Faculty Bibliography

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.

BACKGROUND AND AIM/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

This commentary examines methodological and ethical problems encountered when a multi-arm clinical trial loses access to one or more of its arms, using the Retention Phase of the NIDA Clinical Trials Network CTN-0100 study, Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD) as an example. RDD is a community-based, multi-site trial testing strategies to reduce dropout from medication treatment for opioid use disorder. Among patients with opioid use disorder initiating buprenorphine treatment, the original design was a 3 by 2 factorial comprising 3 pharmacological conditions (Standard-Dose sublingual buprenorphine-16 mg/day target [SL-BUP 16], High-Dose sublingual buprenorphine-32 mg/day target [SL-BUP 32], or extended-release injectable buprenorphine [XR-BUP]), crossed with 2 behavioral conditions: medical management with vs. without a technology-based digital therapeutic app providing cognitive behavioral therapy lessons and contingency management. The trial experienced two major disruptions to study interventions: 1) The supply of XR-BUP became temporarily unavailable due to manufacturing problems; and 2) The company supplying the digital therapeutic app went bankrupt, rendering the original app permanently unavailable. Questions considered by the study lead team included: 1) Whether to pause recruitment into the trial altogether or continue recruitment into truncated designs omitting the unavailable interventions; 2) How to account for participants who did not experience full exposure to the halted interventions; 3) Whether to substitute a similar intervention; and 4) The problem of concurrent randomizations, namely that a truncated design does not contain all the concurrent randomizations of the full design, introducing risk of confounding or bias. This experience from the RDD trial demonstrates how multi-arm clinical trials that lose access to an intervention arm can continue with a truncated design, allowing continued progress on study aims, while balancing methodological purity with the pragmatic imperative to keep the trial running and respect subjects' participation.

BACKGROUND:Standard medications for opioid use disorder (MOUD) provide effective treatment pathways for recovery compared with no treatment or behavioral therapies alone. That said, people who continue to use non-prescribed opioids despite treatment with MOUD are at greater risk for high attrition and OUD-related harms. Novel, more effective approaches are needed for the treatment of OUD. To that end, glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide a promising option as a non-opioid pharmacological intervention for OUD. Observational studies suggest that GLP-1RAs decrease craving measures in a residential OUD population but no controlled clinical trials have been conducted to determine if GLP-1RAs increase opioid abstinence and reduce craving in individuals with OUD in an outpatient population. The purpose of the current protocol is to evaluate the potential for the GLP-1RA, semaglutide, to increase abstinence and reduce craving in an outpatient population enrolled in a MOUD program and continue to use non-prescribed opioids. METHOD/METHODS:This protocol is a randomized, double-blind, placebo-controlled clinical trial designed to test the efficacy of the GLP-1RA, semaglutide, in 200 participants enrolled in an outpatient MOUD program (n = 100 buprenorphine; n = 100 methadone) for the treatment of OUD. Outcomes include the probability of participants being abstinent from illicit and nonprescribed opioids, as well as measures of craving and days of drug use. Measures will be evaluated using urine toxicology screens and self-report assessments across 19 weeks during a screening visit (Study Week 1), 12 treatment visits (Study Weeks 2-13), a washout visit (Study Week 14), and a final follow-up visit (Study Week 19). DISCUSSION/CONCLUSIONS:This manuscript describes a phase II clinical protocol to collect data on the efficacy of a GLP-1RA, semaglutide, in persons enrolled in an MOUD program and with ongoing non-prescribed opioid use despite treatment with methadone or buprenorphine. Completion of the current project will support the feasibility of phase III clinical trials for further evaluation in larger outpatient OUD populations that may lead to a new indication for GLP-1RA as a novel and effective treatment for OUD. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov: NCT06548490. Registered 12 August 2024, https://clinicaltrials.gov/study/NCT06548490 .

OBJECTIVES/OBJECTIVE:People receiving medications for opioid use disorder often continue to experience opioid withdrawal, creating barriers to improved outcomes. Emerging evidence suggests the existence of distinct opioid withdrawal subtypes characterized by high and low levels of withdrawal severity, highlighting the need for personalized treatment approaches. To inform clinical practice, we identified subgroups of adults based on levels of opioid withdrawal over time during opioid use disorder (OUD) treatment. METHODS:We conducted a secondary analysis of the Clinical Trials Network (CTN-0051) Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment trial using latent class growth analysis to identify subgroups of withdrawal. Four hundred and seventy-four participants in an OUD trial were randomized to receive extended-release naltrexone (XR-NTX) or sublingual buprenorphine-naloxone (BUP-NX). Withdrawal symptoms were measured using the Subjective Opiate Withdrawal Scale (SOWS) at 10 timepoints. We identified classes and compared their predictors of withdrawal and time to return to opioid use. RESULTS:Two distinct trajectories - low and high sustained opioid withdrawal - were identified in each treatment arm. Most participants were in the low withdrawal class (n = 176; 86 % XR-NTX and n = 241; 89 % BUP-NX) with fewer in the high sustained withdrawal class (n = 28; 14 % XR-NTX and n = 29; 11 % BUP-NX). Differences in lifetime history of anxiety and depression and in quality of life domains (mobility, usual activities, and pain/discomfort) were primarily observed among XR-NTX participants, with only one baseline mobility difference emerging between BUP-NX classes. In the XR-NTX arm, time to return to use was significantly shorter in the high sustained withdrawal class compared to the low withdrawal class, whereas BUP-NX classes did not differ on time to return to use. DISCUSSION AND CONCLUSIONS/CONCLUSIONS:Our findings demonstrate the existence of distinct high and low opioid withdrawal subtypes among individuals receiving XR-NTX and BUP-NX. These results underscore the importance of personalized withdrawal management strategies and highlight the need to consider individual withdrawal trajectories when optimizing treatments. Future research should focus on identifying predictors of withdrawal severity to improve clinical outcomes.

BACKGROUND AND AIMS/OBJECTIVE:US regulatory changes allowed for additional methadone take-home doses following COVID-19 onset. How dispensing practices changed and which factors drove variation remains unexplored. We determined daily methadone dispensing trajectories over six months before and after regulatory changes due to COVID-19 using state sequence analysis and explored correlates. DESIGN/METHODS:Retrospective chart review of electronic health records. SETTINGS/METHODS:Nine opioid treatment programs (OTPs) across nine US states. PARTICIPANTS/METHODS:Adults initiating treatment in 2019 (n = 328) vs. initiating 1 month after the COVID-19 regulatory changes of March 2020 (n = 376). MEASUREMENTS/METHODS:Type of daily methadone medication encounter (in-clinic, weekend/holiday take-home, take-home, missed dose, discontinued) based on OTP clinic; cohort (pre vs. post-COVID-19); and patient substance use, clinical and sociodemographic characteristics. FINDINGS/RESULTS:Following COVID-19 regulatory changes, allotted methadone take-home doses increased from 3.5% to 13.8% of total person-days in treatment within the first 6 months in care. Clinic site accounted for the greatest variation in methadone dispensing (6.2% and 9.5% of the variation of discrepancy between sequences pre- and post-COVID-19, respectively). People who co-use methamphetamine had a greater increase in take-homes than people who did not use methamphetamine (from 3.7% pre-pandemic to 21.2% post-pandemic vs. 3.5% to 12.5%) and higher discontinuation (average 3.6 vs. 4.7 months among people who did not use methamphetamine pre-COVID-19; average 3.3 vs. 4.6 months post-COVID-19). In the post-COVID-19 cohort, females had a higher proportion of missed doses (17.2% vs. 11.9%) than males. People experiencing houselessness had a higher proportion of missed doses (19% vs. 12.3%) and shorter stays (average 3.5 vs. 4.5 months) when compared with those with stable housing. CONCLUSION/CONCLUSIONS:Daily methadone dispensing trajectories in the US both before and following COVID-19 regulatory changes appeared to depend more on the opioid treatment programs' practices than individual patient characteristics or response to treatment.

OBJECTIVES/OBJECTIVE: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.

INTRODUCTION/BACKGROUND:Little is known about how pharmacists' attitudes and stigma toward naloxone and Medication for opioid use disorder (MOUD) influence effective linkage to treatment. We examine the psychometrics of a new Pharmacist Opioid Use Disorder Perceptions Questionnaire (P-OUDP-Q), a multidimensional measure to examine pharmacists' stigma and perceptions related to MOUD in the New York State (NYS) site of the HEALing Communities Study. METHODS:The study recruited a sample of 324 pharmacists from 16 counties in NYS between January and June 2022. A 74-item questionnaire assessed pharmacists' familiarity with opioid-related medications, protocols, policies and attitudes regarding their role, confidence, and beliefs centered around delivery of MOUD and naloxone in the community. Exploratory factor analysis assessed individual and community-level factors associated with four underlying constructs. Factor scores were compared across the demographic predictors. Variables factor loadings <0.4 were eliminated from the factor analysis and the process was reiterated. RESULTS:Eighty-six percent (n = 280) of the pharmacists were white. A little over half, 57 % (n = 186), were female, 35 % (n = 113) were 30-35 years old. The mean number of years practicing (SD) was 18 (SD: 13). Exploratory factor analysis identified four underlying constructs: (1) practice confidence, (2) practice familiarity, (3) practice attitudes, and (4) methadone attitudes. Statistically significant (p < .05) mean factor scale score differences by race were observed for practice familiarity (white reporting higher than non-white); by pharmacy size for practice familiarity (across all groups; non-significant Tukey post-hoc) and practice attitudes (hospital/clinic greater than big chain pharmacies); by gender (males greater than females) for practice familiarity and methadone attitudes; by poverty quartile for practice attitudes (lowest less than highest quartile); and urban versus rural pharmacist county setting for practice familiarity (rural greater than urban). CONCLUSIONS:Findings show the P-OUDP-Q is a concise measure of pharmacists' perceptions of their role in dispensing MOUD and naloxone, including distinct "stigma" dimensions, which is valuable for use with pharmacists in communities highly impacted by the opioid epidemic. The development and validation of a reliable measure to assess pharmacists' perceptions of stigma and barriers represents a valuable contribution to the field, to inform the design/implementation of targeted interventions and support systems.

INTRODUCTION AND BACKGROUND/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/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/CONCLUSIONS: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/RESULTS:gov Identifier: NCT04464980.