BACKGROUND AND OBJECTIVES:People with opioid use disorder (OUD) who are in safety-sensitive occupations are often not allowed to work if taking methadone or buprenorphine due to concerns about cognitive impairment from opioid agonist effects. Naltrexone, an antagonist which lacks opioid agonist effects, has fewer restrictions. However, comparisons of neurocognitive effects across treatments are limited. METHODS:This post hoc analysis examined observed Trailmaking Test (TMT) difference scores and Stroop Color-Word accuracy and interference scores at 4, 8, 16, and 24 weeks after treatment initiation with either extended-release injection naltrexone (XR-NTX) (N=283) or sublingual buprenorphine-naloxone (BUP-NX) (N=287) in a randomized, nonblinded, trial of patients with OUD. Scores were compared between medication groups across time points with linear mixed-effects regression. RESULTS:There were no significant effects of medication group or time for either the TMT or the Stroop tests. TMT difference scores at baseline were 48.40±24.12 (XR-NTX) and 48.26±25.45 seconds (BUP-NX), with model-estimated means (SE) across post-initiation time points: XR-NTX: 37.53 (1.62); BUP-NX: 37.80 (1.51); difference: -0.26 (1.59), P=0.87; 95% CI [-3.38, 2.86]. Stroop Color-Word accuracy and interference scores at baseline were 49.65 (XR-NTX) versus 50.88 (BUP-NX) and 51.11 (XR-NTX) versus 51.68 (BUP-NX), respectively. Model estimated means (SE) across post-initiation timepoints were: accuracy: XR-NTX: 56.54 (0.90); BUP-NX: 56.22 (0.75); difference: 0.33 (0.73), P=0.65; 95% CI [-1.1, 1.76]; interference: XR-NTX: 54.15 (0.76); BUP-NX: 54.67 (0.73); difference: -0.52 (0.62), P=0.41; 95% CI [-1.74, 0.70]. CONCLUSIONS:Neurocognitive performance did not significantly differ between patients with OUD treated with XR-NTX or BUP-NX. These results suggest that absolute restrictions on buprenorphine use in safety-sensitive occupations may be unwarranted. Individual cognitive assessments may still be appropriate based on specific job demands.

BACKGROUND AND AIMS:Clinicians have little guidance on the ideal length of time patients should remain on medication treatment for opioid use disorder (MOUD) before being able to safely discontinue MOUD. This study estimated how the risk of all-cause mortality changes with the duration of MOUD, controlling for patient characteristics that change the risk profile independent of duration of therapy. DESIGN, SETTING AND PARTICIPANTS:Retrospective cohort study using electronic health record data from the US Veterans Healthcare Administration. Veterans initiating MOUD with buprenorphine, methadone or extended-release naltrexone from October 2010 to September 2020. Our analytic sample included 19 666 buprenorphine initiators, 8675 methadone initiators and 4007 extended-release naltrexone initiators. MEASUREMENT:Duration of MOUD was measured in days. Discontinuation was defined as a gap in any MOUD coverage exceeding 28 days, regardless of MOUD type initiated. The primary outcome was all-cause mortality. We estimated multistate survival models allowing for the modeling of multiple states (i.e. on and off MOUD, death) without having to consider censoring or competing events, while adjusting for sociodemographic, clinical, prescription and facility and provider characteristics. FINDINGS:We observed approximately 226 000 person-years of time at risk for discontinuation or pre-discontinuation death, during which we observed 26 841 discontinuations (118.9 discontinuations per 1000 person-years). We similarly observed a total of about 106 000 person-years of post-discontinuation follow-up, during which we observed 3251 deaths (3.1 deaths per 1000 person-years). We found the largest marginal gain in probability of 6-year survival from an additional year on MOUD appears to occur around 2 years, as compared to 6 months on MOUD. Statistically significant gains continued through approximately 4-5 years of MOUD retention relative to 6-month MOUD retention. After 4-5 years, the marginal gain from one additional year of MOUD was not statistically significant. CONCLUSIONS:Among US veterans, the benefit of retention on medication treatment for opioid use disorder (MOUD) towards overall survival continues through at least 4 years of MOUD treatment. Quality metrics based on 6-month MOUD retention may be insufficient.

Objective: To estimate the extent to which increased use of clonidine and benzodiazepines is associated with the beneficial effect of the rapid versus standard procedure for induction onto extended-release injectable naltrexone (XR-NTX). Methods: We conducted two mediation analyses using a doubly robust nonparametric estimation approach. First, we estimated the extent to which the difference in XR-NTX initiation rates comparing the rapid vs. standard induction operated through: (1) differences in categorized daily doses of clonidine and benzodiazepines averaged over the first 3 days of the study, and (2) differences in categorized clonidine and benzodiazepine usage during each of the first 5 days, treated as time-varying mediators, and accounting for time-varying confounders and competing events. Results: Rapid vs. standard induction increased the probability of initiating XR-NTX by day 14 by an estimated 42.4 percentage points (95% CI: 34.6, 50.2), and the natural indirect effect (i.e., mediated effect) through clonidine and benzodiazepine use was associated with a 24.2 percentage point (95% CI: 10.3, 38.0) increased the initiation probability, explaining 57.1% of the total effect. Estimates were similar in the longitudinal mediation analysis. Conclusions: Use of clonidine and benzodiazepines proactively and at higher dosages during the initial days of inpatient medically managed withdrawal, in conjunction with attentive safety monitoring, could improve XR-NTX initiation rates as part of a rapid induction procedure.

AIM:We evaluated whether community-level naloxone distribution, medication for opioid use disorder treatment and retention and incident high-risk opioid prescribing rates were associated with opioid overdose death rates. DESIGN:Observational cohort conducted using 2019 to 2023 community-level data as an exploratory analysis of the HEALing (Helping to End Addiction Long-term®) Communities Study (HCS). Exposures included: (1) community-level naloxone distribution, past 12-months, categorized as ≤1000 units per 100 000 population vs. 1001-3000 units per 100 000 population vs. >3000 units per 100 000 population; (2) individuals treated with buprenorphine per 100 000 adult population in the current quarter; (3) individuals retained on buprenorphine for ≥ 180 days per 100 000 adult population in the current quarter; and (4) incident high-risk opioid prescribing per 100 000 adult population in the current quarter. SETTING AND PARTICIPANTS:Population-based study of 67 communities with 8.2 million adults in Kentucky, Massachusetts, New York and Ohio, USA, with required annual opioid overdose death rates of > 25 per 100 000 adult population and at least 30% rural. Across the 67 communities participating in the HCS, the adult population was 31% 18-34 years, 31% 35-54 years, 38% 55 years and over, 52% female, 73% non-Hispanic White, 15% non-Hispanic Black and 7.4% Hispanic. MEASUREMENTS:Quarterly community-level opioid overdose death rates from 2020 through 2023. FINDINGS:The 2019 annual rates were 40.4 opioid overdose deaths, 1287 naloxone rescue units distributed, 977.7 people received buprenorphine treatment, 546.3 people retained for more than 180 days on buprenorphine and 1266.7 high-risk opioid prescribing incidents per 100 000 population. In models adjusted for state, community age, sex, race/ethnicity, rurality, HCS intervention group assignment, 2019 rates of opioid overdose death, naloxone distribution, buprenorphine and high-risk opioid prescribing, and the ratio of opioid overdose deaths involving fentanyl, an increase in 100 people treated with buprenorphine per 100 000 population was associated with a decrease of 0.92 [95% confidence interval (CI) = -1.30 to -0.55] in the quarterly opioid overdose death rate, while an increase of 100 people retained on buprenorphine for more than 180 days per 100 000 population was associated with a decrease of 1.3 (95% CI = -1.8 to -0. 76). There were no statistically significant associations between naloxone distribution or incident high-risk opioid prescribing with change in quarterly opioid overdose death rates. CONCLUSIONS:In this exploratory analysis, increases in both buprenorphine treatment and retention were statistically significantly associated with decreases in opioid overdose death rates, after adjusting for baseline rates of buprenorphine treatment and retention.

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

BACKGROUND AND AIM:Extended-release injectable naltrexone (XR-Naltrexone) is an effective treatment for opioid use disorder (OUD); however, initiation can be challenging as it requires an opioid-free period. This exploratory analysis examines patient characteristics associated with successful initiation of XR-Naltrexone in the National Drug Abuse Treatment Clinical Trials Network (CTN-0051) Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (X:BOT) trial. METHODS:Patient demographics and clinical variables associated with successful XR-Naltrexone initiation were examined among 283 participants with OUD randomized to XR-Naltrexone in the X:BOT trial. Variables included severity of opioid use, characteristics of opioid and other substance use, treatment history, psychiatric history, baseline depression, and pain. Logistic regression models were used to estimate the effect of variables on the odds of induction success. RESULTS:204 (72%) of 283 participants randomized to receive XR-Naltrexone completed successful induction. Housing status and pain were significantly associated with XR-Naltrexone induction status. Reported homelessness was significantly associated with higher odds of successful XR-Naltrexone induction (OR: 2.31; 95% CI: 1.12, 4.76). Individuals that reported moderate or extreme pain on the EuroQoL had half the odds of successful induction compared to those without pain (OR: 0.49; 95% CI: 0.27, 0.89). CONCLUSIONS:Among patients with OUD initiating treatment on inpatient units, homelessness was associated with greater likelihood of successfully initiating XR-Naltrexone, while chronic pain was associated with lower likelihood of XR-Naltrexone initiation. Future research on XR-Naltrexone initiation should consider tailoring treatment based on housing status and other social determinants, and evaluation and management of pain.

Background: Nontreatment-seeking individuals with cocaine use disorder (CUD) have been found to exhibit decision-making on laboratory tasks that is risky but also sensitive to monetary incentive, relative to controls. Objective: The purpose of this study was to replicate these findings in treatment-seeking individuals and explore their relationships with voucher-based treatment outcome and striatal dopamine (DA) release. Methods: This study was approved by the Institutional Review Board, and all participants provided written informed consent to participate. Eighteen briefly-abstinent individuals seeking treatment for CUD and 19 control participants were compared on performance of a modified Iowa Gambling task (mIGT) under both hypothetical and cash earning conditions. The CUD participants subsequently received Positron Emission Tomography (PET) scans with [11C]raclopride with methylphenidate (60 mg) challenge and then 12 weeks of Community Reinforcement Approach plus Vouchers (CRA+V) treatment. Results: On the mIGT, the CUD participants’ advantageous card selection was selectively more sensitive to the presence of a monetary incentive, relative to controls (F4,128 = 3.10, p<0.05). Among the male CUD participants, those who exhibited greater DA release in the ventral striatum (VSt), and those who responded to the CRA+V treatment, exhibited greater mIGT incentive sensitivity than those who were nonresponders (F4,44 = 5.84, p<0.01), and who exhibited relatively decreased VSt DA release (F4,48 = 2.55, p<0.05). Conclusions: Participants seeking treatment for CUD exhibited selectively increased decisional incentive sensitivity, relative to controls. For the male CUD participants, greater incentive sensitivity was associated with greater VSt DA release and better CRA+V outcome. These findings appear partially consistent with previous findings on cognition and motivation in individuals with CUD, and suggest a heuristic model connecting striatal DA, incentive sensitivity, and CRA+V outcome.

Objectives: Medically assisted withdrawal (MAW) for opioid use disorders (OUD) remains common. NIDA’s CTN-0051 (X:BOT) trial compared two OUD medications initiated during an acute inpatient MAW admission and continued postdischarge at 8 US sites. This ancillary observational follow-on study explored treatment-as-usual outcomes at 5 X:BOT sites. Methods: Adults admitted for OUD were conveniently and consecutively recruited to an 8-week, prospective, observational, noninterventional study targeting up to 300 participants. Withdrawal protocols and medications for OUD (MOUD) followed site usual practices. Baseline and postdischarge weeks 1, 4, and 8 measures were OUD severity, length-of-stay (LOS), urine samples, self-reported MOUD, nonprescribed opioid use, and overdoses. Data analyses were descriptive. Results: A total of N = 211 enrolled participants were primarily white men (74%) with daily heroin (87.2%) and intravenous (64.0%) use. About 41.7% (n = 88) reported MOUD treatment at discharge: extended-release naltrexone (n = 39), sublingual buprenorphine-naloxone (n = 38), methadone (n = 8), and oral naltrexone (n = 3). Self-reported MOUD use at week 8 was 28.0%, when 52.6% reported no regular use (<7 consecutive days) and 25.6% reported nonprescribed opioid abstinence. Negative urine rates for nonprescribed opioids ranged from 26.1% to 31.3%. One overdose death and 17 nonfatal opioid-related overdose events occurred in 15 participants. Conclusions: Return to nonprescribed opioid use, frequent overdose events, one death, and a relative lack of MOUD treatment uptake characterized this usual care cohort following inpatient OUD admissions. Scientific Significance: These findings underscore the urgent need for individuals and providers to prioritize linkage to evidence-based MOUD treatments following acute inpatient OUD-related admissions, given high rates of return to opioid use and overdose events.

Buprenorphine treatment for opioid use disorder (OUD) is highly effective in decreasing opioid use, risk of opioid overdose, and death, but retention is challenging. Buprenorphine does not always eliminate illicit opioid use and craving and does not treat stimulant or other substance co-use, nor common comorbid sleep problems. Tirzepatide, a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, may help address substance use and sleep problems. The National Drug Abuse Treatment Clinical Trials Network (CTN) is conducting a 9-site outpatient, intent-to-treat, two-arm, double-blind, randomized controlled trial: Evaluation of Tirzepatide as an Adjunct to Buprenorphine for the treatment of OUD (TAB). The primary objective is to evaluate the effect of tirzepatide, relative to placebo, as an adjunct to buprenorphine on retention and on substance-related and sleep outcomes in adults with OUD. The primary outcome is 6-month buprenorphine treatment retention. The key secondary outcome is proportion of illicit opioid-negative urine samples over the 6-month treatment period. Approximately 310 adults with moderate-severe OUD who recently started buprenorphine will be recruited and randomized 1:1 to tirzepatide or placebo, balancing on site and buprenorphine formulation (transmucosal vs extended-release). Participants will be administered study medication, receive Fitbits to track sleep, and attend weekly research visits through 6 months post-randomization with longer research visits occurring at 1, 3, and 6 months. A follow-up visit at week 30 will collect final safety measures. This paper describes the rationale and study design for TAB, the first randomized trial to test tirzepatide for the treatment of OUD.

Objective: This study evaluated whether depressive symptom severity improved early with extended-release naltrexone and bupropion combination (naltrexone bupropion) compared to a placebo in individuals with moderate/severe methamphetamine use disorder and predicted subsequent use of methamphetamine. Methods: This secondary analysis from the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, which was conducted from May 23, 2017-July 25, 2019, included 326 individuals with a 9-item Patient Health Questionnaire (PHQ-9) score ≥5 at baseline. Repeated-measures mixed model analyses evaluated early (baseline-to-week-4) changes in depressive symptom severity with naltrexone-bupropion versus placebo and provided slope estimates for PHQ-9 change. Additional depression outcomes included response (≥50% reduction in PHQ-9 from baseline) and remission (PHQ-9 ≤4). Methamphetamine treatment response was ascribed if 3 out of 4 urine drug screens were negative during weeks 5 and 6. Logistic regression analyses evaluated whether changes in depression predicted methamphetamine treatment response. Covariates included age, sex, race, ethnicity, and baseline PHQ-9. Results: There was a greater reduction in PHQ-9 scores at week 4 with naltrexone-bupropion versus placebo (estimate = -2.52; standard error = 0.81). At week 4, depression response (odds ratio [OR] = 2.54; 95% confidence limit [CL], 1.42-4.55) and remission (OR = 3.04; 95% CL, 1.57-5.87) were more likely with naltrexone-bupropion versus placebo. Greater baseline-to-week 4 reduction in PHQ-9 was associated with a higher likelihood of methamphetamine treatment response (OR = 3.74, 95% CL, 1.28-10.93) and explained 24.8% (95% CI, 6.7%-60.3%) of the effect of naltrexone-bupropion on methamphetamine treatment response. Conclusion: Use of naltrexone bupropion was associated with early reduction in depressive symptom severity compared to a placebo, which was associated with a higher likelihood of reduction in subsequent methamphetamine use. Trial Registration: ClinicalTrials.gov identifier: NCT03078075.

Abstract Background Hospitalizations are increasing among persons with opioid use disorder (OUD) secondary to overdose as well as infections. Hospital settings are a reachable moment not only to offer treatment for OUD and co-occurring infections, but also to offer HIV testing and link to antiretroviral therapy to treat and prevent HIV. Pre-exposure prophylaxis (PrEP) prevents HIV acquisition through both sharing injection drug use equipment and condomless sexual intercourse. Unfortunately, few persons who use drugs including those with OUD are offered PrEP. This descriptive analysis sought to examine patients’ knowledge and attitude about PrEP to better understand if PrEP initiation at time of hospital contact could be used as a way to increase PrEP uptake in patients with OUD.Figure 1.Participants’ perceived risk of HIV on hospital discharge. Methods A retrospective data analysis was performed from the ongoing parent study, Project COMMIT (Coordinated Medical Treatment of Opioid Use Disorder and Infectious Disease). Adult patients (N = 144) hospitalized with bacterial, viral, or fungal infection with moderate to severe OUD were recruited upon admission to hospital and randomized 1:1 to either: 1) infectious disease management of OUD with long-acting injectable buprenorphine vs. 2) treatment as usual. Of the 144, 73 participants who did not report HIV infection, completed a supplemental questionnaire assessing beliefs in PrEP. Basic demographic information, sexual and HIV risk factors, and opioid use risk factors and beliefs about PrEP were reported as frequencies and percentages. Results When exploring HIV risk behavior in the past 30 days, 46 (63%) used injection drugs, 26 (35.6%) had condomless sex, 3 (4.1%) knew of their sexual partner being HIV positive or of unknown status, and 12 (16.4%) shared works. Of the 73 who completed the survey, 29 (39.7%) had never heard of PrEP, and none (n=0, 0.0%) had taken PrEP before. When asked about perceived risk of HIV, on a 4-point scale (high, medium, low or no risk), a majority of participants 64 (87.7%) thought they had no or low risk of HIV infection. Conclusion This study identified the need for increased education about risk for HIV and PrEP among people who use drugs and attention to acute hospitalization as a reachable moment for engaging them in HIV prevention care. Disclosures Sheela Shenoi, MD MPH, Merck Pharmaceuticals: Stocks/Bonds (Private Company) Frances Levin, MD, Aelis Pharmaceuticals: Grant/Research Support|Indivior: Medication for Research|Major League Baseball: Advisor/Consultant|NCATS: Grant/Research Support|NIDA: Grant/Research Support|NYSPI: Salary Support|SAMSHA: Grant/Research Support|US World Meds: Grant/Research Support Edward Nunes, MD, Alkermes: Advisor/Consultant|Alkermes: donated medication or digital therapeutics|Braeburn: donated medication or digital therapeutics|Camurus: Advisor/Consultant|Camurus: donated medication or digital therapeutics|Chess Health: donated medication or digital therapeutics|Indivior: Advisor/Consultant|Indivior: donated medication or digital therapeutics|Pear Therapeutics: Advisor/Consultant|Pear Therapeutics: donated medication or digital therapeutics Alain H. Litwin, MD, MPH, MS, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Merck Pharmaceuticals: Advisor/Consultant Sandra Ann Springer, MD, Alkermes Inc: Honoraria|Alkermes Inc: In kind study drug donation for NIH sponsored research|Indivior Pharmaceutical company: In kind study drug donation for NIH sponsored research

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: Gabapentin may help manage opioid withdrawal symptoms, but its effectiveness during buprenorphine taper and transition to naltrexone is uncertain.Objectives: To assess gabapentin's efficacy in improving outcomes for lifetime prescription opioid use disorder (POUD) during outpatient buprenorphine taper and transition to extended-release naltrexone.Methods: This 12-week randomized, double-blind, placebo-controlled trial enrolled 117 (55% male) POUD participants. Weeks 1-3, participants attended clinic 5 days/week for medication, therapy, and assessments, including weekly craving and thrice-weekly opioid withdrawal and supervised urine screens. Participants were inducted onto buprenorphine (12 mg), randomized to receive either placebo or gabapentin (800 mg BID), and underwent a 10-day buprenorphine taper. In week 4, participants transitioned from oral to extended-release naltrexone. Chi-square and generalized estimating equation models assessed outcomes. A subset with baseline fentanyl tests was also examined for fentanyl's impact on outcomes.Results: Of 117 participants, 75 (64.1%) completed the buprenorphine taper (41 gabapentin, 34 placebo), and 24 (20.5%) transitioned to naltrexone (12 gabapentin, 12 placebo). No significant group differences were observed in taper completion, naltrexone transition, craving, withdrawal, or opioid use. Fentanyl-positive participants had lower taper completion (47.8% vs. 75.8%, OR = 0.286, p = .033) and more opioid-positive urines (z = -4.24, p < .0001). Fentanyl-positive participants on gabapentin had higher COWS (z = 3.70, p = .001) and SOWS (z = 3.73, p = .001) scores, while fentanyl-negative participants on gabapentin had lower SOWS scores than those on placebo (z = -3.52, p = .002).Conclusions: Fentanyl exposure impairs buprenorphine taper success and worsens withdrawal in the presence of gabapentin, underscoring the need to tailor OUD treatment in fentanyl-exposed patients. (Clinicialtrials.gov ID NCT02543944).

BACKGROUND:Buprenorphine is a Food and Drug Administration-approved medication for opioid use disorder. However, individuals with opioid use disorder often report information needs regarding buprenorphine treatment on social media platforms such as Reddit. The field lacks a systematic approach to organizing these data and characterizing treatment information needs that may be unique and unavailable elsewhere. OBJECTIVE:In this study, we curated and analyzed large-scale data from social media to characterize self-reported buprenorphine treatment information needs using a qualitative analysis. METHODS:We collected 15,253 Reddit posts from the subreddit r/Suboxone. Following a standard protocol and guidance from clinical experts, we first identified 5 main themes from the data and then manually coded 6000 posts based on these themes. Finally, we determined the most frequently appearing topics within each theme by analyzing samples from each group. RESULTS:Among the 6000 posts, 2417 (40.3%) contained a single theme, 2160 (36%) contained two themes, and 834 (13.9%) contained three themes. The most frequent topics found across these themes included reports of psychological and physical effects during recovery, complexities in accessing buprenorphine, and significant information gaps regarding medication administration, tapering, and substance use at different stages of recovery. Moreover, self-treatment strategies and peer-driven advice revealed potential rumors and misinformation. CONCLUSIONS:Our findings can guide the design of interventions to improve patient education and communication. They also help address knowledge gaps and misinformation related to treatment. Additionally, the results can support hypothesis generation for future clinical research on medication for opioid use disorder treatment.

Objectives:Opioid use disorder (OUD) is a global concern. Urine drug screening uses opioid immunoassays to monitor OUD treatment response but is limited to yes/no results. Analytical cutoff variation complicates interstudy comparisons. This study investigated whether quantitative urinalysis can provide additional clinically meaningful treatment efficacy information and assessed the impact of different cutoffs on treatment differences.Methods:Quantitative urine drug test data were analyzed from a randomized, active-controlled, parallel-group, double-blind, 31-week phase 3 trial (N = 428; December 29, 2015, to October 19, 2016) assessing CAM2038 subcutaneous (SC) buprenorphine (BPN) extended-release injections compared to daily sublingual (SL) BPN/naloxone (BPN/NX) tablets, and equivalent placebos, in OUD treatment (NCT02651584). Urine samples were analyzed by gas or liquid chromatography with mass spectrometry. The European Medicines Agency (EMA)-directed primary endpoint, based on opioid detection above the lower limit of quantification (LLOQ), was explored using different cutoffs.Results:Using the LLOQ, the mean percentage of opioid-negative samples was 35.1% and 28.4% for CAM2038 and SL BPN/NX, respectively (mean difference [95% confidence interval], 6.7% [-0.1% to 13.6%]). Using standard cutoffs (1 ng/mg creatinine [fentanyl/norfentanyl], 300 ng/mg creatinine [other opioids]), results were 41.2% and 32.2% (9.0% [1.8%-16.1%]). Increasing cutoffs led to greater differences favoring CAM2038. Significant differences in mean concentrations over time and cumulative distribution of exposure to different opioids also favored CAM2038. The difference in fentanyl exposure between treatments was nonsignificant.Conclusions:Quantitative urinalysis provides insights into opioid use beyond assessment of abstinence. Study outcomes are impacted by analytical thresholds, which should be carefully considered when designing, interpreting, and comparing clinical trial results.

Hospitalizations are increasing in the US due to infections related to opioid use disorder (OUD); however, few patients have treatment with medications for OUD (MOUD) initiated. Injectable long-acting buprenorphine (LAB) could help improve MOUD receipt and infection treatment completion. To compare initiation of LAB combined with infectious disease (ID) management (ID-LAB) with treatment as usual (TAU) during inpatient medical hospitalization periods for improving receipt of MOUD at 12 weeks. The Coordinating Opioid Use Treatment Through Medical Management With Infection Treatment (COMMIT) trial was a multisite randomized clinical trial with enrollment from August 19, 2020, through October 31, 2023, at 3 US hospital systems in Connecticut, Pennsylvania, and South Carolina. Eligible participants were individuals hospitalized with a diagnosis of moderate to severe OUD according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) and concurrent infection. Intent-to-treat outcomes were assessed at the end of the 12-week intervention period. Participants were randomized 1:1 to receive ID-LAB or TAU during treatment for infection in a hospital setting or early after discharge. All participants received a nurse care medical management intervention. The primary outcome was the proportion of patients who received any form of MOUD at 12 weeks after randomization. Models were adjusted by site, prescription of MOUD in the 30 days prior to hospitalization, and the baseline value of each outcome when assessable. Of the 171 participants who were enrolled, 86 were randomized to the ID-LAB arm and 85 to the TAU arm. A total of 88 participants (51.5%) were men, and median age was 39 (IQR, 33-47) years. At 12 weeks, there was no statistically significant difference in receipt of MOUD between the ID-LAB and TAU groups, with 51 patients (59.3%) and 46 (54.1%), respectively, receiving MOUD (adjusted rate ratio, 1.01; 95% CI, 0.78-1.30). In this randomized clinical trial comparing initiation of LAB for OUD with ID management in the hospital setting compared with TAU, there was no difference between arms in the receipt of MOUD at 12 weeks. The TAU arm had higher retention than anticipated. These findings suggest that hospitalization with an infection related to drug use may present an opportunity to identify OUD and initiate MOUD that may include injectable LAB. The nurse case management services provided to all participants should be evaluated in future studies. ClinicalTrials.gov Identifier: NCT04180020

Introduction:Prescription opioids can contribute to risk for opioid use disorder and overdoses. Improving prescription opioid safety is a critical component in reducing opioid risks. This report aims to determine whether communities randomized to the Communities That HEAL (CTH) intervention have significantly different rates of prescription opioid safety measures. Study Design:A multisite, 2-arm, community-level, cluster randomized, unblinded, wait-list controlled comparison trial designed to assess the effectiveness of the CTH intervention in reducing opioid-related overdose deaths among community residents 18 years of age or older (adults). Setting/Participants:Sixty-seven (67) communities in Kentucky, Massachusetts, New York, and Ohio. Participants were communities in this study. Intervention:The Communities That Heal intervention consists of multiple dimensions: a coalition-driven community engagement process to select and support implementation of evidence-based practices; the Opioid-overdose Reduction Continuum of Care Approach, a compendium of evidence-based practices and technical assistance resources organized under overdose education and naloxone distribution, medication for opioid use disorder, and prescription opioid safety menus; and communication campaigns intended to reduce opioid use disorder stigma and raise awareness and demand for naloxone and medication for opioid use disorder. Main Outcomes and Measures:The main outcome was the number of adults with new incident high-risk opioid prescribing episodes after at least a 45-day washout. Other outcomes included the number of opioid-naïve adults with new opioid prescriptions limited to a 7-day supply, number of adults who received opioid prescriptions from multiple prescribers or pharmacies, and number of locations providing drug take-back services. Outcomes were assessed from July 2021 to June 2022. Results:There was no statistically significant difference in the adjusted rates for new incident high-risk opioid prescribing per 100,000 adults during the comparison period between intervention (1,094.48; 95% CI=1,063.15; 1,126.74) and wait-list control communities (1,121.90; 95% CI=1,079.62; 1,165.84). The adjusted relative rate comparing intervention to wait-list control communities was 0.98 (95% CI=0.93, 1.02; p-value=0.296). Similarly, there were no statistically significant differences between intervention and wait-list control communities for the other outcomes. Conclusions:Although no statistically significant differences were found in prescription opioid safety measures between study arms, improvement in these measures during the comparison period for both study arms suggested that there may have events outside the trial, such as published revised Center for Disease Control and Prevention clinical practice guidelines for prescribing opioids, that may have impacted study outcomes.

Background: Depression and suicidal ideation are prevalent in patients with opioid use disorder (OUD).Objectives: This study examined changes in suicidal ideation during OUD treatment with buprenorphine-naloxone or extended-release naltrexone.Methods: 570 adults with OUD (29.6% female) were recruited into a National Drug Abuse Clinical Trials Network randomized trial (NCT02032433) comparing extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT). Suicidal ideation was assessed at baseline and regular intervals over 24 weeks using continuous self-reported and binary clinician-rated measures from the Concise Health Risk Tracking-Self Report and the Hamilton Depression Rating Scale, respectively. A mixed-effects model was used to assess the association between continuous outcome self-reported suicidal ideation and treatment over time while adjusted for baseline suicidal ideation.Results: Continuous self-report suicidal ideation scores decreased in both groups with a significant time-by-treatment interaction indicating that the treatment effect differed over time (F(11, 3497) = 1.81, p = .0464). Scores were significantly lower in the buprenorphine group only in weeks 1 and 3 and when averaged across weeks 1-4. Binary clinician-rated suicidal ideation dropped from 15 (5.25%) and 12 (4.24%) at baseline, to 5 (1.89%) and 3 (1.49%) at week 1, for buprenorphine and naltrexone groups, respectively.Conclusion: OUD treatment with extended-release naltrexone or buprenorphine-naloxone was associated with suicidal ideation reductions from the first week. Suicidal ideation was lower with buprenorphine-naloxone in the first 4 weeks, with no significant differences thereafter. Despite overall low suicidal ideation scores and modest differences, these findings suggest beneficial effects of both treatments in individuals with OUD and mild baseline suicidality.