Phenytoin facilitates the elimination of acetaminophen by accelerating its biotransformation.57 Phenobarbital induces acetaminophen metabolism, which can result in an increase in toxic metabolites and may increase the risk of acetaminophen overdose.101


Salicylates compete with phenytoin for plasma protein–binding sites. One study showed an increase from 10% to 16% in the unbound fraction of phenytoin when acetylsalicylic acid (ASA) was taken. Changes were proportional to the ASA dose, which ranged from 900 mg to 3,600 mg per day.102 Although high and repeated doses of ASA may cause a slight increase in free phenytoin and a decrease in the total phenytoin level, there is usually no need to adjust the phenytoin dose.103

An increase of the free fraction but not the total valproate concentration can occur in patients who receive 15 to 30 mg/kg of ASA. This increase is not clinically significant in most cases.


Ibuprofen has not been reported to interact significantly with antiepileptic drugs or to affect the seizure threshold.

Adapted from: Najjar S, Devinsky O, Rosenberg AD, et al. Procedures in epilepsy patients. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;499–513. With permission from Elsevier (

Authored By: 
Orrin Devinsky MD
Souhel Najjar MD
Andrew D Rosenberg MD
Reviewed By: 
Steven C. Schachter MD
Wednesday, March 31, 2004