Methadone in man: Pharmacokinetic and excretion studies in acute and chronic treatment

Verebely, Karl; Volavka, Jan; Mulé, S. J.; Resnick, Richard B.

doi:10.1002/cpt1975182180

Cited by 175 publications

(85 citation statements)

References 5 publications

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“…The variability in this ratio between individuals was less marked (0.72-1.83) and this agrees with results of a recent study carried out in 22 heroin-dependent subjects, where the l-methadone:dmethadone ratio ranged from 0.63 to 2.40 [15]. The sharp increase in EDDP plasma concentration from 7 to 24 ngW ml -1 occurring in the d,l-methadone group after changing to d,l-methadone confirms suggestions that d,lmethadone induces its own metabolism [15,24,25]. The non-significant decrease in the mean l-methadone:dmethadone plasma concentration ratio from 1.20 on day 15 to 1.15 on day 22 is in accord with Eap et al [15], who suggested a preferential metabolism of l-methadone compared to d-methadone when changing to d,l-methadone.…”

Section: Discussionsupporting

confidence: 80%

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

et al. 1998

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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.

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Section: Discussionsupporting

confidence: 80%

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

et al. 1998

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“…Further investigations should also be enzyme induction and other adaptive changes on the metabolism of methadone [25,28,36,49,50]. Whether aimed at clarifying the roles of plasma binding and enantioselective kinetics [48], and the influence of autothese complexities present formidable obstacles to the 4 From population analysis with t 1/2,z as a primary parameter with a log-normal distribution staff of the Leeds Addiction Unit for their assistance.…”

Section: Pharmacokineticsmentioning

confidence: 99%

The pharmacokinetics of methadone in healthy subjects and opiate users

Wolff¹,

Rostami‐Hodjegan

Shires

et al. 1997

Brit J Clinical Pharma

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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).

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“…as a result, its withdrawal or dose reduction result in serious withdrawal symptoms and craving leading to relapse. It also has relatively short half-life of 14.3 hrs [5]. since substances with shorter half-life have greater addictive potential [6], methadone works as a kind of substituted drug of addiction.…”

Section: Do We Really Need To Continue Pharmacotherapy For Opioid Usementioning

confidence: 99%

Do We Really Need to Continue Pharmacotherapy for Opioid Use Disorder (OUD) Indefinitely?

Badgaiyan¹,

Sinha²,

Blum³

2015

J Reward Defic Syndr

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Methadone in man: Pharmacokinetic and excretion studies in acute and chronic treatment

Cited by 175 publications

References 5 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

Do We Really Need to Continue Pharmacotherapy for Opioid Use Disorder (OUD) Indefinitely?

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