Background
Migraine is the most common cause of headache in pediatric neurology outpatient clinics, and it has been recognized as one of the most prevalent neurological disorder in children and adolescents worldwide, affecting 5–10% of the pediatric population in multiple areas of life. Because patients miss school and social activities, migraines can impair the development of friendships that are vital to social development and self-esteem and may destroy family harmony [
1,
2]. The mean age of onset of migraine is 7.2 years in boys and 10.9 years in girls [
3], and the prevalence of migraine increases with age, as demonstrated by clinical studies. The diagnostic criteria for migraine headaches have developed over time; modern migraine classification includes frequency as a criterion, with episodic headaches occurring up to 14 days per month, and chronic migraine is defined as the persistence of headache without aura for at least 15 days per month and for at least 3 consecutive months without medication overuse (ICHD-II) [
4]. Because of the diversity of symptoms, the diagnosis of migraines in children and adolescents needs to be refined even further. Due to the harm caused by migraines, reducing the number of migraine attacks to the greatest extent possible should be a priority.
At present, a variety of prophylactic therapy options are available to reduce the frequency or severity of headaches [
5]. Topiramate is an antiepileptic drug with positive efficacy and safety for older children and adults with epilepsy [
6], and it has been approved for migraine prevention in adults in Europe since 2003 and in the United States since 2004 [
7]. The exact mechanism of topiramate in the treatment of migraine is unknown, although it may be associated with the influence of topiramate on pain transmission in the trigeminocervical complex and the third-order neurons in the ventroposteromedial thalamus [
8]. Several case series and open-label trials [
9‐
13] have shown that topiramate served as a preventive treatment for pediatric migraines, while the research of Scott W [
14] indicated that there were no significant differences between topiramate and placebo in the prevention of pediatric migraine. Hence, in the present study, we performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of topiramate for the prevention of migraine in patients less than 18 years of age.
Discussion
This meta-analysis examined the efficacy of topiramate in comparison with placebo for the prevention of migraines in patients less than 18 years of age. The IHS guidelines for conducting clinical trials indicate that a clinically meaningful end point in a migraine prevention trial is usually defined by a reduction in the total number of headache attacks in a 28-day period or the proportion of patients with a greater than 50% relative reduction in headache frequency [
22].
Topiramate is a first-line option for the treatment of migraines in adults, and in March 2014, the U.S. Food and Drug Administration (FDA) approved topiramate for migraine prevention in the population aged 12 to 17 [
23]. Moreover, this is the first and only medication currently approved for use in migraine patients 12 years and over. Nevertheless, neither the primary outcome of proportion of patients with a greater than 50% reduction in headache frequency nor the secondary outcome of reduced mean headache days in a 28-day period showed topiramate as more efficacious than placebo in our meta-analysis of four RCTs. According to the definition [
22], topiramate showed no statistically significant benefit over placebo in reducing the number of headache days over the treatment period. In fact, the 50% response rate of the topiramate group in 2 trials [
14,
20] was not statistically significant compared with the placebo group, and in another trial [
18] a similar result was presented for the 50 mg/day topiramate treatment group. The finding conflicts with the outcomes of previous case series and open-label trials. There are at least three possible explanations for this finding. (1) Children tend to have a high placebo response rate, with younger patients in clinical trials demonstrating a greater tendency to respond to placebo. This age-dependent placebo response has ranged from 30% to 70% in migraine studies in general [
24‐
27]. The outcome of our study shows that the average number of patients experiencing a ≥ 50% relative reduction in headache frequency in the placebo group is 50.74% (69/136), which is higher than the rates reported in previous studies of topiramate preventing adult migraine (0–34.2%) [
28‐
31]. Rothner et al. [
32] suggested explanations for the higher placebo response rate in clinical trials with children and adolescents, such as the fact that they could not take medication while at school; “good doctor” effects; and the fact that if their symptoms relieved spontaneously, children and adolescents were more likely than adults to believe that they were receiving a drug that had a definite effect on headache. We speculate that this phenomenon is associated with at least the following factors: 1. Different psychological and neurobiological mechanisms exist in pediatric patients compared with adults. There are at least four psychological mechanisms associated with the placebo response: expectation, conditioning, therapeutic relationship and empowerment [
33]; psychological mechanisms, especially the conditioning and expectation may guide people’s behavior. The differential course of the maturation of different neurotransmitter systems may explain the differences. 2. The characteristics of migraine attacks are different [
34]: migraine headaches in children and adolescents are often bilateral and may be of shorter duration than in adults. 3. Children/adolescents and adults have significantly different cognitive levels. The pain sensation is a highly subjective experience that is influenced by cognitive factors, and placebo analgesia is one of the most striking examples of cognitive regulation of pain [
35,
36]. In addition, the lack of pediatric research and the shortage of experience in experimental design may lead to different outcomes. In short, the topic of the difference about placebo response between children/adolescents and adults deserves further discussion. (2) The minimum age at which topiramate was approved for treatment of migraine was 12 years old, but the minimum age of patients in the included trials was 8 years. It is often difficult to calculate the attacks of headache in younger children accurately, and the guardians generally interpret the attacks indirectly from the child’s activity level [
19]. (3) Our included patients included those with either episodic or chronic migraine [
14], which may influence the results of our meta- analysis.
The second finding of our meta-analysis is that topiramate decreased PedMIDAS scores in migraine patients. PedMIDAS is often used to measure disability related to school absences and functioning, home functioning, and social absences and functioning [
16]. This finding, which contradicts our first finding, may indicate that headache-related disability is alleviated by topiramate. However, mean PedMIDAS scores in both the topiramate group and the placebo group decreased between baseline and endpoint, and the fact that only two trials [
14,
19] used this tool as a trial assessment may be the cause of the heterogeneity.
As with all antiepileptic drugs, topiramate has many potential side effects or adverse events, some of which may be serious and life-threatening [
37]. The rate of adverse events in patients treated with topiramate was higher than that with placebo in our included trials. It has been reported that metabolic acidosis, renal calculi and nervous system effects, such as fatigue or somnolence, paresthesia, dizziness and cognitive disorder or aphasia, occurred in adults and pediatric patients taking topiramate in previous trials. Other adverse events, such as changes in visual acuity, including visual field deficits, acute myopia and secondary closed angle glaucoma, have also been reported. In addition, topiramate (100 mg/day) was related to modest increases in psychomotor reaction times [
38]. Another more serious problem is the potential for suicidal behavior and ideation that has been observed in people taking antiepileptic drugs, including topiramate [
39]. Thus, while the pathomechanism of migraine is not completely understood, the choice of medication for personalized therapy tailored to each patient needs to be made cautiously [
40].
Some limitations in our meta-analysis must be acknowledged. First, because our analysis was limited to articles in the English language literature, we may have omitted some evidence. The secondary limitation is related to the data that we acquired from the four included trials. Three of the trials reported the baseline and follow-up data [
14,
18,
19], and one reported baseline and change data [
20]. We combined the follow-up and change data according to the research of da Costa, B. R [
41]. In addition, one trial compared more than 1 dose [
18]; it is likely that dose-finding pharmacologic studies are underrepresented and that additional unpublished industry trials exist. These situations might have resulted in ecological bias. Third, our data had obvious heterogeneity, and none of the variables we abstracted explained this variation. Because we only included four trials and because only three measurements were used in our study, therefore, our findings should be interpreted with caution. The variability in the selection criteria for RCTs and sample size, along with the incomplete reporting of intervention intensity, may also be limitations.