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Abstract: Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual’s information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments’ benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments’ benefits vary as relevant circumstances evolve within an individual. The goal of this paper, part of CTN-0094 (Individual Level Predictive Modeling of Opioid Use Disorder Treatment Outcome), is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. The authors describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. They then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Conclusions: This analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy. Related protocols: CTN-0094

Abstract:

While polysubstance use has consistently been associated with higher rates of relapse, few studies have examined subgroups with specific combinations and time course of polysubstance use (i.e., polysubstance use patterns). This study aimed to classify and compare polysubstance use patterns and their associations with relapse to opioid use in 2637 participants in three large opioid use disorder (OUD) treatment trials in the NIDA Clinical Trials Network (CTN-0027, CTN-0030, and CTN-0051).

Researchers explored the daily patterns of self-reported substance use in the 28 days prior to treatment entry. Market basket analysis (MBA) and repeated measure latent class analysis (RMLCA) were used to examine the subgroups of polysubstance use patterns, and multiple logistic regression was used to examine associations between identified classes and relapse.

MBA and RMLCA identified 34 “associations rules” and 6 classes, respectively. Specific combinations of polysubstance use and time course (high baseline use and rapid decrease of use prior to initiation) predicts a worse relapse outcome. MBA showed individuals who co-used cocaine, heroin, prescription opioids, and cannabis had a higher risk for relapse (OR=2.82, 95%CI=1.13, 7.03). In RMLCA, higher risk of relapse was observed in individuals who presented with high baseline prescription opioid (OR = 1.9, 95% CI = 1.3, 2.76) or heroin use (OR = 3.54, 95%CI = 1.86, 6.72), although use decreased in both cases prior to treatment initiation.

Conclusions: Our analyses identified subgroups with distinct patterns of polysubstance use. Different patterns of polysubstance use differentially predict relapse outcomes. Interventions tailored to these individuals with specific polysubstance use patterns prior to treatment initiation may increase the effectiveness of relapse prevention.

Related protocols: CTN-0027, CTN-0030, CTN-0051

Abstract:

Although there is consensus that having a “high-enough” dose of buprenorphine (BUP-NX) or methadone is important for reducing relapse to opioid use, there is debate about what this dose is and how it should be attained. We estimated the extent to which different dosing strategies would affect risk of relapse over 12 weeks of treatment, separately for BUP-NX and methadone.

This was a secondary analysis of three comparative effectiveness trials (CTN-0027, CTN-0030, and CTN-0051). We examined four dosing strategies: 1) increasing dose in response to participant-specific opioid use, 2) increasing dose weekly until some minimum dose (16 mg BUP, 100 mg methadone) was reached, 3) increasing dose weekly until some minimum and increasing dose in response to opioid use thereafter (referred to as the “hybrid strategy”), and 4) keeping dose constant after the first 2 weeks of treatment. We used a longitudinal sequentially doubly robust estimator to estimate contrasts between dosing strategies on risk of relapse.

For BUP-NX, increasing dose following the hybrid strategy resulted in the lowest risk of relapse. For methadone, holding dose constant resulted in greatest risk of relapse; the other three strategies performed similarly. For example, the hybrid strategy reduced week 12 relapse risk by 13 % (RR: 0.87, 95 %CI: 0.83–0.95) and by 20 % (RR: 0.80, 95 %CI: 0.71–0.90) for BUP-NX and methadone respectively, as compared to holding dose constant.

Conclusions: Doses should be targeted toward minimum thresholds and, in the case of BUP-NX, raised when patients continue to use opioids.

Related protocols: CTN-0027, CTN-0030, CTN-0051

Abstract:

Exercise is a promising treatment for substance use disorders, yet an intention-to-treat analysis of a large, multi-site study found no reduction in stimulant use for exercise versus health education. Exercise adherence was sub-optimal, therefore secondary post-hoc complier average causal effects (CACE) analysis was conducted to determine the potential effectiveness of adequately dosed exercise.

The STimulant use Reduction Intervention using Dosed Exercise (STRIDE) study was a randomized controlled trial comparing a 12 kcal/kg/week (KKW) exercise dose versus a health education control conducted at 9 residential substance use treatment settings across the U.S. that are affiliated with the National Drug Abuse Treatment Clinical Trials Network. Participants were sedentary but medically approved for exercise, used stimulants within 30 days prior to study entry, and received a DSM-IV stimulant abuse or dependence diagnosis within the past year. A CACE analysis adjusted to include only participants with a minimum threshold of adherence (at least 8.3 KKW) and using a negative-binomial hurdle model focused on 218 participants who were 36.2% female, mean age 39.4 years (SD=11.1), and averaged 13 (SD=9.2) stimulant use days in the 30 days before residential treatment. The outcome was days of stimulant use as assessed by the self-report TimeLine Follow Back and urine drug screen results.

The CACE-adjusted analysis found a significantly lower probability of relapse to stimulant use in the exercise group versus the health education group (41% vs. 55.7%, p<.01) and significantly lower days of stimulant use among those who relapsed (5 days vs. 9.9 days, p<.01).

Conclusions: The CACE efficacy analysis was conducted for the STRIDE study to account for exercise dose in the evaluation of exercise as a potential treatment for stimulant use disorders. This analysis demonstrated statistically significant differences for the probability of stimulant use, such that those who would achieve an adequate exercise dose (defined to be an average of 8.3 KKW or more) have an estimated lower probability of relapsing to any stimulant use. Analyses also demonstrated that, even among those who relapsed, the amount of estimated stimulant use was significantly less among those who would achieve an adequate exercise dose. Together, these results suggest a beneficial effect of exercise in the treatment of stimulant abuse. Further research is warranted to develop strategies for exercise adherence that can ensure achievement of an exercise dose sufficient to produce a significant treatment effect.

Related protocols: CTN-0037

Abstract:

This is the primary outcomes article for CTN-0051.

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. This study in the NIDA Clinical Trials Network (CTN-0051) aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.

This 24-week, open-label, randomized controlled, comparative effectiveness trial was initiated at eight U.S. community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had opioid use disorder as defined by the DSM-5, and had used non-prescribed opioids in the past 30 days. Participants were stratified by treatment site and opioid use severity and a web-based permuted block design was used with random equally weighted block sizes of 4 and 6 for randomization (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 outcomes 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.

Between January 30, 2014 and May 25, 2016, 570 participants were randomly assigned to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was January 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283; p<0.0001) than BUP-NX (270 [94%] of 287). 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) favored 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 (2 in the XR-NTX group and 3 in the BUP-NX group).

Conclusions: In this population, it is more difficult to initiate patients to XR-NTX than to 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.

Related protocols: CTN-0051

Abstract:

For opioid-dependent patients in the U.S. and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies.

The National Institute on Drug Abuse’s Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX.

The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness.

Conclusions: XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study deicing choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed.

Related protocols: CTN-0051

Abstract:

This presentation reports on a National Drug Abuse Treatment Clinical Trials Network (CTN) study that aimed to evaluate the potential efficacy of buspirone as a relapse-prevention treatment for cocaine dependence (CTN-0052). This randomized, double-blind, placebo-controlled, 16-week pilot trials was conducted at 6 clinical sites. Adults meeting DSM-IV-TR criteria for current cocaine dependence scheduled to be in inpatient/residential substance use disorder (SUD) treatment for 12-19 days when randomized, and planning to enroll in local outpatient treatment through the end of the active treatment phase, were randomized to buspirone titrated to 60 mg/day (n=35) or to placebo (n=27). All participants received psychosocial treatment as usually provided by the SUD treatment programs in which they were enrolled. Outcome measures included maximum days of continuous cocaine abstinence (primary), proportion of cocaine use days, and days-to-first-cocaine-use during the outpatient treatment phase (study weeks 4-15) as assessed by self-report and urine drug screens.

Study retention was high, with a 94% completion rate, and medication adherence was also strong (85% based on medication events monitoring system). However, there were no significant treatment effects on maximum continuous days of cocaine abstinence or days to first cocaine use. Additionally, buspirone, relative to placebo, actually increased the proportion of cocaine use days in female participants, though not in males.

Conclusions: These results suggest that buspirone is unlikely to have a beneficial effect on preventing relapse to cocaine use and may even worsen cocaine use outcomes for women.

Related protocols: CTN-0052

Abstract:

This is the primary outcomes article for CTN-0052.

The purpose of this study, “A Randomized Controlled Evaluation of Buspirone for Relapse-Prevention in Adults with Cocaine Dependence (BRAC),” was to evaluate the potential efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. This randomized, double-blind, placebo-controlled, 16-week pilot trial was conducted at 6 clinical sites between August 2012 and June 2013. Adult crack cocaine users meeting DSM-IV-TR criteria for current cocaine dependence who were scheduled to be in inpatient/residential substance use disorder (SUD) treatment for 12-19 days when randomized and planning to enroll in local outpatient treatment through the end of the active treatment phase were randomized to buspirone titrated to 60 mg/d (n=35) or placebo (n=27). All participants received psychosocial treatment as usually provided by the SUD treatment programs in which they were enrolled. Outcome measures included maximum days of continuous cocaine abstinence (primary), proportion of cocaine use days, and days to first cocaine use during the outpatient treatment phase (study weeks 4-15) as assessed by self-report and urine drug screens. There were no significant treatment effects on maximum continuous days of cocaine abstinence or days to first cocaine use. In the female participants (n=23), there was a significant treatment-by-time interaction effect, reflecting an increase in cocaine use by those receiving buspirone, relative to placebo, early in the outpatient treatment phase. A similar effect was not detected in the male participants (n=39).

Conclusions: These results suggest that buspirone is unlikely to have a beneficial effect on preventing relapse to cocaine use and that buspirone for cocaine-dependent women may, in fact, worsen their cocaine use outcomes. The results from this pilot trial do not provide a strong rationale for conducting a larger follow-up trial as originally planned.

Related protocols: CTN-0052

Abstract:

This secondary analysis of data from the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0015 (“Women’s Treatment for Trauma and Substance Use Disorders”) examined the associations between post-traumatic stress disorder (PTSD) symptoms, stimulant use, and treatment outcomes among dually diagnosed women. Participants were 141 women who participated in the original multisite clinical trial of group treatments for PTSD and addictions. Generalized linear models indicated Seeking Safety (SS, a cognitive-behavioral intervention) was significantly more effective than Women’s Health Education (WHE, a control group intervention) in reducing stimulant use at follow-up among women who were heavy stimulant users at pre-treatment and who showed improvements in PTSD symptoms. There were no significant differences between the interventions among women who were light stimulant users at treatment entry.

Conclusions: These findings add to the growing body of literature on the functional relationship between traumatic stress responses and substance use. Findings suggest that, among heavy stimulant users, integrated treatments that lead to PTSD symptom reductions can in turn improve stimulant use outcomes. This supports treatment models that address PTSD concurrently with substance use disorder treatment.

Related protocols: CTN-0015

Abstract:

The Recovery Management paradigm provides a conceptual framework for the examination of joint impact of a focal treatment and post-treatment service utilization on substance abuse treatment outcomes. This study tested this framework by examining the interactive effects of a treatment for comorbid PTSD and substance use, Seeking Safety, and post-treatment Twelve-Step Affiliation (TSA) on alcohol and cocaine use. Data from 363 women in a six-site, randomized controlled effectiveness trial within the National Drug Abuse Treatment Clinical Trials Network (CTN-0015, “Women’s Treatment for Trauma and Substance Use Disorders”) were analyzed under latent class pattern mixture modeling. LCPMM was used to model variation in Seeking Safety by TSA interaction effects on alcohol and cocaine use. Significant reductions in alcohol use among women in Seeking Safety (compared to health education) were observed; women in the Seeking Safety condition who followed up with TSA had the greatest reductions over time in alcohol use. Reductions in cocaine use over time were also observed but did not differ between treatment conditions nor were there interactions with post-treatment TSA.

Conclusions: This study extends current knowledge on treating conditions with a high risk for relapse, such as PTSD and comorbid SUDs, and the adjunctive benefits of TSA for extending treatment effects. Findings underscore the importance of maintaining an ongoing connection to some form of recovery services and the need for continued social support, particularly among a population of women who are most vulnerable, and, more specifically, suggest that providers may consider the use of TSA in combination with Seeking Safety to promote potential synergistic effects.

Related protocols: CTN-0015

Abstract:

This 90-minute webinar, produced by the National Drug Abuse Treatment Clinical Trials Network (CTN) Clinical Coordinating Center for CTN members and the public, promotes positive outcomes for providers and patients working through difficult psychiatric disorders. Patients with DSM-IV defined personality disorders have the highest rates of co-morbid substance use disorders. Recovery from addiction is very difficult for patients with antisocial and borderline features due to the affective dysregulation and impulsiveness that are part of these Axis II conditions. This webinar focuses on the elements of treatment associated with evidence-based treatments (e.g. motivational interviewing, dialectical behavior therapy, relapse prevention therapy, 12-step facilitation therapy) that can be integrated to decrease the risk for relapse among patients with personality disorders.

The target audience includes research/clinical counselors and staff both in the CTN and in the general public.

Presented by Thomas Kelly, PhD, and Dennis Daley, PhD (Western Psychiatric Institute and Clinic, U Pittsburgh).

Additional Resources:

• Download slides (pdf)

Abstract:

This 90-minute webinar, produced by the National Drug Abuse Treatment Clinical Trials Network (CTN) Clinical Coordinating Center for CTN members and the public, explores the issue of relapse among individuals with substance use disorders (SUD). Outcome studies, types and effects of lapse and relapse, and factors contributing to relapse are reviewed. A major emphasis of the webinar is on discussing specific clinical strategies to reduce relapse risk, with a focus on current empirical and clinical literature, including findings from quality improvement studies and clinical trials conducted in a drug treatment clinic.

The target audience is CTN members and other researchers and clinicians interested in learning more about relapse prevention.

Presented by Dennis Daley, PhD, LSW (Western Psychiatric Institute and Clinic, AT Node) and Dennis M. Donovan, PhD (Alcohol & Drug Abuse Institute, University of Washington, PN Node).

Additional Resources:

• View workbook (pdf)
• Download slides (pdf)