Methadone and buprenorphine, widely used in the treatment of opioid abuse, are metabolized by cytochrome P450 3A4, while fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors, are known to be P450 2D6 and 3A4 inhibitors in vitro. This study deals with the in vitro interactions between methadone or buprenorphine and fluoxetine or fluvoxamine. Fluoxetine inhibited methadone N-demethylation (Ki = 55 microM), but conversely did not inhibit buprenorphine dealkylation. Norfluoxetine inhibited the metabolism of both methadone and buprenorphine metabolisms (Ki 13 and 100 microM, respectively). Fluvoxamine inhibited methadone N-demethylation with a Ki of 7 microM and buprenorphine dealkylation, uncompetitively, with a Ki of 260 microM. Finally, these results suggest that care should be taken when selective serotonin reuptake inhibitors are administered in the treatment of drug craving. This is particularly true in the case of fluvoxamine which is more potent than fluoxetine in inhibiting methadone and buprenorphine metabolism.