When monotherapy for epilepsy fails, add-on therapy is an alternative option. There are several possible
antiepileptic drug combinations based on their different and multiple mechanisms of action and pharmacokinetic
interactions. However, only when benefits of drug combinations outweigh the harms, polytherapy can be defined as
In the past 20 years, second generation AEDs have been marketed, some of which have better defined mechanisms of
action and better pharmacokinetic profile. The mechanisms of action of AEDs involve, among others, blockade of
voltage-gated sodium channels, blockade of voltage-gated calcium channel, activation of the ionotropic GABAA receptor
and increase of GABA levels at the synaptic cleft, blockade of glutamate receptors, binding to synaptic vesicle protein 2A,
and opening of KCNQ (Kv7) potassium channels.
Aim of this review was to examine published reports on AEDs combinations in animal models and humans focusing on
mechanisms of action and pharmacokinetic interactions.
Studies in animals have shown that AED combinations are more effective when using drugs with different mechanisms of
action. The most effective combination was found using a drug with a single mechanism of action and another with
multiple mechanisms of action. In humans some combinations between a blocker of voltage-gated sodium channels and a
drug with multiple mechanisms of action may be synergistic.
Future studies are necessary to better define rational combinations and complementary mechanisms of action, considering
also pharmacokinetic interactions and measures of toxicity and not only drug efficacy.