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Background and aims: Despite similar substance use levels, Black adults experience greater family, legal, employment and other social-contextual challenges related to recovery than other groups. Substance use treatments that address both substance use and social-contextual factors are uniquely positioned to address these substance-related problems and produce more sustainable improvements in social functioning than treatment as usual (TAU) or behavioral controls (Control). The aim of this study was to evaluate changes in substance-related problems among Black adults, focusing on the comparative effectiveness between social-contextual treatments and TAU/Control.
Design: Individual-level data synthesis based on secondary analysis of Black adults enrolled in the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN).
Setting: All data were collected in the primary studies between 2001 and 2008 at clinics across the United States.
Participants: Black adults who reported cocaine and/or opioid use across nine studies within the NIDA CTN. The sample used herein consisted of individuals from five of these studies who provided data on substance-related problems (n=532; mean age=39.34; standard deviation=9.6).
Measurements: There were two treatment conditions: Social-contextual (e.g. Motivational Interviewing, Seeking Safety, STAGE 12) and TAU/Control. Moderated nonlinear factor analysis estimated latent scores for substance-related problems, using subscales from the Addiction Severity Index, while accounting for measurement noninvariance across studies, time and covariates. Linear mixed models estimated latent score differences over time between social-contextual treatments and TAU/Control during treatment and from the end of treatment through 12-month follow-up.
Findings: Both treatment groups improved across substance-related problem areas from baseline to the end-of-treatment (Cohen’s d = -0.10 to d = -0.47), with effects maintained at 12-month follow-up. Although social-contextual treatments did not statistically significantly outperform TAU/Control from baseline to end-of-treatment, they showed greater effects from end of treatment to 12-month follow-up in family/social [Cohen’s d difference ( d) = -0.47, 95% confidence interval (CI) = -0.57 to -0.38], legal ( d = -0.20, 95% CI = -0.31 to -0.10) and psychiatric problems ( d = 0.29, 95% CI = -0.38 to -0.20) than TAU/Control. Sensitivity analyses indicated that Seeking Safety and STAGE 12 predominantly drove post-treatment improvements in family/social problems.
Conclusions: Substance use treatment may yield broader, delayed benefits beyond substance use reduction among Black adults in the United States. Compared with treatment-as-usual, social-contextual treatments can yield more sustainable effects in legal, family and psychiatric areas among Black adults, with interventions such as Seeking Safety and STAGE 12 showing particular benefits in addressing family-related challenges.
Related protocols: CTN-0125
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
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
Background: Cocaine and methamphetamine use disorders (CcUD/MtUD) have serious public health, medical, and psychiatric consequences. Yet, there are no U.S. Food and Drug Administration (FDA) approved treatments available. The STIMULUS study is a multi-site trial, sponsored by NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN), that aims to investigate the feasibility and preliminary efficacy of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for moderate to severe CcUD/MtUD.
Methods: The study is a double-blind, sham-controlled trial seeking to recruit 160 participants with a current moderate to severe CcUD or MtUD diagnosis, randomized to receive active rTMS (10-Hz stimulation at 120% motor threshold over the left dorsolateral prefrontal cortex) or sham. Feasibility is assessed by a target of at least 20 treatment sessions administered within an 8-week period. Additionally, the study aims to evaluate the efficacy of rTMS in reducing stimulant use and craving, the impact of rTMS on mood, anxiety, sleep, and other measures, and the utility of electroencephalography as a treatment response biomarker.
Discussion: Studies exploring rTMS for stimulant use disorders remain limited by small sample sizes, as well as great heterogeneity in defined study population, treatment parameters, retention in treatment, and number of sessions. In this paper, we highlight key study design decisions, such as safety, sham procedure, and schedule flexibility.
Conclusions:
We hope that the data collected will lay the groundwork for a robust randomized controlled trial of rTMS as a therapeutic intervention for individuals with CcUD/MtUD.
Related protocols: CTN-0108
This is the Primary Outcomes Article for CTN-0125.
Cocaine- and opioid-related overdose deaths have increased among Black people, which makes identifying effective treatments for Black people a high priority. We investigated the comparative effectiveness of behavioral treatments among Black adults who use cocaine and/or opioids.
Methods: Identified multisite randomized clinical trials (RCTs) of behavioral interventions that targeted substance use, had participants who self-identified as Black, and included cocaine use outcome measures from the National Drug Abuse Treatment Clinical Trials Network (CTN) datashare. We estimated cocaine use and opioid use severity scale scores while considering study-level measurement non-invariance. Then, we estimated the inverse probability of treatment-weighted (IPTW) linear mixed models to assess comparative effectiveness of treatments that address social-contextual factors and those focused solely on substance use (e.g., contingency management (CM)) relative to treatment-as-usual/controls on cocaine use and opioid use severity scores during- and post-treatment.
Results: Nine RCTs met inclusion criteria, with a combined sample of 1,381 Black adults who used cocaine and/or opioids. The IPTW linear mixed models indicated that cocaine use severity decreased from baseline to end-of-treatment across three treatment groups, with a greater decrease for social-contextual treatments and CM relative to treatment-as-usual/controls. However, this greater reduction was maintained at 12-month follow-ups for social-contextual treatments, while CM worsened relative to TAU/controls. We found decreases in latent opioid use severity with no or minor differences between treatment groups.
Conclusions: The findings suggest that addressing social-contextual factors is an essential treatment component for long-term reduction of cocaine use among Black adults.
Related protocols: CTN-0125
The Treatment Effectiveness Assessment (TEA) score is derived from a 4-item self-administered assessment utilizing a Likert scale to evaluate changes across four life domains: substance use, personal responsibilities, health, and citizenship. The World Health Organization Quality of Life Brief (WHOQOL-BREF) scale is a shortened version of the original instrument that may be more convenient for use in large research studies or clinical trials. It assesses the individual’s perceptions in the context of their culture and value systems, and their personal goals, standards, and concerns. Cocaine craving is a core symptom of cocaine use disorder and remains a consistent obstacle to achieving sustained reductions in use and relapse prevention.
This secondary analysis of data from CTN-0048 aimed to examine relationships between quality of life and health satisfaction (using the WHO-QOL scale), cocaine use (urine drug screens), and patient ratings of treatment effectiveness, as measured by the TEA over 8 weeks of treatment.
Results found significant negative relationships between cocaine craving and TEA and significant positive relationships between patient quality of life and satisfaction with health. A model including 4 health domains also indicated that there were significant positive relationships between health domains and TEA as well. TEA was not significantly related to longest duration of abstinence (LDA) for cocaine verified by urine drug screens.
Conclusions: Self-reported treatment effectiveness was integrally related to patient level factors, over time, while in treatment for cocaine use disorder and receiving placebo or buprenorphine and extended-release naltrexone, however TEA was not predictive of LDA. Recognizing and providing parallel intervention for these patient level factors during substance use disorder treatment may enhance patient reports of treatment effectiveness, indicating improvement across the patient reported domains of substance use, life satisfaction, health, and community.
Related protocols: CTN-0048
Stimulants are the drivers of the fourth wave of the United States drug overdose epidemic. Kappa opioid receptor antagonists promote feelings of wellbeing and represent a medication addressing the “dark side.” In a pilot study, extended-release naltrexone (XR-NTX) plus oral buprenorphine (BUP), 4mg and 16mg, produced modest, though statistically significant, reductions in cocaine use among those adherent to oral BUP compared to placebo. This presentation describes CTN-0110, a study designed to test monotherapy for buprenorphine as the medication is used for treatment of refractory depression in people with no opioid use disorder (OUD).
Related protocols: CTN-0110
Cocaine craving is a core symptom of cocaine use disorder (CUD) and remains a consistent obstacle to achieving sustained reductions in use and relapse prevention. A systematic review examining pharmacological treatment for cocaine craving reported that in their review of 130 clinical trials, there was an association between craving and multiple cocaine use outcomes in most studies, including both self-report and biochemical evidence of use (i.e., urinary benzoylecgonine). Some studies have examined relationships between craving and treatment efficacy with opioid agonists and shown more mixed results.
This study aimed to examine the relationship between self-reported cocaine craving over time (i.e., 100mm Visual Analog Scale) and cocaine use over time (measured via urine drug screen and self-report) in a sample of patients receiving medication treatment for cocaine use disorder (from CTN-0148).
Results from the urine drug screen model found that there was a significant relationship between cocaine craving and urine drug screens for cocaine use (OR=0.98, p<0.01), such that lower cocaine craving was associated with higher percentages of negative urine drug screens, while holding treatment assignment constant. Results from the self-reported use model found that there was a significant impact of time on self-reported cocaine use, and when examining the time by craving interaction (B=0.0008, p<0.01), such that lower cocaine craving was associated with higher percentages of negative self-reported cocaine use, while holding treatment assignment constant.
Conclusions: Low craving is significantly associated with decreased cocaine use over time while receiving placebo or buprenorphine and extended-release naltrexone. This therapeutic may represent a promising treatment to build on for the medical treatment for cocaine use disorder.
Related protocols: CTN-0148
Polysubstance use may complicate treatment outcomes for individuals who use opioids. This research aimed to examine the prevalence of polysubstance use in an opioid use disorder treatment trial population and polysubstance use’s association with opioid relapse and craving.
This study is a secondary data analysis of individuals with opioid use disorder who received at least one dose of medication (n=474) as part of a 24-week, multi-site, open label, randomized Clinical Trials Network study (CTN-0051, X:BOT) comparing the effectiveness of extended-release naltrexone versus buprenorphine. Models examined pretreatment polysubstance use and polysubstance use during the initial 4 weeks of treatment on outcomes of relapse by week 24 of the treatment trial and opioid craving.
Polysubstance use was generally not associated with treatment outcomes of opioid relapse and craving. Proportion of days of pretreatment sedative use was associated with increased likelihood of opioid relapse (OR: 1.01, 95% CI: 1.00–1.02). Proportion of days of cocaine use during the initial 4 weeks of treatment was associated with increased likelihood of opioid relapse (OR: 1.05, 95% CI: 1.01–1.09) but this effect was no longer significant once the potential of confounding by opioid use was considered. Sedative use during initial 4 weeks of treatment was associated with increased opioid craving (b: 0.77, 95% CI: 0.01–1.52). The study found no other significant relationships.
Conclusions: In the current study population, polysubstance use was only marginally associated with 24-week treatment outcomes.
Related protocols: CTN-0051
A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication.
This is a secondary analysis of a multicenter randomized trial (CTN-0051, X:BOT) that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects.
The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02–7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53–0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score (P < 0.001), used cocaine on more days over the prior 30 days than other quartiles (P < 0.001), and had highest proportions with alcohol and cocaine use disorder (P = 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference (P = 0.02) and all experiencing homelessness (P < 0.001).
Conclusions: Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse.
Related protocols: CTN-0051
Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration-approved pharmacotherapy. Depressive disorders are common psychiatric comorbidity amongst individuals with CUD.
A retrospective cohort study was conducted among 161,544 patients diagnosed with CUD and depression to evaluate the effectiveness of 13 antidepressants on CUD remission. For any antidepressant found to be associated with CUD remission that had an additional indication, we conducted an additional analysis to evaluate the effectiveness of the candidate drug in patients with CUD with that indication. We then analyzed publicly genomic and functional databases to identify potential explanatory mechanisms of action of the candidate drug in the treatment of CUD.
Among these antidepressants, bupropion was associated with higher rates of CUD remission compared to propensity-score matched patients prescribed other antidepressants: hazard ratio (HR) and 95% confidence interval (CI) 1.57 (95% CI: 1.27-1.94). Bupropion is also approved for smoking cessation. We identified CUD patients with co-occurring nicotine dependence and observed that patients prescribed bupropion displayed a higher rate of CUD remission compared to matched individuals prescribed other drugs for nicotine dependence: 1.38 (95% CI: 1.11-1.71). Genetic and functional analyses revealed that bupropion interacts with four protein-encoding genes (COMT, DRD2, SLC6A3, and SLC6A4) which are also associated with CUD and targets CUD-associated pathways including serotonergic synapses, cocaine addiction, and dopaminergic synapses.
Conclusions: Our findings suggest that bupropion might be considered a treatment for improving CUD remission in patients with CUD and co-occurring depression or nicotine dependence.
Related protocols: CTN-0114
This study was a secondary analysis of two CTN trials comparing buprenorphine (BUP-NX) and extended-release naltrexone (XR-NTX), CTN-0051, X:BOT and CTN-0067, CHOICES. The purpose was to estimate how ongoing stimulant use affects return to illicit opioid use after initiation onto medication for opioid use disorder (MOUD).
A total of 528 participants who initiated MOUD as part of trial participation were included; participants were recruited from 13 opioid treatment programs and HIV clinics across 10 states in the U.S. from 2014-2019. Nearly half (49%) were between 30 and 49 years of age, 69% were male and 66% were non-Hispanic White.
The primary outcome was first self-reported day of non-prescribed opioid use following MOUD initiation, and the exposure of interest was daily stimulant use (methamphetamine, amphetamines or cocaine). Both were defined using time-line follow-back. Among participants reporting at least 1 day of illicit opioid use, we also examined relapse to ongoing use, defined as (1) 7 days of continuous opioid use or (2) 4 consecutive weeks with self-reported opioid use, one or more positive urine drug screens (UDS) for opioids or one or more missing UDS.
Forty-seven per cent of participants reported stimulant use following MOUD initiation, 58% returned to illicit opioid use and 66% of those relapsed to ongoing use. Stimulant use was strongly associated with increased risk of misusing opioids after MOUD initiation when measured daily [adjusted hazard ratio (aHR)=9.23, 95% confidence interval (CI)=6.80–12.50, P<0.001] and over a 7-day period (aHR=1.27 for each additional day, CI=1.18–1.37, P<0.001). Using stimulants weekly or more often was associated with increased likelihood of relapse to ongoing opioid use compared with less than weekly or no stimulant use (adjusted odds ratio=2.30, CI=1.05–5.39, P=0.044).
Conclusions: People initiated on medication for opioid use disorder who subsequently use stimulants appear to be more likely to return to and continue using non-prescribed opioids compared with those without stimulant use. The association appears to be stronger among patients who initiate buprenorphine compared with those who initiate extended-release naltrexone.
Related protocols: CTN-0051, CTN-0067
Patients in treatment with medications for opioid use disorder (MOUD) often report use of other substances in addition to opioids. Few studies exist that examine the relationship between use at treatment entry and early non-opioid use in opioid treatment outcome.
In this study, researchers combined and harmonized three randomized, controlled MOUD clinical trials from the National Institutes of Drug Abuse (NIDA) Clinical Trials Network (CTN) (N=2,197) and investigated the association of non-opioid substance use at treatment entry and during early treatment with a return to opioid use. The trials (CTN-0027 [START], CTN-0030 [POATS], and CTN-0051 [X:BOT]) compared MOUD treatment (buprenorphine, methadone, extended-release naltrexone) in populations with opioid use disorder (OUD). Non-opioid substances were identified through harmonizing self-reported use. The primary outcomes were markers of return to opioid use by 12 weeks.
When treatment cohorts were adjusted, no association between self-reported treatment entry use of non-opioid substances and week-12 opioid use was detected. During the first month of treatment, higher use of cocaine and amphetamine was found to be associated with higher likelihood of illicit opioid use by week 12. Exploratory analyses of potential treatment cohort-by-predictor interactions showed that those with heavier cocaine use had a lower rate of returning to opioid use in the extended-release naltrexone group than in the methadone group.
Conclusions: Substance use other than opioids at treatment entry is not associated with relapse. Use of cocaine or amphetamines during the first few weeks of MOUD treatment may signal a worse outcome, suggesting a need for additional interventions.
Related protocols: CTN-0027, CTN-0030, CTN-0051
Cocaine overdose death rates among Black people are higher than that of any other racial/ethnic group, attributable to synthetic opioids in the cocaine supply. Understanding the most effective psychostimulant use treatment interventions for Black people is a high priority. While some interventions have proven effective for the general population, their comparative effectiveness among Black people remains unknown. To address this gap, our NIDA-funded Clinical Trials Network (CTN) study 0125, will use Integrative Data Analysis (IDA) to examine treatment effectiveness across 9 CTN studies. This manuscript describes the study protocol for CTN-0125.
Of the 59 completed randomized clinical trials in the CTN with available datasets, nine met our inclusion criteria: 1) behavioral intervention, 2) targeted cocaine use or use disorder, 3) included sub-samples of participants who self-identified as Black and 4) included outcome measures of cocaine and psychostimulant use and consequences. We aim to 1) estimate scale scores of cocaine use severity while considering study-level measurement non-invariance, 2) compare the effectiveness of psychosocial treatments for psychostimulant use, and 3) explore individual (e.g., concomitant opioid use, age, sex, employment, pre-treatment psychiatric status) and study-level moderators (e.g., attendance/retention) to evaluate subgroup differences in treatment effectiveness.
Conclusions: The NIDA CTN provides a unique collection of studies that can offer insight into what interventions are most efficacious for Black people. Findings from our CTN-0125 have the potential to substantially inform treatment approaches specifically designed for Black people who use psychostimulants.
Related protocols: CTN-0125
Cocaine Use Disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost-effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA-approved drugs for CUD treatment.
Our drug repurposing strategy combines artificial intelligence (AI)-based drug prediction, expert panel review, clinical corroboration, and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI-based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non-ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine’s potential mechanisms of action in the context of CUD.
The study utilized TriNetX to access EHRs from over 90 million patients worldwide. Genetic and functional level analysis used DisGeNet, Search Tool for Interactions of Chemicals, and Kyoto Encyclopedia of Genes and Genomes databases. EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription.
7,742 CUD patients who received anesthesia (3,871 ketamine-exposed and 3,871 anesthetic-controlled) and 7,910 CUD patients with depression (3,955 ketamine-exposed and 3,955 antidepressant-controlled) were identified after propensity score-matching.
Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics (Hazard Ratio (HR): 1.98, 95% confidence interval [CI]: 1.42-2.78). Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR: 4.39, 95% CI: 2.89-6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD-associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand-receptor interaction, cAMP signaling, and cocaine abuse/dependence.
Conclusions: Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder.
Related protocols: CTN-0114