Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers

Olsen, George D.; Wendel, Herbert; Livermore, James O.; Leger, Regina M.; Lynn, R K; Gerber, Nicholas

doi:10.1002/cpt1977212147

Cited by 99 publications

(53 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other studies, although not as extensive as the present study, have also shown higher l-methadone plasma concentrations in subjects receiving d,l-methadone [9,23]. However, a study in 12 non-opiatetolerant volunteers [6] showed consistently lower l-methadone plasma concentrations in comparison with d-methadone. After changing from l-methadone to d,l-methadone on day 15, no significant changes in the l-methadone:dmethadone ratio were observed in the d,l-methadone group between day 15 and day 22.…”

Section: Discussioncontrasting

confidence: 48%

“…Sullivan et al [5] suggested that d-methadone metabolites may have an analgesic effect. In a study using 30 healthy, non-opiate-tolerant volunteers, Olsen et al [6] found similar respiratory and pupillary effects using a 7.5-mg l-methadone dose and a 15-mg d,lmethadone dose. One subject showed slightly depressed respiration on high-dose d-methadone but the changes induced by l-methadone were of longer duration than those of d,l-methadone.…”

Section: Introductionmentioning

confidence: 81%

See 1 more Smart Citation

L-Methadone and D,L-Methadonein Methadone Maintenance Treatment: A Comparison of Therapeutic Effectiveness and Plasma Concentrations

et al. 1998

View full text Add to dashboard Cite

The clinical effectiveness of l-methadone maintenance treatment (LMMT) carried out using d,l-methadone or l-methadone have been compared with ambulatory heroin-dependent subjects. A total of 40 heroin-dependent subjects, previously maintained on l-methadone in Frankfurt am Main, were divided into two groups under randomised double-blind conditions and received either an equivalent dose of l-methadone as d,l-methadone or remained on the previous l-methadone treatment. Requests for a change in the dose of d,l-methadone and l-methadone were recorded, urine samples for determination of illicit drug use were collected and the individual level of opiate craving was determined over a 22-day observation period. There was no significant difference between the two groups in the number requests for a dose change (dose increase <10%). However, there was a significant increase in heroin use in the group which continued to receive l-methadone. Although there was less variability in opiate craving in the group receiving d,l-methadone, the mean intensity of opiate craving did not differ between the two groups. The mean l-methadone dose:l-methadone plasma concentration ratio, an index of the bioavailability of l-methadone in individual subjects, showed no significant change when the treatment was changed to d,l-methadone. The mean d-methadone:l-methadone plasma concentration ratio was 1.17. There was no significant difference between these ratios for day 15 and day 22. The mean l-methadone:EDDP plasma concentration ratio in the l-methadone group was 22.2 and the d,l-methadone:EDDP plasma concentration ratio was 18.4 . The plasma EDDP concentration in the d,l-methadone group increased 3-fold after starting treatment with d,l-methadone. These findings suggest that d,l-methadone can be used in methadone maintenance treatment of heroin-dependent subjects but that further studies are required to evaluate pharmacokinetic interactions between methadone enantiomers.

show abstract

Section: Discussioncontrasting

confidence: 48%

Section: Introductionmentioning

confidence: 81%

L-Methadone and D,L-Methadonein Methadone Maintenance Treatment: A Comparison of Therapeutic Effectiveness and Plasma Concentrations

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Thus, a significant overestimation incidence of nausea and vomiting. This was surprising as others have not reported such a finding [34].…”

Section: Pharmacokineticsmentioning

confidence: 80%

The pharmacokinetics of methadone in healthy subjects and opiate users

Wolff¹,

Rostami‐Hodjegan

Shires

et al. 1997

Brit J Clinical Pharma

View full text Add to dashboard Cite

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).

show abstract

“…Thus, a 50% reduction in inhibition is caused by the isomer that possesses most of the analgesic action of methadone [34] and antiaddictive action [24]. In fact, the r -methadone has a 10-fold higher affinity at the µ- and δ-opioid receptors and possesses up to 50 times the analgesic activity of s -methadone in human and animal models [1, 23, 35]. Fortuitously, the r -isomer would thus possess half the potential to prolong the QT, while twice the potency of the r/s -mixture in terms of analgesia.…”

Section: Discussionmentioning

confidence: 99%

“…1) with known r- and s -isomers [23, 24]. Methadone prolongs the QT interval on the electrocardiogram [25,26,27,28] due to methadone’s known inhibition of the rapid potassium-rectifying channel IKr [29,30,31].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

et al. 2008

View full text Add to dashboard Cite

Objectives: Methadone is a synthetic opioid, an analgesic and an antiaddictive. QT prolongation as well as torsade de pointes ventricular tachycardia and death have been reported with methadone. Methadone’s proarrhythmic toxicity is related to the inhibition of cardiac IKr channel and prolongation of the action potential. We hypothesized that the 2 isomers of methadone may have different effects on the IKr channel. Methods: The effects of the isomers on IKr were evaluated by using an oocytes system with heterogeneously expressed human ether-a-go-go-related gene (HERG) using the 2 electrode voltage clamp technique. r- and s-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of –141 and +143 degrees. Results: At concentrations of 0.01, 0.03, 0.1, 1 and 3 mM, r/s-methadone produced a dose-dependent inhibition of HERG by 17 ± 5, 23 ± 4, 40 ± 4, 57 ± 3, 69 ± 3 and 80 ± 1%, respectively. The IC₅₀ of r/s-methadone was 0.21 ± 0.02 mM. At 0.1, 0.3 and 1 mM, s-methadone reduced HERG current by 50 ± 4, 76 ± 5 and 87 ± 5%, respectively, while r-methadone reduced HERG current by 26 ± 4, 53 ± 3 and 77 ± 3%, respectively. Conclusions: There was a significant difference (p < 0.01) in the percentage of current inhibition between r- and s-methadone, at 0.1 and 0.3 mM (52% reduction). Thus, r-methadone may be a safer agent due to less QT effect.

show abstract

Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers

Cited by 99 publications

References 6 publications

<i>L</i>-Methadone and <i>D,L</i>-Methadonein Methadone Maintenance Treatment: A Comparison of Therapeutic Effectiveness and Plasma Concentrations

<i>L</i>-Methadone and <i>D,L</i>-Methadonein Methadone Maintenance Treatment: A Comparison of Therapeutic Effectiveness and Plasma Concentrations

The pharmacokinetics of methadone in healthy subjects and opiate users

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

Contact Info

Product

Resources

About