Faculty Bibliography

We examine ethical challenges encountered in the design of an effectiveness trial (CTN-0051; X:BOT), comparing sublingual buprenorphine-naloxone (BUP-NX), an established treatment for opioid dependence, to the newer extended-release injectable naltrexone (XR-NTX). Ethical issues surrounded: 1) known poor effectiveness of one possible, commonly used treatment as usual control condition-detoxification followed by counseling without medication; 2) the role of patients' preferences for treatments, given that treatments were clinically approved and available to the population; 3) differences between the optimal "usual treatment" clinical settings for different treatments making it challenging to design a fair comparison; 4) vested interest groups favoring different treatments exerting potential influence on the design process; 5) potentially vulnerable populations of substance users and prisoners; 6) potential therapeutic misconception in the implementation of safety procedures; and 7) high cost of a large trial limiting questions that could be addressed. We examine how the design features underlying these ethical issues are characteristic of effectiveness trials, which are often large trials that compare treatments with varying degrees of existing effectiveness data and familiarity to patients and clinicians, in community-based treatment settings, with minimal exclusion criteria that could involve vulnerable populations. Hence, investigators designing effectiveness trials may wish to remain alert to the possibility of similar ethical issues.

INTRODUCTION: Electronic cigarette (EC) use is growing dramatically with use highest among young adults and current smokers. One of the most common reasons for using ECs is interest in quitting or reducing cigarettes per day (CPD); however there are few randomized controlled trials (RCT) on the effect of ECs on smoking abstinence and reduction. METHODS: We conducted a two-arm; double-blind RCT. Subjects were randomized to receive 3-weeks of either disposable 4.5% nicotine EC (intervention) or placebo EC. The primary outcome was self-reported reduction of >/=50% in the number of CPDs smoked at week 3 (end of treatment) compared to baseline. Study subjects (n=99) were young adult (21-35), current smokers (smoked >/=10 CPDs) living in NYC. RESULTS: Compared with baseline, a significant reduction in CPDs was observed at both study time periods (1 and 3 weeks) for intervention (p<.001) and placebo (p<.001) groups. Between-group analyses showed significantly fewer CPDs in the intervention group compared to the placebo group at week 3 (p=.03), but not at any other follow-up periods. The logistic regression analysis showed that using a greater number of ECs, treatment condition and higher baseline readiness to quit were significantly associated with achieving >/=50% reduction in CPDs at the end of treatment. CONCLUSION: A diverse young adult sample of current everyday smokers, who were not ready to quit, was able to reduce smoking with the help of ECs. Further study is needed to establish the role of both placebo and nicotine containing ECs in increasing both reduction and subsequent cessation.

INTRODUCTION: For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays.Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification.Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized.This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies. METHODS: The National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients.Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX. RESULTS: The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase.Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms).Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness. CONCLUSIONS: XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance.Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed. CLINICAL TRIAL REGISTRATION: NCT02032433.

BACKGROUND: An Audio Computer-assisted Self Interview (ACASI) version of the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST) could reduce barriers to substance use screening and assessment in primary care settings. This study evaluated the diagnostic accuracy of an ACASI ASSIST for identification of unhealthy substance use and substance use disorders (SUD). METHODS: 399 adult patients were consecutively recruited from an urban safety-net primary care clinic. ACASI ASSIST scores for tobacco, alcohol, marijuana, and cocaine were compared against reference standard measures to assess the instrument's diagnostic accuracy for identifying unhealthy use and SUD, first using empirically-derived optimal cutoffs, and second using the currently recommended ASSIST cutoffs. RESULTS: For identifying any unhealthy use, at the empirically-derived cutoffs the ACASI ASSIST had 93.6% sensitivity and 85.8% specificity (AUC=0.90) for tobacco, 85.9% sensitivity and 60.3% specificity (AUC=0.73), for alcohol in men, 100% sensitivity and 62.4% specificity (AUC=0.81) for alcohol in women, 94.6% sensitivity and 81.6% specificity (AUC=0.88) for marijuana, and 86.1% sensitivity, 84.0% specificity (AUC=0.85) for cocaine. For SUD, sensitivity ranged from 79% (for alcohol in males), to 100% (for tobacco), and specificity was 83% or higher (AUCs ranged 0.83-0.91). For substances other than tobacco, empirically-derived cutoff scores were lower than the standard cutoffs, and resulted in higher sensitivity and lower specificity for identifying unhealthy substance use. CONCLUSIONS: The ACASI ASSIST is a valid measure of unhealthy use and SUD for substances that are commonly used by primary care patients, and could facilitate effective and efficient screening for substance use in medical settings.

AIMS: To examine the safety and effectiveness of buprenorphine + naloxone sublingual tablets (BUP, as Suboxone(R)) provided after administration of extended-release injectable naltrexone (XR-NTX, as Vivitrol(R)) to reduce cocaine use in participants who met DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse. METHODS: This multi-centered, double-blind, placebo-controlled study, conducted under the auspices of the National Drug Abuse Treatment Clinical Trials Network, randomly assigned 302 participants at sites in California, Oregon, Washington, Colorado, Texas, Georgia, Ohio, New York, and Washington D.C., USA to 1 of 3 conditions provided with XR-NTX: 4 mg/day BUP (BUP4, n = 100), 16 mg/day BUP (BUP16, n = 100), or no buprenorphine (placebo; PLB, n = 102). Participants received pharmacotherapy for 8 weeks, with 3 clinic visits per week. Cognitive Behavioral Therapy was provided weekly. Follow-up assessments occurred at 1 and 3 months post-intervention. The planned primary outcome was urine drug screen (UDS)-corrected, self-reported cocaine use during the last 4 weeks of treatment. Planned secondary analyses assessed cocaine use by UDS, medication adherence, retention, and adverse events. RESULTS: No group differences were found between groups for the primary outcome (BUP4 vs. PLB, p = 0.262; BUP16 vs PLB, p = 0.185). Longitudinal analysis of UDS data during the evaluation period using generalized linear mixed equations found a statistically significant difference between BUP16 and PLB (p = 0.022, OR = 1.71) but not for BUP4 (p = 0.105, OR = 1.05). No secondary outcome differences across groups were found for adherence, retention, or adverse events. CONCLUSIONS: Buprenorphine + naloxone, used in combination with naltrexone, may be associated with reductions in cocaine use among people who meet DSM-IV criteria for cocaine dependence and past or current opioid dependence or abuse

BACKGROUND: Extended-release naltrexone (XR-NTX) is an injectable monthly sustained-release mu opioid receptor antagonist, which blocks the typical effects of heroin and other opioid agonists. Use of XR-NTX among opioid dependent persons leaving jails and prisons is increasing despite scant high-quality evidence regarding XR-NTX's effectiveness at re-entry. METHODS: This 24-week, open-label randomized controlled trial examines the effectiveness of XR-NTX as opioid relapse prevention at release from jail (N=85) compared to enhanced treatment as usual (ETAU, N=85). A third, non-randomized, quasi-experimental naturalistic arm of participants who have newly initiated a jail-to-community methadone treatment program (MTP, N=85) allows for comparisons to a methadone standard-of-care. RESULTS: We describe the rationale, design, and primary and secondary outcomes of the study. The primary outcome is an opioid relapse event; the primary contrast is a time-to-relapse comparison of XR-NTX and ETAU over a 24-week treatment phase. Secondary outcomes are rates of: (a) post-release opioid treatment participation, (b) opioid, alcohol, and cocaine use, (c) injection drug use and HIV sexual risk behaviors, (d) overdose (fatal and non-fatal) and all-cause mortality, and, (e) re-incarceration. CONCLUSIONS: XR-NTX is a potentially important, effective treatment and relapse prevention option for a large US population of persons with opioid use disorders leaving jails. This study will estimate XR-NTX's effectiveness relative to existing standards of care, including counseling-only treatment-as-usual and methadone maintenance.

AIM: This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence. PATIENTS & METHODS: The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed. RESULTS: Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1. CONCLUSION: Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.

Background: Impulsivity is a core feature of substance use disorders. Temporal discounting (TD) paradigms provide a modelbased approach to studying the dynamics of impulsive decisionmaking as drug-addicted individuals undergo treatment. Here we examine (1) how TD changes as opioid use disorder (OUD) subjects stabilize on maintenance therapy; and (2) how TD is predicted by (or is predictive of) relevant clinical outcomes. Methods: 30 individuals initiating treatment for OUD and 29 matched community controls (CC) were assessed weekly (up to 15 weeks) on a TD task. Drug use was monitored by urine toxicology and chart review. We analyzed the data with a hyperbolic discounting model and derived subject-specific parameters forTD rate, and the non-parametric proportion of immediate choices. Results: OUD subjects showed higher TD rates than CC (Means: 0.039 versus 0.139 respectively, p = 0.005). Although this measure had high test-retest reliability, OUD subjects exhibited more variability across the repeated measures. Subjects in the initial phase of treatment showed a progressive decrease of TD (p = 0.007). Recent heroin use predicted subjects' level of impulsivity: positive use in the previous week correlated with a significantly higher proportion of immediate choices (p = 0.02). We did not And a predictive effect of TD on heroin use the following week. Conclusions: These results suggest that TD greatly fluctuates in treatment-seeking heroin users, in contrast to its stability in CC. TD is both sensitive to the initial phase of treatment for OUD and to recent heroin use, but not predictive of future use in this population

BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

BACKGROUND AND AIMS: To address barriers to implementing the "Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)" in medical settings, we adapted the traditional interviewer-administered (IA) ASSIST to an audio-guided computer assisted self-interview (ACASI) format. This study sought to validate the ACASI ASSIST by estimating the concordance, correlation, and agreement of scores generated using the ACASI versus the reference standard IA ASSIST. Secondary aims were to assess feasibility and compare ASSIST self-report to drug testing results. DESIGN: Participants completed the ACASI and IA ASSIST in a randomly assigned order, followed by drug testing. SETTING: Urban safety-net primary care clinic in New York City, USA. PARTICIPANTS: A total of 393 adult patients. MEASUREMENTS: Scores generated by the ACASI and IA ASSIST; drug testing results from saliva and hair samples. FINDINGS: Concordance between the ACASI and IA ASSIST in identifying moderate-high risk use was 92-99% for each substance class. Correlation was excellent for global scores (ICC = 0.94, CI 0.92-0.95) and for substance-specific scores for tobacco (ICC = 0.93, CI 0.91-0.94), alcohol (ICC = 0.91, CI 0.89-0.93) and illicit drugs (ICC = 0.85, CI 0.85-0.90), and good for prescription drugs (ICC = 0.68, CI 0.61-0.73). Ninety-four percent of differences in global scores fell within anticipated limits of agreement. Among participants with a positive saliva test, 74% self-reported use on the ACASI ASSIST. The ACASI ASSIST required a median time of 3.7 minutes (range 0.7-15.4), and 21 (5.3%) participants requested assistance. CONCLUSIONS: The computer self-administered Alcohol, Smoking and Substance Involvement Screening Test appears to be a valid alternative to the interviewer-administered approach for identifying substance use in primary care patients.