By: Krishna Tamakuwala, PharmD candidate c/o 2023
Migraines are characterized by episodes of head pain that are often throbbing and frequently unilateral. Migraines are divided into two categories: migraines without aura, known as common migraine, and migraines with aura, known as classical migraine. Migraines without aura are oftentimes associated with typical symptoms like nausea, vomiting, or sensitivity to light, sound, or movement. Migraines with aura, in addition to these typical symptoms, are accompanied by transient focal neurological symptoms, which are usually visual, including the illusion of bright stars or geometric patterns. Migraines affect nearly 36 million Americans which is approximately 12% of the population with global estimates being higher. 1
One might wonder, what does epilepsy and antiepileptics have to do with migraines? Epilepsy, also known as a seizure disorder, is a disorder of the brain. A person is diagnosed with epilepsy when they have had two or more seizures. 7 Both migraine and epilepsy are included in the broad category of neurological chronic disorders and are both characterized by episodic events. A recent hypothesis has been postulated suggesting a clinical connection between epilepsy and migraine. 8 Both of these disorders are described as entities resulting from altered neuronal excitability with a similar genetic basis. 2 Epilepsy oftentimes is a comorbid condition of migraine, and it occurs more commonly in patients with migraine than in the general population. Evidence has shown that the prevalence of migraine in patients with epilepsy is higher than in those without epilepsy. 2 Therefore, it is evident that a possible connection between the two disease states exists and because of their similarities, the use of antiepileptic drugs (AEDs) in migraine prophylaxis is a plausible approach.
The rationale behind the use of AEDs in migraine prevention is based on the hypothesis that migraine and epilepsy share several similar pathogenic mechanisms. Shared pathophysiological mechanisms include abnormalities in the function of voltage-gated sodium (Na+) and calcium (Ca2+) channels, reduced gamma-amino butyric acid (GABA)-mediated inhibition, and increased glutamate-mediated excitation at the presynaptic or postsynaptic level. Additionally, both disease states lower the threshold for the induction of cortical spreading depression (SD), and lower the threshold for induction of long-term changes in neuronal excitability (sensitization and kindling). 2 Some of the common AEDs used in migraine prophylaxis include valproic acid, divalproex sodium (Depakote®), and topiramate (Topamax®).
Valproic acid is arguably the most popular agent of the three mentioned above. It was approved by the FDA in 1996 as a treatment option for migraine prophylaxis. Valproic acid exerts its mechanism of action by increasing the availability of GABA, an inhibitory neurotransmitter, and enhancing its action at postsynaptic receptor sites. Valproic acid modulates the biochemical phenomenon of aura and affects nociception by modulating GABA and glutamate-mediated neurotransmission. 2 Numerous double-blind, placebo-controlled trials have documented that valproic acid is an effective preventative treatment for migraines. To summarize, randomized, placebo-controlled trials showed that response rates among patients treated with valproic acid, 800 to 1500 mg/day, ranged from 43% to 86% compared with 14% to 21% in those receiving placebo. Valproic acid reduced the number, severity, and duration of migraine attacks with a modest dose-response effect. Adverse effects, mostly gastrointestinal, occurred in 19% to 86% of cases (7% to 79% with placebo). Data from the two multicenter studies indicated that valproic acid was equally as effective in migraine with aura as in migraine without aura. Upon completion of the open trial, recommendations have been proposed for the optimal use of valproic acid in migraines. 5
Before initiating treatment with valproic Acid, a physical examination and a thorough medical history, with special attention to hepatic, hematological and bleeding abnormalities, should be performed. Baseline liver function tests (LFTs) must be ordered and evaluated within the first 6 months of initiating treatment, with frequent monitoring throughout therapy. The rationale behind LFT monitoring is that valproic acid can cause liver issues and use of this medication is contraindicated in liver disease. Valproic acid is also contraindicated in pregnancy. Exposure of valproic acid in pregnancy is associated with approximately a three-fold increase in the rate of major anomalies, specifically spina bifida which is when a developing baby’s spinal cord fails to develop properly.4 Furthermore, valproic acid has a black box warning for hepatotoxicity, patients with mitochondrial disease, fetal risk, and pancreatitis. Patients with a history of pancreatitis should consider an alternative AED.
Topiramate is another promising AED in migraine prophylaxis being studied, however, only two, relatively small, placebo-controlled trials have been evaluated thus far. Some adverse effects observed during the study included paresthesia, weight loss, altered taste, anorexia, and memory impairment. In the first trial, 30 patients who had migraine with or without aura were randomized to topiramate prophylaxis (n = 15) or placebo (n = 15). After 18 weeks of treatment, the mean 28-day migraine frequency was reduced by 29% in patients receiving topiramate and by 7% in those receiving placebo. The second study lasted 20 weeks and included 40 patients who were randomly assigned to receive topiramate (n = 19), dose ranging from 25 to 200 mg/day, or placebo (n = 21). The mean 28-day migraine frequency was reduced by 36% in topiramate-treated patients as compared with 14% in placebo recipients. However, further evaluation in randomized, double-blind, placebo-controlled trials with larger populations is needed to confirm these preliminary findings. 5 Despite the limited data available, topiramate is FDA approved for migraine prophylaxis in patients 12 years and older.
According to a Cochrane review comparing valproic acid and topiramate, mean headache frequency for topiramate and valproic acid is significantly lower than placebo. Similarly, a comparison between topiramate and divalproex demonstrated favorable results for the proportion of subjects randomized to an AED with results showing ≥ 50% reduction of migraine attacks. For topiramate, 100 mg and 200 mg dosing out-performed the 50 mg dosing, but this came with a disadvantage of a higher adverse event rate. For the valproic acid and divalproex comparison, a dose-effect correlation could not be established. 3 Upon analysis and comparison of the three major antiepileptic agents, the Cochrane review came to the conclusion that valproic acid, topiramate, and divalproex are all effective prophylactic treatments for episodic migraines in adults.
Gabapentin, FDA approved for focal partial seizures in adults and pediatric patients 3 years and older, is another possible AED to be considered in migraine prophylaxis. In a recent 12-week prophylaxis trial of 143 patients with migraine, each randomized to receive either gabapentin (n = 98) or placebo (n = 45), the median four-week migraine rate was 2.7 for patients treated with gabapentin, maintained on a stable dosage of 2400 mg/day, and 3.5 for those treated with placebo (P = 0.006), compared with a median four-week migraine rate of 4.2 and 4.1, respectively, during the baseline period. Additionally, the proportion of patients showing at least 50% reduction in the migraine rate was 46.4% with gabapentin and 16.1% with placebo (P = 0.008). Some of the commonly reported side effects in the gabapentin group included dizziness, somnolence, and asthenia (abnormal physical weakness or lack of energy). At the end of the study, the authors concluded that gabapentin was an effective and well-tolerated prophylactic agent for migraine but more evidence is needed to further support the use of gabapentin at this time. 5 Unlike topiramate, divalproex sodium, and valproic acid, gabapentin is not FDA approved for migraine prophylaxis and is not indicated for off-label use.
Upon analysis of the various AEDs used in migraine prophylaxis, whether new or traditional, evidence for their safety and efficacy, although promising, is still inadequate. There is still a need for a more extensive evaluation of the ongoing controlled studies with a larger number of patients and greater homogeneity of diagnosis in order to establish the efficacy of AEDs in management of clinical conditions other than epilepsy.5 In addition to analyzing the ongoing controlled studies, it is crucial to weigh the safety profile of each AED against its reported efficacy. Not only is the efficacy profile important when choosing an AED; additional characteristics such as tolerability, adverse events profile, comorbid conditions, concomitant drug interactions, and cost must be considered. 2 Although doubts and concerns still exist, at present valproic acid and topiramate are the two agents with the more promising evidence in migraine prophylaxis, with both agents having FDA approval for this indication.
- Burch, R., Buse, D. and Lipton, R., 2019. Migraine. Neurologic Clinics, 37(4), pp.631-649. Accessed 27 August, 2021
- Calabresi, P., Galletti, F., Rossi, C., Sarchielli, P. and Cupini, L., 2021. Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms. ScienceDirect. Accessed 27 August, 2021
- Mulleners, W., McCrory, D. and Linde, M., 2014. Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia, 35(1), pp.51-62. Accessed 27 August, 2021
- Ornoy, A., 2009. Valproic acid in pregnancy: How much are we endangering the embryo and fetus?. Reproductive Toxicology, 28(1), pp.1-10. Accessed August 29, 2021.
- Spina, E., 2021. Antiepileptic drugs: indications other than epilepsy. https://www.jle.com/en/revues/epd/e-docs/antiepileptic_drugs_indications_other_than_epilepsy__263021/article.phtml?tab=texte. Accessed 27 August, 2021
- Valproic Acid and Derivatives. Lexi-Drugs. Hudson, OH: Lexicomp, 2021. http://online.lexi.com/. Last Updated 08/11/2021. Accessed 27 August, 2021.
- Centers for Disease Control and Prevention. Frequently Asked Questions About Epilepsy. https://www.cdc.gov/epilepsy/about/faq.htm. Accessed 26 August 2021.
- Haut S, Bigal M, Lipton R. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. The Lancet Neurology. 2006;5(2):148-157. doi:10.1016/s1474-4422(06)70348-9. Accessed 27 August, 2021.
- Peterlin B, Gupta S, Ward T, MacGregor A. Sex Matters: Evaluating Sex and Gender in Migraine and Headache Research. Headache: The Journal of Head and Face Pain. 2011;51(6):839-842. doi:10.1111/j.1526-4610.2011.01900.x. Accessed 27 August, 2021.