Monotherapy of epilepsy is usually preferable to polytherapy for a variety of reasons. However, investigational or newer antiepileptic drugs (AEDs) are typically evaluated as add-on therapy in patients with refractory seizures. Because coadministered drugs are subject to drug interactions, add-on trials of AEDs do not necessarily address the utility of a new AED as monotherapy or its use in patients with newly diagnosed epilepsy, in whom monotherapy is usually sufficient. Monotherapy clinical trials are difficult to design because randomizing epilepsy patients to placebo or pseudoplacebo is considered unethical, and results from active-drug noninferiority designs are difficult to interpret. Active-drug superiority designs have been developed in an attempt to provide useful information about the monotherapeutic efficacy of new AEDs. The conversion to monotherapy trial design, introduced in the late 1970s, provides for initial add-on of an investigational agent to a preexisting drug in patients with uncontrolled seizures, followed by gradual discontinuation of the preexisting treatment and an eventual monotherapy phase of the investigational agent. Conversion to monotherapy trials are typically of short duration and have been criticized for failing to provide adequate time for titration to optimal dose, an inability to examine tolerance development or long-term safety, and possibly placing enrolled patients at increased risk for morbidity, but they have been used to obtain data about monotherapy efficacy sufficient for regulatory authority approval. Relevant clinical trial data are needed to guide treatment choices in patients who have failed previous monotherapy. To date, large-scale prospective trials comparing monotherapy with old and new AEDs have not shown superior efficacy of the new AEDs but have demonstrated their better tolerability and safety. It is hoped that use of appropriately designed monotherapy clinical trials will help to identify a new generation of AEDs in the future for monotherapy in epilepsy patients.
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