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For patients with refractory epilepsy, a combination of lamotrigine and valproate may be the best option for preventing seizures, a retrospective analysis showed.

When used together, those drugs were associated with a relative 48% reduction in seizure frequency compared with an aggregate measure of all other treatment regimens (P=3x10^-6), according to Nicholas Poolos, MD, PhD, of the University of Washington in Seattle, and colleagues.

In head-to-head comparisons, combinations of two or three drugs that included lamotrigine and valproate were associated with a relative 45% to 61% reduction in seizure frequency compared with six other regimens, including each drug as monotherapy (P<0.05 for all), the researchers reported in the Jan. 3 issue of Neurology.

Although the results suggest that combining lamotrigine and valproate provides efficacy superior to that of other regimens for refractory epilepsy, Poolos and colleagues noted that "this conclusion should ideally be confirmed in a prospective study of refractory patients, preferably from the general population."

They added that the study does not rule out the possibility of other regimens with improved efficacy because of low numbers of patients taking certain combinations.

About one-third of patients with epilepsy are refractory to treatment and they are usually treated with two or more antiepileptics. But it remains unclear whether any one combination is better than the rest.

To explore the issue, Poolos and colleagues retrospectively examined treatment records of 148 institutionalized, developmentally disabled adults with highly refractory epilepsy who received care at two state-run facilities in Washington. There was an average of nearly 12 years of treatment data for each patient.

On average, the patients had 3.2 seizures per month.

The eight most common drugs used at the two institutions alone or in combination were lamotrigine, valproate, carbamazepine, phenytoin, topiramate, levetiracetam, gabapentin, and zonisamide.

Of the 32 most frequently used combinations of up to three drugs, only the combination of lamotrigine and valproate stood out from the aggregate measure of other treatment regimens.

In the head-to-head comparisons, six of the 10 that revealed significant differences in treatment efficacy favored combinations that included those two drugs.

"It has been suggested that lamotrigine/valproate may be more effective based on pharmacodynamic synergism between the two drugs' mechanisms of action," the authors wrote. "Valproate exerts a well-known pharmacokinetic effect on lamotrigine metabolism, reducing its hepatic clearance."

But data from the current study suggested that that could not explain the greater efficacy of that particular combination.

"In the absence of serum drug level data, however, this question remains unresolved," the authors wrote.

An additional analysis revealed that using two drugs together was associated with a 19% decrease in seizure frequency compared with monotherapy (P=0.03), but that adding a third drug did not add any benefit.

"Use of antiepileptic drug combinations in clinical practice might best involve no more than two drugs at a time," Poolos and colleagues concluded. "This approach may lessen the increased toxicity that accompanies increasing the number of [drugs], while not sacrificing efficacy."

They acknowledged some limitations of the study, including the retrospective design, the lack of randomization, the inclusion of the eight most commonly used drugs only, the lack of a correlation of effects with drug dosage or serum levels, and the small sample sizes for some drug combinations.

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