Optimally Choosing Medication Type for Patients With Opioid Use Disorder.

Patients with opioid use disorder (OUD) tend to get assigned to one of 3 medications based on the treatment program to which the patient presents (e.g., opioid treatment programs tend to treat patients with methadone, while office-based practices tend to prescribe buprenorphine). It is possible that optimally matching patients with treatment type would reduce the risk of return to regular opioid use (RROU). We analyzed data from 3 comparative effectiveness trials from the US National Institute on Drug Abuse Clinical Trials Network (CTN0027, 2006-2010; CTN0030, 2006-2009; and CTN0051 2014-2017), in which patients with OUD (n = 1,459) were assigned to treatment with either injection extended-release naltrexone (XR-NTX), sublingual buprenorphine-naloxone (BUP-NX), or oral methadone. We learned an individualized rule by which to assign medication type such that risk of RROU during 12 weeks of treatment would be minimized, and then estimated the amount by which RROU risk could be reduced if the rule were applied. Applying our estimated treatment rule would reduce risk of RROU compared with treating everyone with methadone (relative risk (RR) = 0.79, 95% confidence interval (CI): 0.60, 0.97) or treating everyone with XR-NTX (RR = 0.71, 95% CI: 0.47, 0.96). Applying the estimated treatment rule would have resulted in a similar risk of RROU to that of with treating everyone with BUP-NX (RR = 0.92, 95% CI: 0.73, 1.11).

Implementing Programs to Initiate Buprenorphine for Opioid Use Disorder Treatment in High-Need, Low-Resource Emergency Departments: A Nonrandomized Controlled Trial.

STUDY OBJECTIVE: We hypothesized that implementation facilitation would enable us to rapidly and effectively implement emergency department (ED)-initiated buprenorphine programs in rural and urban settings with high-need, limited resources and dissimilar staffing structures. METHODS: This multicenter implementation study employed implementation facilitation using a participatory action research approach to develop, introduce, and refine site-specific clinical protocols for ED-initiated buprenorphine and referral in 3 EDs not previously initiating buprenorphine. We assessed feasibility, acceptability, and effectiveness by triangulating mixed-methods formative evaluation data (focus groups/interviews and pre/post surveys involving staff, patients, and stakeholders), patients' medical records, and 30-day outcomes from a purposive sample of 40 buprenorphine-receiving patient-participants who met research eligibility criteria (English-speaking, medically stable, locator information, nonprisoners). We estimated the primary implementation outcome (proportion receiving ED-initiated buprenorphine among candidates) and the main secondary outcome (30-day treatment engagement) using Bayesian methods. RESULTS: Within 3 months of initiating the implementation facilitation activities, each site implemented buprenorphine programs. During the 6-month programmatic evaluation, there were 134 ED-buprenorphine candidates among 2,522 encounters involving opioid use. A total of 52 (41.6%) practitioners initiated buprenorphine administration to 112 (85.1%; 95% confidence interval [CI] 79.7% to 90.4%) unique patients. Among 40 enrolled patient-participants, 49.0% (35.6% to 62.5%) were engaged in addiction treatment 30 days later (confirmed); 26 (68.4%) reported attending one or more treatment visits; there was a 4-fold decrease in self-reported overdose events (odds ratio [OR] 4.03; 95% CI 1.27 to 12.75). The ED clinician readiness increased by a median of 5.02 (95% CI: 3.56 to 6.47) from 1.92/10 to 6.95/10 (n(pre)=80, n(post)=83). CONCLUSIONS: The implementation facilitation enabled us to effectively implement ED-based buprenorphine programs across heterogeneous ED settings rapidly, which was associated with promising implementation and exploratory patient-level outcomes.

Trajectories of depression among patients in treatment for opioid use disorder: A growth mixture model secondary analysis of the XBOT trial.

BACKGROUND AND OBJECTIVES: To inform clinical practice, we identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment. METHODS: Participants were 474 adults in a 24-week treatment trial for OUD. Depression symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D) at nine-time points. This was a secondary analysis of the Clinical Trials Network Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (XBOT) trial using a growth mixture model. RESULTS: Three distinct depression trajectories were identified: Class 1 High Recurring-10% with high HAM-D with initial partial reductions (of HAM-D across time), Class 2 Persistently High-5% with persistently high HAM-D, and Class 3 Low Declining-85% of the participants, with low HAM-D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse. DISCUSSION AND CONCLUSIONS: In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment. SCIENTIFIC SIGNIFICANCE: This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment.

Clinical and psychosocial outcomes by sex among individuals prescribed buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX) for opioid use disorder.

BACKGROUND AND OBJECTIVES: Limited research has explored sex differences in opioid use disorder medication (MOUD) treatment outcomes. The purpose of this study was to examine MOUD initiation onto buprenorphine-naloxone (BUP-NX) versus extended-release naltrexone (XR-NTX) by sex, and sex differences in clinical and psychosocial outcomes. METHODS: Using data from a 24-week open-label comparative effectiveness trial of BUP-NX or XR-NTX, this study examined MOUD initiation (i.e., receiving a minimum one XR-NTX injection or first BUP-NX dose) and 24-week self-report outcomes. We used regression models to estimate the probability of MOUD initiation failure among the intent-to-treat sample (N = 570), and the main and interaction effects of sex on outcomes of interest among the subsample of participants who successfully initiated MOUD (n = 474). RESULTS: In the intent-to-treat sample, the odds of treatment initiation failure were not significantly different by sex. In the subsample of successful MOUD initiates, the effect of treatment on employment at week 24 was significantly moderated by sex (p = .003); odds of employment were not significantly different among males by MOUD type; females randomized to XR-NTX versus BUP-NX had 4.63 times greater odds of employment (p < .001). Males had significantly lower odds of past 30-day exchanging sex for drugs versus females (adjusted odds ratios [aOR] = 0.10, p = .004), controlling for treatment and baseline outcomes. DISCUSSION AND CONCLUSIONS: Further research should explore how to integrate employment support into OUD treatment to improve patient outcomes, particularly among women. SCIENTIFIC SIGNIFICANCE: The current study addressed gaps in the literature by examining sex differences in MOUD initiation and diverse treatment outcomes in a large, national sample.

Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Baseline- and treatment-associated pain in the X:BOT comparative effectiveness study of extended-release naltrexone versus buprenorphine-naloxone for OUD.

Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance.

Patient Characteristics Associated with Opioid Abstinence after Participation in a Trial of Buprenorphine versus Injectable Naltrexone.

Background and Objectives: Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial. Methods: This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables. Results: Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use. Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

Association of substance use characteristics and future homelessness among emergency department patients with drug use or unhealthy alcohol use: Results from a linked data longitudinal cohort analysis.

Background: Homelessness and substance use are intricately related, and both are prevalent among emergency department (ED) patients. This study examined the longitudinal association of substance use characteristics with future homeless shelter entry among ED patients with any drug use or unhealthy alcohol use. Methods: We present results from a longitudinal cohort study of public hospital ED patients who screened positive for drug use or unhealthy alcohol use and who were not homeless at their baseline (index) ED visit. The primary outcome was homeless shelter entry within 12 months of baseline, ascertained in city homeless shelter administrative data. Primary independent variables of interest were alcohol use severity (AUDIT), drug use severity (DAST-10), and types of drugs used, as reported on baseline survey questionnaires. Results: Analyses included 1,210 ED patients. By 12 months following the baseline ED visit, 114 (9.4%) had entered a homeless shelter. Among patients with the most severe problems related to drug use (DAST-10 score 9-10), 40.9% entered a shelter within 12 months. Past shelter use was the strongest predictor of future shelter entry; once adjusting for historic shelter use the relationship of AUDIT and DAST-10 scores with future shelter entry was no longer statistically significant in multivariable models. Conclusions: ED patients with past year drug use or unhealthy alcohol use had relatively high likelihood of future shelter entry. Risk for homelessness should be addressed in future interventions with this population. Findings illustrate the complexity of relationships between substance use and homelessness.

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial.

BACKGROUND: The comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT) trial showed that following induction, treatment with the sublingual agonist (buprenorphine-naloxone, BUP-NX) or injected antagonist (extended release naltrexone, XR-NTX) produced similar reductions in opioid relapse in injection users with opioid use disorder (OUD). Because XR-NTX reduces drinking in alcohol use disorder (AUD), we conducted a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine whether XR-NTX (n = 204) was superior to BUP-NX (n = 270) in reducing drinking or heavy drinking in patients with OUD. METHODS: Standard drink units consumed were measured using the Timeline Follow-back method. Mixed-models regression was used to examine the monthly frequency of any drinking and heavy drinking over 6 months of treatment. We used a proportional hazard survival analysis to examine the time to first drink. RESULTS: Both treatment groups reduced drinking from baseline to posttreatment (small to medium effect), but no differences between groups were detected. However, only 29% (n = 136) of the sample had AUD and 19% (n = 26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included 136 individuals with an AUD diagnosis plus 43 who did not have AUD, but reported at least one day of heavy drinking prior to the study. However, this subsample reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy." Within this subsample, at baseline, the BUP-NX group reported more mean drinks per drinking day than the XR-NTX group (p = 0.03); however, there were no other significant group differences on drinking observed before, during, or at the end of treatment. CONCLUSIONS: There was an overall reduction in drinking during treatment of OUD using both agonist and antagonist medications, so that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for OUD.

Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial.

BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) treatment outcomes are poorer for young adults than older adults. Developmental differences are broadly implicated, but particular vulnerability factor interactions are poorly understood. This study sought to identify moderators of OUD relapse between age groups. METHODS: This secondary analysis compared young adults (18-25) to older adults (26+) from a comparative effectiveness trial ("XBOT") that randomized (N = 570) participants to extended-release naltrexone or sublingual buprenorphine-naloxone. We explored the relationship between 25 prespecified patient baseline characteristics and relapse to regular opioid use by age group and treatment condition, using logistic regression. RESULTS: Young adults (n = 111) had higher rates of 24-week relapse than older adults (n = 459) (70.3% vs 58.8%) and differed on a number of specific characteristics, including more smokers, more intravenous opioid use, and more cannabis use. No significant moderators predicted relapse, in either three-way or two-way interactions. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: No baseline factors were identified as moderating the relationship between age group and opioid relapse, nor any interactions between baseline characteristics, age group, and treatment condition to predict opioid relapse. Poorer treatment outcomes for young adults are likely associated with multiple developmental vulnerabilities rather than any single predominant factor. Although not reaching significance, several characteristics (using heroin, smoking tobacco, high levels of depression/anxiety, or treatment because of family/friends) showed higher odds ratio point estimates for relapse in young adults than older adults. This is the first study to explore moderators of worse OUD treatment outcomes in young adults, highlighting the need to identify predictor variables that could inform treatment enhancements. (Am J Addict 2021;00:1-12).

Substance Use and Mental Health in Emerging Adult Vs Older Adult Men and Women With Opioid Use Disorder.

BACKGROUND AND OBJECTIVES: We examined age differences across genders in clinical characteristics in emerging adult (≤25 years) vs older adult patients (26+ years) with opioid use disorder (OUD). METHODS: Participants (N = 570; 30% female) entering a comparative effectiveness medication trial of buprenorphine vs extended-release naltrexone. RESULTS: Differences in clinical characteristics in emerging adult vs older participants were similar across genders. However, women 26+ years reported more mental health problems compared with women ≤25, while men ≤25 years reported more mental health problems compared with men 26+ years. DISCUSSION AND CONCLUSION: Different strategies for emerging adult and older patients seeking OUD treatment may be necessary to address psychiatric comorbidities that differ across genders in this population. SCIENTIFIC SIGNIFICANCE: Comprehensive psychiatric assessment should be systematically included in OUD treatment for all genders. Treatment should focus on the emerging adult developmental phase when appropriate, with psychiatric treatment tailored for women and men, separately, across the lifespan. (Am J Addict 2020;29:536-542).

Clinical Trials for Opioid Use Disorder.

This chapter describes recent clinical trials for opioid use disorder (OUD), an area that has rapidly accelerated in response to the opioid overdose crisis in the USA and newly appropriated funding. Trials involve a wide range of compounds including cannabinoids and psychedelics, new and existing compounds targeting domains emerging from addiction neuroscience, agents repurposed from other indications, and novel strategies including vaccines, enzymes, and other biologicals. In parallel, new formulations of existing compounds offer immediate promise, as do a variety of web-based interventions and smartphone-delivered apps. Trials focused on implementing existing effective interventions in mainstream healthcare settings, and others focused on special populations, e.g., adolescents, criminal justice, pregnant women, native Americans, etc., have the potential to vastly expand treatment in the near term. Given the range of ongoing and recent trials, this chapter is not intended to be an exhaustive review but rather to present an overview of approaches within the framework of the opioid treatment cascade and the context of current OUD pharmacotherapies.

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse.

Background: Not enough evidence exists to compare buprenorphine-naloxone with extended-release naltrexone for treating opioid use disorder. Objective: To evaluate the cost-effectiveness of buprenorphine-naloxone versus extended-release naltrexone. Design: Cost-effectiveness analysis alongside a previously reported randomized clinical trial of 570 adults in 8 U.S. inpatient or residential treatment programs. Data Sources: Study instruments. Target Population: Adults with opioid use disorder. Time Horizon: 24-week intervention with an additional 12 weeks of observation. Perspective: Health care sector and societal. Interventions: Buprenorphine-naloxone and extended-release naltrexone. Outcome Measures: Incremental costs combined with incremental quality-adjusted life-years (QALYs) and incremental time abstinent from opioids. Results of Base-Case Analysis: Use of the health care sector perspective and a willingness-to-pay threshold of $100 000 per QALY showed buprenorphine-naloxone to be preferable to extended-release naltrexone in 97% of bootstrap replications at 24 weeks and in 85% at 36 weeks. Similar results were obtained with incremental time abstinent from opioids as an outcome and with use of the societal perspective. Results of Sensitivity Analysis: The base-case results were sensitive to the cost of the 2 treatments and the success of randomized treatment initiation. Limitation: Relatively short follow-up for a chronic condition, substantial missing data, no information on patient out-of-pocket and social service costs. Conclusion: Buprenorphine-naloxone is preferred to extended-release naltrexone as first-line treatment when both options are clinically appropriate and patients require detoxification before initiating extended-release naltrexone. Primary Funding Source: National Institute on Drug Abuse, National Institutes of Health.

Variants of opioid genes and response to treatment of opioid use disorder with buprenorphine-naloxone versus extended-release naltrexone in Caucasians.

Background: Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. Objectives: Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. Methods: In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to model each outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. Results: There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. Conclusions: The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.

Health-related material needs and substance use among emergency department patients.

Background: Emergency department (ED) visits related to substance use are common. ED patients also have high levels of health-related material needs (HRMNs), such as homelessness and food insecurity. However, little research has examined the intersection between ED patient HRMNs and substance use. Methods: We surveyed a random sample of public hospital ED patients. Surveys included validated single-item screeners for unhealthy alcohol and any drug use and questions on self-reported past-year material needs. We compared individual HRMNs and cumulative number of HRMNs by substance use screening status using bivariate and multivariable analyses. Results: A total of 2312 surveys were completed. Nearly one third of patients (32.3%, n = 747) screened positive for unhealthy alcohol use, and 21.8% (n = 503) screened positive for drug use. Prevalence of HRMNs for all patients-including food insecurity (50.8%), inability to meet essential expenses (40.8%), cost barriers to medical care (24.6%), employment issues (23.8%), and homelessness (21.4%)-was high and was significantly higher for patients with unhealthy alcohol use or drug use. In multivariable analyses, homelessness was independently associated with unhealthy alcohol use (adjusted odds ratio [aOR]: 1.61, 95% confidence interval [CI]: 1.24-2.09) and drug use (aOR: 2.30, 95% CI: 1.74-3.05). There was a significant stepwise increase in the odds of patient unhealthy alcohol or drug use as number of HRMNs increased. Conclusions: ED patients with unhealthy alcohol or drug use have higher prevalence of HRMNs than those without. Our findings suggest that HRMNs may act additively and that homelessness is particularly salient. Patients' comorbid HRMNs may affect the success of ED-based substance use interventions.

Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. METHODS: We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. FINDINGS: Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). INTERPRETATION: In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications. FUNDING: NIDA Clinical Trials Network.

Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders.

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.).

Screening for Substance Use in Rural Primary Care: a Qualitative Study of Providers and Patients.

BACKGROUND: Substance use frequently goes undetected in primary care. Though barriers to implementing systematic screening for alcohol and drug use have been examined in urban settings, less is known about screening in rural primary care. OBJECTIVE: To identify current screening practices, barriers, facilitators, and recommendations for the implementation of substance use screening in rural federally qualified health centers (FQHCs). DESIGN: As part of a multi-phase study implementing electronic health record-integrated screening, focus groups (n = 60: all stakeholder groups) and individual interviews (n = 10 primary care providers (PCPs)) were conducted. PARTICIPANTS: Three stakeholder groups (PCPs, medical assistants (MAs), and patients) at three rural FQHCs in Maine. APPROACH: Focus groups and interviews were recorded, transcribed, and content analyzed. Themes surrounding current substance use screening practices, barriers to screening, and recommendations for implementation were identified and organized by the Knowledge to Action (KTA) Framework. KEY RESULTS: Identifying the problem: Stakeholders unanimously agreed that screening is important, and that universal screening is preferred to targeted approaches. Adapting to the local context: PCPs and MAs agreed that screening should be done annually. Views were mixed regarding the delivery of screening; patients preferred self-administered, tablet-based screening, while MAs and PCPs were divided between self-administered and face-to-face approaches. Assessing barriers: For patients, barriers to screening centered around a perceived lack of rapport with providers, which contributed to concerns about trust, judgment, and privacy. For PCPs and MAs, barriers included lack of comfort, training, and preparedness to address screening results and offer treatment. CONCLUSIONS: Though stakeholders agree on the importance of implementing universal screening, concerns about the patient-provider relationship, the consequences of disclosure, and privacy appear heightened by the rural context. Findings highlight that strong relationships with providers are critical for patients, while in-clinic resources and training are needed to increase provider comfort and preparedness to address substance use.