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.

Shaping cocaine abstinence by successive approximation.

Cocaine-using methadone-maintenance patients were randomized to standard contingency management (abstinence group, n = 49) or to a contingency designed to increase contact with reinforcers (shaping group, n = 46). For 8 weeks, both groups earned escalating-value vouchers based on thrice-weekly urinalyses: The abstinence group earned vouchers for cocaine-negative urines only; the shaping group earned vouchers for each urine specimen with a 25% or more decrease in cocaine metabolite (first 3 weeks) and then for negative urines only (last 5 weeks). Cocaine use was lower in the shaping group, but only in the last 5 weeks, when the response requirement was identical. Thus, the shaping contingency appeared to better prepare patients for abstinence. A 2nd phase of the study showed that abstinence induced by escalating-value vouchers can be maintained by a nonescalating schedule, suggesting that contingency management can be practical as a maintenance treatment.

Improvement in naltrexone treatment compliance with contingency management.

The efficacy of a voucher-based incentive program for improving adherence to outpatient, thrice weekly naltrexone maintenance was tested in a three group, randomized, 12-week clinical trial. Voucher incentives were given as follows: contingent group (n = 19) for each consecutive naltrexone dose ingested; non-contingent group (n = 19) on unpredictable schedule independently of taking naltrexone; no-voucher group (n = 20) none. Vouchers were exchangeable for goods and services. The contingent group had significantly longer treatment retention and ingested significantly more doses of naltrexone (consecutive and total) than either control group. Voucher incentives can significantly increase adherence to naltrexone maintenance in recently detoxified opioid dependent individuals.

Naltrexone shortened opioid detoxification with buprenorphine.

This double-blind, randomized, placebo-controlled clinical trial evaluated the impact on withdrawal symptoms of (i) combining naltrexone with a 4-day buprenorphine taper for short opioid detoxification (NB Group), compared to (ii) using a 4-day buprenorphine taper alone, followed by naltrexone on day 8 (PB Group). Sublingual buprenorphine was administered on days 1-4 (26 mg total). For the NB Group (n = 32) escalating doses of oral naltrexone were given on days 2-8 (placebo day 1). For the PB Group (n = 28) placebo was given on days 1-7 and naltrexone on day 8. Main outcome measures were Observed Opioid Withdrawal scores (OOW, 0-30) and use of medications to treat opioid withdrawal. Of 32 patients in the NB group, 59% experienced clinically relevant withdrawal (defined as OOW > or = 5) on day 2, but, after day 5, none experienced withdrawal. In the PB group, the number of patients experiencing withdrawal increased over time. The first naltrexone dose induced comparable withdrawal in both groups: peak OOW scores were (mean +/- SD) 5.2 +/- 3.3 on day 2 for the NB group, and 4.0 +/- 3.9 on day 8 for the PB group (NS), though, on day 2, 7 patients dropped out in the NB group and none in the PB group, while only one patient dropped out in the PB group on day 8. Throughout the 8-day study, patients in both groups received similar amount of adjunct medication: 0.64 +/- 0.07 mg (NB group) of clonidine vs 0.73 +/- 0.15 mg (PB group; NS). Only 25% of patients required use of sedatives (up to 20 mg diazepam). Starting naltrexone on day 2 appeared to abolish withdrawal symptoms after day 5 and, thus, to shorten the duration of withdrawal symptoms. Peak withdrawal symptoms after naltrexone were of moderate intensity, suggesting that naltrexone combined with buprenorphine is an acceptable and safe treatment for shortened opioid detoxification and induction of naltrexone maintenance.

Family history influence on drug abuse severity and treatment outcome.

Influence of parental alcohol/substance abuse on methadone maintenance therapy (MMT) outcome was examined in 164 DSM-III-R opioid dependent adults with no other current DSM Axis I disorder. Family history positive patients had more DSM-III-R opioid dependence symptoms and were more likely to be classified as severely dependent. However, when placed on identical daily doses of methadone (50 mg), they had lower rates of illicit opioid use but higher rates of cocaine use than family history negative patients. Both effects remained significant after adjusting for gender and race. These results suggest that common genetic factors may underlie both susceptibility to heroin dependence and response to therapeutic methadone treatment.

Monitoring opiate use in substance abuse treatment patients with sweat and urine drug testing.

Although urine testing remains the standard for drug use monitoring, sweat testing for drugs of abuse is increasing, especially in criminal justice programs. One reason for this increase is sweat testing may widen the detection window compared to urine testing. Drug metabolites are rapidly excreted in urine limiting the window of detection of a single use to a few days. In contrast, sweat collection devices can be worn for longer periods of time. This study was designed to compare the efficacy of sweat testing versus urine testing for detecting drug use. Paired sweat patches that were applied and removed weekly on Tuesdays were compared to 3-5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays (355 matched sweat and urine specimen sets) from 44 patients in a methadone-maintenance outpatient treatment program. All patches (N = 925) were extracted in 2.5 mL of solvent and analyzed by ELISA immunoassay for opiates (cutoff concentration 10 ng/mL). A subset (N = 389) of patches was analyzed by gas chromatography-mass spectrometry (GC-MS). Urine specimens (N = 1886) were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL). Results were evaluated to (1) determine the identity and relative amounts of opiates in sweat; (2) assess replicability in duplicate patches; (3) compare ELISA and GC-MS results for opiates in sweat; and (4) compare the detection of opiate use by sweat and urine testing. Opiates were detected in 38.5% of the sweat patches with the ELISA screen. GC-MS analysis confirmed 83.4% of the screen-positive sweat patches for heroin, 6-acetylmorphine, morphine, and/or codeine (cutoff concentration 5 ng/mL) and 90.2% of the screen-negative patches. The sensitivity, specificity, and efficiency of ELISA opiate results as compared to GC-MS results in sweat were 96.7%, 72.2%, and 89.5%, respectively. Heroin and/or 6-acetylmorphine were detected in 78.1% of the GC-MS-positive sweat patches. Median concentrations of heroin, 6-acetylmorphine, morphine, and codeine in the positive sweat samples were 10.5, 13.6, 15.9, and 13.0 ng/mL, respectively. Agreement in paired sweat patch test results was 90.6% by ELISA analysis. For the purposes of this comparison of ELISA sweat patch to EMIT urine screening for opiates, the more commonly used urine test was considered to be the reference method. The sensitivity, specificity, and efficiency of sweat patch results to urine results for opiates were 68.6%, 86.1%, and 78.6%, respectively. There were 13.5% false-negative and 7.9% false-positive sweat results as compared to urine tests. Analysis of sweat patches provides an alternate method for objectively monitoring drug use and provides an advantage over urine drug testing by extending drug detection times to one week or longer. In addition, identification of heroin and/or 6-acetylmorphine in sweat patches confirmed the use of heroin in 78.1% of the positive cases and differentiated illicit heroin use from possible ingestion of codeine or opiate-containing foods. However, the percentage of false-negative results, at least in this treatment population, indicates that weekly sweat testing may be less sensitive than thrice weekly urine testing in detecting opiate use.

Monitoring cocaine use in substance-abuse-treatment patients by sweat and urine testing.

Sweat and urine specimens were collected from 44 methadone-maintenance patients to evaluate the use of sweat testing to monitor cocaine use. Paired sweat patches that were applied and removed weekly (on Tuesdays) were compared with 3-5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays. All patches (N = 930) were extracted in 2.5 mL of solvent and analyzed by ELISA immunoassay (cutoff concentration 10 ng/mL); a subset of patches (N = 591) was also analyzed by gas chromatography-mass spectrometry (GC-MS) for cocaine, benzoylecgonine (BZE), and ecgonine methyl ester (EME) (cutoff concentration 5 ng/mL). Urine specimens were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL) and subsets were analyzed by TDx (semiquantitative, LOD 30 ng/mL) and by GC-MS for cocaine (LOD 5 ng/mL). Results were evaluated to (1) determine the relative amounts of cocaine and its metabolites in sweat; (2) assess replicability in duplicate patches; (3) compare ELISA and GC-MS results for cocaine in sweat; and (4) compare the detection of cocaine use by sweat and urine testing. Cocaine was detected by GC-MS in 99% of ELISA-positive sweat patches; median concentrations of cocaine, BZE, and EME were 378, 78.7, and 74 ng/mL, respectively. Agreement in duplicate patches was approximately 90% by ELISA analysis. The sensitivity, specificity, and efficiency of sweat ELISA cocaine results as compared with sweat GC-MS results were 93.6%, 91.3%, and 93.2%, respectively. The sensitivity, specificity, and efficiency between ELISA sweat patch and EMIT urine results were 97.6%, 60.5%, and 77.7%, respectively. These results support the use of sweat patches for monitoring cocaine use, though further evaluation is needed.

Therapeutic drug monitoring in methadone maintenance: choosing a matrix.

Methadone maintenance is the premier pharmacological treatment for opioid addiction, but it is rarely informed by evidence-based practice guidelines for dosage monitoring and adjustment. Such guidelines are crucial because the pharmacokinetics of methadone vary greatly among patients, and this variation may account for differences in treatment outcome. We review the pharmacokinetics of methadone and factors that may alter it (including drug interactions, disease states, and idiosyncratic differences among patients). Also reviewed are prospects for therapeutic drug monitoring (TDM) of methadone in plasma, urine, sweat, and saliva. Due to its ease of collection and its presumed representation of the bioavailable free-fraction of methadone, saliva may be a promising matrix. However, saliva methadone concentrations are influenced by salivary pH, and future studies are needed to determine how to control for that. Administrative, medical, and social implications of methadone TDM are briefly discussed.

Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans.

BACKGROUND: Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. METHODS: Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography-tandem mass spectrometry with limits of quantitation of 0.1 µg/L. RESULTS: Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3 ± 1.0, 44.5 ± 4.8, 85.2 ± 7.7, 124.6 ± 16.6, and 137.7 ± 18.8 µg/L, respectively. Maximum norbuprenorphine concentrations occurred 10-15 min (3.7 ± 0.7 µg/L) after 16 mg IV administration. CONCLUSIONS: Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2-16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.

Cyclazocine: comparison to hydromorphone and interaction with cocaine.

Kappa-opioid agonists produce neurobiological and behavioral effects opposite to those of cocaine and may be useful for the treatment of cocaine dependence. To evaluate the kappa- and mu-agonist effects of cyclazocine and to test whether cyclazocine pretreatment would attenuate the effects of cocaine, healthy, male and female, experienced opiate and cocaine users (n = 13) were enrolled in a two-phase study. In Phase 1, placebo, cyclazocine (0.2, 0.4 and 0.8 mg) and the mu-agonist hydromorphone (5 and 15 mg) were administered orally in six 4.5-hour sessions separated by at least 72 h. In Phase 2, cocaine (100 mg intranasal) was given 2 h after oral pretreatment with cyclazocine (0, 0.1, 0.2, 0.4, 0.8 and 0 mg, in that order) in each of six sessions conducted daily Monday to Friday and the following Monday. Physiological, subjective and behavioral measures were collected in each session. Nine participants completed Phase 1; eight completed Phase 2. Hydromorphone (15 mg) produced prototypic mu-agonist effects. Cyclazocine exhibited only modest kappa-like effects. Cyclazocine also had only modest, non-dose-related effects on response to cocaine. However, cocaine effects were consistently lower on the last administration (cyclazocine 0 mg pretreatment) following 4 days of cyclazocine pretreatment, compared to the first administration (0 mg pretreatment). This finding is unlikely to be fully attributable to cocaine tolerance and is not accounted for by pharmacokinetic changes; plasma concentrations of cocaine were not altered by cyclazocine. This study is suggestive but not strongly supportive for the use of kappa-opiate drugs to diminish acute effects of cocaine administration or for the use of these kappa agonists in drug abuse treatment applications.