Antiepileptic drugs (AEDs) are frequently used as a preventive treatment for the management of migraine. Topiramate (TPM) and valproic acid (VPA) are 2 AEDs that have demonstrated efficacy in reducing the frequency of migraine attacks, and both carry US Food and Drug Administration indications for the prevention of episodic migraine, based on level A evidence.1

“Topiramate is the most common migraine preventive in the world, used on a prescription basis, and valproic acid would be the next best choice,” Peter MacAllister, MD, told Neurology Advisor. Dr MacAllister is Medical Director of the New England Institute for Neurology and Headache and Chief Medical Officer of the New England Institute for Clinical Research and Ki Clinical Research in Stamford, Connecticut. “Other AEDs that are used for migraine but show less evidence include zonisamide and levetiracetum,” he stated.

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According to Matthew Robbins, MD, a clinical neurologist at Weill Cornell Medicine and New York-Presbyterian Medical Center in New York City, “Lamotrigine may have a niche for migraine with aura specifically, but not migraine overall.” He told us that while gabapentin (GBP) is prescribed frequently, data supporting its use as a migraine preventive agent is not as strong as that of other AEDs. This was reinforced in a 2019 review by Parikh and Silberstein1 stating that, “clinical evidence has suggested that GBP is not beneficial in migraine prevention.” Similarly, they reported that oxcarbazepine “is likely ineffective for migraine prophylactic treatment.”

Levetiracetam has provoked interest compared to other AEDs, due to a unique mechanism of action of binding to the synaptic vesicle protein SV2A, and thereby blocking neuronal hyperexcitability of voltage-gated N-type calcium channels that have been implicated in migraine pathogenesis.1 Small studies of levetiracetam have indicated good efficacy and tolerability, although the evidence from multiple trials is conflicting and somewhat inconclusive, strongly suggesting the need for intensive large-scale study of this agent.1

Why AEDs Work for Migraine

Epilepsy and migraine show a 2-fold higher than average risk for comorbidity, supporting the use of AEDs for treatment of both conditions; however, the mechanisms of these drugs in migraine are not well understood.1-3 It is thought that AEDs are able to block excitation leading to cortical spreading depression that may be a central precipitator in migraine through actions on voltage- and receptor-gated ion channels that promote stabilization of neuronal membranes.1 A unique property of TPM is that it inhibits neuro-excitatory glutamate receptor activity at the cellular level, which has a pronounced effect in migraine as well as in epilepsy. A study in 2017 by Heberstreit and May3 in 27 patients found that TPM reduced blood oxygen level-dependent responses in several areas of the brain responsible for pain transmission, while also improving functional connectivity between the thalamus and somatosensory regions.3  These theories all draw an incomplete picture of how TPM works in migraine, and none have been proven as yet.

Adverse Effects of AEDs

Dr MacAllister observed that most AEDs work well when used with other agents used to treat migraine. “The biggest problem is adherence,” he said, “For example, 70% or more of migraineurs on [TPM] … stop it on their own within 6 months, due to side effects.” Spritzer et al1 reported that, “it is not uncommon in clinical practice for TPM when used for migraine prevention to be given once daily, often at night, in an attempt to improve tolerability.”

The known adverse effects of TPM include a range of cognitive symptoms, such as difficulties with word-finding, concentration, memory, and slowed mental processing, as well as fatigue, dizziness, somnolence, and suicidal ideations.1 More systemic responses may include renal calculi, hypokalemia, and metabolic acidosis, with disturbances to taste (often leading to weight loss) and vision.

Zonisamide has demonstrated efficacy that is potentially comparable to TPM, with improved tolerability. The main side effects appear at doses of 200 mg/d to 500 mg/d, accumulated for more than 24 months.1 These include decreased appetite and weight, memory loss, and reduced hemoglobin levels. Rapid titration of zonisamide was also associated with potential risks for Stevens-Johnson syndrome or toxic epidermal necrolysis.

Contrary to weight loss observed with other AEDs, VPA, given at doses of 500 mg/d to 1000 mg/d for migraine prevention often produced weight gain, along with nausea, fatigue, dizziness and tremor.1 More serious effects include the potential for pancreatitis and liver failure.

Levetiracetam is associated with adverse effects, such as mood swings including irritability, hostility, and hyperactivity, as well as dizziness and somnolence.1

Teratogenicity

Of greater concern are the substantial teratogenic risks with all AED use. Both VPA and TPM have been shown to produce major congenital abnormalities that are likely to occur within the first 60 days after conception occurs.1 Unless used as a last resort, VPA and TPM “should both be avoided as a preventive agent in women of childbearing age, given their potential for birth defects and other consequences,” Dr Robbins cautioned. If AEDs are used, he noted, then contraception is highly recommended, although at higher doses, TPM can also interact negatively with contraceptives.4

“The decision to use an antiepileptic agent, or any migraine preventive agent, is based on individual factors, including side effects, route of administration, comorbidities, and most importantly for women, pregnancy considerations,” Dr Robbins said. “There is very little evidence that one preventive agent is really better than another,” he added.  

References

1. Parikh SK, Silberstein SD. Current status of antiepileptic drugs as preventive migraine therapy. Curr Treat Options Neurol. 2019;21:16.

2. Spritzer SD, Bravo TP, Drazkowski JF. Topiramate for treatment in patients with migraine and epilepsy. Headache. 2016;561081-1085.

3. Heberstreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One. 2017;12(10):e0184406.

4. Reimers A, Brodtkorb E, Sabers A. Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. Seizure. 2015;28:66-70.