Predicting drinking outcomes: Evidence from the United Kingdom Alcohol Treatment Trial (UKATT).

AIMS: To explore client characteristics that predict drinking outcomes using data from the UK Alcohol Treatment Trial (UKATT). METHODS: Multiple linear regression was used to determine if there were any characteristics, measured before the start of treatment, that could predict drinking outcomes at three and 12months, as measured by percent day abstinent (PDA) and drinks per drinking day (DDD) over the preceding 90days. RESULTS: Lower baseline DDD score and greater confidence to resist drinking predicted lower DDD at both three and twelve months following entry to treatment. In addition to baseline PDA and having greater confidence to resist heavy drinking, female gender, aiming for abstinence, more satisfaction with family life and a social network that included less support for drinking were predictors of percent days abstinent. CONCLUSIONS: Overall the strongest and most consistent predictors of outcome were confidence to avoid heavy drinking and social support for drinking. More predictors were identified for percent of days abstinent than for drinks per drinking day. For percent of days abstinent, a number of client characteristics at baseline consistently predicted outcome at both month three and month twelve.

Exploring treatment attendance and its relationship to outcome in a randomized controlled trial of treatment for alcohol problems: secondary analysis of the UK Alcohol Treatment Trial (UKATT).

AIMS: To identify client characteristics that predict attendance at treatment sessions and to investigate the effect of attendance on outcomes using data from the UK Alcohol Treatment Trial. METHODS: Logistic regression was used to determine whether there were characteristics that could predict attendance and then continuation in treatment. Linear regression was used to explore the effects of treatment attendance on outcomes. RESULTS: There were significant positive relationships between treatment attendance and outcomes at Month 3. At Month 12, these relationships were only significant for dependence and alcohol problems for those randomized to motivational enhancement therapy (MET). There were significant differences between groups in attendance, with MET clients more likely to attend than clients allocated to social behaviour and network therapy (SBNT). MET clients were also more likely to attend all sessions (three sessions) compared with SBNT (eight sessions). MET clients with larger social networks and those with confidence in their ability not to drink excessively were more likely to attend. SBNT clients with greater motivation to change and those with more negative short-term alcohol outcome expectancies were more likely to attend. No significant predictors were found for retention in treatment for MET. For those receiving SBNT, fewer alcohol problems were associated with continuation in treatment. CONCLUSION: Attending more sessions was associated with better outcomes. An interpretation of these findings is that, to improve outcomes, methods should be developed and used to increase attendance rates. Different characteristics were identified that predicted attendance and continuation in treatment for MET and SBNT.

Dihydrocodeine: a useful tool in the detoxification of methadone-maintained patients.

We investigated the merit of dihydrocodeine tartrate for withdrawal in detoxifying 20 methadone-maintained patients presenting for treatment at the Leeds Addiction Unit (LAU). Thirteen patients (65%) successfully completed methadone detoxification and were abstinent from both methadone and opiate-type drugs at the end of the 2-week program. On completion, three patients began treatment with Naltrexone and another was abstinent at a follow-up appointment, 1 week later. A further patient relapsed back to heroin use but remained in contact with the LAU. The remaining six patients dropped out of the 2-week detoxification program between days 3 and 11 of the dihydrocodeine cross-over period. We believe dihydrocodeine may have advantages in detoxifying methadone-maintained patients.

Population-based pharmacokinetic approach for methadone monitoring of opiate addicts: potential clinical utility.

AIMS: There is evidence that plasma methadone measurements may be of benefit in dosage adjustment during methadone maintenance treatment for opiate dependence. However, to date the kinetics of oral rac-methadone have been poorly characterized. We describe plasma methadone concentration-time data collected from 35 opiate addicts. SUBJECTS: Oral doses of rac-methadone were given to 24 male and 11 female addicts attending a community-based drug treatment centre. MEASUREMENTS: Plasma methadone concentrations were measured by liquid chromatography (HPLC). PROCEDURES: Plasma concentration-time data were collected from patients prescribed oral rac-methadone in order to describe the complex kinetics of the drug incorporating its long elimination half-life. FINDINGS: Auto-induction of methadone metabolism was demonstrated and it was observed that clearance of methadone was significantly lower (p < 0.05) in opiate addicts at the start of treatment (median elimination half-life, 128-hours) than in those who had reached steady-state (median elimination half-life, 48 hours). Our data has provided the basis for a population-based pharmacokinetic (POP-PK) model which is intended for use as a clinical tool in association with plasma measurements in methadone maintenance patients. CONCLUSIONS: Using plasma monitoring in combination with the application of Bayesian forecasting it should be possible to predict trough levels of methadone during daily dosing. The model is able to utilize sparse sampling, and two blood samples are expected to be sufficient to define patient compliance. Random samples during treatment could be used to assess methadone dosing by comparing predicted with observed measurements for each individual. The clinical tool could therefore help to detect incomplete (failure to consume the whole daily dose as prescribed) and poor (due to ingestion of extra illicit methadone) compliance as well as therapeutic failure due to drug-drug interactions. Targeting resources in this way could be a cost-effective tool for supervision of methadone dosing.

Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes.

AIMS: Although methadone is widely used to treat opiate dependence, guidelines for its dosage are poorly defined. There is increasing evidence to suggest that a strategy based on plasma drug monitoring may be useful to detect non-compliance. Therefore, we have developed a population-based pharmacokinetic (POP-PK) model that characterises adaptive changes in methadone kinetics. METHODS: Sparse plasma rac-methadone concentrations measured in 35 opiate-users were assessed using the P-Pharm software. The final structural model comprised a biexponential function with first-order input and allowance for time-dependent change in both clearance (CL) and initial volume of distribution (V ). Values of these parameters were allowed to increase or decrease exponentially to an asymptotic value. RESULTS: Increase in individual values of CL and increase or decrease in individual values of V with time was observed in applying the model to the experimental data. CONCLUSIONS: A time-dependent increase in the clearance of methadone is consistent with auto-induction of CYP3A4, the enzyme responsible for much of the metabolism of the drug. The changes in V with time might reflect both up- and down-regulation of alpha1-acid glycoprotein, the major plasma binding site for methadone. By accounting for adaptive kinetic changes, the POP-PK model provides an improved basis for forecasting plasma methadone concentrations to predict and adjust dosage of the drug and to monitor compliance in opiate-users on maintenance treatment.

The pharmacokinetics of methadone in healthy subjects and opiate users.

AIMS: There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. METHODS: Single oral doses of rac-methadone were given to 13 drug-naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P-Pharm software. RESULTS: Comparison of kinetic models incorporating mono- or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9+/-1.5 s.d. l h(-1) (5.3+/-1.2 s.d. l h(-1) using 0-24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2+/-0.3 s.d. l h(-1), P<0.001); 95% CI for the difference = -3 to -6 l h(-1) and no difference in the population mean values of V/F (212+/-27 s.d. l and 239+/-121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V/F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half-life of methadone in healthy subjects was 33-46 h depending on the method used to calculate this parameter. CONCLUSIONS: Estimates of the long terminal elimination half-life of methadone (33-46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

Costing substance misuse services.

AIMS: To develop a methodology for obtaining the detailed costs of different substance misuse services and illustrate some of the specific problems by means of a case study. DESIGN: Data on the resources required, clinical activity, and patient characteristics for one year were combined to provide detailed costs for different types of clinical events and patients. SETTING: The clinical services of a publicly funded addiction unit in a large industrial city in the UK. The unit provides for alcohol and other drug misusers mainly on an outpatient basis but with inpatient care. PARTICIPANTS: Over 1500 patients were included in the analysis with 75 per cent being male, and 80 per cent aged between 20 and 49. Nearly half of the clients had alcohol as their main drug of misuse with opiate users being the next largest group. MEASUREMENT: Detailed costing by event and patient was possible as the staff type and time taken for each event were routinely recorded. A cost for each individual event was estimated and summed for each individual patient to give a cost estimate by patient for the financial year 1992/3. FINDINGS: Core treatment outpatient events had an average cost of Pounds 48, with new assessments costing Pounds 87 but these averages hid high variations. The average cost per year for those receiving only outpatient care was Pounds 358; it was Pounds 1857 for those receiving both outpatient and inpatient care. Opiate misusers were on average more costly than alcohol misusers. The costs were skewed with 10 per cent of patients accounting for 56 per cent of the total annual costs. CONCLUSIONS: Dealing with costs of non attendance, including all resource use, and coping with large individual variations in costs across individuals and intervention types are the main problems in devising cost figures. Cost data are useful but need to be combined with outcome data if they are to be used to improve patient services.

Benzodiazepine misuse by drug addicts.

Using a high-performance liquid chromatography method, we measured seven commonly prescribed benzodiazepines (chlordiazepoxide, nitrazepam, nordiazepam, oxazepam, lorazepam, temazepam and diazepam) in 100 urine samples obtained from patients attending the Leeds Addiction Unit. All of the urines selected for investigation were positive for benzodiazepines using an EMIT (Enzyme Immunoassay) screen. Forty-four of the urines contained a range of benzodiazepines, none of which had been prescribed. Nitrazepam was detected most frequently (61 urine samples), but had not been prescribed to any of the patients in this study. Chlordiazepoxide was detected in 49 urine samples, although it had been prescribed to only five patients. Temazepam was detected in 28 urine samples. Fourteen patients providing 21 urine samples had been prescribed temazepam for treatment. However, temazepam was detected in only 14 of these samples. Multiple benzodiazepine abuse was evident from the high rate of detection of unrelated benzodiazepines.

Non-prescribed drug use during methadone treatment by clinic- and community-based patients.

We investigated the efficacy of methadone maintenance treatment in clinic-based (n = 10) and community-based (n = 10) patients by studying the relationships between dose, plasma concentrations of methadone and non-prescribed drug-use using logistic regression. We found that clinic-based patients had significantly reduced odds of having a urine sample test positive for illicit drugs when compared to community-based patients (OR = 0.20; 95% confidence interval 0.10-0.38: p < 0.001). There was no relationship between either methadone dose or plasma methadone concentration and testing positive for non-prescribed drugs (including cocaine, cannabis, amphetamine, ecstasy, benzodiazepines). We looked specifically at the misuse of opiate drugs. Location was again important and clinic-based patients had significantly reduced odds of having a urine sample test positive for opiate drugs (OR = 0.36, 95% confidence interval 0.18-0.71: p approximately 0.004). Opiate drug use in our patients was also significantly related to plasma methadone concentration, increasing noticeably when the drug concentration < 0.48 nmol/L (p approximately 0.04). We found no relationship between methadone dose and odds of having a positive urine drug test in either clinic- or community-based patients.

Deliberate self-harm and substance dependence: the management of patients seen in the general hospital.

The aim of this study was to examine management decisions made at the time of assessment of an episode of deliberate self-harm seen in the general hospital and examine the extent of referral to a specialized addiction unit. Factors involved in making a clinical decision regarding the appropriate management of self-harm cases when alcohol factors were identified are reviewed. Simply referring to a specialized addiction unit was found to be an unsatisfactory method of providing a comprehensive response to the problem of substance misuse and deliberate self-harm. It is suggested that services should be developed using active posthospital discharge community follow-up. Motivational interviewing used in such a setting may increase the number of patients who will go on to accept specialist care.

Development of the Leeds Dependence Questionnaire (LDQ): a questionnaire to measure alcohol and opiate dependence in the context of a treatment evaluation package.

The Leeds Dependence Questionnaire (LDQ) has been developed as part of a treatment evaluation package. The LDQ is a 10-item, self completion questionnaire designed to measure dependence upon a variety of substances; it has been shown to be understood by users of alcohol and opiates. The questionnaire was designed to be sensitive to change over time and to be sensitive through the range from mild to severe dependence; the follow-up data are insufficient to demonstrate change over time, but are encouraging. It is expected that both clinicians and researchers will find it useful to have a single measure relating to substance use, but not limited by specific substances. All items are scored 0-1-2-3; there are no normative data. The procedure for establishing content validity is described and estimates of concurrent, discriminant and convergent validities are reported; these validities are thought to be satisfactory. A principal components analysis produced a single factor accounting for 64% of the variance. Cronbach's alpha was 0.94. Test-retest reliability was found to be 0.95.

Use of 'very low-dose phenobarbital' to investigate compliance in patients on reducing doses of methadone (detoxification).

Incorporation of very low doses of phenobarbital into a methadone linctus has enabled us to monitor the compliance of 7 patients receiving a reducing dose of methadone (detoxification) for treatment for opioid addiction. By measuring both plasma phenobarbital and methadone we detected 4 patients who consumed extra illicitly obtained methadone during the detoxification regime. Treatment outcome was poor; 11 of the original 18 patients dropped out of treatment within 14 days and of those who remained, 4 patients relapsed and reabused illicit drugs and 2 returned to a fixed dose of methadone. Laboratory measurements were successfully used to detect poor methadone compliance.

Steady-state pharmacokinetics of methadone in opioid addicts.

Kinetic parameters were investigated in tolerant methadone maintenance patients. The disposition of methadone at steady-state was assessed on 8 occasions-in 5 opioid addicts prescribed wide ranging doses of methadone (10 mg to 60 mg per day)-providing unique pharmacokinetic data. Statistical analysis showed that the kinetics of oral methadone at steady-state were described using a single compartment model. Analysis of the plasma concentration-time curves gave estimates of the variance of methadone clearance and apparent volume of distribution, and indicate that methadone is rapidly absorbed (mean Ka, 1.7 h-1) with a detectable increase in the plasma drug concentration 15 to 30 min after dosing. The elimination of methadone from plasma was found to occur slowly (mean t1/2 26.8 h) beginning soon after the administration of the daily oral prescription. The apparent volume of distribution-assuming the oral bioavailability (f) of methadone to be 0.95--was large (mean 6.7 l.kg-1). The slow clearance of this drug from the body (mean 3.1 ml.min-1.kg-1) confirms that daily dosing at steady-state is adequate to maintain effective plasma concentrations throughout the dosing interval.

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.

High-dose methadone and the need for drug measurements in plasma.

We report a case of high-dose methadone prescribed to a heroin addict for pain control. The patient was prescribed methadone during convalescence from surgery and subsequently for maintenance treatment. Dosing was started at 360 mg of methadone per day and reduced over 12 days to an 80 mg/day maintenance dose. Although the patient was drowsy on the initial dose, his recovery was uneventful. However, there were complaints of pain and withdrawal discomfort when the plasma concentration decreased to less than 1 mg/L. Measurements of methadone in plasma were helpful for monitoring the recovery of this patient after surgery and are likely to prove useful in similar cases.