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At least 19 recordsLinked to original sources
PubMed2002

Methadone at tapered doses for the management of opioid withdrawal.

BACKGROUND: Despite use in many countries of tapered methadone for detoxification from opiate, the evidence of efficacy to prevent relapse and promote lifestyle change has not been systematically evaluated. OBJECTIVES: To determine whether tapered methadone is effective to manage withdrawal from opioids. SEARCH STRATEGY: We searched: Cochrane Controlled Trial Register (Issue 1, 2000), MEDLINE (OVID 1966-2000), EMBASE (1980-2000); reference list of relevant articles; personal communication; conference abstracts; trials from pharmaceutical industry; Internet. SELECTION CRITERIA: All randomised controlled trials on the use of tapered methadone versus all other detoxification treatments, placebo and different modalities of methadone detoxification programs for the treatment of opiate withdrawal. DATA COLLECTION AND ANALYSIS: One reviewer assessed studies for inclusion and undertook data extraction. The overall process were confirmed by consultation between reviewers. MAIN RESULTS: 20 studies were included, with 1357 people randomised. 10 studies compared methadone with adrenergic agonists, 7 compared different modalities of methadone detoxification, 2 compared methadone with other opioid agonists, 1 study compared methadone with chlordiazepoxide one with placebo. 10 studies that compared methadone with adrenergic agonists showed clinical differences of the treatments; 6 studies that compared different methadone schedules, showed different withdrawal responses; 2 studies that compared methadone and other opioid agonists showed that methadyl acetate performed similarly to methadone, while propoxyphene produced more severe withdrawal symptoms and more drop-outs than methadone; chlordiazepoxide and methadone (1 study) resulted similar in terms of overall effectiveness; more severe withdrawal and more drop outs in the placebo group than in methadone one (1 study). The results indicate that tapered methadone and other medications used are effective although symptoms experienced differed according to the medication used and the program adopted. The medications are similar in terms of overall effectiveness. Improvements were achieved when other services supporting services were offered contemporaneously with detoxification. REVIEWER'S CONCLUSIONS: Data from literature are hardly comparable; programs vary widely with regard to duration, design and treatment objectives, along with reporting impairing the application of meta-analysis. The studies included confirm that slow tapering with temporary substitution of long acting opioid can reduce withdrawal severity. Nevertheless the majority of patients relapsed to heroin use, abstinence cannot be considered a goal as heroin dependence is a chronic, relapsing disorder and the purpose of detoxification should be to remove or reduce dependence on heroin in a controlled and human fashion and not a treatment for heroin dependence.

Humans↗
PubMed1998

L-Methadone and D,L-methadone in methadone maintenance treatment: a comparison of therapeutic effectiveness and plasma concentrations.

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.

Adult↗
PubMed1998

Differentiation in the Amsterdam methadone dispensing circuit: determinants of methadone dosage and site of methadone prescription.

AIMS: To evaluate the Methadone Dispensing Circuit in Amsterdam by identifying determinants of methadone dosage and client characteristics in the different types of methadone programmes. DESIGN AND PARTICIPANTS: Four hundred and forty-four participants of a cohort study of drug users in Amsterdam who had consented to link data of the Central Methadone Register to the cohort data. FINDINGS: From 1985 to 1994, methadone dosage increased from 41 to 59 mg/day. The mean methadone dosage was higher for ethnic West Europeans, Germans, older drug users, HIV-positive drug users, those with a longer duration of prostitution, current injectors, those with a longer duration of injecting, longer duration of methadone use, higher frequency of being dispensed methadone and clients of the prostitutes' and foreigners' outpatient clinic. For clients of the general practitioner, at the police station and in prison the methadone dosage was lower. We found different sets of client characteristics in those receiving methadone at the methadone outpost, the methadone bus, the prostitutes' and foreigners' outpatient clinic, the general practitioner and the outdoor addiction clinic. CONCLUSIONS: These results indicate that the Amsterdam system is highly differentiated in a way that is largely concordant with the intended general policy on methadone treatment.

Adult↗
PubMed1990

Binding of d-methadone, l-methadone, and dl-methadone to proteins in plasma of healthy volunteers: role of the variants of alpha 1-acid glycoprotein.

The plasma concentrations of alpha 1-acid glycoprotein (AAG), albumin, triglycerides, cholesterol, and total proteins, as well as the plasma binding of racemic, d-methadone, and l-methadone were measured in 45 healthy subjects. The AAG phenotypes and the concentrations of AAG variants were also determined. The measured free fractions for racemic, d-methadone, and l-methadone were, respectively, 12.7% +/- 3.3%, 10.0% +/- 2.9%, and 14.2% +/- 3.2% (mean +/- SD). A significant correlation was obtained between the binding ratio (B/F) for dl-methadone and the total AAG concentration (r = 0.724; p less than 0.001). A multiple stepwise regression analysis showed that AAG was the main explanatory variable for the binding of the racemate. When concentrations of AAG variants were considered, a significant correlation was obtained between the binding ratio of dl-methadone and orosomucoid2 A concentration (r = 0.715; p less than 0.001), a weak correlation between dl-methadone and orosomucoid1 S concentration (r = 0.494; p less than 0.001), and no correlation between dl-methadone and orosomucoid1 F1 concentration (r = 0.049; not significant). Similar findings were obtained with the enantiomers. This study shows the importance of considering not only total AAG but also concentrations of AAG variants when measuring the binding of methadone and possibly of other drugs in plasma.

Adult↗
PubMed1998

Detection of methadone, methadone metabolites, and other illicit drugs of abuse in hair of methadone-treatment subjects.

The disposition of methadone, its metabolites, and other illicit drugs of abuse was investigated in head hair samples collected from heroin users (N = 20) enrolled in an outpatient detoxification study. Hair samples were assayed for methadone, methadone primary metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, EDDP), methadone secondary metabolite (2-ethyl-5-methyl-3,3-diphenylpyrroline, EMDP), cocaine, phencyclidine, heroin, and 6-acetylmorphine. Hair samples were cut, washed, and incubated in methanol. The methanolic hair wash and incubation fractions were purified with solid-phase extraction and assayed by gas chromatography-mass spectrometry. Methadone, methadone metabolites, cocaine, and phencyclidine were assayed quantitatively, and other drugs were measured qualitatively. The number of positive results and the corresponding concentration ranges were as follows: methadone, 0-15.0 ng/mg (N = 18); EDDP, trace (N = 13); EMDP, trace (N = 1); cocaine, 0->40 ng/mg (N = 14); phencyclidine, 0-1.5 ng/mg (N = 2); heroin, positive (N = 3); and 6-acetylmorphine, positive (N = 4). These data suggest that testing hair for methadone, methadone metabolites, and other illicit drugs of abuse may be useful to drug-treatment specialists as a means of verifying drug-use history, monitoring compliance, and providing a broad measure of drug exposure.

Gas Chromatography-Mass Spectrometry↗
PubMed1996

Replacement of (R)-methadone by a double dose of (R,S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics.

METHODS: Twenty-two patients receiving (R)-methadone maintenance treatment were switched to a double dose of (R,S)-methadone: blood samples were collected before and after the change, and the concentrations of the enantiomers were measured. In the second period, during racemic methadone treatment, important interindividual variability in the stereoselective disposition of the enantiomers of methadone was measured, with (R)/(S) ratios ranging from 0.63 to 2.40. This point should be taken into account particularly with respect to therapeutic drug monitoring of racemic methadone. RESULTS: A significant decrease P < 0.005 in the mean serum concentration/dose ratios of the active (R)-enantiomer before and after the change was measured (mean 3.97 and 3.33). CONCLUSION: Although of small amplitude (16%), this decrease confirms previously described adaptive changes in methadone pharmacokinetics during racemic methadone maintenance treatment and may necessitate, in some patients, a dose adjustment.

Adult↗
PubMed1977

Sustained release methadone salts and methadone-naloxone mixtures. Part 2: In vitro studies of methadone release.

Various tablet formulations, using two methadone salts namely methadone-alpha-naphthalenesulfonate and methadone-o-benzoylbenzoate and a number of methadone-naloxone combinations were prepared. The quantities of methadone released from these tablets in simulated gastric and intestinal fluids were examined using spectrophoto-metric studies. All formulations followed a typical release pattern, indicating a high degree of consistency of the formulations.

Delayed-Action Preparations↗
PubMedDate not supplied

Long acting methadone formulation. Part 3: Preparation and in vivo evaluation of tablets containing methadone salts and methadone-naloxone combinations.

The preparation and in vivo evaluation of the methadone salts, methadone-o-benzoylbenzoate and methadone-alpha-naphthalenesulfonate, and a number of methadone-naloxone formulations, in the form of three layered slowly eroding tablets, were examined. Male albino rats of the Wistar strain were used as experimental animals and the results indicated that a prolongation of the resistance to pain threshold was attained, though severe side-effects were observed. A number of animals died during these experimental procedures.

Animals↗
PubMed2004

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 (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 rac-methadone 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 > or = 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 > or = 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.

Adult↗
PubMed1999

Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment.

RATIONALE: One of the major problems in methadone maintenance treatment is to find optimal individual doses for the patients. OBJECTIVE: The present study investigated whether the use of rating scales together with enantioselective analysis of l-methadone might facilitate dose adjustments in a clinical situation. METHODS: Rating scales were used to evaluate subjective and objective signs of well-being in relation to plasma methadone concentrations in two groups of patients receiving methadone maintenance treatment. The first group (n = 25) was well-adjusted according to clinical observations and were satisfied with their methadone doses (86.2+/-4.3 mg). The second group (n = 25) was in need of the methadone dose adjustment; they complained of low dosing, despite a dose level of 69.2+/-4.0 mg/day. RESULTS: Results indicated a significant correlation between dose and methadone concentration among dissatisfied patients only. The trough levels of d,l-methadone and l-methadone, as well as their elimination rates, were similar in the two groups of patients. There was a variable predominance of l- over d-methadone in plasma (ratio approximate to 1.2; range 0.7-3.6). Illicit use of drugs by the patients was related to the methadone dose and to satisfaction with the dose received. Increased illicit drug use among dissatisfied patients was successfully eliminated by raising the methadone dose. Subjective and objective ratings of the satisfied patients were quite stable throughout the evaluation period, whereas the ratings of the dissatisfied patients were unstable. These patients seemed to be more sensitive to low trough levels of methadone than the satisfied patients. Associations between the subjective and objective ratings and plasma methadone, along with background characteristics, were characterized by multiple regression analyses. The plasma concentrations of l-methadone were one of the most important explanatory variables in these analyses. Associations between well-being and methadone concentrations in plasma were stronger for l-methadone than for d,l-methadone. CONCLUSIONS: Selective measurements of the active isomer and the use of rating scales should be of clinical value when monitoring methadone maintenance treatment patients.

Adult↗
PubMed1985

Enhanced development of dispositional tolerance to methadone by desipramine given together with methadone.

Rats given 2-day oral administration of methadone (15 mg/kg, twice on day 1 and once on day 2) by gastric tube developed dispositional tolerance to methadone analgesia as demonstrated by a decrease in analgesic response and by an increase in methadone metabolism. The increased metabolism of methadone was evidenced by a decrease in brain concentration of 14C-methadone and increases in the percentages of total 14C in liver or urine as 14C-water-soluble metabolites (14C-WSM) after the rats were challenged with a test dose of 14C-methadone. Two-day pretreatment with a combination of desipramine (DMI) (10 mg/kg, ip) and methadone (15 mg/kg, po) enhanced the development of dispositional tolerance to methadone analgesia which was evidenced by a greater decrease in the brain concentration of methadone and a greater increase in methadone metabolism as compared to those changes in rats pretreated with only methadone. Repeated treatment with DMI alone neither decreased the analgesic effect of methadone nor stimulated methadone metabolism. It is suggested that DMI given together with methadone promoted the induction of methadone metabolism in the liver by prolonging the enzyme-stimulating state of methadone, thus enhancing the development of dispositional tolerance to methadone.

Analgesia↗
PubMed2002

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.

BACKGROUND: Buprenorphine has recently been reported to be an alternative to methadone and LAAM for maintenance treatment of opioid dependent individuals, differing results are reported concerning its relative effectiveness indicating the need for an integrative review. OBJECTIVES: To evaluate the effects of buprenorphine maintenance against placebo and methadone maintenance in retaining patients in treatment and in suppressing illicit drug use. SEARCH STRATEGY: We searched the following databases up to 2001, inclusive: Cochrane Drugs and Alcohol Review Group Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Current Contents, Psychlit, CORK [www. state.vt.su/adap/cork], Alcohol and Drug Council of Australia (ADCA) [www.adca.org.au], Australian Drug Foundation (ADF -VIC) [www.adf.org.au], Centre for Education and Information on Drugs and Alcohol (CEIDA) [www.ceida.net.au], Australian Bibliographic Network (ABN), and Library of Congress databases, available NIDA monographs and the College on Problems of Drug Dependence Inc. proceedings, the reference lists of all identified studies and published reviews and authors of identified RCT's were asked about any other published or unpublished relevant RCT. SELECTION CRITERIA: Randomised clinical trials of buprenorphine maintenance compared with either placebo or methadone maintenance for opioid dependence. DATA COLLECTION AND ANALYSIS: Reviewers evaluated the papers separately and independently, rating methodological quality of concealment of allocation; data were extracted independently for meta-analysis and double-entered. MAIN RESULTS: Thirteen studies met the inclusion criteria, all were randomised clinical trials, all but one were double-blind. The method of concealment of allocation was not clearly described in 11 of the studies, otherwise methodological quality was good. Buprenorphine given in flexible doses appeared statistically significantly less effective than methadone in retaining patient in treatment (RR= 0.82; 95% CI: 0.69-0.96). Low dose buprenorphine is not superior to low dose methadone. High dose buprenorphine does not retain more patients than low dose methadone, but may suppress heroin use better. There was no advantage for high dose buprenorphine over high dose methadone in retention (RR=0.79; 95% CI:0.62-1.01), and high dose buprenorphine was inferior in suppression of heroin use. Buprenorphine was statistically significantly superior to placebo medication in retention of patients in treatment at low doses (RR=1.24; 95% CI: 1.06-1.45), high doses (RR=1.21; 95% CI: 1.02-1.44), and very high doses (RR=1.52; 95% CI: 1.23-1.88). However, only high and very high dose buprenorphine suppressed heroin use significantly above placebo. REVIEWER'S CONCLUSIONS: Buprenorphine is an effective intervention for use in the maintenance treatment of heroin dependence, but it is not more effective than methadone at adequate dosages.

Buprenorphine↗
PubMed2000

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment.

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.

Adult↗
PubMed2003

Increase of oral methadone dose in methadone injecting patients: a pilot study.

A pilot study was initiated in seven methadone injecting patients to examine whether intravenous methadone use in patients in oral methadone maintenance treatment could be decreased by increased oral methadone dose. During the study, patients had a standardized methadone dose increase for three weeks, followed by a 12-week follow-up period. Mean methadone doses prior to, and at the end of the study, were 99 mg/day and 163 mg/day, respectively. On week 15, the mean frequency of injection and the mean proportion of methadone dose injected were reduced to 46% of the values measured at week 0 (p = 0.043 and p = 0.028, respectively). Two patients did not modify their fre- quency, nor their dose of injected methadone, four patients decreased their use of injectable methadone, while one completely stopped injecting methadone. Since the completion of the pilot study, an augmentation of oral methadone dose has been proposed as a therapeutic option to 18 other methadone injecting patients. Five patients did not change their frequency of injection. They did, however, either completely stop or decrease their illicit opiate consumption. Nine patients decreased their frequency of methadone injection from a mean 95% down to 35%. Finally, four patients completely stopped injecting methadone. Although the present results have to be confirmed by controlled studies including a larger number of patients, when considering the high frequency of methadone injection in some places and the associated problems, the therapeutic option of increasing methadone dose should be considered further.

Administration, Oral↗
PubMed2000

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients.

AIMS: To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. METHODS: Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay. RESULTS: (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. CONCLUSIONS: Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

Adult↗
PubMed2001

Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study.

This paper provides a detailed analysis of the 2-year outcomes for 351 drug misusers allocated on an intention-to-treat basis to methadone maintenance or methadone reduction treatments. Both groups showed substantial reductions in their use of illicit drugs and in other outcome areas. However, whereas most methadone maintenance patients received maintenance, only about one third of those allocated to methadone reduction received methadone reduction, and many actually received a form of methadone maintenance. Reduction patients were more likely to receive low doses of methadone, and were less likely to remain in treatment. For maintenance patients, higher doses and retention in treatment were both associated with improvements in illicit heroin use at 2 years. For the reduction patients, the more rapidly the methadone was reduced, the worse the heroin use outcomes. For patients in both treatment conditions, reductions in heroin use were associated with improvements in other outcome areas. The more severely dependent patients showed better outcomes in methadone maintenance. Methadone reduction treatment processes were associated with poor outcomes, and many patients who were allocated to methadone reduction treatment did not receive reduction treatment as intended. This calls into question the appropriateness of either the initial treatment planning process or the treatment delivery process, or both. A clearer distinction should be made between methadone maintenance and methadone reduction. Treatment goals should be made explicit both to the patient and to the clinical staff at the start of treatment. We suggest the need for a reappraisal of the goals and procedures of methadone reduction treatment.

Chi-Square Distribution↗
PubMed1979

Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state.

A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methoadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD +/- 5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (T1/2) for both methadone-do and methadone-d3 were calculated from samples obtained 8--24 H following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22 +/- 2 h) than that of methadone-d0 (52 +/- 20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.

Administration, Oral↗
PubMed1984

Diazepam and methadone interactions in methadone maintenance.

Survey study data and high rates of diazepam use/abuse in methadone maintenance suggest that acute administration of diazepam with daily methadone doses may enhance methadone effects. Acute subjective and physiologic effects of single oral doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150%, and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose) were assessed under double-blind conditions. The subjects were five adult male patients on methadone maintenance with histories of diazepam abuse who were receiving 50 to 60 mg methadone a day. Physiologic measures were continuously monitored for 30 min before and for 2 hr after dosing. Pupil diameter and subjective responses were measured 15 min before dosing and 15, 30, 45, 60, 90, and 120 min after dosing. Methadone induced dose-dependent increases in pupil constriction and scores on a subjective opioid effects rating scale, but diazepam had no significant effect on either. The combination of methadone at 150% of the maintenance dose with 40 mg diazepam induced increases in these measures greater than those induced by either drug dose alone. Drug combinations, however, were more frequently identified as being benzodiazepine/barbiturate-like than as methadone-like. Thus although the subjective effects of the drug combination are distinguishable from those of methadone alone, diazepam with methadone in methadone maintenance appears to increase some physiologic and subjective opioid effects that may be related to the relatively great use/abuse of diazepam in this population.

Administration, Oral↗