Effect of epilepsy drugs may wane over time

NEW YORK (Reuters Health) - Over time, a significant minority of patients being treated for epilepsy show signs of tolerance to antiepileptic drugs (AEDs), according to a critical review of published studies. Tolerance is the reduction in response to a drug after repeated administration.

"Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent," note Dr. Wolfgang Loscher from the University of Veterinary Medicine in Hannover, Germany, and co-author Dr. Dieter Schmidt from the Epilepsy Research Group, Berlin.

Development of tolerance to AEDs "may be an important reason for failure of drug treatment," they add. Tolerance may lead to a lessening of side effects of AEDs, but also to loss of efficacy. However, tolerance is reversible with discontinuation of the drug or drugs.

"Because of diverse confounding factors," the authors continue, "detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response."

There are two types of tolerance, Loscher and Schmidt note in a report in the journal Epilepsia.

"Pharmacokinetic (metabolic) tolerance due to induction of AED-metabolizing enzyme has been demonstrated for most first-generation AEDs and may be easily to overcome by increasing the dosage of the drug." However, if the drug tolerance is not overcome by dose increments, the epilepsy may be considered drug resistant, they add.

Pharmacodynamic (functional) tolerance due to "adaptation of AED targets (e.g., loss of receptor sensitivity) has been shown experimentally for all AEDs that lose activity during prolonged treatment."

The authors note that while AED tolerance "seems to affect only a small portion of patients, it can be a significant problem for some patients, particularly those with medically intractable epilepsy who may develop cross-tolerance to similar medications.

Summing, up Loscher and Schmidt say there is a "pressing need" for controlled, long-term studies assessing tolerance "and determining the impact of tolerance for long-term seizure outcome and the health of patients with epilepsy."

SOURCE: Epilepsia 2006.