This Viewpoint explores the ethical questions involved in the design and conduct of the RDD trial among individuals stopping medications for opioid use disorder.

INTRODUCTION AND BACKGROUND:The three medications approved to address OUD are effective in decreasing opioid use and morbidity and mortality; however, their utility is limited by high rates of dropout from treatment. The CTN-0100 trial will develop an evidence base for strategies to improve retention on buprenorphine and extended-release naltrexone. RESEARCH DESIGN AND METHODS:The National Drug Abuse Treatment Clinical Trials Network (CTN) study CTN-0100, "Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy" (RDD), is a multicenter, randomized, non-blinded trial enrolling more than a thousand patients from 18 community-based substance use disorder treatment programs. Participants are adult volunteers seeking to initiate medication treatment for OUD (MOUD). Individuals choose between buprenorphine or extended-release injectable naltrexone. The trial randomizes participants choosing buprenorphine, in a 3 × 2 factorial design, to a medication condition (standard-dose sublingual buprenorphine, high-dose sublingual buprenorphine, or extended-release injectable buprenorphine) and to a behavioral condition (Medical Management or Medical Management plus a digital therapeutic (smartphone) app). Individuals choosing extended-release naltrexone are randomized only to a behavioral condition. Participants receive study medication for 74 weeks and are then followed for a further 24 weeks. The primary outcome is successful retention on MOUD at 26 weeks (six months), with 50- and 74-week retention among the secondary outcomes. DISCUSSION/CONCLUSION:Dropout from treatment is a major barrier to the effectiveness of MOUD. The CTN-0100 study will determine whether strategies such as high dose sublingual or extended-release buprenorphine, or an app-based behavioral intervention improve retention on MOUD. CLINICALTRIALS:gov Identifier: NCT04464980.

BACKGROUND AND OBJECTIVES:Clinical follow-up data after substance use disorder (SUD) treatment provides important information about treatment effectiveness, yet compliance is a challenge. We compared financial incentives for obtaining follow-up data from adults receiving inpatient SUD treatment. METHODS:Participants (N = 237) were randomized to receive a guaranteed incentive, raffle-based incentive, or no incentive for completing a 1-month follow-up assessment. Logistic regression tested the effect of incentives on follow-up completion. RESULTS:Those in the raffle condition had >2 times higher odds of completing a follow-up assessment compared to those in the no-incentive or guaranteed-incentive conditions. DISCUSSION AND CONCLUSIONS:The raffle-based financial incentive was most effective in obtaining follow-up data. SCIENTIFIC SIGNIFICANCE:Raffle-based incentives may improve follow-up after treatment and help clinicians evaluate SUD treatment outcomes.

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

INTRODUCTION AND BACKGROUND:Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD. RESEARCH DESIGN AND METHODS:The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine. DISCUSSION/CONCLUSION:It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue. CLINICALTRIALS:gov Identifier: NCT04464980.

BACKGROUND AND OBJECTIVES Early recovery from substance use disorder (SUD) is often characterized by hopelessness and despair about the future. Optimism, or the expectation that good things will happen, may provide a buffer against despair, and motivate adaptive goal engagement and coping. Study objectives were to (1) compare levels of optimism among individuals in substance use disorder inpatient treatment to other populations and (2) examine correlates of optimism. METHODS This exploratory study utilized a cross-sectional survey design. Participants (n = 355) completed self-report measures assessing sociodemographic and clinical characteristics. The main variable of interest, optimism, was assessed by Life Orientation Test-Revised scores. Multivariate regression was used to examine the association among sociodemographic and clinical variables and optimism. RESULTS Our sample (n = 342) scored lower on optimism (mean = 11.7) than general population and SUD patients reported in the literature (range = 13.0-18.5). Optimism was higher for SUD inpatients who were college-educated and those with higher scores on the recovery protection factor, while greater anxiety severity was associated with lower optimism scores. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE This study contributes to emerging research on the association between optimism and SUDs. Optimism has not been previously studied among patients in acute, short-term inpatient SUD treatment and doing so may be clinically useful in addressing low optimism as an obstacle to motivation for treatment. Bolstering optimism may be a promising target for intervention and future research.

Background: Chronic pain is common in patients with prescription opioid use disorder (OUD), and pain severity has been shown to predict opioid use for those with chronic pain. However, recent research suggests that focusing on pain status (i.e., the presence or absence of chronic pain) at treatment initiation may not reflect the clinical significance of pain over the long-term course of OUD. Reports of variability in chronic pain and its clinical significance over time have yet to be investigated in patients with prescription OUD. The present study examined variability in chronic pain status from entry into prescription OUD treatment through 3.5-year follow-up. Additionally, we examined the association between concurrent chronic pain and opioid use at three follow-up time points. Methods: This secondary analysis (N = 309) of a national, randomized, controlled trial of prescription OUD treatment used generalized estimating equations to assess variability in the prevalence of chronic pain from study entry to 3.5-year follow-up, and the association between chronic pain status and concurrent opioid use. Results: Fifty-three percent of participants reported variability in chronic pain status over time. The prevalence of chronic pain decreased from study entry through follow-up (aOR = 0.47, p < 0.001). Chronic pain was associated with increased opioid use at each follow-up assessment (aOR = 3.56, p < 0.001). Conclusions: Chronic pain status may vary over time in those with prescription OUD, and chronic pain appears to be associated with concurrent opioid use. The present findings highlight the importance of assessing chronic pain throughout the course of prescription OUD.

This study explores the content family members find helpful in family meetings that occur while patients are in short-term treatment for substance use disorders. Four focus groups were conducted: 3 with 23 family members and 1 with 10 patients who were asked to identify those topics that are helpful or unhelpful for families with and without prior treatment experiences. Families identified education about substance use disorders and an overview of treatment options as useful for family members new to treatment, and an emphasis on response to relapse and family supports as important for those with prior treatment experiences.

BACKGROUND:Although prescription opioid use disorder has recently increased sharply in the United States, relatively little is known about the general well-being of this population. Assessment of quality of life in patients with substance use disorders has been recommended to improve clinical care.OBJECTIVES:Health-related quality of life was examined in prescription opioid-dependent patients at entry to a national multi-site clinical trial, to compare quality of life scores in the study sample to other populations; further, background variables associated with quality of life in the literature were examined.METHODS:Prescription opioid-dependent patients (N = 653) were compared to general populations on the Medical Outcome Study Short Form-36 (SF-36) quality of life measure; and the association between patient background variables and quality of life was examined.RESULTS:Compared to a general population, the current sample of prescription opioid-dependent patients had worse physical (-1.7 points, p < .001) and mental quality of life (-12.3 points, p < .001) as measured by the SF-36, similar to other opioid-use disorder populations. Within our sample, women showed more impairment than men in mental quality of life (-4.3 points, p < .001); older patients scored worse on physical (-5.2 points, p < .001), but not mental, quality of life. Chronic pain was associated with poorer physical quality of life (-9.0 points, p < .001).CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE:The growing focus on wellness underscores the importance of measuring quality of life in addition to substance use outcomes. Routine assessment of health-related quality of life can add an important dimension to overall evaluation of patients' treatment response.

Background: Despite the growing prevalence of prescription opioid dependence, longitudinal studies have not examined long-term treatment response. The current study examined outcomes over 42 months in the Prescription Opioid Addiction Treatment Study (POATS).Methods: POATS was a multi-site clinical trial lasting up to 9 months, examining different durations of buprenorphine-naloxone plus standard medical management for prescription opioid dependence, with participants randomized to receive or not receive additional opioid drug counseling. A subset of participants (N = 375 of 653) enrolled in a follow-up study. Telephone interviews were administered approximately 18, 30, and 42 months after main-trial enrollment. Comparison of baseline characteristics by follow-up participation suggested few differences.Results: At Month 42, much improvement was seen: 31.7% were abstinent from opioids and not on agonist therapy; 29.4% were receiving opioid agonist therapy, but met no symptom criteria for current opioid dependence; 7.5% were using illicit opioids while on agonist therapy; and the remaining 31.4% were using opioids without agonist therapy. Participants reporting a lifetime history of heroin use at baseline were more likely to meet DSM-IV criteria for opioid dependence at Month 42 (OR = 4.56, 95% CI = 1.29-16.04, p < .05). Engagement in agonist therapy was associated with a greater likelihood of illicit-opioid abstinence. Eight percent (n = 27/338) used heroin for the first time during follow-up; 10.1% reported first-time injection heroin use.Conclusions: Long-term outcomes for those dependent on prescription opioids demonstrated clear improvement from baseline. However, a subset exhibited a worsening course, by initiating heroin use and/or injection opioid use. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Despite the high prevalence of prescription opioid dependence in the U.S., little is known about the course of this disorder and long-term response to treatment. We therefore examined 18-month post-randomization outcomes of participants in the Prescription Opioid Addiction Treatment Study, a multi-site, randomized controlled trial examining varying durations of buprenorphine-naloxone treatment and different intensities of counseling for prescription opioid dependence. Thus the current follow-up study provides a unique contribution to the field by reporting longer-term outcomes of a well-characterized population of treatment-seeking prescription opioid dependent patients. Participants from the treatment trial (N=252/653) completed an 18-month follow-up telephone assessment. Multivariable analyses examined associations between participant characteristics and key indicators of month-18 status: opioid abstinence, DSM-IV opioid dependence, and opioid agonist treatment. Overall, participants showed improvement from baseline to month 18: 49.6% were abstinent in the previous 30 days, with only 16.3% opioid-dependent. Some participants, however, had initiated past-year heroin use (n=9) or opioid injection (n=17). Most participants (65.9%) engaged in substance use disorder treatment during the past year, most commonly opioid agonist therapy (48.8%). Of particular interest in this population, multivariable analysis showed that greater pain severity at baseline was associated with opioid dependence at 18 months. In conclusion, although opioid use outcomes during the treatment trial were poor immediately following a buprenorphine-naloxone taper compared to those during 12 weeks of buprenorphine-naloxone stabilization, opioid use outcomes at 18-month follow-up showed substantial improvement over baseline and were comparable to the rate of successful outcomes during buprenorphine-naloxone stabilization in the treatment trial.

Background: Unemployment is associated with negative outcomes both during and after drug abuse treatment. Interventions designed to increase rates of employment may also improve drug abuse treatment outcomes. The purpose of this multi-site clinical trial was to evaluate the Job Seekers' Workshop (JSW), a three session, manualized program designed to train patients in the skills needed to find and secure a job.Method: Study participants were recruited through the NIDA Clinical Trials Network (CTN) from six psychosocial counseling (n = 327) and five methadone maintenance (n = 301) drug treatment programs. Participants were randomly assigned to either standard care (program-specific services plus brochure with local employment resources) (SC) or standard care plus JSW. Three 4-h small group JSW sessions were offered weekly by trained JSW facilitators with ongoing fidelity monitoring.Results: JSW and SC participants had similar 12- and 24-week results for the primary outcome measure (i.e., obtaining a new taxed job or enrollment in a training program). Specifically, one-fifth of participants at 12 weeks (20.1-24.3%) and nearly one-third at 24 weeks (31.4-31.9%) had positive outcomes, with "obtaining a new taxed job" accounting for the majority of cases.JSW group participants did not have higher rates of employment/training than SC controls. Rates of job acquisition were modest for both groups, suggesting more intensive interventions may be needed. Alternate targets (e.g., enhancing patient motivation, training in job-specific skills) warrant further study as well. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

CONTEXT No randomized trials have examined treatments for prescription opioid dependence, despite its increasing prevalence. OBJECTIVE To evaluate the efficacy of brief and extended buprenorphine hydrochloride-naloxone hydrochloride treatment, with different counseling intensities, for patients dependent on prescription opioids. DESIGN Multisite, randomized clinical trial using a 2-phase adaptive treatment research design. Brief treatment (phase 1) included 2-week buprenorphine-naloxone stabilization, 2-week taper, and 8-week postmedication follow-up. Patients with successful opioid use outcomes exited the study; unsuccessful patients entered phase 2: extended (12-week) buprenorphine-naloxone treatment, 4-week taper, and 8-week postmedication follow-up. SETTING Ten US sites. Patients A total of 653 treatment-seeking outpatients dependent on prescription opioids. INTERVENTIONS In both phases, patients were randomized to standard medical management (SMM) or SMM plus opioid dependence counseling; all received buprenorphine-naloxone. MAIN OUTCOME MEASURES Predefined "successful outcome" in each phase: composite measures indicating minimal or no opioid use based on urine test-confirmed self-reports. RESULTS During phase 1, only 6.6% (43 of 653) of patients had successful outcomes, with no difference between SMM and SMM plus opioid dependence counseling. In contrast, 49.2% (177 of 360) attained successful outcomes in phase 2 during extended buprenorphine-naloxone treatment (week 12), with no difference between counseling conditions. Success rates 8 weeks after completing the buprenorphine-naloxone taper (phase 2, week 24) dropped to 8.6% (31 of 360), again with no counseling difference. In secondary analyses, successful phase 2 outcomes were more common while taking buprenorphine-naloxone than 8 weeks after taper (49.2% [177 of 360] vs 8.6% [31 of 360], P < .001). Chronic pain did not affect opioid use outcomes; a history of ever using heroin was associated with lower phase 2 success rates while taking buprenorphine-naloxone. CONCLUSIONS Prescription opioid-dependent patients are most likely to reduce opioid use during buprenorphine-naloxone treatment; if tapered off buprenorphine-naloxone, even after 12 weeks of treatment, the likelihood of an unsuccessful outcome is high, even in patients receiving counseling in addition to SMM.