Fluctuations in (R,S)-methadone pharmacokinetics and response among long-term methadone maintenance patients

Knowledge of how methadone disposition may fluctuate during the course of maintenance treatment is presently limited. This study investigated long-term fluctuations in methadone pharmacokinetics in five methadone maintenance patients who participated in two 24-hour testing sessions separated by at least one year. Results indicated substantial fluctuations between sessions in dose-corrected average steady-state plasma (R)-methadone concentrations (Cav), ranging from a 51% decrease to a 466% increase. These fluctuations were not consistently associated with changes in methadone dose or self-reported withdrawal status. The plasma (S)-:(R)-methadone Cav ratio increased significantly (12%, P = 0.04) between the sessions, suggesting a different pattern of long-term change in the pharmacokinetics of each enantiomer over time. The pronounced and variable fluctuations in methadone disposition evident in these patients highlight the need for an individualized approach to patient dosing and monitoring.