Phenobarbital for childhood epilepsy: systematic review

INTRODUCTION: Against a background of concern about the safety of new pharmaceutical products, there has been renewed interest in one of the oldest antiepileptic drugs (AEDs), phenobarbital. Although still in widespread use in developing countries, its popularity has slipped in Western countries over the past century, partly because of controversy about its adverse effect profile. This critical review examines the evidence supporting its effectiveness and its associated behavioural adverse effects for febrile convulsions and childhood epilepsy. METHODS: Relevant randomised controlled trials (RCTs) of phenobarbital vs other antiepileptic drugs or placebo between 1970-2005 were identified through a comprehensive manual and computer database search of the world biomedical literature. Eleven RCTs of febrile convulsions and nine RCTs of childhood epilepsy were systematically reviewed against a conventional set of quality criteria. RESULTS: With a few exceptions, the overall quality of clinical trial methodology, especially in the early studies conducted in the 1970s and 1980s, was poor. There is no evidence for a difference in antiepileptic efficacy between phenobarbital and any other compared AED, yet no evidence for absolute efficacy. No convincing evidence exists for an excess of behavioural adverse effects, over other AEDs, attributable to phenobarbital. Masked studies of phenobarbital in childhood epilepsy have shown no significant differences in behavioural or cognitive adverse effects compared to other AEDs. This is in contrast to the excess of such adverse effects reported in studies open to observer bias. However, the one finding of reduction in cognitive ability associated with phenobarbital treatment for febrile convulsions remains a concern. Future areas of clinical and genetic epidemiological research are outlined.