Time of day of methadone consumption and illicit heroin use

One hundred clients receiving methadone substitution treatment participated in an investigation of the relationship between methadone dose, time of daily self-administration and reported illicit heroin and other drug use. The study was conducted at two outpatient clinics operating from a single site at the Maudsley Hospital, London. Forty-seven per cent of clients reported using illicit heroin on one or more occasions in the week before interview. Multivariate analysis of methadone dose, time of methadone administration and duration of treatment indicated that the time of methadone administration was the most important predictor of illicit heroin use. Clients who took their methadone before 1500 h were less likely to use heroin than those who consumed methadone later in the day. This finding suggests the possibility of reducing illicit heroin use by methadone maintenance clients through the structuring of treatment programmes so that supervision of methadone consumption occurs during the early part of the day.     

Improvements in retention rates and changes in client group with methadone maintenance streaming

This study evaluated changes in client population and in retention rates following the introduction of a system of methadone maintenance streaming. A low intervention and low supervision stream was combined with two abstinence-orientated streams. Privileges of take-home doses and local pharmacy dose collection were contingent on successful participation in the abstinence-orientated streams. The clinic also modified policy to allow clients greater control over dose levels. The case notes of the first 100 clients entering the programme in the year prior to the changes (1991) and in the year following the changes (1993) were compared. The results showed a significant increase in retention rates. The demographic and heroin using histories did not change, but the newer programme attracted a greater proportion of clients with no previous history of methadone maintenance treatment. Mean clinic dose increased from 45 mg to 63 mg when clients were allowed to exert control over dose. These findings reveal improved outcomes in a public methadone maintenance programme as a result of policy changes designed to give clients greater control of their treatment.     

An evaluation of community methadone services in Victoria, Australia: results of a client survey

One hundred and ninety-five metropolitan clients enrolled in the community-based methadone programme in Victoria, Australia were surveyed in order to evaluate client perspectives of methadone treatment delivered from primary health care settings. Results indicated that the average daily methadone dose was 41 mg, ranging from 7 mg to 140 mg. The majority of clients were satisfied with the programme and the services delivered by dispensing pharmacies and prescribing doctors. Most clients were found to have reduced their heroin use and criminal activity since commencing methadone. A number of concerns about the programme were identified, however, including the high proportion of weekly income spent on methadone-related activities and a high use of tranquillizers by clients on higher methadone doses. In general the community-based methadone programme was found to be an acceptable methadone of service delivery to metropolitan clients in Victoria, Australia.     

Correlates of methadone client retention: a prospective cohort study in Guizhou province, China

BackgroundMethadone client retention levels and treatment doses of patients vary widely in methadone clinics across China. Because methadone clinics have been available in China only recently, this study explored the relationship between methadone dosage and client retention in methadone maintenance programmes in Guizhou province.MethodsThe study used a prospective cohort study design. Injecting and non-injecting heroin-using clients who had been treated for no more than two and half months in one of eight methadone maintenance treatment clinics in Guizhou province were recruited into the cohort, beginning on 3 June 2006 and followed up until 1 June 2007. A total of 1003 participants were enrolled. Face-to-face interviews were conducted to collect baseline information, and clients’ daily doses were recorded.ResultsThe 14-month retention rate was 56.2%. Controlling for other covariates in the multivariate Cox model, a higher methadone dose was found to predict higher client retention. Retention was also associated with intention to remain in treatment for life and the clinic attended.ConclusionClients need to receive an adequate methadone dose to assure continued retention. Patients who expect to be treated for life have higher retention rates than patients who anticipate only short-term treatment. Key factors associated with successful clinics in China need to be elucidated.     

Tolerance, dependence and lethality in morphine-dependent mice after repeated oral administration of methadone

Mice were rendered tolerant to and dependent on morphine via a morphine pellet implantation. Three days later methadone hydrochloride was administered at a dose of 100mg/kg per os 3 hours after pellet removal and then daily for a total of 5--6 days. This dose of methadone was shown to exhibit a high efficacy for the blockade of morphine abrupt withdrawal jumping and only minimal toxicity. Under these conditions, the level of analgetic tolerance with respect to morphine and methadone and the level of dependence as measured by the naloxone ED50 were initially elevated by the morphine treatment. However, upon substitution with oral methadone these levels declined with time at a rate which did not differ from that of a group of mice receiving only water after morphine pellet removal. Despite these findings, the methadone treatment was associated with an increasing tolerance to methadone lethality during the administration of this narcotic which was nearly double that of a similarly treated water control group by the sixth day. This observation could not be explained by an elevation in the level of cellular tolerance rendered by the methadone treatment since the morphine LD50 was not elevated following identical treatment with morphine and then methadone. The significance of these results is discussed with respect to the role of methadone administration and its metabolism in the modification of tolerance and dependence.     

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects

There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose +/- standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 +/- 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.     

Supplementary methadone self administration among methadone maintenance clients.

The present study derives from two related questions: (1) Can methadone dose alterations act as reinforcers? (2) Do methadone dose alterations affect symptomatology of methadone maintained clients? Twenty three clients were offered six opportunities to alter their own methadone dose on a single day by as much as ±20 mg. Dose increases were selected on the vast majority of occasions (94.3%). Thus, supplemental methadone did function as a reinforcer for these clients. There was little evidence that dose increases which clients chose had any appreciable subjective effects. Neither symptomatology self reports nor judgements of dosage adequacy were significantly altered following acute methadone dose increases.The amount of supplemental methadone which clients self-administered could not be predicted by demographic characteristics, by length of time enrolled in maintenance treatment, by type or amount of illicit supplementary drug use, or by adequacy judgements of stable methadone dose. However, dosage self-regulation may have predictive potential as a measure of degree of behavioral dependence on narcotic drugs.     

Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis

The efficacy of methadone maintenance in opioid addiction was assessed in terms of programme retention rate and reduction of illicit opioid use by means of a meta-analysis of randomised, controlled and double blind clinical trials. The results were compared with interventions using buprenorphine and levo-acetylmethadol (LAAM). Trials were identified from the PubMed database from 1966 to December 1999 using the major medical subject headings 'methadone' and 'randomised controlled trial'. Data for a total of 1944 opioid-dependent patients from 13 studies were analysed. Sixty-four percent of patients received methadone, administered either as fixed or adjusted doses. Thus, 890 patients received > or = 50 mg/day (high dose group) and 392 were given < 50 mg/day (low dose group). Of 662 controls, 131 received placebo, 350 buprenorphine (265 at doses > or = 8 mg/day and 85 at doses < 8 mg/day) and 181 LAAM. High doses of methadone were more effective than low doses in the reduction of illicit opioid use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.26--2.36). High doses of methadone were significantly more effective than low doses of buprenorphine (< 8 mg/day) for retention rates and illicit opioid use, but similar to high doses of buprenorphine (> or = 8 mg/day) for both parameters. Patients treated with LAAM had more risk of failure of retention than those receiving high doses of methadone (OR 1.92, 95% CI 1.32--2.78). It is proposed that in agonist-maintenance programmes, oral methadone at doses of 50 mg/day or higher is the drug of choice for opioid dependence.     

Hemodynamic and cognitive effects of lofexidine and methadone coadministration: a pilot study

STUDY OBJECTIVE: To determine the hemodynamic and cognitive effects of lofexidine and methadone coadministration. DESIGN: Prospective, double-blind study. SETTING: Outpatient drug treatment research clinic. SUBJECTS: Fourteen participants (aged 18-45 yrs) with physical dependence on opioids. INTERVENTION: Subjects were stabilized on methadone maintenance therapy, starting with 30 mg/day and increasing by 10-mg/day increments, based on each subject's tolerability to achieve a target dose of 80 mg/day. After 3 weeks of methadone stabilization, lofexidine 0.4 mg/day or matching placebo were coadministered with methadone, in doses escalating by 0.2-mg/week increments, to achieve a target dose of 1.6 mg/day over the next 8 weeks. MEASUREMENTS AND MAIN RESULTS: Acute orthostatic vital signs and neuropsychological effects of lofexidine and methadone coadministration were monitored for 5 hours after the dose on the first day of each new lofexidine dose. Orthostatic vital signs and adverse events were assessed daily thereafter to determine the effects of repeated doses. Lofexidine significantly decreased sitting systolic and diastolic blood pressure (p=0.045 and p=0.033, respectively) compared with placebo (i.e., methadone alone). With lofexidine 0.4 mg/day, mean decreases in systolic and diastolic blood pressure were 27 +/- 17 and 15 +/- 16 mm Hg, respectively. No significant association was noted between changes in orthostatic vital signs and lofexidine dose. Decreased cognitive efficiency was associated with lofexidine administration, and higher lofexidine doses adversely affected performance on a mathematical task compared with placebo (p=0.0035). The rate of adverse events was no higher with lofexidine than with placebo; the majority (54.3%) were common adverse effects of lofexidine. CONCLUSION: Significant changes in hemodynamic and cognitive efficiency were observed with coadministration of lofexidine and methadone compared with methadone alone. When patients receiving methadone are prescribed lofexidine, they should be closely monitored for cardiovascular and cognitive changes.     

Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug users

The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. DESIGN: The methadone dose (20-140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. RESULTS: Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. CONCLUSIONS: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir.     

Electrocardiogram Characteristics of Methadone and Buprenorphine Maintained Subjects

ABSTRACT

There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose ± standard deviation, 69 ± 29 mg) and buprenorphine (n = 19, mean daily dose 11 ± 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 ± 29 mg/day) than methadone subjects without U waves (60 ± 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 ± 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 ± 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.     

A phase I study of temozolomide and everolimus (RAD001) in patients with newly diagnosed and progressive glioblastoma either receiving or not receiving enzyme-inducing anticonvulsants: an NCIC CTG study

Purpose This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately. Patients and Methods Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression. Temozolomide was administered at a starting dose of 150?mg/m(2)/day for 5?days every 28?days, and everolimus was administered continuously at a starting dose of 2.5?mg orally on a daily schedule starting on day 2 of cycle 1 in 28-day cycles. Results Thirteen patients receiving EIAEDs and 19 not receiving EIAEDs were enrolled and received 83 and 116 cycles respectively. Everolimus 10?mg daily plus TMZ 150?mg/m(2)/day for 5?days was declared the recommended phase II dose for the NEIAEDs cohort. In the EIAEDs group, doses were well tolerated without DLTs, and pharmacokinetic parameters indicated decreased everolimus exposure. Temozolomide pharmacokinetic parameters were unaffected by EIAEDs or everolimus. In the subset of 28 patients with measurable disease, 3 had partial responses (all NEIAEDs) and 16 had stable disease. Conclusion A dosage of 10?mg everolimus daily with TMZ 150?mg/m(2)/day for five consecutive days every 28?days in patients is the recommended dose for this regimen. Everolimus clearance is increased by EIAEDs, and patients receiving EIAEDs should be switched to NEIAEDs before starting this regimen.     

The use of token economy to reduce illicit drug use among methadone maintenance clients

The effects of a token economy in modifying the illicit polydrug use of 97 methadone maintenance clients was investigated over a period of two and a half years. Subjects' drug-free urinalysis reports were reinforced with points which could be redeemed to obtain methadone. Each subject's daily dose level varied with the point balance. A multiple baseline analysis showed that when methadone acquisition was in part made contingent upon drug-free urinalyses, illicit drug use declined rapidly. After six months, the token economy group's urines were 14% positive for illicit drugs compared to 39% in the traditional treatment group. As time in treatment increased, illicit drug use further declined. These results suggest a more effective and practical strategy for the treatment of polydrug abusing methadone maintenance clients than has previously been available.     

Craving despite extremely high methadone dosage

A clinical case study is presented of an opiate addict, currently under methadone maintenance treatment (MMT), who claims the need of a higher daily methadone dose. He is admitted to a closed metabolic ward, where he receives 250 mg methadone per day. During 24 h both pharmacokinetic parameters and craving levels are measured simultaneously. Results show extremely high methadone concentrations and its primary metabolite EDDP in plasma and urine. The craving level shows a distinguished peak around the methadone administration on both measured days. Withdrawal symptoms as well as self-reported craving did not correspond at all to the extremely high methadone concentration level in plasma. So we suggest that in individual cases if high methadone doses and plasma methadone levels are not able to diminish craving symptoms, dose adjustment should be accompanied by education regarding daily anticipatory increase of opiate craving.     

The use of plasma levels to optimize methadone maintenance treatment

The question of the optimal methadone dose during maintenance therapy is controversial. For both philosophical and practical reasons, therapeutic drug monitoring has not been generally used. Some therapists prescribe low doses of methadone more for psychological than pharmacological reasons. This study examines, in 104 methadone patients, the relation between self-rating, observer-rating, urine tests, HIV-1 serostatus, daily methadone doses and plasma levels of methadone. No differences were found between HIV-1 infected and seronegative patients in these respects. The optimal methadone plasma level as judged by self- and observer-rating was more than 150 ng/ml. For oral methadone, the best results are obtained in patients receiving more than 90 mg daily. We found a significant relationship between methadone dose and plasma levels, also in patients who also used illicit drugs. We conclude that therapeutic drug monitoring should become routine in methadone treatment to achieve optimum results, especially in patients who complain of withdrawal symptoms and continue high-risk behaviour.     

Notes from practice: Methadone prescribing in north central London—doses,compliance, goals and treatment setting

Aims: To examine methadone prescribing in public drug treatment services in inner London; compare levels of methadone prescribing with national guidelines and surveys; investigate whether methadone reduces illicit opiate use; and compare clients treated in specialist clinics with those in shared-care in general practice.

Methods: A cross-sectional survey of four drug treatment services in north central London.

Findings: Data were collected on 715 clients. Mean methadone dose was 57.2?mg but for clients on methadone maintenance, the mean dose was 63.4?mg. Reported heroin use fell from 24.8 days in the last 30 at initial assessment to 11 days (p?<?0.001). Clients on methadone doses greater than 60?mg were more likely than those on lower doses to test negative for morphine on urinalysis (49% vs. 39.4%, p?<?0.01). Clients in GP shared-care were more likely to have been in treatment for less time, be on lower doses of methadone and have stabilization or detoxification as their treatment goal.

Conclusions: Methadone treatment is associated with a reduction in illicit opiate use but not abstinence. Inadequate doses and lack of supervised consumption may in part explain the relatively poor response to treatment. Clients in GP shared-care received substantially different treatment from those in the specialist clinics.     

Factors predicting retention in treatment: 10-year experience of a methadone maintenance treatment (MMT) clinic in Israel

The aims were to identify predictors of treatment retention in an Israeli methadone maintenance treatment (MMT) clinic, and to compare the findings to other international settings. We prospectively studied 492 patients admitted since 1993 through 10 years to an Israeli MMT clinic associated with a university-affiliated tertiary care medical center. Analyses (Kaplan Meier and Cox regression) included methadone dose and urinalysis results (for methadone, cocaine, opiates, benzodiazepines, THC, amphetamines) of each patient in the first month and after 1 year in treatment (or during the last month if the stay was >3 months and <1 year) and patients' characteristics (modified ASI). The 1-year retention rate was 74.4%; 65.8% stopped opiate abuse after 1 year in treatment. On admission, 13.6% of patients had used cocaine: there was a net decrease of 61.6% after 1 year. Factors predicting prolonged retention in MMT treatment (Cox regression) were daily methadone dose of 100mg or greater, negative urine for opiates after 1 year, and being a parent on admission. We conclude that our good outcome results (high rate of retention after 1 year (74.4%), high proportion of opiate abuse cessation (65.8%), and net reduction in cocaine abuse, similar to normal standards in other MMT clinics elsewhere in the world, justify the expansion of the MMT clinic network in Israel in order to make treatment available to all those who need it. A protocol favoring higher methadone dosage as appropriate is recommended.     

Reducing benzodiazepine self-administration with contingent reinforcement.

The purpose of the present study was to determine whether drug self-administration by methadone maintenance clients can be influenced by offering methadone clinic privileges contingent upon reductions in drug use, and to compare the reinforcing efficacy in this regard of two different clinic privileges. Eight methadone maintenance clients who had histories of supplemental benzodiazepine use participated. In order to transfer illicit drug use to the treatment clinic, clients were prescribed diazepam, 20 mg/day, at the methadone clinic dispensary. Following assessment of baseline diazepam use, clients were offered, during 6-week blocks of time, either the chance to obtain a single methadone take-home dose or the chance to self-regulate their methadone dose for a single day. These privileges were contingent upon refusing prescribed diazepam at the clinic. During baseline weeks, 95.6% of available diazepam doses were requested. When take-home privileges were available, only 11.2% of diazepam doses were requested, while when dose self-control was available, 69.7% of doses were requested. The study showed that the supplemental drug use of methadone maintenance clients can be influenced by clinic privileges which are available contingent upon reductions of drug use. The medication take-home privilege was more effective as a reinforcer than was limited methadone dosage self-control. Methadone clinic privileges can be used as intervention tools to promote desirable therapeutic behavior change in drug addicts, and in particular to promote reductions in supplemental drug use.     

Book review of the psychodynamics of addiction by Martin Weegmann & Robert Cohen London: whurr publishers 2002, 180 pp. £19.50, ISBN 1 86156 335 3

Aims: To ascertain the level of knowledge about some of the effects of methadone and buprenorphine among 956 clients receiving treatment for opioid dependence at 9 public clinics and 50 community pharmacies in New South Wales, Australia.

Methods: A cross-sectional survey using both research-administered and self-complete questionnaires assessed medication-specific knowledge (derived from a literature review and information contained within client treatment information booklets), answered only by those receiving that treatment type. Assessment of knowledge was performed by asking participants to agree or disagree with four statements about their medication.

Findings: The majority of methadone clients were aware of the risks of overdose when methadone is taken by non-tolerant people and when methadone is mixed with other CNS depressants. Methadone clients were less aware of the protective effects of methadone in overdose and most believed that it rotted their teeth. Almost 50% of those on buprenorphine were not aware of the effects of dose increase on duration of action nor its relatively good safety profile compared to methadone. Buprenorphine clients were well informed about the importance of sublingual absorption and the risks of precipitated withdrawal.

Conclusions: This study identifies significant gaps in the knowledge that opioid-dependent clients have about methadone and buprenorphine that may lead to suboptimal use of medications and ambivalence over treatment. In addition to the provision of written material service providers need to consider systems to ensure that clinical information concerning treatment is received and understood by clients.     

Drug-seeking behavior during methadone maintenance

Six subjects were given the opportunity to work for saline placebo and hydromorphone (4 mg i.v.) several times weekly before and during a period of maintenance on methadone (100 mg p.o. daily). Measures of pupillary change and reports of liking in response to hydromorphone dropped to saline control levels when the daily dose of methadone was approximately 60 mg. Half of the subjects continued to work intermittently for hydromorphone for four weeks while they were receiving 100 mg of methadone daily. These data support the assumption that methadone maintenance reduces the reinforcement value of other opiates and behaviors associated with obtaining them.