The use of anti-epileptic drugs in prevention of migraine in children and adolescents

Many studies have investigated the efficacy and safety of anti-epileptic drugs (AEDs) in adulthood migraine prophylaxis. Divalproex sodium with the mixture of sodium valproate and valproic acid, topiramate, and sodium valproate are the only recognized AEDs with the high levels of efficacy by guidelines of the American Academy of Neurology/American Headache Society (Level-A drugs) (1,2). Divalproex sodium and topiramate were also the first US Food and Drug Administration (FDA) approved medications for the prevention of adulthood migraine (3). Migraine in children and adolescents, however, remained under-appreciated in studies. The safety and efficacy of few drugs were assessed in randomized clinical trials (RCTs). Topiramate was the only US FDA-approved preventive migraine medication for the pediatric population, but a recent multi-center population-based study showed that its efficacy was similar to placebo (4). A few small, sample-sized RCTs investigated the safety and efficacy of divalproex sodium, sodium valproate, and levetiracetam in migraine prophylaxis of children and adolescents (5–7). Non-controlled studies also assessed the efficacy of zonisamide, gabapentin, and pregabalin in prevention of migraine in a pediatric population (8). Conducting high-quality studies is, therefore, essential to find the most appropriate preventive medications for migraine in children and adolescents.

Different adverse events were identified for broad spectrum AEDs. The teratogenic effects of topiramate (category D) and sodium valproate (category X) are scientific facts among medical doctors that they have mostly not explained in detail in original papers. Pregnant women with migraine should avoid using these drugs, but no protocol for using contraception was explained in the methods of popular studies (4).

In this context, we read the recent letter to the editor (9) about our published clinical trial investigating the safety and efficacy of sodium valproate, cinnarizine, and placebo in the prevention of migraine in children and adolescents (10). Our study showed that there was no statistical difference between sodium valproate and cinnarizine compared to placebo, regarding safety profile, and we reported this observation. Sodium valproate was extremely effective in the reduction of migraine frequency in some of our cases. Nine individuals (three females and six males) were migraine-free after 12 weeks of treatment with sodium valproate. Furthermore, three young females with 13 migrainous episodes at baseline had one or two mild migraine attacks after 12 weeks of treatment. As was clearly explained, pregnancy was an exclusion criterion in our trial. A urine pregnancy test was performed at the baseline (phase 1) of the study. In the conclusion section of the full text, cinnarizine was compared to sodium valproate: “Cinnarizine could be considered as a new preventive option especially for long-term treatment of pediatric migraine, particularly in females”. We understand the concerns of authors, as the use of sodium valproate in pregnant females is associated with increased risk of neural tube defects, cleft lip and palate, cardiovascular abnormalities, and developmental delay in their infants. This was the reason that we excluded pregnant females at the initial step. The need for using contraception was also explained to our young females who participated in the study.

As no definite pharmaceutical treatment has been introduced to decrease the frequency and severity of migraine episodes in children and adolescents, using medications that are safe and effective in adults can be one option to decrease the burden of this condition in children and adolescents too. Close follow-ups and consideration of the contraindications are essential to decrease the risk of any harm for individuals.