A polymorphism in the OPRM1 3'-untranslated region is associated with methadone efficacy in treating opioid dependence.

The µ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females.

Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determining treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (P=0.03, relative risk (RR)=1.67, 95% confidence interval (CI) 1.06-2.1). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (P=0.006, RR=2.15, 95% CI 1.3-2.29). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however, confirmation in an independent sample is warranted.

Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial.

BACKGROUND: Divalproex sodium, an anticonvulsant and antikindling agent and gamma-aminobutyric acid enhancer, has been proposed as an alternative to benzodiazepines for treating alcohol withdrawal. This study reports on a randomized, double-blind, placebo-controlled trial of divalproex sodium in acute alcohol withdrawal. METHODS: Thirty-six hospitalized patients experiencing moderate alcohol withdrawal as measured by a score of at least 10 on the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar) were randomized to receive either divalproex sodium 500 mg three times per day for 7 days or matched placebo in a double-blind manner. All subjects received a baseline dose of oxazepam and had additional oxazepam available as a rescue medication in accordance with a standard, symptom-triggered detoxification protocol. Mean total milligrams of oxazepam received, progression of withdrawal symptoms, psychological distress as measured by the Symptom Checklist-90, side effects, and adverse outcomes were compared between groups. RESULTS: Use of divalproex sodium resulted in less use of oxazepam (p < 0.033). Group differences seemed primarily driven by those subjects who experienced symptoms above threshold level (CIWA-Ar >or=10) after 12 hr. The progression in severity of withdrawal symptoms (increase in CIWA-Ar above baseline) was also significantly greater in the placebo group (p < 0.05). CONCLUSIONS: This placebo-controlled pilot study suggests that divalproex sodium significantly affects the course of acute alcohol withdrawal and reduces the need for treatment with a benzodiazepine. A more aggressive loading dose strategy may demonstrate a more robust or earlier response.

Trauma, symptoms of posttraumatic stress disorder, and associated problems among incarcerated veterans.

OBJECTIVE: To help improve treatment for incarcerated veterans, the study examined exposure to trauma, symptoms of posttraumatic stress disorder (PTSD), functional status, and treatment history in a group of incarcerated veterans. METHODS: A convenience sample of 129 jailed veterans who agreed to receive outreach contact completed the Life Event History Questionnaire, the PTSD Checklist-Civilian Version (PCL-C), and the Addiction Severity Index. Participants who had scores of 50 or above on the PCL-C, designated as screening positive for PTSD, were compared with those whose scores were below 50, designated as screening negative for PTSD. RESULTS: Some 112 veterans (87 percent) reported traumatic experiences. A total of 51 veterans (39 percent) screened positive for PTSD, and 78 veterans (60 percent) screened negative. Compared with veterans who screened negative for PTSD, those who screened positive reported a greater variety of traumas; more serious current legal problems; a higher lifetime use of alcohol, cocaine, and heroin; higher recent expenditures on drugs; more psychiatric symptoms; and worse general health despite more previous psychiatric and medical treatment as well as treatment for substance abuse. CONCLUSIONS: The findings encourage the development of an improved treatment model to keep jailed veterans with PTSD from repeated incarceration.

Changes in Millon Clinical Multiaxial Inventory scores among opiate addicts as a function of retention in methadone maintenance treatment and recent drug use.

The Millon Clinical Multiaxial Inventory (MCMI) was administered to 144 men and 86 women within 1 month of admission to methadone maintenance treatment and was readministered 18 months following admission. Based on prior research, we hypothesized there would be significant decreases on scales measuring affective disturbance, anxiety, and social isolation and little change in scales measuring antisocial and narcissistic traits. In addition, it was hypothesized that changes on the MCMI would be related to retention in treatment and illicit drug use during the interim between initial assessment and follow-up. Data were analyzed using a multivariate analysis of variance (MANOVA) for repeated measures. There was an overall decrease in MCMI scores, indicating less psychopathology between initial assessment and follow-up. MCMI scales did not change as a function of retention status, but decreases in MCMI scale scores were greater for subjects who were light drug users in the 6 months prior to the follow-up compared to heavy users. Inspection of individual MCMI scales supported our hypothesis; there were decreases on scales measuring affective disturbance, anxiety, and social isolation, but not on scales measuring antisocial and narcissistic traits.

Detecting bipolar disorder among treatment-seeking substance abusers.

Bipolar disorder is increasingly recognized to have frequent comorbidity with substance use disorders, but may be difficult to diagnose among patients with active substance use. The purpose of this paper is to describe a brief, self-report form for the efficient detection of bipolar disorder. The 19-item form was piloted in 373 consecutive applicants for substance abuse treatment at an urban Veterans Affairs (VA) medical center. Results show reasonable internal consistency (alpha = .850) and high rates of manic symptomatology (36%), previous bipolar diagnosis (30%, 51% of whom report prior psychiatric hospitalization), and exposure to mood stabilizers (20%, 66% of whom reported therapeutic benefit). Comparison of nine different scoring algorithms with chart diagnosis as the validating criterion found that self-report of bipolar diagnosis was optimally sensitive. Either self-report of bipolar diagnosis with hospitalization or self-report of exposure to mood stabilizers with therapeutic response was optimally specific. Symptom self-report items had significantly poorer sensitivity and specificity (F = 7.60, p < .01). We conclude that questions pertaining to diagnostic and treatment history (especially hospitalization or therapeutic medication response) are considerably superior to symptom-based screening for clinically diagnosed bipolar disorder. Further work using structured interview as the diagnostic criterion is under way to validate this instrument.

An innovative approach to reducing cannabis use in a subset of methadone maintenance clients.

Cannabis use rates among methadone maintenance clients are high. We attempted to decrease cannabis use in our most stable clients by adding a requirement to the take home dose policy that clients provide cannabis free urines to achieve twice a week pick up status (2 x /week). The urine records and take home status of all clients were monitored for the 6 months prior to implementation of the policy change and 1 year following. A total of four of eight clients (50%) on 2 x /week status who were using cannabis discontinued their use in order to maintain 2 x /week status or to return to 2 x /week status if it had been lost.

A pilot study comparing severely and persistently mentally ill opiate-addicted patients in dual-diagnosis treatment with patients in methadone maintenance.

The authors describe a severely and persistently mentally ill (SPMI) opiate-addicted (OA) patient sample (n = 43) in a dual-diagnosis outpatient treatment program by demographic, clinical, and treatment characteristics and compare these with other dually diagnosed SPMI patients in the same treatment center (n = 297). Also, those SPMI/OA patients with physiological dependence (n = 20) were compared with a matched sample of OA patients in traditional methadone maintenance (n = 20). The authors then present a clinical evaluation of treatment course and outcome for the SPMI/OA patients (n = 43) and discuss implications from these pilot data.

Disulfiram use in patients with abnormal liver function test results.

BACKGROUND: Concern about the precipitation of severe hepatitis by disulfiram often causes clinicians to avoid using this effective treatment in patients who have elevated baseline transaminase levels, even though no empirical evidence has so far shown severe hepatotoxicity to be related to such laboratory abnormalities. This study examines the effects of disulfiram in alcohol-dependent patients with elevated liver function test results and/or serologic evidence of hepatitis C virus (HCV) infection. METHOD: Hepatitis serologies and baseline transaminase levels were obtained for 57 male alcoholics starting treatment with disulfiram. Sequential liver function test results were obtained for up to 12 weeks while subjects took disulfiram. RESULTS: Although subjects with elevated baseline transaminase levels and serologic evidence of HCV infection were the most likely to evidence marked elevations in transaminase levels while taking disulfiram, most subjects took disulfiram without other adverse consequences. In only 1 subject did elevations appear directly related to disulfiram. CONCLUSION: Monitoring of liver function test results is warranted for patients taking disulfiram and permits most patients with moderately elevated transaminase levels to take it safely.

An open trial of transdermal nicotine replacement therapy for smoking cessation among alcohol- and drug-dependent inpatients.

An open trial of transdermal nicotine replacement for smoking cessation was conducted. Over a 7-month period, all patients admitted to the inpatient alcohol and drug treatment unit of the Seattle Veterans Affairs Medical Center, (n = 207) were offered the opportunity to participate in an open trial of transdermal nicotine replacement for smoking cessation. Forty-nine (23.7%) elected to attempt cessation with transdermal nicotine during their inpatient treatment episodes. These subjects received no psychosocial treatments directed specifically at smoking cessation. They smoked a mean of 28.5 (SD = 16.4) cigarettes per day and obtained a mean score of 8.3 (SD = 1.9) on the Fagerstrom Test for Nicotine Dependence. Subjects remained on transdermal nicotine an average of 18.8 (SD = 8.2) days with desire to resume smoking the major reason for discontinuation. Seven subjects (14.3%) self-reported tobacco abstinence at 21 days, and 5 (10.2%) self-reported abstinence as outpatients at 6 weeks. These results show that a substantial proportion of alcohol- and drug-dependent patients entering inpatient treatment are willing to attempt alcohol and illicit drug cessation and tobacco cessation simultaneously and that transdermal nicotine holds promise as a treatment modality in this population.

Outcome of a second episode of methadone maintenance.

This paper reports the treatment progress of methadone maintenance clients who were discharged or withdrew from treatment and then were readmitted for a second episode of treatment. Thirty-nine clients in a contingency contract condition remained in treatment long enough (6 months) during both the initial and a second treatment episode, to be exposed to discharge sanctions that were part of the contingency contract. Of these clients 34 failed treatment during the initial treatment episode. Nine (26%) of these initial treatment failures improved their performance in the second episode compared to the first, and only one (20%) of five initial treatment successes who left treatment during their first treatment episode for non-contract reasons showed a poorer performance (failing the second after succeeding in the first episode). Of 17 clients in a condition that applied no contingencies for positive urines, three of 14 (21%) who failed during the initial treatment episode improved their performance, and two of three (67%) who succeeded during the initial treatment episode failed in the second episode. For a subset of clients the efficacy of contingency contracting may not be realized until it is reapplied during a subsequent admission.

Retention in methadone maintenance is associated with reductions in different HIV risk behaviors for women and men.

Using AIDS Initial Assessment questionnaire (AIA) data from 353 injection drug users (IDUs) newly admitted to methadone maintenance (MM), three dimensions of injection risk behavior ("sharing with sexual partner," "sharing with others," and "new needle use") were identified. Among IDUs who continued to inject drugs at 1 year, men retained in treatment obtained lower scores on the "sharing with others" scale than men not retained, even when controlling for initial scale scores and injection frequency. Associations between retention in MM and changes in sexual risk were examined using two AIA measures of sexual risk behavior ("number of IDU sexual partners" and "relative frequency of protected vaginal intercourse"). Controlling for injection frequency, prior sexual risk, and age, there was no difference in sexual risk for men retained in treatment versus those not retained. Among women, those who stayed in MM for 1 year reported significantly fewer IDU partners.

Pre-treatment characteristics, program philosophy and level of ancillary services as predictors of methadone maintenance treatment outcome.

Predictors of methadone maintenance treatment outcome have not been extensively studied as they relate to variations in program philosophy, nor have such predictors received much examination among recently treated, older cohorts of opioid addicts for whom drug use patterns have changed. Predictors of outcome were examined at 18 months post-treatment entry for 353 admissions to methadone maintenance who received random assignment to one of three counseling conditions: (1) medication only, (2) standard counseling and (3) enhanced services; and one of two contingency conditions: (1) no contingencies, and (2) contingency contracting in a six-cell 3 x 2 design. Subjects in contingency contracting conditions were placed on contingency contracts for positive urine toxicology results and ultimately discharged for unremitting drug use. All subjects completed the Addiction Severity Index (ASI) and provided weekly urine specimens. Predictors of urinalysis results and treatment retention were determined using bivariate and multivariate techniques. Interactions between subject characteristics by experimental condition assignment were also examined as predictors. Higher rates of total positive urine specimens were predicted by younger age, greater pre-treatment frequency of smoking cocaine, lower ASI psychiatric composite scores, and higher ASI legal composite scores. Higher rates of opiate positive specimens were predicted by younger age, lower pre-treatment frequency of alcohol intoxication, higher ASI legal and lower ASI employment and psychiatric composite scores, and assignment to medication only/no contingencies condition. Higher rates of cocaine positives were predicted by younger age, black race, lower ASI psychiatric composite score, greater pre-treatment frequency of intravenous and smoked cocaine use, less pre-treatment frequency of marijuana use, and lower methadone dose level. Assignment to enhanced/contingency contracting predicted lower rates of cocaine positives. Treatment retention was predicted by older age, non-black race, lower ASI legal composite score, higher methadone dose level and assignment to non-contingent conditions. While subject variables over which treatment providers have little control were, thus, related to outcome, type of treatment provided and methadone dose also influenced outcome.

Clinical issues related to the costs of alcoholism.

Alcohol (ethanol) use disorders are prevalent in many countries and are associated with significant social and health costs. Little is known, however, about the comparative cost effectiveness of treatments for alcoholism. Pharmacoeconomic evaluations are largely (if not wholly) absent from the alcoholism treatment outcome database. We discuss pharmacological approaches to the treatment of alcohol withdrawal and dependence, describing agents that ameliorate withdrawal symptoms, deter alcohol consumption, reduce alcohol craving and produce conditioned alcohol aversion. Cost-relevant clinical considerations are elucidated and recommendations for cost-conscious pharmacological treatment of alcohol dependence are proffered.

Effects of psychiatric care for dual diagnosis patients treated in a drug dependence clinic.

This study examines outcome of treatment for psychoactive substance dependence in a clinic which made psychiatric care readily available. Veterans entering outpatient treatment for substance dependence (n = 222) received psychiatric evaluation for additional Axis I disorders using DSM-III-R criteria. Patients provided urine toxicology specimens at least weekly. Outcome (urinalysis results and treatment retention) was compared for patients with dual diagnosis (n = 103, 46.4%) and with substance only diagnosis (n = 119, 53.6%). Psychotropic medications were prescribed for 80.4% of the dual diagnosis subjects. In the first 6 months of treatment, dual diagnosis subjects compared to substance only diagnosis subjects gave a significantly greater percentage of urines positive for cocaine and opioids. In the second 6 months, dual diagnosis subjects who remained (n = 72, 70.0%) significantly reduced from the first 6 months their percentage of cocaine and opioid positives and did not differ in percent positives from substance only diagnosis subjects who continued past 6 months (n = 70, 58.8%). Treatment retention of dual diagnosis subjects (median months = 14.3) exceeded that of substance only diagnosis subjects (8.9; Lee-Desu Statistic = 9.02, p < .003). Dual diagnosis patients may initially perform more poorly than substance only diagnosis patients in substance dependence treatment. However, in the presence of psychiatric care, they eventually exhibit comparable success.

Users of free treatment slots at a community-based methadone maintenance clinic.

At a community-based methadone clinic in Seattle, WA, 360 opiate-addicted individuals were enrolled in a treatment demonstration project. The treatment slots were free to clients and, unlike other funded treatment slots, did not require proof of eligibility based on documentation of indigence. The clients were compared with 70 clients enrolled in a research project begun 2 years earlier in which the sample was drawn from a population using normal funding sources at the same program. Subjects in the later demonstration project were older and had fewer years of education. A higher percentage of the demonstration project subjects were African American. These differences indicate that introduction of free treatment opened opportunities to individuals who have difficulty accessing treatment under normal circumstances. Subjects in the treatment demonstration project were more likely to have obtained needles from legal sources and used bleach to clean needles. These findings probably reflect the impact of needle exchange and outreach programs, established in the year prior to the demonstration project.

Reporting of HIV risk behaviors by injection drug using heterosexual couples in methadone maintenance.

This study sought to identify differences within injection drug using (IDU) couples in reporting of sexual and needle risk behavior. Subjects were thirty-nine heterosexual couples entering methadone maintenance. In 33.3% of couples, one member reported sharing needles while the other member reported no sharing. In 12.9% of couples, one member reported sharing injection equipment, while the other member reported no sharing. Agreement was 77.4% between members of monogamous couples regarding frequency of condom use, 80.7% regarding vaginal intercourse with condoms, and 25.8% regarding vaginal intercourse without condoms. Within couples, a number of differences between members of the couple in injection equipment sharing were noted, suggesting that individuals who attempt to protect themselves by not sharing injection equipment may be placed at risk by their sexual partners. Further clinical and research efforts should be directed toward reducing barriers to behavior that would protect both partners. Implications for self-report measurement of HIV risk behavior and for preventive interventions are discussed.

Analysis of urinary benzodiazepines using solid-phase extraction and gas chromatography-mass spectrometry.

A solid-phase extraction and GC-MS confirmation method was developed for certain urinary diazolo- and triazolobenzodiazepines, including the metabolites of lorazepam, clonazepam, alprazolam, and triazolam. The latter two do not form benzophenones, and the others are not readily confirmed by conventional thin-layer chromatography or GC-MS techniques. Samples were hydrolyzed with glucuronidase at 37 degrees C, adjusted to pH 4.5, extracted with Bond Elut Certify columns, dried, and derivatized using BSTFA with 1% TMCS. Sample preparation time averaged 4 hours. A GC-MS selected-ion-monitoring acquisition method targeting retention time, molecular ion abundances, and qualifier ion ratios was used to determine positive results. The recovery of 7-NH2-clonazepam was 95%, and recoveries of alpha-hydroxyalprazolam, alpha-hydroxytriazolam, and lorazepam were greater than 66%. Linearity was demonstrated from 0.1 to 1.0 microgram/mL for each drug. Within-run CVs were less than 11%, and between-run CVs were less than 16%. Using this technique, we have been able to confirm suspected cases of abuse that had not been confirmed by previous techniques.

Longitudinal changes in injection behaviors in a cohort of injection drug users.

To determine how the injecting behaviors of injection drug users (IDUs) change over time in the context of the epidemic of acquired immunodeficiency syndrome (AIDS) and what factors may be associated with such changes, a cohort of IDUs (n = 313) initially in treatment provided structured interviews regarding drug injecting behaviors. Repeat interviews in 18 months assessed behavior change in subjects who could be contacted for follow-up (n = 220, 70.3%). The study occurred in a state where sterile syringes can be purchased without prescription in drug stores. Injection drug use occurred for 180 (81.8%) of the 220 subjects in the 12 months prior to the initial interview but in only 121 (55.0%) in the 10 months prior to the follow-up interview (p < 0.0001). Similarly, sharing of equipment decreased from 63.1% to 31.8% (p < 0.0001). Sharing with multiple partners declined from 41.9% to 10.6% (p < 0.0001). Factors associated with ongoing risk included use of injected and non-injected psychoactive substances, less time in drug dependence treatment during follow-up interval, having a sexual partner who was an IDU and not using a drug store as the primary source of syringes. Factors associated with multiple-partner sharing included use of psychoactive substances, younger age and nonwhite race.