Rational polypharmacy.

The development of assays for plasma antiepileptic drug concentrations has led to the discovery of many pharmacokinetic interactions, some causing drug intoxication and others resulting in ineffective drug concentrations. In the 1970s, a number of epileptologists began to argue that single drug therapy was desirable in the treatment of epilepsy and this has become the accepted policy when initiating therapy. About 75% of patients treated in this way will achieve remission with a minimum of adverse drug reactions. The remainder, however, continue to have unacceptable seizures and usually receive combinations of drugs. Evidence indicates that the response rate on adding a second drug is low, although in some studies of new drugs such as vigabatrin up to one-half of patients receiving add-on therapy experience a 50% or greater reduction in seizure frequency, and 10-15% are seizure-free in the short term. Unfortunately, randomized placebo-controlled studies have not been undertaken to compare the relative merits of monotherapy and combination therapy with respect of seizure control and adverse effects. It is argued that the time has come to do so, particularly in view of the known mode of action of some of the new drugs. Perhaps blocking excitation with one drug at the same time as enhancing inhibition with another may be better than doing only one or the other.