Faculty Bibliography

BACKGROUND & OBJECTIVES/OBJECTIVE:We investigated gender differences in individuals with opioid use disorder (OUD) receiving inpatient services and entering a randomized controlled trial comparing extended-release naltrexone to buprenorphine. METHODS:Participants (N = 570) provided demographic, substance use, and psychiatric information. RESULTS:Women were significantly younger, more likely to identify as bisexual, live with a sexual partner, be financially dependent, and less likely employed. Women reported significantly greater psychiatric comorbidity and risk behaviors, shorter duration but similar age of onset of opioid use. DISCUSSION/CONCLUSIONS/CONCLUSIONS:Findings underscore economic, psychiatric, and infection vulnerability among women with OUD. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:Interventions targeting these disparities should be explored, as women may face complicated treatment initiation, retention, and recovery. (Am J Addict 2018;XX:1-6).

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.

BACKGROUND: Opioid use disorders have reached epidemic proportions, with overdose now the leading cause of accidental death in the United States. Extended release naltrexone (XR-NTX) has emerged as a medication treatment that reduces opioid use and craving. However, the effect of XR-NTX therapy on acute healthcare utilization, including emergency department visits and inpatient hospitalizations, remains uncertain. The objective of the current study is to evaluate hospital-based healthcare resource utilization in adults involved in the criminal justice system with a history of opioid use disorder randomized to XR-NTX therapy compared with treatment as usual (TAU) during a 6-month treatment phase and 12months post-treatment follow up. METHODS: This retrospective exploratory analysis uses data collected in a published randomized trial. Comparisons of the number of emergency department visits and hospital admissions (for drug detox, psychiatric care and other medical reasons) were performed using chi square tests for any admission and negative binomial models for number of admissions. RESULTS: Of the 308 participants randomized, 96% had utilization data (76% complete 6months, 67% complete follow up). No significant differences were seen in overall healthcare utilization (IRR=0.88, 95%CI 0.63-1.23, p=0.45), or substance use-related drug detox hospitalizations (IRR=0.83, 95%CI 0.32-2.16, p=0.71). Despite having more participants report chronic medical problems at baseline (43% vs. 32%, p=0.05), those receiving XR-NTX generally experienced equivalent or lower rates of healthcare utilization compared to TAU. The XR-NTX group had significantly lower medical/surgical related hospital admissions (IRR=0.55, 95%CI 0.30-1.00, p=0.05) during the course of the entire study. CONCLUSIONS: XR-NTX did not significantly increase rates of healthcare utilization compared to TAU. Provider concerns regarding healthcare utilization should not preclude the consideration of XR-NTX as therapy for opioid use disorders.

BACKGROUND: Opioid use disorder is often treated with short term hospitalization and medically supervised withdrawal from opioids followed by counseling alone without medication assisted treatment (MAT). More evidence is needed to confirm the expectation that the rate of relapse would be high after short term inpatient treatment and withdrawal from opioids without follow-up MAT. OBJECTIVE/METHODS: To examine relapse to opioid use disorder in a randomized, multi-site effectiveness trial of extended-release injection naltrexone (XR-NTX) vs community-based treatment as usual (TAU) without medication, as a function of the type of clinical service where treatment was initiated-short-term inpatient (N=59), long-term inpatient (N=48), or outpatient (N=201). Inpatients typically were admitted to treatment actively using opioids and had completed withdrawal from opioids before study entry. Outpatients typically presented already abstinent for varying periods of time. RESULTS: One month after randomization, relapse rates on TAU by setting were: short-term inpatient: 63%; long term inpatient: 14%; outpatient: 28%. On XR-NTX relapse rates after one month were low (<12%) across all three settings. At the end of the 6 month trial, relapse rates on TAU were high across all treatment-initiation settings (short term inpatient 77%; long term inpatient 59%; outpatient 61%), while XR-NTX exerted a modest protective effect against relapse across settings (short term inpatient: 59%; long term inpatient 46%; outpatient 38%). CONCLUSIONS: Short term inpatient treatment is associated with a high rate of relapse among patients with opioid use disorder. These findings support the recommendation that medically supervised withdrawal from opioids should be followed by medication assisted treatment.

BACKGROUND: Extended release naltrexone (XR-NTX) injected intramuscularly monthly has been shown to reduce relapse in persons with opioid use disorder. Baseline factors, including patients' demographics, comorbidities and lifestyle, may help identify patients who will benefit most or least from XR-NTX treatment. METHODS: Potential moderators of XR-NTX's effect were examined in the largest North American randomized open-label effectiveness trial of XR-NTX. Relapse status (Yes/No) at 6-month follow-up was regressed on treatment group (XR-NTX, N=153; or Treatment-as-Usual [TAU], N=155), baseline covariates, and their two-way interaction to identify moderator effects. Baseline covariates included age, gender, summary scores for depression, suicidal thoughts, drug abuse risk, substance use, medical, psychiatric and employment status, socialization, legal and family/social issues, history of abuse and quality of life measures. RESULTS: Alcohol use to intoxication in the 30days before randomization was a significant moderator: during the treatment phase, those who reported being recently intoxicated before randomization to XR-NTX relapsed to opioids at a rate (56%) similar to TAU (58%), while those without alcohol intoxication in the prior 30days had a lower rate of opioid relapse (41% vs. 65%, respectively, P<0.04). CONCLUSIONS: XR-NTX appeared to work equally well across subgroups with diverse demographic, addiction, mental health and environmental characteristics, with the possible exception of working better among those without recent alcohol intoxication. These findings should be reassuring to practitioners increasingly using XR-NTX as medical addiction therapy in diverse and often vulnerable populations.

The Therapeutic Education System (TES), an Internet version of the Community Reinforcement Approach plus prize-based motivational incentives, is one of few empirically supported technology-based interventions. To date, however, there has not been a study exploring differences in substance use outcomes or acceptability of TES among racial/ethnic subgroups. This study uses data from a multisite (N = 10) effectiveness study of TES to explore whether race/ethnicity subgroups (White [n = 267], Black/African American [n = 112], and Hispanic/Latino [n = 55])moderate the effect of TES. Generalized linear mixed models were used to test whether abstinence, retention, social functioning, coping, craving, or acceptability differed by racial/ethnic subgroup. Findings demonstrated that race/ethnicity did not moderate the effect of TES versus TAU on abstinence, retention, social functioning, or craving. A three-way interaction (treatment, race/ethnicity, and abstinence status at study entry) showed that TES was associated with greater coping scores among nonabstinent White participants (p = .008) and among abstinent Black participants (p < .001). Acceptability of the TES intervention, although high overall, was significantly different by race/ethnicity subgroup with White participants reporting lower acceptability of TES compared to Black (p = .006) and Hispanic/Latino (p = .008) participants. TES appears to be a good candidate treatment among a diverse population of treatment-seeking individuals with substance use disorders.

OBJECTIVE:To examine prize-earning costs of contingency management (CM) incentives in relation to participants' pre-study enrollment drug use status (baseline (BL) positive vs. BL negative) and relate these to previously reported patterns of intervention effectiveness. METHODS:Participants were 255 substance users entering outpatient treatment who received the therapeutic educational system (TES), in addition to usual care counseling. TES included a CM component such that participants could earn up to $600 in prizes on average over 12-weeks for providing drug negative urines and completing web-based cognitive behavior therapy modules. We examined distribution of prize draws and value of prizes earned for subgroups that were abstinent (BL negative; N=136) or not (BL positive; N=119) at study entry based on urine toxicology and breath alcohol screen. RESULTS:Distribution of draws earned (median=119 vs. 17; p<.0001) and prizes redeemed (median=54 vs. 9; p<.001) for drug abstinence differed significantly for BL negative compared to BL positive participants. BL negative earned on average twice as much in prizes as BL positive participants ($245 vs. $125). Median value of prizes earned was 5.4 times greater for BL negative compared to BL positive participants ($237 vs. $44; p<.001). CONCLUSIONS:Two-thirds of expenditures in an abstinence incentive program were paid to BL negative participants. These individuals had high rates of drug abstinence during treatment and did not show improved abstinence outcomes with TES versus usual care (Campbell et al., 2014). Effectiveness of the abstinence-focused CM intervention included in TES may be enhanced by tailoring delivery based on patients' drug use status at treatment entry.

OBJECTIVE:Coping strategies are a predictor of abstinence among patients with substance use disorders. However, little is known regarding the role of coping strategies in the effectiveness of the Community Reinforcement Approach (CRA). Using data from a 12week randomized control trial assessing the effectiveness of the Therapeutic Education System (TES), an internet-delivered version of the CRA combined with contingency management, we tested the role of coping strategies as a mediator of treatment effectiveness. METHODS:507 participants entering 10 outpatient addiction treatment programs received either treatment-as-usual (TAU), a counselor-delivered treatment (Arm 1), or reduced TAU plus TES wherein 2h of TAU per week were replaced by TES (Arm 2). Abstinence from drugs and alcohol was evaluated using urine toxicology and self-report. Coping strategies were measured using the Coping Strategies Scale-Brief Version. Mediation analyses were done following Baron and Kenny's and path analysis approaches. RESULTS:=8.3, p=0.004). Additionally, higher coping strategies scores at week 12 were associated with an increased likelihood of abstinence during the last 4weeks of the treatment, while accounting for treatment assignment and baseline abstinence. The effect of TES intervention on abstinence was no longer significant after controlling for coping strategies scores at week 12. CONCLUSION:Our results support the importance of coping skills as a partial mediator of the effectiveness of an internet-version of the CRA combined with contingency management.

OBJECTIVE:To estimate how results would have varied if a substance abuse clinical trial had been conducted with nationally representative adults with substance use and with representative adults receiving substance use treatment. METHODS:Results were analyzed from a multisite clinical trial comparing the effectiveness of the Therapeutic Education System to treatment as usual for outpatient addiction treatment (n = 507). Patients were recruited between June 2010 and August 2011. Abstinence was the primary outcome. The general population sample and general population-treated samples were derived from Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (n = 43,093). Propensity scores provided a standardized measure of the difference between clinical trial participants and the 2 NESARC samples. The clinical trial was reanalyzed by reweighting the sample with propensity scores derived from the 2 samples to obtain generalizable estimates of treatment effects. RESULTS:Before the clinical trial sample was reweighted, the odds ratio (OR) of response to Therapeutic Education System versus treatment as usual in the trial was 1.62 (95% CI, 1.12-2.35). After the sample was reweighted to be representative of the 2 NESARC groups, ORs were 1.33 (95% CI, 0.34-5.26) for the representative sample with any substance use and 1.64 (95% CI, 0.82-3.27) for the representative treated sample. CONCLUSIONS:Applying propensity score weighting to clinical trial results provides a method for estimating the population generalizability of clinical trial findings that relies on effect moderators observed in the study sample and population. Broader confidence intervals in the reweighted samples do not necessarily indicate lack of efficacy of the Therapeutic Education System but rather greater uncertainty concerning effectiveness in general population samples.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Extended-release naltrexone (XR-NTX) is FDA-approved to prevent relapse in patients with Opioid Use Disorder. However little is known about long-term use among community-based outpatients. METHODS:Retrospective chart review and long-term follow-up survey among individuals (N = 168) who entered an outpatient XR-NTX trial between 2011 and 2015, during which participants were offered three monthly injections of XR-NTX at no cost. The survey consisted of 35 questions covering a total of four domains: (1) substance use; (2) treatment continuation; (3) barriers; and (4) attitudes. RESULTS:Fifty-seven respondents were successfully surveyed, including 50% of those initially receiving all three XR-NTX injections ("study completers") in the parent study. Study completion was associated with superior outcomes and less likely relapse (defined as daily use), with a much greater time to relapse despite higher rates of concurrent non-opioid substance use. However the majority of participants discontinued treatment with XR-NTX at study completion, largely due to attitudes of "feeling cured" and "wanting to do it on my own" rather than external barriers such as cost or side effects. CONCLUSION/CONCLUSIONS:Patients who initiate treatment with XR-NTX might benefit from anticipatory guidance and motivational techniques to encourage long-term adherence as many will experience internal barriers to continuation. Our findings are reassuring that few patients experience side effects or adverse events complicating the effectiveness or safety of long-term use of XR-NTX. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:Among outpatients who successfully receive 3 monthly XR-NTX injections, many will prematurely discontinue treatment due to internal attitudes, such as "feeling cured." (Am J Addict 2017;26:319-325).