Valproate in Headache
ABSTRACTS & COMMENTARY
Synopsis: Valproate should be considered as the initial prophylactic choice for patients with seizure disorders and psychiatric conditions who also have hard-to-treat headache.
Sources: Silberstein SD. Headache 1996;36:547-555; Cutrer FM, Moskowitz MA. Headache 1996;36:579-585.
Divalproex sodium (depakote) has emerged as a first-line medication in headache treatment. Silberstein reviews the clinical experience of valproate and offers sensible clinical guidelines for its use. To date, four double-blind, placebo-controlled studies (n = 238) have confirmed the efficacy of valproate as prophylaxis in migraine. Other headache disorders such as chronic daily headache and cluster headache have shown a lesser response. The consensus is that at least one-half of the migraine subjects treated enjoy a 50% reduction in headache frequency, intensity, and duration. Efficacy correlated to serum valproate levels, but no specific conclusions could be drawn about dose and pain relief. Adverse effects were the same as those experienced in the epilepsy population and included anorexia, nausea, vomiting, dyspepsia, asymptomatic serum hepatic transaminase elevations, tremor, sedation, weight gain, alopecia, and rash.
Recommendations for treating migraine with divalproex are similar to those used in epilepsy with some exceptions: 1) The suggested starting dose is 250 mg and is increased slowly to 500-750 mg/d in divided amounts, but ultimate doses of 2000 mg/d were reported. 2) Strict adherence to "therapeutic" levels (50-100 mcg/mL) is not needed. 3) Follow-up valproate levels to measure compliance, toxicity, and drug interactions should be done only when needed. 4) Obtain an initial CBC and liver function profile, but routine monitoring is not necessary in healthy, asymptomatic patients. 5) In the event of a mild transaminitis, reduce the valproate dose. For a transaminitis 2-3 times normal, however, stop and restart valproate when the LFTs return to normal. 6) Do not use valproate for migraine in children under 10 years of age or pregnant women with headache. 7) Silberstein anecdotally recommends zinc and multivitamins to control valproate associated hair loss, but evidence of efficacy for such medications is lacking.
Cutrer and Moskowitz describe a specific GABAergic mechanism by which valproate might exert its antimigraine effect. In the Moskowitz model, trigeminal pain can be studied in guinea pigs using an intracisternal injection of capsaicin to activate trigeminal c-fiber afferents. Quantification of the "pain response" can then be determined by measuring the expression of the c-fos gene/protein in the trigeminal nucleus caudalis. In the animals pretreated with valproate, there was a 52% reduction in c-fos protein expression (P < 0.05), implying a 52% reduction in trigeminal or "pain" activation. This reduced response could be blocked by bicuculline (GABAA antagonist) but not by baclofen (GABAB antagonist) demonstrating the importance of the GABAA receptor. They also observed a 42% reduction in c-fos expression in subjects pretreated with allopregnanolone, a progesterone metabolite that modulates GABAA (P < 0.01).
In an earlier study with Limmroth et al (Cephalalgia 1995;15 [Suppl 14]:102), Moskowitz showed that valproate can block neurogenic inflammation within the meninges via GABAA receptors. Although GABA receptors in brainstem and cortex may also be implicated, valproate seems to exert its effect on migraine through modulation of the GABAA receptors in the peripheral meningeal trigeminal vascular system.
COMMENT BY JEFFREY REICH, MD
Valproate has been a valuable addition in headache treatment. Already it enjoys wide applications as an antiepileptic drug for multiple seizure types and for a range of psychiatric conditions including mania and schizoaffective disorder. Among such patients who also have hard-to-treat headache, valproate should be considered as the initial prophylactic choice. (Dr. Reich is Assistant Professor of Neurology, Director of Headache Service, New York Hospital-Cornell Medical Center.) v
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