Side effects of phenobarbital in epilepsy: a systematic review

In recent years, phenobarbital, as an antiepileptic drug, has become less popular based on adverse events, especially cognitive and behavioural side effects. Despite the development of better tolerated new generation AEDs, phenobarbital is still widely used particularly in developing countries because of its low cost. The purpose of this review was to: (i) investigate whether phenobarbital can be safely used as an antiepileptic drug and (ii) determine the questions which need to be addressed in order to comprehensively and adequately evaluate the safety of phenobarbital for the treatment of epilepsy.

The literature was searched using the Cochrane Central Register of randomised controlled trials (1800-2009), Medline (1966-2009), Embase (1966-2009) and three Chinese databases.

Twenty studies were finally included in this systematic review. The determination of adverse effects of combined antiepileptic drugs (AEDs) from different studies was complicated by numerous factors including study design, different descriptions of adverse events and a lack of standardised data collection. These factors may also have been responsible for the heterogeneity present in the meta-analysis. The data did not demonstrate any evidence of association between phenobarbital and a higher risk of adverse events. However, phenobarbital appeared to be associated with a higher rate of adverse drug reaction related withdrawal (ADR-related withdraw), compared to carbamazepine, valproic acid and phenytoin. This may have been due to a concern for possible adverse effects of phenobarbital.

Phenobarbital was associated with a higher rate of drug withdrawal although there was no evidence to suggest that phenobarbital caused more adverse events compared to carbamazepine, valproic acid or phenytoin. However, in the case of pregnant women, it is important for clinicians to evaluate the benefits and risks of phenobarbital administration before making a final recommendation. Furthermore, unified scales for the assessment of cognitive function should be applied for future studies particularly in children.