Rational combination therapy in epilepsy. I. Concepts and foundations

It is an accepted fact that it is wise to start antiepileptic treatment with monotherapy, but 30% of patients do not respond to it or to several monotherapies; in that moment an association of two or more antiepileptic drugs is commonly utilised (the appearance of ten second-generation antiepileptic drugs on the market has not changed this scenario to any significant extent). Yet, on the other hand, the use of bitherapy in epilepsies that are usually resistant to treatment has been suggested as a interesting way to begin treatment. This article consists of three parts. In this first part we review the concept of rational combination therapy, the concept of how and when it should be used and the studies about associations of antiepileptic drugs conducted in animals and in humans. Although combination therapy is frequent as treatment for epilepsy, it is not always so obvious that it offers more benefits in terms of greater effectiveness with a lower, or at least equal, degree of toxicity. Few methodologically correct clinical trials have been conducted and recent reviews continue to consider that no controlled clinical trials have been carried out that confirm the benefits of combination therapy. This does not mean, however, that rational combination therapy is totally void of any kind of usefulness, but rather it stresses the fact that it offers a low level of evidence.