Faculty Bibliography

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.

BACKGROUND:The randomized X:BOT trial showed that following induction, sublingual agonist (buprenorphine-naloxone, BUP-NX) or antagonist injection (extended release naltrexone, XR-NTX) produced similar benefits for reducing opioid relapse in injection users with opioid use disorder. Given that XR-NTX reduces drinking in alcohol use disorder (AUD), we completed a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine if XR-NTX (n=204) was superior to BUP-NX (n=270) to reduce drinking or heavy drinking in patients with opioid use disorder. METHODS:Timeline follow-back recorded standard drink units consumed. Mixed-models regression examined monthly frequencies of any drinking or heavy drinking over 6 months of treatment and proportional hazard survival examined time to first drink. RESULTS:Both treatment groups reduced drinking from baseline to post-treatment (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 n=136 with an AUD diagnosis plus n=43 who did not have AUD, but reported at least one day of heavy drinking prior to study. Even so, this subsample still reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy". Within this subsample, the BUP-NX group reported greater mean drinks per drinking day than did the XR-NTX group at baseline (p=0.03); however, there were no other significant group differences in drinking observed before, during, or at the end of treatment. CONCLUSIONS:An overall improvement in drinking occurred for treatment of OUD using both agonist and antagonist approaches indicating 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 opioid use disorder.

BACKGROUND AND AIMS/OBJECTIVE:In a US randomized-effectiveness trial comparing extended-release naltrexone (XR-NTX) with buprenorphine-naloxone (BUP-NX) for the prevention of opioid relapse among participants recruited during inpatient detoxification (CTN-0051), the requirement to complete opioid detoxification prior to initiating XR-NTX resulted in lower rates of initiation of XR-NTX (72% XR-NTX versus 94% BUP-NX). DESIGN/METHODS:This was a retrospective secondary analysis of CTN-0051 trial data, including follow-up data over 24-36 weeks. SETTING/METHODS:Eight community-based, inpatient-detoxification and follow-up outpatient treatment facilities in the United States. PARTICIPANTS/METHODS:A total of 283 participants randomized to receive XR-NTX. MEASUREMENTS/METHODS:Efficiency was estimated using a multivariable generalized structural equation model to explore simultaneous determinants of XR-NTX induction and induction duration (detoxification + residential days). Cost-effectiveness was estimated from the health-care sector perspective and included expected costs and quality-adjusted life-years (QALYs). FINDINGS/RESULTS:Treatment site was the only modifiable factor that simultaneously increased the likelihood of XR-NTX induction and decreased induction duration. Incorporating the higher predicted probability of XR-NTX induction, and fewer predicted days of detoxification and subsequent residential treatment into the cost-effectiveness framework, reduced the incremental average 24-week total cost of XR-NTX treatment from $5317 more than that of BUP-NX (P = 0.01) to a non-statistically-significant difference of $1016 (P = 0.63). QALYs gained remained similar across arms. CONCLUSION/CONCLUSIONS:Adopting an efficient model of extended-release naltrexone initiation could result in extended-release naltrexone and buprenorphine-naloxone being of comparable economic value from the health-care sector perspective over 24-36 weeks for patients seeking treatment for opioid use disorder at an inpatient detoxification facility.

BACKGROUND:Relapse rates during opioid use disorder (OUD) treatment remain unacceptably high. It is possible that optimally matching patients with medication type would reduce risk of relapse. Our objective was to learn a rule by which to assign type of medication for OUD to reduce risk of relapse, and to estimate the extent to which risk of relapse would be reduced if such a rule were used. METHODS:This was a secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial of injection extended-release naltrexone (XR-NTX), delivered approximately every 28 days, or daily sublingual buprenorphine-naloxone (BUP-NX) for treating OUD, 2014-2017 (N = 570). Outcome was a binary indicator of relapse to regular opioid use during the 24 weeks of outpatient treatment. RESULTS:We found that applying an estimated individualized treatment rule-i.e., a rule that assigns patients with OUD to either XR-NTX or BUP-NX based on their individual characteristics in such a way that risk of relapse is minimized-would reduce risk of relapse by 24 weeks by 12% compared to randomly assigned treatment. CONCLUSIONS:The number-needed-to-treat with the estimated treatment rule to prevent a single relapse is 14. A simpler, alternative estimated rule in which homeless participants would be treated with XR-NTX and stably housed participants would be treated with BUP-NX performed similarly. These results provide an estimate of the amount by which a relatively simple change in clinical practice could be expected to improve prevention of OUD relapse.

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).

BACKGROUND AND AIMS:A recent study found that homeless individuals with opioid use disorder (OUD) had a lower risk of relapse on extended-release naltrexone (XR-NTX) versus buprenorphine-naloxone (BUP-NX), whereas non-homeless individuals had a lower risk of relapse on BUP-NX. This secondary study examined differences in mediation pathways to medication effect between homeless and non-homeless participants. DESIGN:Secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial, 2014-17. SETTING:Eight community addiction treatment programs in the United States. PARTICIPANTS:English-speaking adults with DSM-5 OUD, recruited during inpatient admission (n = 570). INTERVENTION(S):Randomization to monthly injection of XR-NTX or daily sublingual BUP-NX. MEASUREMENTS(S):Mediation analysis estimated the direct effect of XR-NTX versus BUP-NX on relapse and indirect effect through mediators of medication adherence, use of illicit opioids, depressive symptoms and pain, separately by homeless status. FINDINGS:For the homeless subgroup, the protective indirect path contributed a 3.4 percentage point reduced risk of relapse [95% confidence interval (CI) = -12.0, 5.3] comparing XR-NTX to BUP-NX (explaining 21% of the total effect). For the non-homeless subgroup, the indirect path contributed a 9.4 percentage point increased risk of relapse (95% CI = 3.1, 15.7) comparing XR-NTX to BUP-NX (explaining 57% of the total effect). CONCLUSIONS:A novel approach to mediation analysis shows that much of the difference in medication effectiveness (extended-release naltrexone versus buprenorphine-naloxone) on opioid relapse among non-homeless adults with opioid use disorder appears to be explained by mediators of adherence, illicit opioid use, depressive symptoms and pain.

OBJECTIVE:Sublingual buprenorphine-naloxone and extended-release injection naltrexone are effective treatments, with distinct mechanisms, for opioid use disorder. The authors examined whether patients' demographic and clinical characteristics were associated with better response to one medication or the other. METHODS:In a multisite 24-week randomized comparative-effectiveness trial of assignment to buprenorphine-naloxone (N=287) compared with extended-release naltrexone (N=283) comprising inpatients planning to initiate medication treatment for opioid use disorder, 50 demographic and clinical characteristics were examined as moderators of the effect of medication assignment on relapse to regular opioid use and failure to initiate medication. Moderator-by-medication interactions were estimated using logistic regression with correction for multiple testing. RESULTS:In the intent-to-treat sample, patients who reported being homeless had a lower relapse rate if they were assigned to receive extended-release naltrexone (51.6%) compared with buprenorphine-naloxone (70.4%) (odds ratio=0.45, 95% CI=0.22, 0.90); patients who were not homeless had a higher relapse rate if they were assigned to extended-release naltrexone (70.9%) compared with buprenorphine-naloxone (53.1%) (odds ratio=2.15, 95% CI=1.44, 3.21). In the subsample of patients who initiated medication, the interaction was not significant, with a similar pattern of lower relapse with extended-release naltrexone (41.4%) compared with buprenorphine (68.6%) among homeless patients (odds ratio=0.32, 95% CI=0.15, 0.68) but less difference among those not homeless (extended-release naltrexone, 57.2%; buprenorphine, 52.0%; odds ratio=1.24, 95% CI=0.80, 1.90). For failure to initiate medication, moderators were stated preference for medication (failure was less likely if the patient was assigned to the medication preferred), parole and probation status (fewer failures with extended-release naltrexone for those on parole or probation), and presence of pain and timing of randomization (more failure with extended-release naltrexone for patients endorsing moderate to severe pain and randomized early while still undergoing medically managed withdrawal). CONCLUSIONS:Among patients with opioid use disorder admitted to inpatient treatment, homelessness, parole and probation status, medication preference, and factors likely to influence tolerability of medication initiation may be important in matching patients to buprenorphine or extended-release naltrexone.

BACKGROUND:Smoking prevalence in individuals with opioid use disorder (OUD) is over 80%. Research suggests that opioid use significantly increases smoking, which could account for the strikingly low smoking-cessation rates observed in both methadone- and buprenorphine-maintained patients, even with the use of first-line smoking-cessation interventions. If opioids present a barrier to smoking-cessation, then better smoking outcomes should be observed in OUD patients treated with extended-release naltrexone (XR-NTX, an opioid antagonist) compared to those receiving buprenorphine (BUP-NX, a partial opioid agonist). METHODS:The current study is a secondary analysis of a 24-week, multi-site, open-label, randomized clinical trial conducted within the National Drug Abuse Treatment Clinical Trials Network comparing the effectiveness of XR-NTX vs. BUP-NX for adults with OUD. Longitudinal mixed effects models were used to determine if there was a significant reduction in cigarette use among daily smokers successfully inducted to treatment (n = 373) and a subset of those who completed treatment (n = 169). RESULTS:Among daily smokers inducted onto OUD medication, those in the XR-NTX group smoked fewer cigarettes per day (M = 11.36, SE = 0.62) relative to smokers in the BUP-NX group (M = 13.33, SE = 0.58) across all study visits, (b (SE) = -1.97 (0.55), p < .01). Results were similar for the treatment completers. CONCLUSIONS:OUD patients treated with XR-NTX reduced cigarette use more than those treated with BUP-NX, suggesting that XR-NTX in combination with other smoking cessation interventions might be a better choice for OUD smokers interested in reducing their tobacco use.

Importance/UNASSIGNED:Guidelines recommend that adult patients receive screening for alcohol and drug use during primary care visits, but the adoption of screening in routine practice remains low. Clinics frequently struggle to choose a screening approach that is best suited to their resources, workflows, and patient populations. Objective/UNASSIGNED:To evaluate how to best implement electronic health record (EHR)-integrated screening for substance use by comparing commonly used screening methods and examining their association with implementation outcomes. Design, Setting, and Participants/UNASSIGNED:This article presents the outcomes of phases 3 and 4 of a 4-phase quality improvement, implementation feasibility study in which researchers worked with stakeholders at 6 primary care clinics in 2 large urban academic health care systems to define and implement their optimal screening approach. Site A was located in New York City and comprised 2 clinics, and site B was located in Boston, Massachusetts, and comprised 4 clinics. Clinics initiated screening between January 2017 and October 2018, and 93 114 patients were eligible for screening for alcohol and drug use. Data used in the analysis were collected between January 2017 and October 2019, and analysis was performed from July 13, 2018, to March 23, 2021. Interventions/UNASSIGNED:Clinics integrated validated screening questions and a brief counseling script into the EHR, with implementation supported by the use of clinical champions (ie, clinicians who advocate for change, motivate others, and use their expertise to facilitate the adoption of an intervention) and the training of clinic staff. Clinics varied in their screening approaches, including the type of visit targeted for screening (any visit vs annual examinations only), the mode of administration (staff-administered vs self-administered by the patient), and the extent to which they used practice facilitation and EHR usability testing. Main Outcomes and Measures/UNASSIGNED:Data from the EHRs were extracted quarterly for 12 months to measure implementation outcomes. The primary outcome was screening rate for alcohol and drug use. Secondary outcomes were the prevalence of unhealthy alcohol and drug use detected via screening, and clinician adoption of a brief counseling script. Results/UNASSIGNED:Patients of the 6 clinics had a mean (SD) age ranging from 48.9 (17.3) years at clinic B2 to 59.1 (16.7) years at clinic B3, were predominantly female (52.4% at clinic A1 to 64.6% at clinic A2), and were English speaking. Racial diversity varied by location. Of the 93,114 patients with primary care visits, 71.8% received screening for alcohol use, and 70.5% received screening for drug use. Screening at any visit (implemented at site A) in comparison with screening at annual examinations only (implemented at site B) was associated with higher screening rates for alcohol use (90.3%-94.7% vs 24.2%-72.0%, respectively) and drug use (89.6%-93.9% vs 24.6%-69.8%). The 5 clinics that used a self-administered screening approach had a higher detection rate for moderate- to high-risk alcohol use (14.7%-36.6%) compared with the 1 clinic that used a staff-administered screening approach (1.6%). The detection of moderate- to high-risk drug use was low across all clinics (0.5%-1.0%). Clinics with more robust practice facilitation and EHR usability testing had somewhat greater adoption of the counseling script for patients with moderate-high risk alcohol or drug use (1.4%-12.5% vs 0.1%-1.1%). Conclusions and Relevance/UNASSIGNED:In this quality improvement study, EHR-integrated screening was feasible to implement in all clinics and unhealthy alcohol use was detected more frequently when self-administered screening was used at any primary care visit. The detection of drug use was low at all clinics, as was clinician adoption of counseling. These findings can be used to inform the decision-making of health care systems that are seeking to implement screening for substance use. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02963948.