Reappraisal of polytherapy in epilepsy: A critical review of drug load and adverse effects

Purpose: We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered. Methods: We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/A ToxL ratio to do so from serum levels of individual drugs. The PDD/DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/A ToxL is the sum of each observed serum level divided by its average toxic level. Results: We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al. (35). Conclusions: Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of AE is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate.