Divalproex Sodium in Headache: Literature Review and Clinical Guidelines

Abstract

Divalproex sodium is an anticonvulsant agent approved for use either alone or in combination with other antiepileptic drugs for simple and complex absences seizures and mania. Four double-blind placebo-controlled studies have confirmed that divalproex sodium/valproate is an effective migraine treatment. In all of the clinical studies, whether open, retrospective, or placebo-controlled and double-blind, valproate was an effective preventive treatment for migraine. There was a reduction in the number of migraine attacks, and migraine duration and intensity were also reduced in some instances. It is equally as effective in patients with severe frequent migraines as in those with less severe migraines. In clinical trials, the most frequent adverse events reported by patients treated with divalproex sodium were nausea, asthenia, dyspepsia, dizziness, somnolence, and diarrhea, with most adverse events being mild to moderate in severity.

GABA receptors modulate trigeminovascular nociceptive neurotransmission in the trigeminocervical complex

“…GABA agonist mechanisms have been implicated in both the prophylactic and acute treatment of migraine. Valproate, a well established migraine prophylactic medicine (Silberstein, 1996), enhances GABAergic neurotransmission by activation of the GABA synthetic enzyme, glutamic acid decarboxylase (Loscher, 1981), and by inhibition of the GABA degradative enzymes, GABA aminotransferase (Loscher, 1981;Maitre et al, 1978) and succinate semialdehyde dehydrogenase (van der Laan et al, 1979). Although valproate does not block mechanically induced cortical spreading depression in the cat (Kaube & Goadsby, 1994), it has been proposed that an increase in inhibitory GABAergic neurotransmission may suppress the pathophysiological events that underlie migraine aura (Cutrer et al, 1997).…”

Preventive treatment of migraine

“…The most frequent AEs are nausea, alopecia, tremor, asthenia, dyspepsia, somnolence and weight gain [51]. Hepatotoxicity and pancreatitis are the most serious AEs but irreversible hepatic dysfunction is extremely rare in adults [52]. Divalproex carries a high risk of congenital abnormality [46].…”

A patient with SUNCT syndrome responsive to sodium valproate

“…The enhancement of GABA activity is thought to be the mechanism in preventing migraine attack [5]. Several clinical studies have demonstrated the efficacy of sodium valproate as prophylactic agent in migraine [9,10]. The drug was therefore recently included in the Italian [11] and American guidelines [12] on diagnosis and treatment of migraine, at dosages of 800-1500 mg/day.…”