Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)- vs. (R)-methadone exposure

Aims To investigate the possibility that (S)-methadone influences therapeutic and adverse responses to rac-methadone maintenance treatment, by examining how subjective and physiological responses among rac-methadone maintenance patients vary in relation to relative exposure to (S)- vs. (R)-methadone. Methods Mood states (Profile of Mood States), opioid withdrawal (Methadone Symptoms Checklist), physiological responses (pupil diameter, heart rate, respiration rate, blood pressure), and plasma concentrations (CP) of (R)- and (S)-methadone were measured concurrently 11–12 times over a 24-h interdosing interval in 55 methadone maintenance patients. Average steady-state plasma concentrations (Cav) and pharmacodynamic responses were calculated using area under the curve (AUC). Linear regression was used to determine whether variability in pharmacodynamic responses was accounted for by (S)-methadone Cav controlling for (R)-methadone Cav and rac-methadone dose. Ratios of (S)-:(R)-methadone using AUCCP and trough values were correlated with pharmacodynamic responses for all subjects and separately for those with daily rac-methadone doses ≥ 100 mg. Results (S)-methadone Cav accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone Cav and rac-methadone dose, showing positive associations (partial r) with the intensity of negative mood states such as Tension (0.28), Fatigue (0.31), Confusion (0.32), and opioid withdrawal scores (0.30); an opposite pattern of relationships was evident for (R)-methadone. The plasma (S)-:(R)-methadone AUCCP ratio (mean ± SD 1.05 ± 0.21, range 0.65–1.51) was not significantly related to pharmacodynamic responses for the subjects as a whole but showed significant positive associations (r) with the intensity of negative mood states such as Total Mood Disturbance (0.61), Tension (0.69), Fatigue (0.65), Confusion (0.64), Depression (0.49) and heart rate (0.59) for the ≥ 100-mg dose range. Conclusions These findings agree with previous evidence that (S)-methadone is associated with a significant and potentially adverse profile of responses distinct from that of (R)-methadone. Individual variability in relative (S)- vs. (R)-methadone exposure may be associated with variability in response to rac-methadone maintenance treatment.