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PubMed2006

Stereoselective quantification of methadone and a d(6)-labeled isotopomer using high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry: application to a pharmacokinetic study in a methadone maintained subject.

There is evidence that the apparent oral clearance of rac-methadone is induced during the early phase of methadone maintenance treatment. However, it is not known if this is due to changes in bioavailability or if this phenomenon is stereoselective. This knowledge can be obtained by administering a dose of stable-labeled methadone at selected times during ongoing treatment. Therefore, the authors developed a stereoselective high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry assay for the quantification of the enantiomers of methadone and a d(6)-labeled isotopomer. The compounds were quantified in a single assay after liquid-liquid extraction and stereoselective high performance liquid chromatograph with atmospheric pressure chemical ionization-mass spectrometry detection. The following ions were monitored: m/z 310.15 for unlabeled methadone; m/z 316.15 for methadone-d(6); and m/z 313.15 for the methadone-d(3) (internal standard). Calibration curves ranged from 0.5 to 75 ng/mL for each compound. Extraction recovery was approximately 80% for all analytes, without evidence of differences between the unlabeled and stable-labeled compounds or concentration dependency. Minor ion promotion was observed (<15%) but this was identical for all analytes including the d(3)-labeled internal standard, with peak area ratios in extracted samples identical to control injections. The isotopomers did not alter each others' ionisation, even at 10:1 concentration ratios, and 10-fold diluted samples were within 10% of the nominal concentration. Assay performance was acceptable, with interassay and intra-assay bias and precision <10% for all compounds, including the upper and lower limits of quantitation. In conclusion, the assay was successfully applied to quantify the concentration of the methadone enantiomers of both orally administered unlabeled methadone and an intravenous 5 mg dose of methadone-d(6) in a patient receiving chronic oral methadone maintenance therapy.

Administration, Oral↗

PubMed1995

Cocaine abuse in methadone maintenance patients is associated with low serum methadone concentrations.

Cocaine abuse in methadone maintenance patients has emerged as a significant clinical problem. To determine if raising the daily methadone dosage is an effective way to eliminate cocaine abuse, 74 methadone maintenance patients maintained at daily dosages between 30 and 80 mg and who chronically abused cocaine were studied by a standard protocol. A total of 21 (28.4%) subjects ceased cocaine abuse when their methadone dosage was progressively raised to a maximal daily dose of 160 mg. Cocaine abuse appeared to accelerate elimination of methadone, since inadequate methadone serum concentrations (below 100 ng/ml) were found in 48 of 67 (71.6%) subjects tested 24 hours after a 100 mg oral methadone dose. Although cocaine abuse in methadone maintenance patients may respond to raising the daily methadone dosage, alternative treatments for cocaine abuse in methadone maintenance patients must be identified since cocaine abuse may lower serum methadone concentrations.

Adult↗

PubMedDate not supplied

Brain and plasma levels of methadone and their relationships to analgesic activity of methadone in rats.

The levels of methadone in brain and plasma of rats after acute administration of several different doses of methadone were measured at several time points and relationships to analgesic activity were examined. Both brain and plasma levels of methadone as well as the analgesic activity of methadone, expressed as analgesic area and as percentage of maximum possible effect, were all increased by increasing dosage. All these measurements dropped rapidly after reaching the peak levels 30 min after administration of methadone. At the time of maximal analgesia, the analgesic effect of methadone was quantitatively related to both brain and plasma levels of methadone with 50% of the analgesic maximum possible effect corresponding to the concentrations of 1.44 nmol/g and 0.52 nmol/ml of methadone in brain and plasma, respectively. Our data suggest that measurement of changes in the plasma concentration of methadone at the time of maximal analgesia reflects changes in the brain concentration of methadone and may provide an index of changes in the analgesic effect of methadone.

Analgesics, Opioid↗

PubMed2000

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.

BACKGROUND: Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. METHODS: Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). RESULTS: Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. CONCLUSIONS: In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

Adult↗

PubMed2001

Intravenous methadone in the management of chronic cancer pain: safe and effective starting doses when substituting methadone for fentanyl.

BACKGROUND: Patients often are rotated from other opioids to methadone when side effects occur before satisfactory analgesia is achieved. Various strategies have been proposed to estimate safe and effective starting doses of methadone when rotating from morphine and hydromorphone; however, there are no guidelines for estimating safe and effective starting doses of methadone when rotating from fentanyl. METHODS: The authors prospectively observed 18 consecutive patients experiencing chronic pain from cancer who underwent opioid rotation from intravenous patient-controlled analgesia (PCA) with fentanyl to intravenous PCA with methadone. Patients were switched from fentanyl to methadone because of uncontrolled pain associated with sedation or confusion. A conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone was used to calculate the initial dose of methadone in all patients. RESULTS: Mean pain scores decreased from 8.1 to 4.8 on Day 1 after the switch and to 3.22 on Day 4 after the switch. Mean sedation scores were 1.5 before the switch and 0.44 and 0.16 on Days 1 and 4, respectively. Among the 6 patients who experienced confusion while on fentanyl before the switch, 5 improved within 2 days of the switch. None of the patients experienced toxicity from methadone. CONCLUSIONS: On the basis of this preliminary study, the authors suggest that when switching from intravenous fentanyl to methadone a conversion ratio of 25 microg/hour of fentanyl to 0.1 mg/hour of methadone may be safe and effective.

Adult↗

PubMedDate not supplied

Methadone-disulfiram interaction during methadone maintenance.

In an attempt to characterize a possible drug interaction between methadone and disulfiram, 500 mg/day insulfiram was administered orally for seven days to seven subjects on methadone maintenance. Plasma methadone concentrations and urinary excretion of methadone and its pyrrolidine and pyrrolidone metabolites were measured and subjective symptoms of opiate intoxication and abstinence were noted before, during, and after disulfiram administration. Mean trough plasma methadone concentrations and terminal half-lives were lowest and shortest during disulfiram treatment, although this finding was not statistically significant. The ratio of urinary methadone to its pyrrolidine metabolite decreased during disulfiram treatment in all subjects. There is no evidence to support our original hypothesis that disulfiram might inhibit methadone metabolism. In contrast, urinary excretion of the major pyrrolidine metabolite increased relative to excretion of methadone. This suggests enhanced N-demethylation during disulfiram treatment. Disulfiram had no effect on opiate intoxication or abstinence symptoms. Disulfiram may alter methadone disposition, but in this study it was shown that in doses used for management of alcoholism there was no significant interaction between disulfiram and methadone.

Adult↗

PubMed1986

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single 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). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.

Adult↗

PubMed2005

Free and bound enantiomers of methadone and its metabolite, EDDP in methadone maintenance treatment: relationship to dosage?

OBJECTIVES: To determine the effects of metabolism and protein binding on the relationship between administered dose, blood levels of R methadone and biological response by measuring the free and protein-bound forms of the R and S enantiomers of methadone and EDDP, its metabolite. DESIGN AND METHODS: To measure free and total drug, trough levels were collected from 45 methadone clients. To measure free methadone, samples were filtered using ultrafiltration with a MW weight cut-off of 10,000 and extracted using liquid-liquid extraction. The solvent was evaporated and samples reconstituted in mobile phase for analysis by LC/MS/MS. Total analyte was determined by extracting unfiltered samples. Enantiomeric separation of methadone and EDDP was by chiral chromatography. RESULTS: The presence of unmetabolized methadone suggested that none of the patients were very fast metabolizers. R and S forms were metabolized at the same rate at all administered doses. Free R methadone levels correlated both with methadone dose and with the total amount of R methadone. The free fraction of R methadone (%free R) was higher at lower doses than at high doses, varied from 5 to 25% and was inversely proportional to the total dose of administered drug in a relationship that was logarithmic and non-linear. CONCLUSIONS: By measuring the free, biologically active form of the drug, we were unable to account for the large variations in dose required between different patients to prevent the onset of withdrawal symptoms. The reason for the large range in dosage may be multifactorial.

Blood Proteins↗

PubMed1999

The difference between methadone and morphine in regulation of delta-opioid receptors underlies the antagonistic effect of methadone on morphine-mediated cellular actions.

To investigate the cellular and molecular basis for using methadone in substitution therapy for morphine addiction, the difference between methadone and morphine in causing desensitization of delta-opioid receptors was examined, and the effects of methadone pretreatment on opiate-induced inhibition of forskolin-stimulated cAMP accumulation was studied. Methadone substantially attenuated the ability of [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and methadone to inhibit forskolin-stimulated cAMP accumulation. Methadone was able to block the morphine-induced compensatory increase in intracellular cAMP levels and naloxone-precipitated cAMP overshoot after chronic exposure to morphine. The protein kinase inhibitor (1-5-isoquinolinesulfony)-2-methylpiperazine) (H7) could significantly block the chronic methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. The protein kinase inhibitor chelerythrine was able to block the acute methadone treatment-induced loss of the ability of DADLE to inhibit adenylate cyclase. In contrast, morphine did not cause a substantial desensitization of the delta-opioid receptor. These results indicate that methadone is different from morphine in its regulation of the delta-opioid receptor. In addition, these results also indicate that the mechanisms of delta-opioid receptor desensitization induced by acute and chronic methadone treatment are different.

Adenylyl Cyclases↗

PubMed1997

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme.

AIMS: Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug. METHODS: Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20-80 mg (0.3-1.14 mg kg-1). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms. RESULTS: The mean (95% CI) milk/plasma ratio was 0.44 (0.24-0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15 l kg-1 day-1 and a bioavailability of 100% was 17.4 (10.8-24) microg kg-1 day-1. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07-3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5 microg l-1. Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen. CONCLUSIONS: We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.

Adult↗

PubMed2003

Methadone and metabolite urine concentrations in patients maintained on methadone.

As regulatory control over methadone maintenance relaxes, the need for methods of monitoring compliance will increase. In community clinics, monitoring would most likely involve immunoassays of outpatients' trough urine specimens. There are no published norms for such data. Therefore, we determined concentrations of methadone in 1093 urine specimens collected thrice weekly in 27 outpatients during up to 17 weeks of observed methadone ingestion (35 to 80 mg/day) using a semiquantitative homogeneous enzyme immunoassay (CEDIA). We used a separate CEDIA assay to measure methadone's main metabolite, 2-ethylidene-3,3-diphenylpyrrolidine (EDDP), which may help detect compliance in fast metabolizers or patients who adulterate samples to simulate compliance. Methadone concentrations were more variable than those of EDDP. Concentrations of methadone were < 100 ng/mL in one specimen, between 100 and 300 ng/mL in 27, and >or= 300 ng/mL in all others. EDPP concentrations were >or= 100 ng/mL in all specimens, suggesting that EDDP should be detectable in urine from compliant patients. Methadone and EDDP concentrations significantly increased with methadone dose and (in one participant with poor clinic attendance) significantly decreased following missed methadone doses. Nevertheless, variability was too great to permit estimation of methadone dose (or detect a single missed administration) from any single specimen.

Drug Monitoring↗

PubMed1984

Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration--response relationships.

The aim of the study was to establish whether there exists a relationship between blood methadone concentration and analgesic response and the intrasubject and intersubject variability in this relationship. Sixteen general surgical (upper abdominal) and orthopedic (spinal fusion) patients were administered methadone (20 mg, iv) as part of the general anesthetic and supplementary methadone doses (usually 5 mg, iv) in the recovery ward until postoperative pain was controlled effectively. The criteria established for the administration of supplementary methadone doses were the co-existence of 1) spontaneous reporting of significant pain by the patient; 2) an unstimulated respiratory rate of greater than 10 breaths/min, and 3) no significant depression of the level of consciousness. A median of two supplementary iv methadone doses (range 1-3) were administered to the patient by a titration method in the recovery ward to obtain effective pain control. This was achieved by a median dose of 10 mg (range 5-20 mg) in addition to the 20 mg intraoperative dose. Serial blood samples were collected for the estimation of blood methadone concentration following all doses. The methadone concentration in the blood sample collected immediately prior to a supplementary dose was termed the minimum effective concentration (MEC [methadone]). The mean (+/- SD) coefficient of variation in MEC (methadone) for the 16 patients was 21 +/- 10% (range: 7-38%), while the mean MEC for methadone was 57.9 +/- 15.2 ng/ml (range: 34.5-80.3 ng/ml) in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1982

Quantitation of methadone enantiomers in humans using stable isotope-labeled [2H3]-, [2H5]-, and [2H8]Methadone.

A new technique for simultaneous stereoselective kinetic studies of methadone enantiomers was developed using three deuterium-labeled forms of methadone and GLC-chemical-ionization mass spectrometry. A racemic mixture (1:1) of (R)-(-)-[2H5]methadone (l-form) and (S)-(R)-[2H3]methadone (d-form) was administered orally in place of a single daily dose of unlabeled (+/-)-[2H0]methadone in long-term maintenance patients. Racemic (+/-)-[2H8]methadone was used as an internal standard for the simultaneous quantitation of [2H0]-, [2H3]-, and [2H5]methadone in plasma and urine. A newly developed extraction procedure, using a short, disposable C18 reversed-phase cartridge and improved chemical-ionization procedures employing ammonia gas, resulted in significant reduction of the background impurities contributing to the ions used for isotopic abundance measurements. These improvements enabled the measurement of labeled plasma methadone levels for 120 hr following a single dose. This methodology was applied to the study of methadone kinetics in two patients; in both patients, the analgesically active l-enantiomer of the drug had a longer plasma elimination half-life and a smaller area under the plasma disappearance curve than did the inactive d-form.

Adult↗

PubMed1977

Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome.

The relationship between the quantity of methadone ingested by the pregnant mother, the quantity of methadone in maternal and neonatal body fluids, and the subsequent neonatal withdrawal course was studied. The severity of the neonatal withdrawal syndrome was found to be related to the total dose of methadone ingested by the mother during the last 12 weeks of pregnancy (p less than 0.02), the maternal dose of methadone at delivery (p less than 0.01), and the intrapartum serum methadone levels (p less than 0.01). The cord blood levels of methadone were consistently lower than the maternal serum levels. Amniotic fluid methadone levels were not constantly related to maternal or neonatal serum methadone levels. Concentrations of methadone 10 to 60 times greater than that of cord blood were found in neonatal urine.

Amniotic Fluid↗

PubMed2001

Methadone analgesia in cancer pain patients on chronic methadone maintenance therapy.

Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy.

Adult↗

PubMed1999

Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture for drug users in methadone maintenance.

BACKGROUND: Tuberculosis is common in drug users, although compliance with therapy may be difficult in this population. OBJECTIVE: To evaluate an approach to enhancing compliance with tuberculosis chemoprophylaxis in drug users enrolled on methadone maintenance utilizing an isoniazid (INH)-methadone admixture. DESIGN: A prospective cohort study. SETTING: A drug treatment program in New Haven, Connecticut, USA. PATIENTS: Opioid-dependent drug users enrolled in methadone maintenance. INTERVENTION: Liquid isoniazid was mixed into subjects' daily dose of methadone. Vitamin B6 was given to subjects for self-administration. MEASUREMENTS AND MAIN RESULTS: Number of eligible subjects, reasons for not starting therapy, number starting therapy, proportion completing therapy and median duration of INH therapy were calculated. Thirty-nine subjects were eligible for INH chemoprophylaxis: 34 (87%) received INH mixed directly in their methadone and five (13%) had their INH consumption supervised by a nurse. Among these subjects, 72% (28/39) completed therapy. Among the 11 subjects who discontinued INH, discharge from the methadone maintenance program was the most common reason--73% (8/11). Thus, among the 31 subjects who were not discharged from methadone maintenance, 90% (28/31) successfully completed INH prophylaxis. The median duration of therapy was 182 days. CONCLUSIONS: Tuberculosis chemoprophylaxis using a liquid isoniazid-methadone admixture appears to be an effective approach to enhancing compliance with this therapy in methadone-maintained drug users.

Antitubercular Agents↗

PubMed1996

The efficacy of L-methadone and racemic methadone in substitution treatment for opiate addicts--a double-blind comparison.

In a two-week double-blind trial l-methadone and racemic methadone were compared for efficacy in substitution treatment for opiate addicts. Before the trial the twenty-six participants had been on stable doses of l-methadone. Patients with evidence of current serious psychological problems were excluded. Patients were evaluated twice a week using a modified FSUCL, physician's withdrawal checklist, self-rating withdrawal scale, and the Beschwerden-Liste (complaint list) according to von Zerssen. Between addicts continuing on l-methadone (n = 13) and those now receiving racemic methadone (n = 13) there were no statistically significant differences. In particular, patients receiving racemic methadone did not complain more frequently of withdrawal symptoms. In a follow-up period of nine weeks after replacement of l-methadone with racemic methadone, there was also no significant increase in complaints about withdrawal symptoms, although six patients needed an elevation of their daily dosage by at least 20 mg racemic methadone.

Adult↗

PubMed1992

[Health status of methadone recipients before entering a methadone program].

Data were analyzed from 905 opiate addicts who participated for the first time in a methadone maintenance program in the Canton of Bern, Switzerland, between 1979 and 1989. Data of their physical and psychological state at the time of application for the methadone maintenance program were related to data of the addiction history and program progress. Only one fifth of the participants in the methadone maintenance program report to be in good health. Poorer health corresponds to reported psychological disorders. No correlation between demographical data and health status could be found, except that less qualified patients were in poorer health. Poorer health status is associated with the consumption of a higher amount of heroin per kg body weight and often with consumption of benzodiazepines before entrance into the methadone maintenance program. Methadone maintenance patients with a lower health status are given higher methadone doses. Compared to patients in better shape, more do not work before and during the methadone program. The physicians express less optimism with regard to the success of the program in patients in poorer health, and these are more often expelled from the program by their physicians or the health department. The results indicate that patients generally profit from the methadone maintenance treatment. However, better integrated patients and persons in better health may derive greater benefit from the methadone maintenance treatment.

Adult↗