Sodium Divalproate in Low Alternating Daily Doses for Migraine Prevention

A Retrospective Study

Abouch V. Krymchantowski, MD, PhD, FAHS; Ana Gabriela Krymchantowski, MS; Carla Jevoux, MD, PhD


Headache. 2019;59(7):1080-1083. 

In This Article

Abstract and Introduction


Background and Objective: Sodium divalproate is an effective neuromodulator for migraine prevention. Recommended doses vary from 1,000 to 1,500 mg/day, which may provoke unpleasant side effects as weight gain, tremor, and hair loss. Some patients do respond to lower doses even used once daily in ER presentations, but alternating low daily doses was never studied so far. The aim of this study was to evaluate the adherence, the tolerability, and the efficacy of sodium divalproate (SD) in low alternating daily doses for migraine prevention in patients of a tertiary center.

Methods: Consecutive migraineurs from a tertiary center to whom SD was prescribed as monotherapy from January 2017 until September 2018 were studied retrospectively. The doses were 250 mg alternated with 500 mg and were used based on the treating physician expertise and previous experience with tolerability issues when using higher doses. Headache frequency compared to baseline, adherence expressed by returning to a visit after 2 and 4 months and side effects reported by the patients, were evaluated.

Results: Sixty-eight patients (53 women and 15 men, aged 18-58) were included. The average headache frequency (HF) during baseline was decreased from 8.2 to 5.1 headache days/month among the 50 out of 68 patients returning at 2 months (adherence rate 73.5%). Weight gain was reported by 15 patients (30%, mean 2.1 kg). At 4 months, HF was reduced to 4.2 days/month (adherence rate 61.8%, n = 42) and weight gain reported by 18 patients (42.8%, mean 2.3 kg).

Conclusions: Despite the retrospective open design, which cannot allow definitive conclusions, SD in low alternating daily doses seems to be effective as with higher doses, but still induce modest weight gain. Controlled studies are necessary to confirm these observations.


Migraine is a highly debilitating and prevalent neurological disease.[1,2] It affects nearly 16% of the population and promotes a considerable burden to the individuals and Society.[1,2] The preventive treatment with the use of daily drugs is indicated depending on the frequency of the headache attacks and its degree of incapacitation. However, even those patients who have formal indication for drug prevention may not adhere due to tolerability and efficacy issues.[3] In addition, even among those who adhere, the long-term use of daily preventive agents is consistently limited by the presence of adverse events or fear for its future occurrence.[3,4]

Sodium divalproate (SD) is a neuromodulator approved for migraine prevention since the nineties.[5] It acts mainly blocking neuronal low-threshold T-type calcium ion channels as well as the degradation of gamma-aminobutyric acid (GABA) by GABA transaminase, therefore potentiating GABA-mediated responses and GABA-mediated inhibition.[6] In general terms, SD targets one or more molecular sites in the brain altering and modulating neurotransmission thru its actions on ion channels, neurotransmitter receptors, and metabolism.[6]

SD has been proved effective with doses of up to 1,500 mg daily.[7–10] Some studies performed with SD demonstrated uncomfortable side effects as weight gain, gastrointestinal events, tremor and hair loss, which were not impeditive of treatment's adherence in most of the patients.[7–11] However, the studies were conducted basically in United States, therefore possibly impairing conclusions in relation to other patients and populations. In Brazil, physical fitness, especially among women from the Southeast region, is a critical issue.[12,13] Gaining weight is not an accepted consequence and some patients do report preferring the headache than becoming fat.[14]

The aim of our study was to evaluate whether migraineurs from a tertiary center, who received SD as their only agent for preventing migraine, would adhere, tolerate, and improve the headache frequency even using low alternating daily doses.