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

Abstract

AimsTo 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. MethodsMood 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 ( C av ) 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 C av controlling for (R)-methadone C av and racmethadone dose. Ratios of (S)-:(R)-methadone using AUC CP 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 C av accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone C av 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 AUC CP 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. T. B. Mitchell et al. 61058 :6 Br J Clin Pharmacol ConclusionsThese 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.

Dominance of pre-analytical over analytical variation for measurement of methadone and its main metabolite in postmortem femoral blood

“…Considerable inter-individual variation in plasma R/S-ratios has been observed. Typically reported ranges extend from around 0.5 to 2.5 with average values around unity [17][18][19]. Apparently, chiral determination of methadone has not been performed previously in postmortem cases, so whether our finding of a significantly higher concentration of R-compared to S-methadone is a general phenomenon or not cannot be decided at present.…”

Tell-Tale SNPs: The Role of CYP2B6 in Methadone Fatalities

“…The analgesic properties of methadone are attributed to the (R)-enantiomer, which has a 10-fold greater affinity for the MOR (10,11) and is 8-50 times more potent than (S)-methadone (2). As concentrations of (R)-methadone increase above therapeutic levels, negative side effects on MORs in the brainstem respiratory centers can be potentiated, thus mediating respiratory depression (12,13). On the other hand, elevated (S)-methadone causes cardiotoxicity by prolonging the QT interval and subsequently leads to torsade de pointes by blocking the voltage-gated potassium channel of the human ether-ago-go related gene (hERG) (14,15).…”

Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients

“…6Y11 More recently, (S)-methadone has been associated with negative mood states and opioid withdrawal. 12 Also, (R)-and (S)-methadone have different pharmacokinetic profiles (greater free fraction of (R)-methadone and a slower clearance rate of (R)-methadone relative to (S)-methadone). 13 Because of these differences, it may be useful to quantify both (R)-and (S)-methadone plasma concentrations when investigating the pharmacokinetics of methadone.…”