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Abstract: Background: Despite effective treatments for opioid use disorder (OUD), relapse and treatment drop-out diminish their efficacy, increasing the risks of adverse outcomes, including death. Predicting important outcomes, including non-prescribed opioid use (NPOU) and treatment discontinuation among persons receiving medications for OUD (MOUD) can provide a proactive approach to these challenges. Our study uses ecological momentary assessment (EMA) and deep learning to predict momentary NPOU, medication nonadherence, and treatment retention in MOUD patients. Methods: Study participants included adults receiving MOUD at a large outpatient treatment program. We predicted NPOU (EMA-based), medication nonadherence (Electronic Health Record [EHR]- and EMA-based), and treatment retention (EHR-based) using context-sensitive EMAs (e.g., stress, pain, social setting). We used recurrent deep learning models with 7-day sliding windows to predict the next-day outcomes, using Area Under the ROC Curve (AUC) for assessment. We employed SHapley additive ExPlanations (SHAP) to understand feature latency and importance. Results: Participants comprised 62 adults with 14,322 observations. Model performance varied across EMA subtypes and outcomes with AUCs spanning 0.58–0.97. Recent substance use was the best performing predictor for EMA-based NPOU (AUC = 0.97). Life-contextual factors were best performers for EMA-based medication nonadherence (AUC = 0.68) and retention (AUC = 0.89), and substance use risk factors (e.g., nicotine and alcohol use) and self-reported MOUD adherence performed best for predicting EHR-based medication nonadherence (AUC = 0.79). SHAP revealed varying latencies between predictors and outcomes. Conclusions: Findings support the effectiveness of EMA and deep learning for forecasting actionable outcomes in persons receiving MOUD. These insights will enable the development of personalized dynamic risk profiles and just-in-time adaptive interventions (JITAIs) to mitigate high-risk OUD outcomes. Related protocols: CTN-0084-A-2

Abstract:

Illicit stimulant use among individuals initiating medication for opioid use disorder (MOUD) has significantly increased over the past decade. Co-use of these substances is associated with increased risk of mortality as well as worse treatment outcomes. This study examines the potential predictive role of stimulant urinalysis result at baseline on treatment retention and opioid and stimulant use outcomes amongst individuals initiating MOUD treatment.

This is a cross-sectional secondary analysis of data from a multi-site randomized clinical trial (CTN-0027). A total of 1269 individuals were randomized to receive 24 weeks of buprenorphine (n=740) or methadone (n=529) treatment across nine sites. Multiple linear and logistic regressions were conducted to determine the impact of baseline stimulant urinalysis results on treatment retention, and stimulant and opioid use outcomes.

Individuals initiating MOUD with a stimulant negative urinalysis result at baseline submitted more negative stimulant and opioid urinalyses during treatment, were more likely to complete treatment, and had better outcomes at six-month follow-up, measured as negative urinalysis for stimulant, and opioid.

Conclusions: Baseline stimulant use is associated with worse MOUD treatment outcomes, underscoring the need for novel integrated interventions designed to address opioid and stimulant co-use.

Related protocols: CTN-0027

Abstract:

Introduction and background: The three medications approved to address OUD are effective in decreasing opioid use and morbidity and mortality; however, their utility is limited by high rates of dropout from treatment. The CTN-0100 trial will develop an evidence base for strategies to improve retention on buprenorphine and extended-release naltrexone.

Research design and methods: The National Drug Abuse Treatment Clinical Trials Network (CTN) study CTN-0100, “Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy” (RDD), is a multicenter, randomized, non-blinded trial enrolling more than a thousand patients from 18 community-based substance use disorder treatment programs. Participants are adult volunteers seeking to initiate medication treatment for OUD (MOUD). Individuals choose between buprenorphine or extended-release injectable naltrexone. The trial randomizes participants choosing buprenorphine, in a 3 × 2 factorial design, to a medication condition (standard-dose sublingual buprenorphine, high-dose sublingual buprenorphine, or extended-release injectable buprenorphine) and to a behavioral condition (Medical Management or Medical Management plus a digital therapeutic (smartphone) app). Individuals choosing extended-release naltrexone are randomized only to a behavioral condition. Participants receive study medication for 74 weeks and are then followed for a further 24 weeks. The primary outcome is successful retention on MOUD at 26 weeks (six months), with 50- and 74-week retention among the secondary outcomes.

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.

Related protocols: CTN-0100

Abstract:

The effectiveness of motivational enhancement therapy (MET) in comparison with counseling as usual (CAU) for increasing retention and reducing substance use was evaluated in the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0004, a multisite randomized clinical trial. Participants were 461 outpatients treated by 31 therapists within 1 of 5 outpatient substance abuse programs. Contrary to the study hypothesis, MET did not appear to be more effective than CAU for either retention measure or urine drug outcome. However, though both 3-session interventions resulted in reductions in substance use during the 4-week therapy phase, MET resulted in sustained reductions during the subsequent 12 weeks whereas CAU was associated with significant increases in substance use over this follow-up period. MET also resulted in more sustained substance use reductions than CAU among primary alcohol users, but no difference was found for primary drug users. An independent evaluation of session audiotapes indicated that MET and CAU were highly and comparably discriminable across sites. Although the researchers did not directly assess the efficacy of their training model, the results of this study and its companion single-session protocol (Carroll et al, 2006) indicated that community-based therapists can learn to deliver MET effectively even in the absence of a priori allegiance, interest, or training in the model. Future analyses will evaluate the relationship between therapist experience, skill, adherence, and treatment outcomes.

Abstract:

The importance of implementing evidence-based practices has taken over health care, whether in the mental health, medical, or substance use treatment realms. While well-intentioned and important, the implementation of evidence-based practices is only one aspect of quality care. In fact, there are many other elements of treatment that are at least as important as offering evidence-based practices, and this is particularly true in levels of care other than traditional outpatient. Other elements of care essential to quality treatment include: 1) Monitoring and ensuring a positive therapeutic alliance between clients and providers – Much research has documented the relationship between positive treatment outcome and a positive therapeutic alliance; 2) Monitoring and ensuring high customer satisfaction: Regardless of the specific treatment offered, it is essential to monitor and address customer satisfaction, as without this, clients will not obtain benefit from treatment; 3) Monitoring administrative discharges – In residential treatment programs, clients are often discharged for non-compliance with treatment. This needs close monitoring, as from experience, administrative discharges have more to do with staff than with clients; 4) Ensuring readily-available treatment access – When individuals are ready to enter treatment, treatment needs to be available. Treatment not being available or long waiting periods to enter treatment will result in lost opportunities; 5) Monitoring no-show rates and overall treatment retention – People have to come to treatment and be retained for treatment to be effective. Thus, a focus on this is necessary; 6) Ensuring clients – multiple treatment needs are addressed – Either in-house or through linkages, clients – other problems need to be addressed; and 7) Ongoing quality improvement – To ensure quality treatment, a culture of continuous quality improvement must be developed.

This presentation will highlight other important aspects of care that must not be forgotten while programs are focused on implementing evidence-based practices.

Abstract:

There is limited research examining factors impacting MOUD retention in rural settings, especially within the context of the COVID-19 pandemic. Using electronic health records data collected as part of a NIDA Clinical Trials Network study (CTN-0102), this study explored how the onset of the COVID-19 pandemic may have impacted MOUD retention in a sample of 563 rural primary care patients.

Cox regression model was applied to examine if COVID-19 was related to treatment retention, controlling for demographics, clinic, insurance type, and other diagnoses. The independent variable was the number of days between the patient’s first MOUD prescription date during the pre-COVID observation period (10/1/2019–3/13/2020) and the start of the COVID-19 pandemic. The dependent variable was retention on MOUD, defined as the time from the first MOUD prescription documented during the pre-COVID observation period to the first break in consecutive MOUD prescriptions (right censored at 180 days).

The findings demonstrated that there was a reduced risk of a prescription break for every 10-day increase in the time from the first documented MOUD prescription to the onset of the COVID-19 pandemic (HR = 0.96, 95% CI = 0.92–0.99; p = 0.011).

Conclusions: While the data did not include complete treatment histories to determine who was new to MOUD treatment, the findings suggest that patients whose first documented MOUD prescription in the dataset was closer to the onset of the pandemic had a greater likelihood of experiencing retention challenges. This underscores the importance for clinics to establish comprehensive contingency plans for future emergencies to ensure uninterrupted MOUD treatment and support, particularly for individuals in the early stabilization phase of their recovery.

Related protocols: CTN-0102

Abstract:

Opioid use disorder (OUD) and opioid dependence lead to significant morbidity and mortality, yet treatment retention, crucial for the effectiveness of medications like buprenorphine-naloxone, remains unpredictable. Our objective was to determine the predictability of 6-month retention in buprenorphine-naloxone treatment using electronic health record (EHR) data from diverse clinical settings and to identify key predictors.

This retrospective observational study, supported by CTN-0136, developed and validated machine learning-based clinical risk prediction models using EHR data. Data were sourced from Stanford University’s healthcare system and Holmusk’s NeuroBlu database, reflecting a wide range of healthcare settings. The study analyzed 1800 Stanford and 7957 NeuroBlu treatment encounters from 2008 to 2023 and from 2003 to 2023, respectively.

Measurements: Predict continuous prescription of buprenorphine-naloxone for at least 6 months, without a gap of more than 30 days. The performance of machine learning prediction models was assessed by area under receiver operating characteristic (ROC-AUC) analysis as well as precision, recall and calibration. To further validate our approach’s clinical applicability, we conducted two secondary analyses: a time-to-event analysis on a single site to estimate the duration of buprenorphine-naloxone treatment continuity evaluated by the C-index and a comparative evaluation against predictions made by three human clinical experts.

Attrition rates at 6 months were 58% (NeuroBlu) and 61% (Stanford). Prediction models trained and internally validated on NeuroBlu data achieved ROC-AUCs up to 75.8 (95% confidence interval [CI]=73.6–78.0). Addiction medicine specialists’ predictions show a ROC-AUC of 67.8 (95% CI=50.4–85.2). Time-to-event analysis on Stanford data indicated a median treatment retention time of 65 days, with random survival forest model achieving an average C-index of 65.9. The top predictor of treatment retention identified included the diagnosis of opioid dependence.

Conclusions: US patients with opioid use disorder or opioid dependence treated with buprenorphine-naloxone prescriptions appear to have a high (~60%) treatment attrition by 6 months. Machine learning models trained on diverse electronic health record datasets appear to be able to predict treatment continuity with accuracy comparable to that of clinical experts.

Related protocols: CTN-0136

Abstract:

Although buprenorphine is an effective treatment for opioid use disorder (OUD), much remains to be understood about treatment non-response and methods for improving treatment retention. The addition of behavioral therapies to buprenorphine has not yielded consistent benefits for opioid outcomes, on average. However, several studies suggest that certain subgroups may benefit from the combination of buprenorphine and behavioral therapy, highlighting the potential for personalized approaches to treatment. Furthermore, little is known about whether behavioral therapies improve buprenorphine retention or non-opioid (e.g., functional) outcomes.

The objective of this project is to harmonize four previously conducted clinical trials, including three independent trials and one NIDA Clinical Trials network multi-site trial (CTN-0030), testing the addition of behavioral therapy to buprenorphine maintenance for OUD and to use this larger dataset to answer critical clinical questions about the role of behavioral therapy in this population. Study aims include identifying potential moderators of the effect of the addition of behavioral therapy and quantifying the effect of behavioral therapy on buprenorphine retention and functional outcomes.

Analyses will consider outcomes of weeks of opioid use, weeks of retention in buprenorphine treatment, and functional outcomes as measured by the Addiction Severity Index. Analyses will include an indicator for each study to account for heterogeneity of samples and design.

Conclusions: Results will help to inform clinical and research efforts to optimize the use of behavioral therapies in the treatment of OUD.

Related protocols: CTN-0030

Abstract:

Transition Age Youth (TAY), aged 18-25 years, face barriers to medication treatment for opioid use disorder (MOUD) resulting in lower retention. We evaluated OUD prevalence and MOUD receipt comparing TAY to adults aged 26 or older residing in rural settings.

Electronic Health Records (October 2019 – January 2021) for 36,762 patients across six primary care clinics involved in a large feasibility trial (CTN-0102) in US rural communities were analyzed. All clinics implemented a standardized intervention. Mixed effects logistic/linear regression estimated odds of OUD diagnosis among all patients; and among those with OUD, the odds of receiving MOUD and days prescribed MOUD during the 15-month study period, comparing age categories (TAY=18-25 years vs. adults 26 or older). Covariates included gender, race, ethnicity, mental health comorbidities, and insurance status.

OUD prevalence was 2.82% among TAY (n=3,122) and 3.24% among adults aged 26 or older (n=33,208). After adjusting for covariates and clustering, TAY had significantly lower odds of OUD diagnosis compared to adults 26 years or older (OR=0.58, 95% CI 0.45 to 0.73). There were no significant differences in MOUD receipt between age groups. Compared to adults 26 or older, TAY with OUD had significantly fewer MOUD days during the study, -43.81 days (-76.85 to -10.77).

Conclusions: While no differences were observed in MOUD prescription receipt between TAY and adults 26 or older, TAY with OUD had fewer total days prescribed MOUD indicating lower retention. Further research generalizable to rural communities is needed to assess retention among rural TAY with OUD.

Related protocols: CTN-0102

Abstract:

This is the outcomes article for CTN-0084-A-1.

Buprenorphine is an effective medication for opioid use disorder that reduces mortality; however, many patients are not retained in buprenorphine treatment, and an optimal length of treatment after which patients can safely discontinue treatment has not been identified. This study measured the association between buprenorphine treatment duration and all-cause mortality among patients who discontinued treatment. Secondary objectives were to measure the association between treatment duration and drug overdose and opioid-related overdoses.

This study use data from 8 US health systems participating in CTN-0084-A-1, focusing on patients who initiated and discontinued buprenorphine treatment between January 2012 and 31 December 2018 (n=6550). Outcomes occurring after patients discontinued buprenorphine treatment were compared between patients who initiated and discontinued treatment after 8–30, 31–90, 91–180, 181–365 and >365 days.

Covariate data were obtained from electronic health records (EHRs). Mortality outcomes were derived from EHRs and state vital statistics. Non-fatal opioid and drug overdoses were obtained from diagnostic codes. Four sites provided cause-of-death data to identify fatal drug and opioid-related overdoses. Adjusted frailty regression was conducted on a propensity-weighted cohort to assess associations between duration of the final treatment episode and outcomes.

The mortality rate after buprenorphine treatment was 1.82 per 100 person-years (n=191 deaths). In regression analyses with >365 days as the reference group, treatment duration was not associated with all-cause mortality and drug overdose (P>0.05 for both). However, compared with >365 days of treatment, 91–180 days of treatment was associated with increased opioid overdose risk (hazard ratio =2.94, 95% confidence interval=1.11–7.79).

Conclusions: Among patients who discontinue buprenorphine treatment, there appears to be no treatment duration period associated with a reduced risk for all-cause mortality. Patients who discontinue buprenorphine treatment after 91–180 days appear to be at heightened risk for opioid overdose compared with patients who discontinue after >365 days of treatment.

Related protocols: CTN-0084-A-1

Abstract:

Opioid use and opioid-related overdose continue to rise among racial/ethnic minorities. Social determinants of health negatively impact these communities, possibly resulting in poorer treatment outcomes. Research is needed to investigate how to overcome the disproportionate and deleterious impact of social determinants of health on treatment entry, retention, drug use and related outcomes among racial/ethnic minorities. The current commentary provides recommendations that may help researchers respond more effectively to reducing health disparities in substance use treatment.

In this commentary piece, the authors begin with recommendations of best research practices (e.g., ensuring adequate recruitment of racial/ethnic minorities in research, central components of valid analysis, and adequate methods for assessing effect sizes for racial/ethnic minorities). Then, they propose that more NIDA research focus on issues disproportionately affecting racial/ethnic minorities. Next, techniques for increasing the number of underrepresented racial/ethnic treatment researchers are suggested. The authors then recommend methods for infusing racial/ethnic expertise onto funding decision panels. The commentary ends with a case study that features NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN).

Conclusions: The proposed recommendations can serve as guidelines for substance use research funders to promote research that has the potential to reduce racial/ethnic disparities in substance use treatment and to increase training opportunities for racial/ethnic minority researchers.

Abstract:

This report examined naturalistic opioid use outcomes and utilization of medications for opioid use disorder (MOUD) 36 weeks post-randomization in the National Drug Abuse Treatment Clinical Trials Network (CTN) Extended-Release Naltrexone (XR-NTX) versus Buprenorphine-Naloxone (BUP-NX) for Opioid Treatment trial (CTN-0051, X:BOT).

X:BOT was a multisite, randomized, 24-week comparative effectiveness trial of BUP-NX (N=287) and XR-NTX (N=283). Study medications were discontinued following treatment completion, relapse, or dropout. Participants, adults with opioid use disorder (OUD) recruited from 8 community treatment programs acxross the U.S., were encouraged to continue medications for opioid use disorder (MOUD). This report examined opioid use outcomes in 428 (75%) of the 570 participants who attended the 36-week follow-up visit.

Outcomes included medication status (on/off MOUD), type of MOUD (BUP-NX, XR-NTX, or methadone), abstinence from non-prescribed opioids, opioid use days, relapse, and other substance use 30 days prior to the 36-week visit. Relapse was defined as opioid use for 4 consecutive weeks or 7 consecutive days in the past month. Baseline and clinical variables included opioid use severity, intravenous drug use, study medication assignment, and induction status.

Of the 428 participants who completed the 36-week visit, 225 (53%) of participants were receiving MOUD and 203 (47%) were not. Compared to those off medication, participants on medication had fewer opioid use days (4.4 days (SD 9.0) versus 9.8 days (SD 12.1), fewer met relapse criteria (37 (16.4%) versus 79 (38.9%)), and reported less stimulant use (34 (15.2%) versus 56 (27.7%)) and sedative use (14 (6.3%) versus 31 (15.3%)). There was no difference in abstinence rates between those on or off MOUD. A greater proportion of participants on XR-NTX (47 (53.4%) of 88 participants) were abstinent from non-prescribed opioids compared to those on buprenorphine (28 (23.3%) of 120 participants).

Conclusions: Naturalistic outcomes data showed that despite potential barriers to continuing treatment in the community, about half of individuals were on opioid use disorder pharmacotherapy at follow-up and those on medication generally had better outcomes. Future research should explore barriers and facilitators to treatment retention in community settings; and developing interventions tailored to improve treatment engagement and adherence.

Related protocols: CTN-0051

Abstract:

Opioid use disorder continues to be a significant problem in the United States and worldwide. Three medications — methadone, buprenorphine, and extended-release injectable naltrexone — are efficacious for treating opioid use disorder (OUD). However, the utility of these medications is limited, in part due to poor rates of retention in treatment. In addition, minimum recovery milestones and other factors that influence when and whether individuals can safely discontinue medications are unknown.

The National Drug Abuse Treatment Clinical Trials Network (CTN) study “Optimizing Retention, Duration and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy” (RDD, CTN-0100) will be among the largest clinical trials on treatment of OUD yet conducted, consisting of two phases: the Retention phase and the Duration-Discontinuation phase.

The Retention phase, open to patients initiating treatment, will test different doses and formulations of buprenorphine (standard dose sublingual, high dose sublingual, or extended-release injection), and a digital therapeutic app delivering contingency management and cognitive behavioral counseling on the primary outcome of retention in treatment.

The Discontinuation phase, open to patients in stable remission from OUD and choosing to discontinue medication (including participants from the Retention phase or from the population of patients treated at the clinical site, referred by an outside prescriber or self-referred) will study different tapering strategies for buprenorphine (sublingual taper vs taper with injection buprenorphine), and a digital therapeutic app which provides resources to promote recovery, on the primary outcome of relapse-free discontinuation of medication.

This paper describes how the RDD trial derives from two decades of research in the CTN. Initial trials (CTN-0001; CTN-0002; CTN-0003) focused on opioid detoxification, showing buprenorphine-naloxone was effective for detoxification, but that acute detoxification did not appear to be an effective treatment strategy. Trials on comparative effectiveness of medications for opioid use disorder (MOUD) (CTN-0027; CTN-0030; and CTN-0051) highlighted the problem of dropout from treatment and few trials defined retention on MOUD as the primary outcome. Long-term follow-up studies on those patient samples demonstrated the importance of long-term continuation of medication for many patients to sustain remission. Overall, these trials highlight the potential of a stable research infrastructure such as CTN to advance treatment effectiveness through a programmatic succession of large clinical trials.

Related protocols: CTN-0100

Abstract:

This is the outcomes paper for CTN-0051-A-1.

Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse.

This study aimed to determine whether gene variants in the opioid gene system are associated with better or worse treatment response.

In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the NIDA Clinical Trials Network (X:BOT protocol, CTN-0051), DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to each model outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction.

Analysis found no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions.

Conclusions: The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.

Related protocols: CTN-0051, CTN-0051-A-1

Abstract:

Few studies examine the effectiveness of treatments for opioid use disorder (OUD) among Black individuals despite recent evidence suggesting opioid overdose death rates are, in some cases, highest and increasing at a faster rate among Black people compared to other racial/ethnic groups. This secondary analysis study investigated treatment preference, retention, and relapse rates amongst a subgroup of 73 Black participants with OUD (81% male, mean age 39.05, SD=11.80) participating in a 24-week multisite randomized clinical trial (X:BOT, CTN-0051) comparing the effectiveness of extended-release naltrexone (XR-NTX) and sublingual buprenorphine-naloxone (BUP-NX) between 2014-2017.

Chi-square analyses were used to investigate treatment preference assessed at baseline, and logistic regression analyses were used to investigate differences in the odds of retention and relapse assessed over the 24-week course of treatment between treatment groups.

Findings suggest no differences in preference for XR-NTX versus BUP-NX. However, similar to the parent trial, there was an induction hurdle such that only 59.5% of those randomized to XR-NTX successfully initiated medication compared to 91.6% of those randomized to BUP-NX. No significant differences were found in treatment retention or relapse rates between treatment groups.

Conclusions: Although there is a significant initiation hurdle with XR-NTX, once inducted, both medications appear similar in effectiveness, but as in the main study, dropout rates were high. Future research is needed on how to improve adherence.

Related protocols: CTN-0051