The pharmacokinetics of methadone in healthy subjects and opiate users

Abstract

Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

The Pharmacotherapy of Chronic Pain: A Review

“…Methadone: Methadone has been available for approximately a half-century (160). It is traditionally known for its role in assisting heroin addicts to exit street drug use, and in this context, its long half-life and duration of action have been known for some time.…”

Therapeutic Drug Monitoring for Methadone: Scanning the Horizon

“…Methadone on the other hand is distinctive because, unlike the natural opiates, this drug is not only orally efficacious (bio-availability 190%) but it is also, for most patients [27], very long-acting [28] and can thus be prescribed once daily. Therefore, prescribing methadone provides times for the narcotic receptors to become adapted to the steady-state concentration of methadone.…”

A Review of the Use of Methadone for the Treatment of Chronic Noncancer Pain

“…Methadone does not accumulate in patients with renal failure (15,21). In a single-dose study (1), the terminal elimination half-life for methadone was found to be 33 h to 46 h in healthy subjects, and it was possibly longer in a group of heroin addicts scheduled to start a methadone maintenance program. In a controlled single-dose trial (19) of methadone in eight patients with chronic pain, the mean elimination half-life was found to be 37.5 h for R-methadone and 28.6 h for S-methadone.…”

“…There is a rapid and extensive initial distribution phase within 2 h to 3 h (15). Because of its relatively high lipid solubility, methadone is redistributed in fat stores with slow release into plasma and a prolonged elimination phase (1,12). Methadone exhibits efficient transport across the bloodbrain barrier with cerebrospinal fluid concentrations at 73% of serum concentrations (20).…”

“…ethadone has been available for approximately half a century (1). It is traditionally known for its role in assisting heroin addicts to exit street drug use and, in this context, its long half-life and duration of action have been known for some time.…”