence of adverse events was higher in the group treated with topiramate at the dosage of 200 mg, which did not appear to confer additional efficacy as opposed to the dosage of 100 mg a day.

One class IV study [14], assessing the efficacy of topiramate for pediatric migraine, included 97 children, 75 of which were reevaluated at a first follow-up visit (after 88.7 ± 35.7 days) and 41 at a second follow-up visit (after 203.1 ± 45.6 days). Included were children reporting more than three headaches per month. Topiramate was administered at the dose of 1.4 ± 0.74 mg/kg/day and headache frequency decreased from 16.5 ± 10 headaches/month to 11.6 ± 10.2 headaches/month (P < 0.001) at the first follow-up visit, with 43.1% of the patients experiencing a 50% or greater reduction in the number of headaches. By the second follow-up visit, headache frequency had decreased to 9.4 ± 8.4, with 56.1% of the patients experiencing a 50% or greater reduction in the number of headaches. Mean headache severity, duration and accompanying disability were also reduced. Disability was measured using the PedMIDAS score: a 50% reduction occurred in 48.6% of the patients at the first follow-up visit and in 62.5% of patients at the second follow-up visit. One quarter of patients complained of side effects, which declined in subsequent visits and included cognitive changes (12.5%), weight loss (5.6%) and sensory symptoms (2.8%). A possible bias of this study is that 50.7% of patients were on additional prophylactic medication (most often amitriptyline or divalproex).

In an open, prospective case series (class IV) study [15], topiramate was administered to 24 children with migraine, who had failed to respond to other prophylactics, at the mean dosage of 3.5 ± 1.7 mg/kg for 4 months. Authors report a reduction in the duration and in the intensity of headaches; headache frequency reduction, however, did not reach statistical significance. Adverse events (emotional instability, paresthesia, anorexia, asthenia, weight loss) were experienced by one-third of patients. In our opinion, the baseline headache frequency (3.6 ± 2.7 a month with a range of 1–12) and duration (2–6 h) did not necessarily constitute an indication for prophylactic treatment in all treated cases.

Unfortunately, the studies we reviewed were not homogeneous with regard to inclusion and exclusion criteria and with regard to outcome measures such as the “responder rate,” which was not considered in all studies. Furthermore, the degree of disability caused by the migraine episodes, which is essential in the decision to initiate prophylactic treatment, was not assessed in all studies.