Faculty Bibliography

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.

Dysregulation of the stress response is implicated in drug addiction; therefore, polymorphisms in stress-related genes may be involved in this disease. An analysis was performed to identify associations between variants in 11 stress-related genes, selected a priori, and heroin addiction. Two discovery samples of American subjects of European descent (EA, n = 601) and of African Americans (AA, n = 400) were analyzed separately. Ancestry was verified by principal component analysis. Final sets of 414 (EA) and 562 (AA) variants were analyzed after filtering of 846 high-quality variants. The main result was an association of a non-coding SNP rs255105 in the CRH (CRF) receptor 2 gene (CRHR2), in the discovery EA sample (Pnominal = .00006; OR = 2.1; 95% CI 1.4-3.1). The association signal remained significant after permutation-based multiple testing correction. The result was corroborated by an independent EA case sample (n = 364). Bioinformatics analysis revealed that SNP rs255105 is associated with the expression of a downstream long intergenic non-coding RNA (lincRNA) gene AC005154.6. AC005154.6 is highly expressed in the pituitary but its functions are unknown. LincRNAs have been previously associated with adaptive behavior, PTSD, and alcohol addiction. Further studies are warranted to corroborate the association results and to assess the potential relevance of this lincRNA to addiction and other stress-related disorders.

Background: With both agonist and antagonist medications available to treat opioid dependence, and with these differing markedly on a spectrum of parameters - including philosophy of treatment, need for detoxification to initiate treatment, ongoing dependence and withdrawal on stopping treatment, diversion risk, community acceptability and controlled substance restrictions - it's difficult to know which approach to take. What do we tell our patients? How should we choose? Is one approach better for some patients, the other for others? Does choice matter, do patients do better with their preferred treatment than with the alternative? CTN-0051 grows out of these questions and will establish the evidence-base to inform treatment decisions. Methods: Close to a dozen designs, including no-medication treatment-as-usual conditions, SMART designs, and designs taking choice into consideration were considered. The final design was a randomized two-arm, head-to-head effectiveness trial comparing extended-release naltrexone to buprenorphine, both FDA approved treatments, in 570 patients across 8 sites. Recruitment was from inpatient detoxification and short term residential programs. We selected a flexible point of randomization to reflect community medication initiation practices. We predicted differential induction success, and included a mitigation plan to manage the detoxification hurdle. Treatment was for up to six months with follow up visits through nine months postrandomization. The primary outcome measure was timeto- relapse, defined as 7 consecutive use-days or 4 consecutive use-weeks. Secondary outcomes included successful induction, abstinence from opioids, alcohol, tobacco and other drugs, craving, subacute withdrawal, etc., and mediators and moderators of treatment response. Results: Recruitment was completed in May 2016 with 722 participants consented and 570 randomized. Treatment visits were completed in November 2016 and follow up visits in February 2017. Women made up 30% of the population; 17% were Hispanic, 26% non-white; 69% were 25-45 years old, 15% were under 25; 57% had a high school education or less, 66% were never married, 63% were unemployed; 82% identified heroin as their primary abused opioid, 16% prescription drugs; 63% were IV users; 40% were high users defined as IV use of at least 6 bags a day, a stratification variable that we predicted to influence outcome; although all participants expressed willingness to take either medication, 29% indicated that they preferred extended-release naltrexone, and 33% buprenorphine. AEs and SAEs were those expected in this population. Data lock will be in May 2017 after which we will be able to look at outcomes data. Conclusions: We expect to be able to present comparative effectiveness data on induction success, survival without relapse, time-to-relapse, abstinence from opioids and other drugs, successful completion of 24 weeks of treatment, craving, cognitive function, and adverse events including overdose during and after treatment. Findings on the role of choice in influencing outcome, and mediators and moderators of treatment success or failure will be presented. None of these data will be available until after data-lock, precluding more specific "conclusions" per se until early summer

BACKGROUND: Alcohol and drug use is a leading cause of morbidity and mortality that frequently goes unidentified in medical settings. As part of a multi-phase study to implement the NIDA Common Data Elements for collecting substance use screening information in electronic health records (EHRs), we interviewed key clinical stakeholders with a goal of identifying barriers and facilitators affecting the implementation of substance use screening in primary care clinics. METHODS: Focus groups and individual qualitative interviews were conducted with 67 stakeholders, including primary care patients, medical providers (faculty and resident physicians, nurses), and medical assistants, in two urban academic health systems. Themes were identified, discussed, and revised through an iterative process, and mapped to the Knowledge to Action (KTA) framework (Graham, 2006), which guides the selection and implementation of new clinical practices. RESULTS: Factors affecting implementation based on KTA elements were identified from participant narratives. Identifying the problem: Participants unanimously agreed that having knowledge of a patient's substance use is important because of its impacts on health andmedical care, that substance use is not properly identified in medical settings, and that universal screening is the best approach. Adapting knowledge: The majority of patients and providers stated that the primary care provider should play a key role in substance use screening and interventions. There was discrepancy of opinion regarding the optimal approach to delivering screening. Some felt that patients should self-administer questionnaires, while others thought that patients would be more comfortable having face-to-face discussions with their primary care provider - though not with other members of the care team. Many providers reported that being able to take effective action once unhealthy substance use is identified is crucial. Assessing barriers: Patients expressed concerns about confidentiality, 'denial', and providers' lack of empathy. Barriers identified by providers included individual-level factors such as lack of knowledge and training, and systems-level factors including lack of time, resources, and space, disjointed communication between members of the medical team, and difficulty accessing addiction treatment. CONCLUSIONS: Based on these findings, we designed and are testing an implementation strategy utilizing universal screening, patient self-administered questionnaires, and EHR-integrated clinical decision support to assist providers in conducting brief motivational counseling and linking patients to behavioral health services, to address unhealthy substance use in primary care clinics

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.