Monotherapy trials in antiepileptic drugs: are modified "presurgical studies" a way out of the dilemma?

Monotherapy trials in epilepsy are confronted with a dilemma: either they a re in conflict with ethical requirements, or they are scientifically not me aningful. Monotherapy trials, which are performed as controlled studies ran domizing patients to ineffective (pseudo)placebo treatment, are incompatibl e with the Helsinki Declaration. On the other hand, equivalence or noninfer iority studies using an active-control design do not permit valid conclusio ns on the efficacy of the lest drug. Therefore, they do not fulfill scienti fic requirements for trials on new drugs. As an alternative approach, a mon otherapy trial design for epilepsy patients undergoing presurgical evaluati on was outlined. During presurgical evaluation, antiepileptic drugs are rou tinely tapered down for seizure recording. This situation is used for a pla cebo-controlled short-term monotherapy trial. Four trials according to this design have been completed so far. Recently, several points of concern hav e been raised against this design, especially for matters of ethics and ext ernal validity. In the present article, these objections are outlined and d iscussed. In the proposed modification the randomization and the titration of the test drug or control begins prior to the presurgical investigations. The advantages are: the test drug does not have to be titrated quickly, pu re monotherapy conditions are achieved, and the subjects do not have to exp erience more seizures than are required for the presurgical evaluation. (C) 2001 Elsevier Science B.V. All rights reserved.