Advances in topiramate as prophylactic treatment for migraine

Abstract It is well‐known that topiramate as a kind of antiepileptic drug has been proved effective for migraine prevention in North America and Europe. However, topiramate is still viewed as an off‐label medication for migraine treatment in China, partly because of the limited evidence in Chinese patients. We summarize the effects of topiramate on the frequency, severity, quality‐of‐life, and adverse event among migraine patients, including children and adolescent in this review, so as to provide reference for Chinese doctors.

for Chinese neurologists, especially headache specialists, in TPM prescriptions.

MECHANISMS OF TOPIRAMATE ON MIGRAINE PREVENTION
TPM was first discovered in 1979 as an intermediate in studies of the treatment of diabetes. It was found to be structurally similar to acetazolamide, a weak carbonic anhydrase isoenzyme inhibitor, that selectively inhibited carbonic anhydrase isoenzymes II and IV (Dodgson et al., 2000). The pathogensis of carbonic anhydrase inhibition in migraine prophylaxis remained unclear, but preclinical studies demonstrated that TPM acts at multiple molecular targets to enhance neuronal inhibition and decrease neuronal excitation (DeLorenzo et al., 2000;Gibbs et al., 2000;McLean et al., 2000;Shank et al., 2000;Skradski & White, 2000;White, 2005;White et al., 1997;Zhang et al., 2000). From many previous studies of animal seizure models in rat and mice, we known that TPM blocks voltage-activated Na + (DeLorenzo et al., 2000;McLean et al., 2000) and high-voltage-activated calcium channels (Zhang et al., 2000) modulates voltage-gated K + channels to prevent the propagation of action potentials and reduce persistent membrane depolarization (White, 2005), thus, it can stabilize neuronal membrane and reduce neuropeptide release and excessive neuronal discharge by reducing excitability. Second, TPM increases the activity of the gamma-aminobutyric acid A (GABAa) receptor and thus enhances GABA inhibition (Skradski & White, 2000;White et al., 1997). In addition, unlike other antiepileptic drugs, TPM also negatively modulates aminomethylphosphonic acid (AMPA)/kainate receptors and indirectly inhibits the activity of the N-methyl-Daspartate (NMDA) receptor (Gibbs et al., 2000), a glutamate receptor found on neurons cells. In the present day, calcitonin gene-related peptide (CGRP), an important neuropeptide in migraine neurochemistry, is an emerging therapeutic target, and it has been suggested that TPM inhibits the release of CGRP and glutamate from trigeminal neurovascular nerve endings by blocking high-voltage-gated Ca 2+ channels (Dodick, 2018;Durham et al., 2006). Thus, TPM blocks cortical spreading depression (CSD) and has been shown to be effective in an anticonvulsant and antimigraine drug (Dodick, 2018) ( Figure 1). TPM has several potential mechanisms of action on migraine, and the exact mechanism by which it is effective in migraine treatment is not yet known. Based on the results of the animal and cellular studies described above, it is suggested that TPM can have an effect through the opening of ion channels, leading to a reduction in the release of excitatory neurotransmitters, thus negatively regulating neuronal excitability and ultimately relieving migraine, so does TPM have a similar effect in humans? What dose and timeframe is needed to achieve this effect? Many clinical studies in the follow-up have further elaborated on the emergence of TPM as one kind of prophylactic treatment agent for migraine.

EFFICACY OF TPM IN MIGRAINE PREVENTION
Topiramate was initially widely used as an anticonvulsant for the treatment of epilepsy, and several randomized controlled trials had recently proven the efficacy of topiramate on migraine prophylaxis.

Effects of TPM on migraine frequency
There was growing interest in the prophylactic use of TPM in migraine patients through a number of randomized controlled clinical trials.
Overall effectiveness rates of TPM on migraine attacks (defined as a ≥ 50% reduction in monthly headache attack frequency) ranged from 26 (Storey et al., 2001) to 63% (Gupta et al., 2007) (Table 1). We provide further detailed results from some population-based control studies below. and 200 mg/day (35%) TPM groups (Diener et al., 2004;Mei et al., 2004). It was found that the above multicenter randomized clinical trials were conducted among patients with episodic migraine aged 12-65 years from North America and Europe. The results of the trial showed that topiramate was significantly more effective than placebo in the preventive treatment of episodic migraine and was comparable to propranolol.

F I G U R E 1
Proposed mechanisms of TPM on migraine prevention. In the preclinical model of seizure, TPM blocks Na + and Ca 2+ channels (a) on hippocampal, spinal cord neurons and dentate granule cells, then inhibition the release of glutamate via pre-synaptic mechanism. Besides that, TPM has negative effect on AMPA (a), and positive effect on GABAa receptor (b) to reduce excessive neuronal discharge. In the rat model of migraine and medication overuse headache, TPM reduces the CGRP release (c) via blocking Ca 2+ channels in trigeminal nerve engdings to prevent the development of CSD and headache.TPM = topiramate; AMPA = aminomethylphosphonic acid; GABAa = gamma-aminobutyric acid A; CGRP = calcitonin generelated peptide; CSD = cortical spreading depression In 2007, a randomized, double-blind, placebo-controlled, phase 4 crossover trial (Lotolamp study) conducted by Gupta et al. (2007)   . These trials clearly documented its efficacy as a migraine preventive drug.

Effects of TPM on migraine severity and quality of life
In addition to the significant improvement in migraine attack frequency, TPM also significantly improved overall headache severity, as well as daily living capacity and overall quality of life. In 2007, a study

Effects of TPM on migraine in children and adolescent
To date, there were limited treatment options for migraine among children or adolescents patients (Table 4) patients included in the intention-to-treat analysis received topiramate versus placebo for a mean reduction in headache days per month of 2.6 and 2.0 migraine days, respectively (p = 0.061), but this reduction approached statistical significance. In the double-blind period, the percentage of patients experienced with a ≥50% reduction in migraine days per month was 54.6% in TPM group compared with 46.9% in the placebo group (p = 0.39). And the percentage of patients experienced with a ≥ 75% reduction in migraine days per month was significantly higher in TPM group (32.4%) than placebo group (14.3%, p = 0.02). (Winner et al., 2005) Another one randomized, double-blind, placebocontrolled study of migraine in adolescents (12-17 years old) at Children's Hospital of the King's Daughters in the United States, showed that patients who received 100 mg/day TPM had significant lower frequency in migraine attacks when compared with patients received placebo in the last 12-week of double blind period (median: 72.2 vs 44.4%, p = 0.016). No significant difference was detected between patients who received 50 mg/day TPM and placebo (median: 44.6 vs 44.4%, p = 0.798). The above data demonstrated that the most effective TPM dosage in children and adolescent was similar as that in adults (Lewis et al., 2009).
However, the childhood and adolescent migraine prevention (CHAMP) trial (Powers et al., 2017)  and placebo. After 24-week treatment, Powers et al. (2017) found that both TPM and amitriptyline were less effective than placebo on reduction of the headache days after a 24-week treatment (55% for topiramate, 52% for amitriptyline, 61% for placebo; topiramate vs placebo, p = 0.48; amitriptyline vs placebo, p = 0.26; amitriptyline vs topiramate, p = 0.49). Compared with placebo-treated patients, TPM and amitriptyline had no significant benefit in migraine patients aged 8-17 years. Also, there was no significant difference between-groups in terms of headache-related disability or the percentage of patients completed the 24-week treatment period. Patients treated with either topiramate or amitriptyline had higher rates of adverse events than those treated with placebo, including abnormal sensations (31 vs 8%, p < 0.001) and weight loss (8 vs 0%, p = 0.02) in the topiramate group, and fatigue (30 vs 14%, p = 0.02) and dry mouth (25 vs 12%, p = 0.02) in the amitriptyline group. It was showed that topiramate is a limited and controversial in the treatment of migraine for children and adolescents. There have been fewer clinical trials of topiramate for pediatric migraine compared to adults. Therefore, topiramate should be used with caution in children and adolescent patients.