Rational polytherapy: Myth or reality?

Abstract

SUMMARY Background. The concept of rational polytherapy implies using a combination of antiepileptic drugs with synergistic effect, which in turn, may result in additive or reduced toxicity. This concept is not consensually accepted. Aim. To present evidence in favour and against rational polytherapy. Methods. Narrative literature review on PubMed and Medline databases using the following terms: epilepsy treatment, rational therapy/polytherapy, supraadditive treatment, drug-resistant epilepsy treatment. Cited references within selected articles were also evaluated. Results. Against rational therapy is the evidence of clinical efficacy of the use of antiepileptic drugs with the same mechanism of action and without increased side-effects. Rational therapy may fail because while the addition of one antiepileptic drug to others with the same or different mechanisms of action leads to additive therapeutic efficacy, it also leads to more side effects. The evidence for the robust, unique, true synergism found between valproate and lamotrigine is questionable because the two drugs together may lead to complex pharmacokinetic interactions jeopardizing a consistent interpretation of the data. Data from studies with antiepileptic drugs with multiple mechanisms of action may be questionable because the same mechanism of action might not be responsible for drug efficacy or toxicity in different patients. Favouring rational therapy is the evidence that genetic animal models of seizures and drug-related neurotoxicity are ideal to evaluate the efficacy and toxicity of drug combinations, and that the most successful experimental combination of two antiepileptic drugs would be the one with a single mechanism of action and the other with a multiple mechanism of action. Conclusion. Rational therapy is a sub-optimal, but worth being attempted strategy for the use of antiepileptic drugs in combination.