Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment.

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.

Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment.

AIMS: To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT). METHODS: Eighty-eight patients (58 male; 21-55 years; 84 White) on MMT were studied. CYP2D6 activity [3 h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24-55 years), CYP1A2 activity (salivary caffeine elimination half-life) in 44 patients (21 male; 24-55 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23-55 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by LC/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates. RESULTS: Between 61 and 68% of the overall variation in total plasma trough concentrations of (RS)-, (R)- and (S)-methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (R)-, unbound (S)-, total (RS)- and total (S)-methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition. CONCLUSIONS: CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone.

Post-treatment outcomes of buprenorphine detoxification in community settings: a systematic review.

A systematic review was undertaken to examine studies of buprenorphine detoxification that has included post-treatment outcomes as well as more immediate aspects of progress. Studies were required to report details of buprenorphine withdrawal regime and post-treatment outcomes including abstinence rates. Only five studies met these criteria, with buprenorphine regimes lasting 3 days to several weeks, and with variable follow-up. Detoxification completion rates were 65-100%, but relatively few treatment completers were then drug free at their follow-up appointments. In subsequent prescribing, more patients had returned to opioid maintenance than complied with naltrexone. Our preliminary review indicates that buprenorphine is a suitable medication for the process of opiate detoxification but that this newer treatment option has not led to higher rates of abstinence following withdrawal. Further studies are required to more substantially examine abstinence outcomes, as well as characteristics which predict success.

Can saliva replace plasma for the monitoring of methadone?

The aims of this study were to determine the relationship between saliva and plasma methadone concentrations and the influence of variability in saliva pH. Saliva and plasma samples were taken before the daily dose of methadone in 60 patients undergoing methadone maintenance treatment (MMT). Saliva pH was measured immediately after sampling, and concentrations of (RS)-, (R)-, and (S)-methadone in saliva and plasma were assayed by LC/MS. In addition, unbound (R)- and (S)-methadone concentrations were measured in plasma samples by ultrafiltration. Plasma binding and pH differences between plasma and saliva were then used to estimate methadone saliva/plasma ratios and to compare them with observed values. Saliva pH ranged from 5.1 to 7.6 (mean +/- SD, 6.7 +/- 0.5). Plasma and saliva concentrations correlated weakly [(RS)-, r = 0.14, P = 0.007, n = 44; (R)-, r = 0.10, P = 0.04, n = 43; (S)-, r = 0.22, P = 0.002, n = 43], and the mean saliva-to-plasma methadone concentration ratios were 1.1 (+/-1.3 SD), 1.5 (+/-1.5), and 0.8 (+/-0.8), for (RS)-, (R)-, and (S)-methadone, respectively. Corresponding values based on unbound concentrations of methadone in plasma were 21 (+/-20.6, n = 31), 21 (+/-19, n = 34), and 17 (+/-15, n = 36). The salivary concentration-to-dose ratios showed statistically significant but weak inverse correlations with saliva pH [(RS)-, r = 0.27, P < 0.001; (R)-, r = 0.25, P < 0.001; (S)-, r = 0.29, P < 0.001, respectively]. There were significant correlations between predicted and observed saliva/plasma ratios [(RS)-, r = 0.44, P < 0.001, n = 31; (R)-, r = 0.58, P < 0.001, n = 32; (S)-, r = 0.10, P = 0.04, n = 34], but the mean predicted saliva concentrations were about 5 times lower than the mean observed values. The poor correlations between salivary and plasma methadone concentrations observed in this study are partly related to the effect of variable saliva pH. However, saliva pH explained only 10%-36% of the total variation. As a conclusion, monitoring methadone concentrations in saliva may not be a useful alternative to plasma concentration measurements. Correction for saliva pH measured immediately after collection improves the relationship between saliva and plasma methadone concentration, but most of the variation remains unexplained.

Prevalence of personality disorder in alcohol and drug services and associated comorbidity.

AIMS: To compare the prevalence of personality disorder in alcohol and drug populations with special attention to its impact on psychopathology and service characteristics. DESIGN: Cross-sectional survey. SETTING: Three alcohol and four drug services in four urban UK centres. PARTICIPANTS: Two hundred and sixteen drug and 64 alcohol service patients randomly sampled from current treatment populations. MEASUREMENTS: A treatment population census recorded demographic and diagnostic data. Patient interviews assessed the presence, cluster type and severity of personality disorder using the Quick Personality Assessment Schedule (PAS-Q). Other psychopathology was measured using the Comprehensive Psychopathological Rating Scale (CPRS). A case-note audit recorded psychotic psychopathology using the OPCRIT schedule and data regarding social morbidity. FINDINGS: The overall prevalence of personality disorder was 37% in the drug service sample and 53% in the alcohol service sample. The distribution of severity and clusters differed markedly between the two samples. There was a significant association between the severity of personality disorder and psychopathology in both samples. Levels of morbidity associated with clusters B and C were similar. Clinical diagnosis of personality disorder showed high specificity but low sensitivity when compared to PAS-Q. CONCLUSIONS: In both alcohol and drug service populations, personality disorder is associated with significantly increased rates of psychopathology and social morbidity that worsens with increasing severity of the disorder. Despite this, personality disorder is poorly identified by clinical staff. The PAS-Q may be useful as a clinical assessment tool in the substance misuse population for the early identification and management of patients with personality disorder.

Prescribing to drug misusers in practice--often effective, but rarely straightforward.

Many reviews describe the effectiveness of methadone treatment in reducing illicit drug use and associated behaviours among opiate misusers. The strongest evidence includes social outcomes such as reduced debt and crime, and relates overwhelmingly to maintenance rather than detoxification treatment. Drug clinics are often dominated by individuals unable to withdraw fully from methadone, while the "harm reduction" model accepts some ongoing drug use, with attendant risks. Security measures are necessary to avoid abuse of treatments, but these may be undermined by the agenda of "partnerships with patients" in decision-making. Buprenorphine appears both safer and less addictive than methadone, and lofexidine is effective as a non-substitute detoxification method. Naltrexone can clearly reduce relapse rates, provided consumption is assured, while for individuals unable to detoxify or avoid euphoriant opiates, morphine and diamorphine are sometimes used. In non-opiate misuse, clinical studies of a wide range of medications have produced relatively few positive findings.