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Background: Cannabis is the most commonly used drug in the United States, and among people who use cannabis, polysubstance use is common and understudied. We aimed to examine the association of tetrahydrocannabinol (THC) positive urine drug screen (+UDS) with the odds of submitting a cocaine + UDS during cocaine use disorder treatment.

Methods: We conducted a secondary data analysis of a previously reported double-blind, placebo-controlled clinical trial, CTN0048. Participants meeting criteria for opioid abuse/dependence were assigned to receive extended-release naltrexone and one of three conditions of buprenorphine (placebo, 4 mg/day, 16 mg/day) for 8 weeks. Generalized estimating equations (GEE) were used to analyze urine samples (Liu et al., 2018) collected over time, examining the association between THC + UDS and cocaine + UDS during treatment.

Results: Participants (n = 301) averaged 46 (SD = 8.64) years of age, were majority male (78.41 %), non-Hispanic (89.70 %), and African American (66.45 %). GEE results indicated that patients who submitted THC + UDS had significantly higher odds of submitting cocaine + UDS compared to participants who submitted THC-negative UDS across the 25 time points examined (OR = 1.47, 95 % CI = 1.21–1.79, p = 0.00). Time (OR = 0.9998, 95 % CI: 0.9997, 0.9999, p = 0.018) and the covariate of sex assigned at birth (OR = 1.77, 95 % CI = 1.13–2.77, p = 0.013) were also significant in the model, indicating very small decreases in the odds of submitting a cocaine + UDS over time for all patients and 77 % higher odds of submitting cocaine + UDS for females.

Conclusion: THC + UDS was associated with increased odds of submitting a cocaine + UDS during treatment. Further investigation is needed to discern whether decreasing THC use will result in reduced cocaine use; however, these results suggest that it may be beneficial to counsel patients on cannabis use cessation both before and during treatment for cocaine use, as it is related to cocaine use treatment outcomes.

Related protocols: CTN-0048

Poster describing a study that examined type-specific medications for opioid use disorder (MOUD) awareness (i.e., heard of) and referral willingness among CBO providers and clients. The data was acquired via cross-sectional survey of 13 Southern U.S. CBOs in FL, GA, LA, MS, and TN. Analysis revealed that compared with methadone, buprenorphine and naltrexone awareness is lower for both providers and clients, though providers are more aware of all types of MOUD than clients. Additionally, providers report greater willingness to refer for buprenorphine and naltrexone than clients report willingness to be referred (especially for naltrexone).

This type of misalignment can hinder MOUD uptake, weaken provider-client linkage, and contribute to high overdose rates and limited provider and MOUD access in the South.

Related protocols: CTN-0082

Importance: Health plan disenrollment may interrupt treatment for opioid use disorder (OUD) and overall care, increasing risk for serious outcomes, including overdose and death. There is limited evidence on the association of disenrollment with all-cause and overdose mortality after initiating medications for OUD (MOUD) treatment.

Objective: To assess the association of health plan disenrollment with all-cause and overdose mortality in patients treated with MOUD.

Design, setting, and participants: This cohort study conducted by the CTN Health Systems Node, included privately and publicly insured patients aged 16 years or older who initiated buprenorphine or naltrexone for OUD treatment between January 1, 2012, and December 31, 2021, at 3 integrated health insurance and care delivery systems in 2 US states. Patients were followed up to 2 years until December 31, 2022. Data were analyzed July 2024 to November 2025.

Exposure: Health plan disenrollment following MOUD initiation.

Main outcomes and measures: All-cause mortality and drug-related and alcohol-related overdose mortality within 2 years of MOUD initiation ascertained from the National Death Index. Survival analyses were adjusted for patient sociodemographic and clinical characteristics.

Results: Among 20,011 patients (mean [SD] age 38.7 [15.1] years; 12 299 males [61.5%]) who were treated for OUD, 6948 (34.7%) experienced disenrollment and 586 (2.9%) died during follow-up. The crude rate was 15.3 (95% CI, 14.1-16.6) per 1000 person-years for all-cause mortality and 6.2 (95% CI, 5.4-7.0) per 1000 person-years for overdose mortality. Ever experiencing disenrollment showed elevated all-cause mortality (17.6 [95% CI, 14.9-20.8] vs 14.7 [95% CI, 13.4-16.1] per 1000 person-years) and overdose mortality (8.9 [95% CI, 7.1-11.3] vs 5.4 [95% CI, 4.7-6.3] per 1000 person-years) relative to remaining enrolled. In adjusted analyses, ever experiencing disenrollment was associated with increased hazards of all-cause (hazard ratio [HR], 1.51; 95% CI, 1.23-1.84) and overdose mortality (HR, 1.56; 95% CI, 1.17-2.09). Compared with remaining enrolled and receiving MOUD treatment, being disenrolled (HR, 4.34; 95% CI, 3.19-5.89) and being enrolled and not receiving MOUD treatment (HR, 4.19; 95% CI, 3.24-5.43) were associated with overall mortality.

Conclusions and relevance: In this cohort study of patients who initiated MOUD, experiencing health plan disenrollment was associated with increased mortality risk compared with remaining enrolled. Strategies are needed to improve continuity of health coverage and mitigate the elevated mortality risk during insurance transitions for patients receiving medications for OUD.

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.

Related protocols: CTN-0051

Medications for opioid use disorder (MOUD), such as methadone, buprenorphine, and extended-release naltrexone (XR-NTX), have been shown to reduce or eliminate opioid use and craving, protecting against opioid overdose and death. Stopping medication is associated with risk of relapse and potential overdose. Unsurprisingly, patients may desire to stop MOUD because of adverse effects, burden, or preference for recovery without medication, asking, “How long do I need to take medication?” Clinicians who treat OUD often encounter this uncomfortable risk-benefit discussion with patients who want to stop MOUD, hoping that the patients can do so successfully, while acknowledging the major risks. Prospective data are needed to inform those discussions. In designing one of the first clinical trials focused on MOUD discontinuation—the Discontinuation Phase of the Optimizing Retention, Duration, and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD) trial (NCT04464980)2—the investigators identified ethical issues that needed consideration in designing the study.

The authors of this Viewpoint are study investigators, including a social worker (S.E.P.) and 2 psychiatrists experienced with MOUD (R.D.W. and E.V.N.). In this Viewpoint, we describe those ethical challenges and our attendant solutions to inform the design of other studies of medication discontinuation, where discontinuing treatment could have grave consequences.

Related protocols: CTN-0100

Introduction:
Primary care patients with opioid use disorder (OUD) may receive treatment in primary care clinics or co-located specialty addiction treatment models. To help guide operational leaders in organizing OUD care delivery systems, we described rates of OUD medication treatment among primary care patients in PRimary care Opioid Use Disorders treatment (PROUD, CTN-0074) trial intervention clinics and four primary care clinics not in the trial because they already had OUD treatment programs in place (exemplar clinics).

Methods:
Primary care patients seen at six PROUD trial intervention clinics that implemented the Massachusetts model of office-based addiction treatment (PROUD clinics) and four exemplar clinics (two co-located specialty models; two primary care models with universal prescribing, in which all primary care providers were expected to treat OUD) were compared. Primary outcomes were person-years (PY) of medication treatment for OUD with buprenorphine or extended-release naltrexone during follow up (3/2018–2/2020) and changes from baseline (3/2016–2/2018).

Results:
Baseline primary care samples included 109,196 patients in PROUD clinics and 101,631 patients in exemplar clinics. Baseline OUD treatment rates varied across exemplar clinics (range: 10.9 to 328.7 PY per 10,000 primary care patients) but were higher than in PROUD clinics at baseline (3.9 PY per 10,000), with exemplar clinics with primary care models (established 2005 and 2017) providing the highest treatment rates to their primary care patients. During follow-up, PROUD clinics nearly tripled treatment, to 14.4 PY per 10,000, whereas most exemplar clinics increased treatment by less than 10% but still had higher treatment rates (range: 12.0 to 359.4 PY per 10,000).

Conclusions:
Primary care OUD treatment rates varied markedly. Exemplar clinics in which all primary care providers were expected to treat OUD had the highest treatment rates at baseline and follow-up, suggesting that universal prescribing is a promising approach to increasing OUD treatment in primary care.

Related protocols: CTN-0074

Background: Patient-perceived Quality-of-Life (QOL) and treatment effectiveness (TEA) have previously been shown to be positively associated with better substance use treatment outcomes.

Objectives: This study examined potentially causal relationships amongst QOL, TEA, and cocaine abstinence.

Methods: Secondary data analyses (CTN-0148) were conducted on the NIDA Clinical Trial Network study, Cocaine Use Reduction with Buprenorphine (CTN-0048). N = 301 participants with DSM-IV cocaine dependence and opioid use history were administered injectable naltrexone and randomized to one of three buprenorphine/naloxone doses, 4 mg/1 mg, 16 mg/4 mg or placebo. Mediation models estimated direct and indirect effects amongst QOL, TEA, and cocaine abstinence.

Results: The QOL Environment domain exerted a significant indirect effect (B=0.01, SE=0.01, 95% CI=[0.00, 0.02]) on cocaine abstinence and a direct effect on TEA (B=0.57, SE=0.22, 95% CI=[0.16, 1.01]). Other QOL domains and individual QOL items exerted no statistically significant direct effects on cocaine abstinence. Overall QOL exerted a significant direct effect on TEA (95% CI=[0.32, 2.45]) along with a significant indirect effect on cocaine abstinence (95% CI=[0.01, 0.05]). TEA had a significant positive direct effect on cocaine abstinence (95% CI=[0.01, 0.02]).

Conclusion: Overall QOL and environmental QOL are related to treatment response through their relationship with patients’ perception of treatment effectiveness. TEA is directly related to cocaine abstinence at the end of treatment. QOL and TEA measures may serve as indicators of a need for additional support within care plans. These findings highlight the impact of a patient’s sense of well-being and their perceived treatment effectiveness on biochemically validated cocaine abstinence.

Related protocols: CTN-0148

This study applied the Theory of Reasoned Action (TRA) and Theory of Planned Behavior (TPB) to assess predictors of willingness to use three medications (methadone, buprenorphine, naltrexone) for opioid use disorder (MOUD), among people who use opioids (PWUOs). A single assessment survey, with measures aligned to the TRA/TPB were administered to 235, majority male, predominately White, PWUOs attending syringe services programs (SSPs) in the Southeastern United States, administered as part of CTN-0082. Hierarchical multiple regressions were used to analyze predictors of willingness to take each type of MOUD.

Conclusions: Findings partially supported the TRA but not TPB, with positive attitudes associated with greater willingness to use all three types of MOUD: pinpointing to the value of SSPs as a low threshold hub for treatment engagement.

Related protocols: CTN-0082

Aims: To estimate the effectiveness of different thresholds for administering opioid withdrawal medications (clonidine and clonazepam) on the probability of successfully initiating extended-release naltrexone (XR-NTX) among participants with opioid use disorder (OUD) during medically managed withdrawal.

Design: Secondary analysis of a multisite clinical trial comparing a rapid vs. standard approach for XR-NTX initiation, 2021–2022.

Setting: Six community inpatient addiction treatment units in the United States.

Participants: English-speaking adults seeking treatment for DSM-5 OUD and expressing interest in XR-NTX treatment (n = 415).

Measurements: We estimated the extent to which the following thresholds for adjunctive medication administration would affect the probability of initiating XR-NTX over time: 1) where adjunctive medications were given in response to at mild-to-moderate withdrawal symptoms or greater [Clinical Opiate Withdrawal Scale (COWS) score ≥ 5), 2) where adjunctive medications were given in response to minimal withdrawal symptoms or greater (COWS score ≥ 3) and 3) where adjunctive medications were given regardless of withdrawal symptoms. Using a longitudinal sequentially doubly robust estimator, we estimated the cumulative probability of XR-NTX initiation under each of these three treatment regimes while accounting for dropout and initiation of other medications as competing events.

Findings: The estimated probability of initiating XR-NTX by day 14 was 50.4% [95% confidence interval (CI) = 41.8–58.9) under the no-threshold regime, 43.9% (95% CI = 39.1–48.7) under the regime of waiting for minimal withdrawal symptoms and 38.5% (95% CI = 34.3–42.6) under the regime of waiting for mild-to-moderate withdrawal symptoms. Probability of XR-NTX initiation was a statistically significant 11.9 percentage points higher (95% CI = 3.6–20.2) under the no-threshold regime versus the mild-to-moderate threshold regime, and a non-statistically significant 6.4 percentage points (95% CI = −0.8 to 13.7) higher under the no-threshold regime versus the minimal threshold regime.

Conclusions: Providing clonidine and clonazepam daily during the first five days of medically managed opioid withdrawal appears to statistically significantly increase the likelihood of initiating extended-release naltrexone treatment compared with waiting for mild-to-moderate withdrawal symptoms to administer adjunctive medications. To improve initiation rates, providers may consider lowering the threshold at which they provide adjunctive medications, giving these medications preemptively or to manage even minimal withdrawal symptoms.

Related protocols: CTN-0097

This is the primary outcomes article for CTN-0095.

Nearly 727,000 individuals in the US died of opioid overdoses between 1999 and 2022. The current workforce of addiction medicine specialists is inadequate to address the scale of this crisis, and primary care clinicians (PCCs) do not feel sufficiently supported to treat opioid use disorder (OUD).

Objective: To evaluate whether an electronic health record–integrated clinical decision support system (CDSS) increases OUD diagnosis and treatment in primary care.

Design, Setting, and Participants: This pragmatic cluster randomized clinical trial was conducted from April 2021 to December 2023. Primary care clinics in 3 health systems in 4 US states were randomized to receive or not receive an electronic health record–integrated CDSS aimed at improving OUD diagnosis and treatment. Eligible patients were aged 18 to 75 years, visited a randomized clinic, and had an OUD diagnosis in the last 2 years, opioid overdose in the last 6 months, or risk score indicating high risk of OUD or opioid overdose. Data were analyzed from September 2023 to October 2024.

Interventions: The OUD CDSS provided personalized treatment recommendations to patients and PCCs in intervention clinics.

Main Outcomes and Measures: Primary outcomes were likelihood to receive (1) an OUD diagnosis (among high-risk patients without a baseline OUD diagnosis), (2) a naloxone prescription, or (3) a prescription of a medication for OUD (MOUD) or specialty referral, all within 30 days of first eligible (index) visit, and (4) days covered by a MOUD prescription in the 90 days after index.

Results: Among 10,891 patients meeting eligibility criteria, 5918 (54.3%) were female, and the mean (SD) age was 48.0 (13.9) years. There was no difference in OUD diagnoses within 30 days between groups. Patients in the intervention group had more naloxone orders (80 of 5538 [1.4%] vs 40 of 5353 [0.7%]; odds ratio, 1.76; 95% CI, 1.14-2.72) and orders for MOUDs or treatment referral (775 of 5538 [14.0%] vs 503 of 5353 [9.4%]; odds ratio, 1.48; 95% CI, 1.05-2.08) within 30 days. There were no differences in median (IQR) days covered by MOUD over 90 days postindex between intervention (84 [55-90] days) and usual care (83 [55-90] days; rate ratio, 1.00; 95% CI, 0.93-1.08) or in overdose or death rates during the intervention period.

Conclusions and Relevance: In this cluster randomized clinical trial, the intervention improved rates of naloxone orders and OUD treatment in primary care but did not affect days covered by a MOUD over 90 days postindex or overdose or death rates. These findings demonstrate an OUD CDSS can help increase access to OUD treatment in primary care.

Related protocols: CTN-0095

Background & Objectives: Depression and suicidal ideation are prevalent in patients with opioid use disorder (OUD). This study examined changes in suicidal ideation during OUD treatment with buprenorphine-naloxone or extended-release naltrexone using data from CTN-0051.

Methods: 570 adults with OUD (29.6% female) were recruited into a National Drug Abuse Clinical Trials Network randomized trial (CTN-0051) 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.

Conclusions: 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.

Related protocols: CTN-0051

Objectives: The accelerated development of additive pharmacotherapy treatment (ADAPT-2) for methamphetamine use disorder (MUD) trial demonstrated the efficacy of extended-release injectable naltrexone (NTX) and oral bupropion (BUP). In this secondary analysis, we determined whether craving and impulsivity levels could predict subsequent use of methamphetamine.

Methods: Participants (N = 357) of the ADAPT-2 trial with at least one transition point [transition from positive-to-negative urine drug screen (UDS) or vice versa] during stage 1 (baseline through week-6) were included in this secondary analysis. Craving was assessed using the Visual Analog Scale (VAS). Impulsivity was assessed using the 2-item impulsivity factor of the Concise Health Risk Tracking (CHRT) Scale.

Results: A significant treatment by craving by time interaction was noted (P = 0.018), where higher craving levels were consistently associated with a lower likelihood positive-to-negative UDS transition at the next visit in both NTX-BUP and placebo groups. However, no such effect was present by week 6 of treatment in the placebo group. CHRT Impulsivity also had a significant effect on the probability of a positive-to-negative UDS transition (P = 0.019) in addition to the 3-way interaction of VAS, week, and treatment group. Individuals with lower craving levels but higher impulsivity exhibited a lower probability of transitioning to negative UDS at the next visit. Higher craving, but not impulsivity, was associated with a higher likelihood of negative-to-positive UDS transition at the next visit in both treatment groups.

Conclusions: Further investigations are necessary to optimize NTX-BUP treatment, focusing on the impact of craving and impulsivity on outcomes.

Related protocols: CTN-0068

Aim: This study: (1) estimated the effect of early discontinuation of medication for opioid use disorder (MOUD) on overdose probability and (2) measured the relationship between patient characteristics and early discontinuation probability for each MOUD type.

Design, setting and participants: This was a retrospective cohort using electronic health record data from the US Veterans Healthcare Administration. Participants were veterans initiating MOUD with buprenorphine (BUP), methadone (MET) or extended-release naltrexone (XR-NTX) from fiscal years 2012-19. A total of 39 284 veterans met eligibility with 22 721 (57.8%) initiating BUP, 12 652 (32.2%) initiating MET and 3911 (10.0%) initiating XR-NTX.

Measurements: Measurements (1) determined whether the veteran experienced an overdose in the 365 days after MOUD initiation (primary) and (2) early discontinuation of MOUD, defined as discontinuation before 180 days (secondary). We assumed that unobserved patient characteristics would jointly influence the probability of discontinuation and overdose. and estimated the joint distribution with a bivariate probit model.

Findings: We found that 9.0% of BUP initiators who experienced an overdose above the predicted 3.9% had no veteran-discontinued BUP early; findings for XR-NTX were similar, with 12.2% of initiators overdosing above the predicted 4.5%, but this was statistically inconclusive. We found no relationship between early discontinuation and overdose for MET initiators, probably due to the high risk of both events. The patient characteristics included in our post-estimation exploratory analysis of early discontinuation varied by MOUD type, with between 14 (XR-NTX) and 25 (BUP) tested. The only characteristics with at least one level showing a statistically significant change in probability of early discontinuation for all three MOUD types were geography and prior-year exposure to psychotherapy, although direction and magnitude varied.

Conclusions: Early discontinuation of buprenorphine, and probably extended-release naltrexone, appears to be associated with a greater probability of experiencing a fatal or non-fatal overdose among US veterans receiving medication for opioid use disorder (MOUD); methadone does not show the same association. There is no consistent set of characteristics among early discontinuers by MOUD type.

Related protocols: CTN-0142

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, CTN-0068) 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.

Related protocols: CTN-0068

Background: Cocaine remains the most abused stimulant, causing considerable morbidity and mortality. Despite decades of research, there is no FDA-approved medication to treat cocaine use disorder (CUD). In individuals with cocaine and opioid dependence/abuse, extended-release injectable naltrexone (XR-NTX) and sublingual buprenorphine (BUP; 16 mg with naloxone; Suboxone) reduced cocaine use compared to placebo and XR-NTX in the “Cocaine Use Reduction with Buprenorphine” (CURB; CTN-0048) study.

Objectives: The CURB-2 (CTN-0109) study aims to examine whether administering XR-NTX in combination with extended-release injectable buprenorphine (XR-BUP), thus creating a “kappa antagonist,” is an effective pharmacotherapy compared to placebo for the treatment of CUD.

Study design: CURB-2 is a fully powered, phase IIb, randomized, placebo-controlled trial. Approximately 426 participants will be randomized across 12 study sites in the United States. There will be a 1-week medication induction phase, an 8-week active medication phase, and a 4-week follow-up phase. XR-NTX (Day 1, Week 3, Week 6) will be administered before XR-BUP (Day 4, Week 4). With naltrexone blocking the mu-opioid receptors, the reinforcing effects of buprenorphine will be blocked while leaving the kappa antagonist effects.

Discussion: If this kappa antagonist approach demonstrates efficacy in reducing urine-verified cocaine use compared to placebo, XR-NTX and XR-BUP combination therapy would be an important tool in addressing cocaine use disorder.

Related protocols: CTN-0109