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.

BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

BACKGROUND: Buprenorphine maintenance for opioid dependence remains of limited availability among underserved populations, despite increases in US opioid misuse and overdose deaths. Low threshold primary care treatment models including the use of unobserved, "home," buprenorphine induction may simplify initiation of care and improve access. Unobserved induction and long-term treatment outcomes have not been reported recently among large, naturalistic cohorts treated in low threshold safety net primary care settings. METHODS: This prospective clinical registry cohort design estimated rates of induction-related adverse events, treatment retention, and urine opioid results for opioid dependent adults offered buprenorphine maintenance in a New York City public hospital primary care office-based practice from 2006 to 2013. This clinic relied on typical ambulatory care individual provider-patient visits, prescribed unobserved induction exclusively, saw patients no more than weekly, and did not require additional psychosocial treatment. Unobserved induction consisted of an in-person screening and diagnostic visit followed by a 1-week buprenorphine written prescription, with pamphlet, and telephone support. Primary outcomes analyzed were rates of induction-related adverse events (AE), week 1 drop-out, and long-term treatment retention. Factors associated with treatment retention were examined using a Cox proportional hazard model among inductions and all patients. Secondary outcomes included overall clinic retention, buprenorphine dosages, and urine sample results. RESULTS: Of the 485 total patients in our registry, 306 were inducted, and 179 were transfers already on buprenorphine. Post-induction (n = 306), week 1 drop-out was 17%. Rates of any induction-related AE were 12%; serious adverse events, 0%; precipitated withdrawal, 3%; prolonged withdrawal, 4%. Treatment retention was a median 38 weeks (range 0-320) for inductions, compared to 110 (0-354) weeks for transfers and 57 for the entire clinic population. Older age, later years of first clinic visit (vs. 2006-2007), and baseline heroin abstinence were associated with increased treatment retention overall. CONCLUSIONS: Unobserved "home" buprenorphine induction in a public sector primary care setting appeared a feasible and safe clinical practice. Post-induction treatment retention of a median 38 weeks was in line with previous naturalistic studies of real-world office-based opioid treatment. Low threshold treatment protocols, as compared to national guidelines, may compliment recently increased prescriber patient limits and expand access to buprenorphine among public sector opioid use disorder patients.

BACKGROUND AND AIMS/OBJECTIVE:There are currently no brief quantitative assessments that capture the drug patterns of people who engage in use of more than one drug on the same day or simultaneously. The current study examined the retest reliability, acceptability and feasibility of a new quantitative assessment to measure polysubstance use. DESIGN/METHODS:A tool for assessing simultaneous and same-day polysubstance behaviors, the polysubstance assessment tool (PAT) was developed in interviewer-administered and electronic self-administered formats. Participants were allocated 1:1 to receive either version of the PAT and returned one to three days later to repeat the assessment. SETTING/METHODS:New York City, New York, USA. PARTICIPANTS/METHODS:Adults (18 + years, n = 115) who reported use of more than one drug per day in the last 30 days. MEASUREMENTS/METHODS:Test-retest reliability estimates for dichotomous items were assessed using Cohen's kappa, Gwet's Agreement Coefficient 1 (AC1) and percent agreement. Continuous items were assessed with two-way mixed effects intraclass correlations. Bivariate analyses examined acceptability using nine Likert-type survey questions. Feasibility was examined via time to completion. FINDINGS/RESULTS:Overall reliability was moderate to excellent [Gwet's AC1 range 0.70-0.96; intraclass correlation (ICC) range 0.62-0.88]. Reliability was higher for simultaneous polysubstance use (Gwet's AC1 = 0.90) as compared with same-day (Gwet's AC1 = 0.70). Acceptability was high, with no statistically significant difference between the self- and interviewer-administered versions of the tool. Median time to completion was 7 minutes, and was statistically significantly lower for the self-administered tool (median = 5 minutes) compared with the interviewer-administered version (median = 8 minutes) (P < 0.001). CONCLUSIONS:A new polysubstance assessment tool appears to have good reliability and can be considered by researchers seeking a quantitative measure of polysubstance use behaviors given its simplicity, high acceptability and quick completion time.

BACKGROUND/UNASSIGNED:Histotripsy is a novel, non-invasive, non-ionising, non-thermal method of mechanical tumour disruption that received US FDA approval in October 2023 for the treatment of liver tumours. This study aims to summarise and evaluate the safety and outcomes data following histotripsy of primary and secondary liver tumours. METHODS/UNASSIGNED:statistic and Cochran's Q test. Publication bias was assessed using funnel plot visual inspection and Egger's regression test. Finally, the histotripsy technology was assessed using the IDEAL framework to inform the design of future trials. This work was registered with PROSPERO (CRD420261299804). FINDINGS/UNASSIGNED:= 6.6%). No significant publication bias was detected for mortality and safety outcomes; however, formal assessment of publication bias was limited by the small number of studies for these and all outcomes. All radiological control outcomes showed substantial heterogeneity across studies. INTERPRETATION/UNASSIGNED:Although there is notable heterogeneity across studies, pooled results indicate that histotripsy has high rates of technical feasibility and local control with a favourable side effect profile. Interpretation of these findings is limited by the small number of available studies, variability in outcome definitions and imaging assessment methods, and short follow-up durations. These results underscore the need for larger, prospectively designed studies with standardised reporting frameworks and longer follow-up to more precisely characterise the clinical, radiologic, and quantitative imaging outcomes following histotripsy. FUNDING/UNASSIGNED:None.

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.

BACKGROUND:Individuals with opioid use disorder (OUD) may experience fewer barriers to treatment following incarceration if offered in-jail medications for OUD (MOUD). We aimed to identify care trajectories of community OUD treatment after incarceration and examine the association between receiving in-jail MOUD and experiencing specific community treatment trajectories. METHODS:This retrospective cohort study using matched New York City (NYC) health care administrative data included adults with OUD incarcerated on or after May 2011 and discharged during 2014-2017. We defined states of community OUD treatment at the weekly level over one year following index jail discharge and performed state sequence analysis (SSA) to identify trajectories of treatment after jail and assessed the influence of receiving in-jail MOUD on treatment trajectories. RESULTS:Of 14,923 eligible individuals, 26.2% received in-jail MOUD. SSA identified eight clusters of community care trajectories: continuous methadone treatment (9.7%), methadone treatment discontinuation (3.7%), methadone treatment and reincarceration (6.7%), methadone treatment initiation (4.8%), continuous reincarceration (3.5%), short reincarceration with little community treatment (20.3%), long reincarceration with little community treatment (7.0%), and no community OUD treatment or reincarceration (44.5%). Receiving in-jail MOUD was associated with belonging to the continuous methadone treatment cluster compared to the no community OUD treatment or reincarceration cluster (adjusted OR: 12.5, 95% CI: 9.9-15.7). CONCLUSION/CONCLUSIONS:We identified eight unique patterns of community OUD treatment after jail release. Receipt of in-jail MOUD was associated with belonging to the continuous methadone treatment cluster. These findings suggest that provision of in-jail MOUD could improve methadone uptake in the community.

RATIONALE AND OBJECTIVES/OBJECTIVE:Prostate multiparametric magnetic resonance imaging (MRI) is recommended for prostate cancer detection, staging, and surveillance. Incidental bladder lesions are encountered on these studies but remain under-characterized in the literature. The patient characteristics associated with malignancy for these lesions are not well defined. We evaluated the prevalence, histopathologic outcomes, clinical characteristics, and associations with malignancy for incidental bladder lesions on prostate MRI. MATERIALS AND METHODS/METHODS:A retrospective review included 31,241 patients undergoing prostate MRI examinations from January 2013 to January 2023. Imaging reports and medical records were analyzed for incidental bladder lesions, demographic data, clinical symptoms, urinalysis findings, and histopathologic outcomes. Lesions were categorized based on biopsy results or negative clinical follow-up for bladder tumors in chart review. Logistic regression analysis and receiver operating characteristic analyses were performed. RESULTS:Incidental bladder lesions occurred in 0.74% (230/31,241) of examinations, with biopsy-confirmed bladder cancer in 0.11% of patients (34/31,241) or 14.8% (34/230) of cases with lesions. In multivariable analysis, gross hematuria had the strongest association with biopsy-proven bladder cancer (OR 9.26, 95% CI 4.12-20.79, p<0.001). A logistic regression model incorporating age, smoking status, and gross hematuria yielded area under the curve of 0.762 for bladder cancer. CONCLUSION/CONCLUSIONS:Incidental bladder lesions on prostate MRI may represent opportunities for early detection of bladder cancer, but also have potential for harms related to unnecessary procedures. Considering the presence of gross hematuria, possibly stated as part of the MRI referral or patient questionnaire, could improve risk stratification of encountered bladder lesions and early cancer detection.

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:It is unclear if findings from randomized controlled trials (RCT) of medications for opioid use disorder apply to real-world settings. We estimated the effectiveness of buprenorphine-naloxone (BUP-NX) versus extended-release naltrexone (XR-NTX) on treatment interruption in a RCT and an observational study based on real-world data. DESIGN/METHODS:Target trial emulation to harmonize the protocol and statistical analyses of X:BOT (target trial) and the observational study (observational emulation). Baseline was randomization in the target trial and medically managed opioid withdrawal (MMOW) discharge in the observational emulation. SETTINGS/METHODS:X:BOT trial and Massachusetts Public Health Data Warehouse observational data (United States). PARTICIPANTS/METHODS:The target trial included all X:BOT participants. The observational emulation trial included MMOW discharges from January 2014 to May 2016. MEASUREMENTS/METHODS:Treatment strategies were BUP-NX versus XR-NTX initiation within 28 days of baseline. The outcome was treatment interruption (earliest of treatment discontinuation, incarceration, MMOW readmission, death). We estimated the 24-week risk and risk difference. FINDINGS/RESULTS:In the target trial, 94% (269/287) and 66% (187/283) of participants randomized to BUP-NX or XR-NTX initiated their assigned treatment within 28 days, respectively. In the observational emulation, BUP-NX and XR-NTX were initiated within 28 days in 9% (5209/59 076) and 3% (1813/59 076) of MMOW discharges, respectively. The adjusted 24-week treatment interruption risks (95% confidence interval) for BUP-NX and XR-NTX were 68% (60%,77%) and 72% (60%,83%) in the target trial [risk difference, -4 percentage points (pp; -17 pp,11 pp)] and 82% (81%,83%) and 93% (92%,95%) in the observational emulation [risk difference,-11 pp (-13 pp,-10 pp)]. CONCLUSIONS:Buprenorphine-naloxone might be superior to extended-release naltrexone in real-world settings where the majority of people struggle to remain on medications for opioid use disorder. Buprenorphine-naloxone initiators had a lower risk of treatment interruption than extended-release naltrexone initiators in an observational emulation, but similar risks in a randomized controlled trial, although confidence intervals were wide. Trial participation, study size and residual confounding may explain these differences.