A new critical review by Dr. Wolfgang Loscher and Dr. Dieter Schmidt shows that repeated administration of antiepileptic drug (AED) therapy has diminishing results in preventing seizures in epileptic patients. In clinical trials, the number of patients remaining seizure-free declines over time with prolonged treatment. This review explores how acquired tolerance, the adaptive response of the body to foreign substances, as opposed to innate tolerance (which occurs in patients naturally resistant to certain medications) is responsible for this diminishing effect.
The risk of developing a tolerance to AEDs was traditionally thought to be small. Loscher and Schmidt, however, conclude that while AED tolerance is not a serious issue for most sufferers of epilepsy, it is a significant aspect of treatment in some patients. A few may even develop a cross-tolerance to similar medication. This "multi-drug resistance" is of serious concern to patients with medically intractable epilepsy.
The findings directly conflict with the treatment method many doctors are currently using. It is standard practice to increase AED dosage until adequate seizure control is obtained. However, this protocol presents a number of issues. The threat of medication tolerance is generally overlooked, as is the idea that epilepsy can be a progressive disease and does not develop at a fixed rate. Further, patients may acquire a tolerance to some effects of a particular drug, but not all.
Loscher and Schmidt have spent decades studying the effects of AEDs, however, Loscher believes that AED tolerance is a topic that has yet to be fully explored, and that more long-term clinical trials are becoming increasingly necessary. "Despite the convincing experimental evidence," Loscher says, "tolerance to the effectiveness of AEDs seems to have been forgotten."
Research is currently being done on the effects of placebo and conditional tolerance (a mental, conditioned-response effect that the mind has over the body). Doctors are also studying the effects of lower initial and target doses of AEDs. The possibility exists that many patients are being initially over medicated poses a significant challenge to doctors and scientists working toward effective seizure control.
This study is published in the current issue of Epilepsia.
Dr. Wolfgang Loescher is Professor and Director of the Department of Pharmacology, Toxicology and Pharmacy at the University of Veterinary Medicine, Hannover as well as Head of the Centre for Systems Neuroscience in Hannover, Germany.
Epilepsia is published on behalf of The International League Against Epilepsy (www.ilae-epilepsy.org), the world’s preeminent association of physicians and other health professionals working towards a world where no person’s life is limited by Epilepsy. Its mission is to provide the highest quality of care and well-being for those afflicted with the condition and other related seizure disorders.
