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PubMed2003

Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses.

We examined in vivo the influence of cytochrome P4503A4 (CYP3A4) activity, measured by the 30 min plasma 1'OH-midazolam/midazolam ratio after oral administration of 7.5 mg midazolam, on the methadone steady-state trough plasma concentrations in a group of 32 patients in methadone maintenance treatment. Patients were grouped as receiving 'low' (up to 99 mg/day, n = 10), 'high' (100-199 mg/day, n = 11) and 'very high' (> or = 200 mg/day, n = 11) doses of methadone, and the CYP3A4 metabolic activity was compared between the three groups. (S)-methadone and (R,S)-methadone, but not (R)-methadone, concentrations to dose ratios significantly correlated with the midazolam ratios (r(2) = -0.17, P = 0.018; r(2) = -0.14, P = 0.032; r(2) = -0.10, P = 0.083, respectively), with a 76% higher CYP3A4 activity in the very high-dose group as compared with the low-dose group. Significant differences in the CYP3A4 activity were calculated between the three groups (P = 0.0036), and group-to-group comparisons, using the Bonferroni correction, showed a significant difference between the low-dose and the very high-dose group (P = 0.0039), between the high-dose and the very high-dose group (P = 0.0064), but not between the low-dose and the high-dose group (P = 0.070). The higher CYP3A4 activity measured in patients receiving very high methadone doses could contribute to the need for higher doses in some patients, due to an increased metabolic clearance. This, however, must be confirmed by a prospective study.

Adult↗

PubMed2000

Methadone, methadone treatment and non-fatal overdose.

This paper provides a mainly qualitative investigation of the role of methadone and methadone treatment in non-fatal illicit drug overdose. During 1997 and 1998, semi-structured interviews were conducted with 33 individuals in six hospital accident and emergency departments in two Scottish cities. The research identified four overdose situations related to methadone/methadone treatment. These were: (1) topping up a legitimate methadone prescription; (2) abusing another's methadone prescription; (3) preferring illegal drugs to prescribed methadone; and (4) failing to obtain prescribed methadone. The implications of these findings for methadone treatment policy and practice are discussed.

Adult↗

PubMed2002

Methadone-related deaths and mortality rate during induction into methadone maintenance, New South Wales, 1996.

The aims of this study were to describe the causes of death in cases found positive for methadone post-mortem, the proportion of cases involving methadone syrup, and of this group, the proportion not registered in methadone maintenance treatment (MMT) at time of death, and the number of deaths during induction into MMT in New South Wales in 1996. Coronial files of cases were reviewed. Data on file with the Pharmaceutical Services Branch, NSW Health Department on number of people admitted to and discharged from MMT in 1996, and details of methadone treatment for cases in MMT, were examined. Eighty-seven methadone positive cases were identified, of which 62 (71%) died of drug-related causes. Of 9835 people inducted into MMT in 1996, seven died within the first 7 days (21% of all deaths in MMT), for an overall mortality rate (MR) of 7.1 deaths per 10,000 inductions (95% CI 1.8-12.4). Fifty-one per cent (51%) of methadone syrup-related cases occurred in people not registered in MMT. This high proportion of diversion related deaths continues to be of concern. The findings reinforce to providers of MMT the necessity of careful procedures for initiation of treatment and support the need for ongoing surveillance of methadone related deaths both in and out of MMT.

Adult↗

PubMed2005

The relationship between take-away methadone policies and methadone diversion.

The development of policies in relation to unsupervised doses of methadone (take-away doses) should be based upon the best available evidence. There are both risks and benefits associated with take-away doses. This study aimed to explore the relationship between take-away policies and one measure of harm: methadone injection rates. Six different states in Australia were compared in relation to their methadone take-away policy and rates of methadone injection within their population of injecting drug users. At a simplistic level, those states with restrictive and less flexible take-away policies tended to have the lowest reported prevalence of methadone injection. However, this does not fully explain variability in methadone injecting. There were also considerable differences between those states with similar take-away policies. Variables which appear to impact upon methadone injecting rates include: take-away policies, drug preference, drug availability, treatment availability and degree of treatment penetration. Consideration of the benefits, rather than merely the harms, of various take-away policy options may provide an evidence-based platform for take-away policy development.

Australia↗

PubMed1999

Detection of methadone, LAAM, and their metabolites by methadone immunoassays.

l-Alpha-acetylmethadol (LAAM) was recently approved as a substitute for methadone. LAAM, methadone, and their common metabolite, methadol, are extensively N-demethylated. The structural similarities of LAAM and its metabolites to methadone suggest that they may cross-react in methadone immunoassays. To test this hypothesis, drug-free urine was fortified with LAAM, norLAAM, dinorLAAM, methadol, normethadol, dinormethadol, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), or 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) at 12 concentrations (0.03 to 100 microg/mL). Samples were analyzed using two enzyme immunoassays (Behring Diagnostics, EIA-b; Diagnostic Reagents, EIA-d); a fluorescent polarization immunoassay (Abbott, FPIA); two enzyme-linked immunosorbant immunoassays (Diagnostix, ELISA-d; STC Technologies, ELISA-s); a kinetic microparticles in solution immunoassay (Roche Diagnostic Systems, KIMS); and a radioimmunoassay (Diagnostic Products, RIA). LAAM had high cross-reactivity with ELISA-d (318.3%), RIA (249.5%), EIA-d (100.8%), KIMS (91.1%), and ELISA-s (75.3%). Methadol also displayed relatively high cross-reactivity as follows: EIA-d (97.8%), KIMS (85.4%), ELISA-d (70.3%), and FPIA (37.7%). Successive N-demethylations of LAAM and methadol were associated with loss of cross-reactivity. The methadone metabolites EDDP and EMDP showed little cross-reactivity. These findings suggest that LAAM use could result in positive immunoassay test results when using many of the commercially available methadone immunoassay kits and that confirmation of LAAM and its metabolites should be considered.

Cross Reactions↗

PubMed2006

Fluctuations in (R,S)-methadone pharmacokinetics and response among long-term methadone maintenance patients.

Knowledge of how methadone disposition may fluctuate during the course of maintenance treatment is presently limited. This study investigated long-term fluctuations in methadone pharmacokinetics in five methadone maintenance patients who participated in two 24-hour testing sessions separated by at least one year. Results indicated substantial fluctuations between sessions in dose-corrected average steady-state plasma (R)-methadone concentrations (Cav), ranging from a 51% decrease to a 466% increase. These fluctuations were not consistently associated with changes in methadone dose or self-reported withdrawal status. The plasma (S)-:(R)-methadone Cav ratio increased significantly (12%, P = 0.04) between the sessions, suggesting a different pattern of long-term change in the pharmacokinetics of each enantiomer over time. The pronounced and variable fluctuations in methadone disposition evident in these patients highlight the need for an individualized approach to patient dosing and monitoring.

Adolescent↗

PubMed2004

Comparison of perioperative racemic methadone, levo-methadone and dextromoramide in cats using indicators of post-operative pain.

OBJECTIVE: To compare three opioid agonist drugs for perioperative analgesia in cats. STUDY DESIGN: Prospective, blind, controlled, randomised trial. ANIMALS: Ninety client-owned cats, weighing 3.1 (2.1-4.5) kg, aged 14.6 (6.0-84.0) months, were studied. METHODS: Seventy-six cats, scheduled for ovariectomy, received either 0.6 mg kg(-1) racemic methadone, 0.3 mg kg(-1) levo-methadone, 0.05 mg kg(-1) dextromoramide or a saline placebo IM. Behaviour and body position were assessed and scored 20 minutes later by a single 'blinded' observer. Anaesthesia was induced with propofol and maintained with halothane. Heart rate (HR), respiratory rate (RR), Fe'CO2 and SpO2 were recorded during anaesthesia. Post-operatively, pain was categorised as absent, moderate or severe, on the basis of appearance, behaviour and response to palpation of the surgical wound (pain score). Appearance, pain scores and physiological variables were monitored every 30 minutes, for a duration of 4 hours. Differences between time-dependent continuous variables were analysed using mixed models for repeated measurements. Differences in categorical, time-dependent variables were analysed using chi2-tests. Significance was set at p < or = 0.05. RESULTS: There were no significant changes in appearance after pre-anaesthetic medication. After surgery, there was no association between appearance and pain score with HR or RR. The assessment of pain depended on comparison with the placebo group, by comparing animals' reactions to wound palpation. Sixteen of the 18 cats in the placebo group and 14 of the 19 cats in the dextromoramide group showed signs of moderate-to-severe pain after surgery. In the levo-methadone group (n = 20), one animal showed pain after 60 minutes and two after 120 minutes. One cat in the racemic methadone group (n = 19) showed pain signs and behavioural changes at 60 minutes. Compared to the two methadone groups, 'rescue' analgesia was required more often in cats treated with dextromoramide or saline. CONCLUSION AND CLINICAL RELEVANCE: Dextromoramide (0.05 mg kg(-1)) was ineffective, while racemic methadone (0.6 mg kg(-1)) and levo-methadone (0.3 mg kg(-1)) provided effective analgesia in cats following ovariectomy, without behavioural, respiratory or cardiovascular side effects.

Analgesics, Opioid↗

PubMed2002

Withdrawal from methadone maintenance treatment. Reasons for not trying to quit methadone.

Although factors associated with successful termination of methadone maintenance treatment (MMT) have been well studied, the question of why certain methadone patients try to taper off methadone while others do not is still unanswered. Those patients who wish to continue MMT should of course be allowed to stay in treatment. However, even if only a small portion of the MMT patients wish to quit maintenance treatment, they should be offered all possible support by the treatment staff to maximize the possibility of a successful outcome. In the present study, we compared two groups of well-functioning MMT patients with respect to background factors, methadone-related factors, drug-related factors and psychological characteristics: one group consisted of patients who were trying to terminate their MMT (group 1) and the other group consisted of patients who were not trying (group 2). Each of the groups contained 25 well-rehabilitated subjects matched by age, gender and the number of years in MMT. The results show that the patients who were not trying to terminate MMT (in comparison to group 1) were not influenced by others to try to quit methadone, had a long history of opiate use as well as mixed drug use prior to MMT, had a higher methadone dose and reported a lower degree of anticipated abstinence symptoms. According to the statements of the subjects in group 2, the most important reason for not quitting treatment was the belief that they needed the methadone. The fact that they knew others who had failed to quit MMT and low confidence in succeeding were other common answers. Further, our results suggest that patients who were satisfied with their overall drug situation were less inclined to make a withdrawal attempt.

Adult↗

PubMed2002

Methadone and heroin antinociception: predominant delta-opioid-receptor responses in methadone-tolerant mice.

Antinociceptive tail flick responses to heroin and 6-monoacetylmorphine mediated in the brain by mu-opioid receptor are switched by morphine pellet implantation to delta1- and delta2-opioid-receptors mediation, respectively. Present results showed that the mu-receptor response (inhibited by beta-funaltrexamine) to methadone was changed by morphine pellet implantation to delta1 (inhibited by 7-benzylidenenaltrexone)- and delta2 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from mu- to delta-opioid receptors for heroin and methadone but not for morphine (beta-funaltrexamine continued to inhibit). Methadone mu action in the brain was linked through a descending system to activate spinal serotonin receptors (inhibited by methysergide), but this link was gone in the methadone-pellet-implanted group. In the latter group, the new delta1- and delta2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that mu receptors on a given neuron were not changed into delta receptors. Preliminary results showed that delta-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 129S6/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover delta-agonist actions?

Analgesics, Opioid↗

PubMed1978

Serum methadone as an aid in managing methadone maintenance patients.

Serial serum methadone levels were obtained in two patients who were experiencing significant difficulties (including subjective and objective evidence of the opiate withdrawal syndrome) while on methadone maintenance. A precipitous drop in blood levels of methadone was recorded 2 to 6 hours after ingestion. It was during this same time period that withdrawal symptoms were most severe. When methadone was administered on a divided dosage regimen, there was a dramatic clinical improvement in both patients and a marked flattening of the curve of serum methadone levels. This pilot study suggests that the current practice of administering methadone as a single daily dose to all patients needs reconsideration; serial serum methadone levels may be helpful in determining which patients do better on a divided dosage regimen.

Adult↗

PubMed2005

Illicit methadone injecting during methadone maintenance treatment in a specialised out-patient clinic.

AIM: The injection of non-sterile methadone designed for oral consumption is associated with serious health risks. There is only a small number of studies on this topic, with divergent results. The main aim of the present study was to obtain data on the frequency of methadone injecting in a state out-patient clinic specialised in substance use disorders. METHODS: Eighty patients in methadone maintenance treatment were interviewed with a short questionnaire. Mean age was 32 years, 76% were male, mean methadone dose was 55 mg. RESULTS: Twenty-six patients (32%) indicated having injected methadone at least once in their life. Only four patients (5%) reported having injected methadone within the preceding month (mean dose 56 mg). All four had injected additional substances during this month. CONCLUSIONS: Frequency rates appeared low compared with other studies despite a generous take-away policy. The results suggest an association between methadone injecting and a more general tendency to inject substances.

Adult↗

PubMed1992

Plasma methadone measurements and their role in methadone detoxification programs.

We monitored eight patients who were receiving a decreasing dose of methadone for treatment for opioid addiction (detoxification). Patients with plasma concentrations of methadone less than 0.05 mg/L experienced withdrawal symptoms, relapsed, and re-abused illicit drugs. Four patients took extra methadone (illicitly obtained) during detoxification. None of the eight patients in our study were successfully weaned off methadone: all left the methadone detoxification program before the completion of treatment. Two patients subsequently returned to a fixed methadone program elsewhere, and four relapsed and returned to illicit drug misuse. Plasma measurements may help clinicians assess patients during methadone detoxification.

Adult↗

PubMed1987

Application of a new method for measurement of plasma methadone levels to the use of epidural methadone for relief of postoperative pain.

A method is described for measurement of plasma methadone concentrations using a gas chromatic technique that is rapid and specific and enables the detection of concentrations of less than 1 ng/ml in plasma samples of only 1 ml. The method, when used to determine the plasma methadone levels in patients given continuous epidural infusions of methadone plus on-demand supplementation for relief of postoperative pain, showed plasma methadone plateaus of around 10 ng/ml (starting at 15 min and lasting over 2 hr) and 20 ng/ml (starting at 3 hr and lasting over the period of treatment) (P less than 0.001) after an initial 2-mg methadone epidural bolus and with continuous epidural methadone. Mean plasma methadone levels of around 10 ng/ml were associated with pain relief. Analgesia could be safely maintained for 24 hr.

Adult↗

PubMed1977

Stereospecific antibodies to methadone. I. Radioimmunoassay of d,l-methadone in human serum.

Anti-d,l-methadone antibodies were produced in rabbits immunized with d,l-methadol-hemisuccinate thyroglobulin conjugate. Using the antiserum, a radioimmunoasay (RIA) for determination of d,l-methadone in human serum has been developed and is described. Concentration of d,l-methadone of 1.4 pmol in a native serum sample (volume 0.1 ml or less) could be measured directly by RIA. The antibodies crossreact 100% with d,l-methadone, 50% with d-methadone, 50% with l-methadone and 100% with alpha-d-methadol. No crossreactivity was found with alpha 1-methadol, morphine, meperidine, dextropropoxyphene, 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline and 2-ethylidene-l, 5-dimethyl-3,3-diphenylpyrrolidene. High sensitivity and small sample requirements make this method suitable for future monitoring of patients on methadone maintenance and for studies where other procedures have lack of sensitivity.

Animals↗

PubMed1980

Biliary secretion of methadone and methadone metabolites in man.

A method for the simultaneous quantitative analysis of human bile for methadone, and two of its metabolites: pyrrolidine, the major metabolite formed by N-demethylation, and pyrroline, formed by a second N-demethylation, using gas liquid chromatography and both radiolabeled methadone and pyrrolidine as standards for determinations of recovery has been developed. This method has been applied to the quantitative analysis of methadone and its metabolites in bile collected over three days from T-tube drainage in a methadone-maintained patient who had undergone cholecystectomy and common bile duct exploration but who had no liver disease. The concentrations and total amounts of the pyrrolidine metabolite far exceeded those of methadone and of the pyrroline metabolite. The amounts of unchanged methadone found in bile (as in previous studies of feces) were found to be very low. Therefore, at least in this patient, a significant enterohepatic circulation of unchanged methadone is unlikely.

Bile↗

PubMed2001

The effect of tobacco smoking on subjective symptoms of inadequacy ("not holding") of methadone dose among opiate addicts in methadone maintenance treatment.

The objective of this study was to examine the relationship between subjective symptoms of inadequacy of methadone dose (not feeling "held") and tobacco smoking in patients in methadone maintenance treatment (MMT). This was a cross-sectional study of smoking behaviour, investigating subjective, physiological and psychological symptoms. The study took place in a community-based methadone maintenance clinic of a psychiatric teaching hospital in South London. Fifty adult opiate addicts (37 males and 13 females) were on a stable daily methadone dose; the number of cigarettes smoked during the day and previous day of investigation, salivary cotinine measurements and carbon monoxide (CO) from expired air were measured. The Methadone Symptom Checklist (MSC) was used to score withdrawal symptoms encountered in patients not feeling "held" during MMT The Hamilton Anxiety Score was also used. The prevalence of tobacco-smoking was high (98%), with two-thirds (68%) smoking self-fabricated cigarettes ("roll-ups"). Scores from rating scales measuring symptoms of not being "held" correlated with number of cigarettes smoked the previous day (p < 0.05). A similar correlation was found with the Hamilton Anxiety Score. However, there was no correlation between rating scale scores and either salivary cotinine concentration or CO from expired air. Methadone patients who smoke more are significantly more likely to report problems of not feeling "held" by their methadone dose and they also show a higher level of anxiety. However, this increased cigarette consumption is not reflected in increased salivary continine levels or levels of CO in expired air, and it may be that the raised level of anxiety leads to a smoking-pattern consisting of frequent lighting-up of cigarettes or "roll-ups" which are consumed incompletely and/or not smoked by inhalation.

Journal Article↗

PubMed1975

Disposition of methadone in methadone maintenance.

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C-methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N-monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.

Adult↗

PubMed1996

Postnatal methadone exposure doe not prevent prenatal methadone-induced changes in striatal cholinergic neurons.

On postnatal day 4, rats exposed to methadone prenatally but fostered to control dams, as well as those fostered to dams treated with methadone, exhibited significant reductions in striatal acetylcholine (ACh) content. This suggests that neonatal withdrawal from methadone is not responsible for the effects of prenatal exposure on cholinergic development in the early perinatal period. The effects of perinatal exposure to methadone on serotonin (5HT) and dopamine (DA) metabolism do not appear to be strictly related to changes in ACh content. Although prenatal exposure reduces 5-hydroxyindole acetic acid (5HIAA) content, changes in 5HT content prevent significant changes in the ratio 5HIAA/5HT. Pups exposed to methadone only prenatally (withdrawal group) exhibited a decreased DOPAC/DA ratio, whereas pups in the treatment group exposed to methadone both pre- and postnatally exhibited an increased DOPAC/DA ratio.

3,4-Dihydroxyphenylacetic Acid↗