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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:

Psychosocial support is recommended in conjunction with medication for opioid use disorder (MOUD), although optimal “dose,” modality, and timing of participation is not established. This study used data from CTN-0051 to examine counseling and 12-Step attendance and subsequent opioid use in a MOUD randomized clinical trial.

The parent study randomly assigned 570 participants to receive buprenorphine-naloxone (BUP-NX, n=287) or extended-release injectable naltrexone (XR-NTX, n=283). Mixed-effects logistic regression models were fit with opioid use as the response variable, and a counseling/12-Step attendance predictor. Differences by treatment assignment were examined.

Any counseling or 12-Step attendance was associated with reduced odds of opioid use at the subsequent visit, whether considered individually or aggregated across type. A continuous relationship was observed for 12-Step attendance (F(1,5083)=5.01, p=.025); with each additional hour associated with 13% (95% CI: 0.83, 0.90) reduction in odds of opioid use. The strength of this association grew over time. In the BUP-NX arm, group counseling was associated with a greater reduction in odds of opioid use than for XR-NTX, (OR=0.32 (95% CI: .22, 0.48) vs. OR=0.69 (95% CI: 0.43, 1.08)). For XR-NTX, 12-Step was associated with a greater reduction in odds of opioid use (OR=0.35 (95% CI: 0.22, 0.54) vs. OR=0.65 (95% CI: 0.47, 0.89) for BUP-NX)).

Conclusions: Psychosocial engagement has a proximal association with opioid use and the strength of that association may grow with dose and time. Alternatively, more motivated individuals may both attend more counseling/12-Step and have better treatment outcomes, or the relationship may be reciprocal. While the results of the present study suggest that when it comes to psychosocial support, “more is better,” the present findings also suggest that “any is better than none.” Future research could expand upon the present study by examining the contributions of different psychosocial treatment modalities to opioid use and relapse.

Related protocols: 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:

Better understanding of predictors of opioid abstinence among patients with opioid use disorder (OUD) may help to inform interventions and personalize treatment plans. This analysis examined patient characteristics associated with opioid abstinence in the X:BOT (Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment) trial (CTN-0051).

This post-hoc analysis examined factors associated with past-month opioid abstinence at the 36-week follow-up visit among participants in the X:BOT study. 428 participants (75% of original sample) attended the visit at 36 weeks. Logistic regression models were used to estimate the probability of opioid abstinence across various baseline sociodemographics, clinical characteristics, and treatment variables.

Of the 428 participants, 143 (33%) reported abstinence from non-prescribed opioids at the 36-week follow-up. Participants were more likely to be opioid abstinent if randomized to XR-NTX (compared to BUP-NX), were on XR-NTX at week 36 (compared to those off OUD pharmacotherapy), successfully inducted onto either study medication, had longer time on study medication, reported a greater number of abstinent weeks, or had longer time to relapse during the 24-week treatment trial. Participants were less likely to be abstinent if Hispanic, had a severe baseline Hamilton Depression Rating (HAM-D) score, or had baseline sedative use.

Conclusions: A substantial proportion of participants was available at follow-up (75%), was on OUD pharmacotherapy (53%), and reported past-month opioid abstinence (33%) at 36 weeks. A minority of patients off medication for OUD reported abstinence and additional research is needed exploring patient characteristics that may be associated with successful treatment outcomes.

Related protocols: CTN-0051

Abstract:

The concept of “deaths of despair” (suicide, overdose, and alcohol-related liver disease) highlights the importance of detecting and understanding the course of co-occurring depression in patients with opioid use disorder (OUD). To that end, this study examined the prevalence of depression (assessed with the Hamilton Depression Rating Scale [HDRS]) at baseline and after 4 weeks of treatment, as well as the association between depression and relapse to opioid use, using data from CTN-0051, a 24-week trial of 570 patients with OUD randomized to buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX).

Among 473 patients who initiated medication, 14.2% (67/473) had moderate/severe depression (HDRS ≥ 17) and 34.9% (165/473) had mild depression (8 ≤ HDRS ≤ 16) at baseline. Patients with moderate/severe depression had more frequent histories of anxiety disorders and suicidal ideation. After 4 weeks of treatment, approximately two-thirds of participants with depression either responded (HDRS reduced ≥ 50% from baseline) ore remitted (HDRS ≤ 7), with no significant differences between medication treatment groups. Those with moderate/severe depression were less likely to remit (52.8%; 28/53) compared to those with mild depression (76%; 98/129) at week 4 (OR=0.43, 95% CI=0.21-0.89, P=0.02). Further, those who remitted at week 4 had lower, but not significantly different, risk of relapse to opioids compared to those who did not remit (OR=0.55, 95% CL=0.28-1.08, P=0.08).

Conclusions: Depression is common among patients with OUD and often remits after initiation of BUP-NX or XR-NTX, although when it does not remit it may be associated with worse opioid use outcomes. Depression should be screened and followed during initiation of treatment and, when it does not remit, specific depression treatment should be considered.

Related protocols: CTN-0051

Abstract:

Methamphetamine use is increasing among persons with opioid use disorder (OUD). The study aims were to describe methamphetamine/amphetamine (MA/A) use among patients treated for OUS with buprenorphine/naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and to explore associations between treatment arm and MA/A use.

The study used data from the CTN X:BOX trial (CTN-0059), a multi-site, open-label, randomized controlled trial of XR-NTX vs. BUP-NX for 24 weeks. The outcome variable was MA/A use defined by either positive urine drug toxicology or self-report. The main predictor was treatment assignment (BUP-NX vs. XR-NTX). Longitudinal mixed-effects logistic regression models were fit to model the odds of MA/A use during the study. Additional predictors included study visit and baseline MA/A use.

Among the sample of 570 participants with OUD, baseline use of MA/A was observed in 105 (18.4%). There was no significant treatment effect over the study period, though BUP-NX subjects, on average, had about half the odds of MA/A use compared to XR-NTX subjects. In the same model, baseline MA/A use and study visit were both significantly associated with MA/A use over time.

Conclusions: In this sample of treated OUD patients, nearly a fifth (18.4%) of participants had MA/A use at baseline and the frequency of use did not decline over time: in fact, the odds of use slightly increased for each later visit. These secondary analyses found no significant difference in MA/A use between BUP-NX and XR-NTX treatment arms, however, the observation of less MA/A in the buprenorphine arm merits further investigation.

Related protocols: CTN-0051

Abstract:

This paper illustrates survival models for analysis of trials of substance use treatment programs. It uses public release data from a study of extended-release naltrexone (XR-NTX), relative to buprenorphine-naloxone (BUP-NX), the CTN-0051 (X:BOT) study. X:BOT compared XR-NTX to BUP-NX on 2 efficacy outcomes (opioid relapse, use of nonprescribed opioids; positive opioid urine test) and 1 safety outcome (overdose). Intention-to-treat (ITT) and per-protocol approaches were implemented using surviving models that included treatment-by-time interactions.

Consistent with original trial findings, 72% of XR-NTX and 94% of BUP-NX subjects initiated treatment: the ITT hazard ratio for XR-NTX relative to BUP-NX was 1.4 for opioid relapse and 1.31 for positive urine test. Using treatment-by-time interactions, researchers examined the time-dependent effect of XR-NTX and found an elevated ITT overdose hazard ratio of 2.4 overall and 3.8 during the study treatment phase. This result (28 overdoses overall; 17 during the study treatment phase) contrasts with previous analysis, which reported minimal differences in overdose between XR-NTX and BUP-NX.

Conclusions: An advantage of using time-dependent Cox models is its ability to isolate effects during specific periods. In general, our survival analyses concur with the conclusions of Lee et al (2018) for the efficacy outcomes, which demonstrated superiority of BUP-NX. In contrast to the original report, this analysis indicates a greater risk of overdose for XR-NTX, dominantly during the study treatment phase. Further investigation of this finding is a pressing research priority.

Related protocols: CTN-0051

Abstract:

The objective of this study was to further the precision medicine goal of tailoring medical treatment to individual patient characteristics by providing a method of analysis of the effect of test treatment, T, compared to a reference treatment, R, in participants in a RCT who are likely responders to T.

Likely responders to T are individuals whose expected response at baseline exceeds a prespecified minimum. A prognostic score, the expected response predicted as a function of baseline covariates, is obtained at trial completion. It is a balancing score that can be used to match likely responders randomized to T with those randomized to R; the result is comparable treatment groups that have a common covariance distribution. Treatments are compared based on observed outcomes in this enriched sample. The approach is illustrated in a RCT comparing two treatments for opioid use disorder: CTN-0051, the X:BOT trial.

A standard statistical analysis of the X:BOT data found no treatment difference in the total sample. However, a subset of likely responders to T were identified and in this group, T was statistically superior to R.

Conclusions: The causal treatment effect of T relative to R among likely responders may be more important than the effect in the whole target population. The prognostic score function provides quantitative information to support patient specific treatment decisions regarding T furthering the goal of precision medicine.

Related protocols: CTN-0051

Abstract:

Opioid use disorder (OUD) and chronic pain frequently co-occur. Little is known about change in pain during buprenorphine/naloxone (BUP/NX) maintenance and whether outcomes vary by pain levels. The present study examined changes in pain intensity and pain interference over 12 weeks of BUP/NX maintenance among participants with OUD and chronic pain (N=194). Differences in outcomes were assessed during BUP/NX maintenance (Week 12) and 2 months following a BUP/NX taper (Week 24). Data from Phase 2 of the CTN Prescription Opioid Addiction Treatment Study (POATS, CTN-0030) were used. Two latent transition models were conducted to characterize profiles and transitions between profiles of pain intensity or pain interference (estimated separately). Each model identified a high and low profile. In the pain interference model, the majority were classified in the low profile at baseline. In the pain intensity model, the majority were classified in the high profile at baseline. In both models, patients were more likely to remain in or transition to the low profiles by Week 12. Worse depression was associated with membership in the high pain interference profile at both timepoints. Women were more likely to be in the high pain intensity profile at baseline. Those in the high intensity and high pain interference profiles at Week 12 reported worse mental health quality of life (MH-QOL) at Week 12, as well as high pain intensity and high pain interference at Week 24.

Conclusions: For a subgroup of patients, high pain intensity and high pain interference remains unchanged during BUP/NX maintenance treatment.

Related protocols: CTN-0030

Abstract:

The aim of this secondary analysis of CTN-0048 was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP).

Cocaine-dependent participants (N=302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines.

In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P=0.0021). The interactions of genetic variant x treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N=35) had fewer cocaine-positive urines (P=0.0006) than did the PLB group (N=26) and in the rs1997794 A-allele carrier group where the BUP16 group (N=49) had fewer cocaine-positive urines (P=0.0003) than did the PLB group (N=58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response.

Conclusions: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

Related protocols: CTN-0048

Abstract:

Recent studies indicate that sex-based differences exist in co-occurring psychiatric symptoms and disorders among individuals with opioid use disorders (OUD). Whether these associations are present in adolescent samples and change during OUD treatment is poorly understood.

In this study, researchers examined sex-based differences in psychiatric symptoms and relationships among sex, psychiatric symptoms, and opioid use outcomes in youth with OUD receiving buprenorphine/naloxone (Bup/Nal) and psychosocial treatment.

The study randomly assigned 152 youth (15-21 years old) diagnosed with OUD to either 12 weeks of treatment with Bup/Nal or up to 2 weeks of Bup/Nal detoxification with both treatment arms receiving weekly drug counseling as part of a multisite clinical trial (CTN-0010). Researchers compared psychiatric symptoms, assessed via the Youth Self Report (YSR) at baseline and week 12, across male and female OUD participants. The study used logistic regression models to identify sex and psychiatric symptom variables that were predictors of opioid positive urine (OPU) at week 12.

Compared to males, females with OUD had higher mean psychiatric symptom scores at baseline across broad-band and narrow-band symptom domains. The study observed significant reductions in psychiatric symptoms scores in both males and females during treatment, and by week 12, females only differed from males on anxious-depressive symptom scores. Females, in general, and youth of both sexes presenting to treatment with higher anxious depression scores were less likely to have a week-12 OPU.

Conclusions: Clinically significant sex-based differences in psychiatric symptoms are present at baseline among youth with OUD receiving Bup/Nal-assisted treatment and mostly resolve during treatment.

Related protocols: CTN-0010

Abstract:

Evidence-based interventions for treating opioid use disorder (OUD) in youth are limited and little is known about specific and general mechanisms of OUD treatments and how they promote abstinence. This study used data from the CTN-0010 trial to evaluate the mediating effects of psychosocial treatment-related variables (therapy dose and therapeutic alliance) on end-of-treatment opioid abstinence in a sample of youth with OUD (n=152, 40% female, mean age=19.7 years) randomized to receive either 12 weeks of treatment with Bup/Nal (“Bup-Nal”) or up to 2 weeks of Bup/Nal detoxification (“Detox”) with both treatment arms receiving weekly individual and group drug counseling +/- family therapy.

Participants in the Bup-Nal group attended more therapy sessions (16 vs 6 sessions), had increased therapeutic alliance at week 4, and had less opioid use by week 12 compared to those in the Detox group. In both treatment arms, youth who attended more therapy sessions were less likely to have a week 12 opioid positive urine. In a multiple mediator model, therapy dose mediated the association between treatment arm and opioid abstinence.

Conclusions: These findings provide preliminary support for a “dose-response” effect of addiction-focused therapy on abstinence in youth OUD. Further, the results identified a mediating effect of therapy dose on the relationship between treatment assignment and opioid treatment outcomes, suggesting that extended Bup-Nal treatment may enhance abstinence, in part, through a mechanism of therapy facilitation, by increasing therapy dose during treatment.

Related protocols: CTN-0010

Abstract:

Dynamic, adaptive pharmacologic treatment for opioid use disorder (OUD) has been previously recommended over static dosing to prevent relapse, and is aligned with personalized medicine. However, there has been no quantitative evidence demonstrating its advantage. The objective of this study was to estimate the extent to which a hypothetical intervention that increased buprenorphine dose in response to opioid use would affect risk of relapse over 24 weeks of follow-up.

Researchers used data from the buprenorphine arm of CTN-0051 (X:BOT), an open-label randomized controlled 24-week comparative effectiveness trial conducted in 8 community addiction treatment programs in the U.S. 270 participants were included, all of whom were English speaking adults with DSM-5 OUD. Participants were mainly white (65%) and male (72%). In the X:BOT trial, they were treated with daily sublingual buprenorphine-naloxone (BUP-NX), with dose based on clinical indication, determined by the provider. Researchers examined a hypothetical intervention of increasing dose in response to opioid use.

Outcome was relapse to regular opioid use during the 24 weeks of outpatient treatment, assessed in a survival framework. Researchers estimated the relapse-free survival curves of participants under a hypothetical (i.e. counterfactual) intervention in which their BUP-NX dosage would be increased following their own subject-specific opioid use during the first 12 weeks of treatment versus a hypothetical intervention in which dose would remain constant.

After analysis, researchers estimated that increasing BUP-NX dose in response to recent opioid use would lower risk of relapse by 19.17 percentage points and 32%. The number-needed-to-treat with this intervention to prevent a single relapse is 6.

Conclusions: In people with opioid use disorder, a hypothetical intervention that increases sublingual buprenorphine-naloxone dose in response to opioid use during the first 12 weeks of treatment appears to reduce the risk of relapse over 24 weeks, compared with holding the dose constant after week 2.

Related protocols: CTN-0051

Abstract:

The randomized X:BOT trial (CTN-0051) showed that following induction, sublingual agonist (buprenorphine-naloxone, BUP-NX) or antagonist injection (extended release naltrexone, XR-NTX) produced similar benefits for reducing opioid relapse in injection users with opioid use disorder. Given that XR-NTX reduces drinking in alcohol use disorder (AUD), researchers completed a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine if XR-NTX (n=204) was superior to BUP-NX (n=270) to reduce drinking or heavy drinking in patients with opioid use disorder.

Researchers examined timeline follow-back recorded standard drink units consumed and used mixed-models regression to analyze monthly frequencies of any drinking or heavy drinking over 6 months of treatment and proportional hazard survival examined time to first drink.

Both treatment groups reduced drinking from baseline to post-treatment (small to medium effect), but no differences between groups were detected. However, only 29% (n=136) of the sample had AUD and 19% (n=26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included n=136 with an AUD diagnosis plus n=43 who did not have AUD, but reported at least one day of heavy drinking prior to study. Even so, this subsample still reported only 32% of days of any drinking with a median of only 13% of days designated as “heavy”. Within this subsample, the BUP-NX group reported greater mean drinks per drinking day than did the XR-NTX group at baseline (p=0.03); however, there were no other significant group differences in drinking observed before, during, or at the end of treatment.

Conclusions: An overall improvement in drinking occurred for treatment of OUD using both agonist and antagonist approaches indicating that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for opioid use disorder.

Related protocols: CTN-0051

Abstract:

This study aimed to evaluate the longitudinal treatment effect on depression measured by Hamilton Depression Rating Scale (HAM-D) score in a randomized clinical trial for the treatment of opioid use disorder (OUD). The authors conducted a secondary data analysis of data from the National Institute on Drug Abuse’s Clinical Trials Network protocol CTN-0051. Patients with OUD (N=570) were randomized to receive buprenorphine/naloxone (BUP-NX, n=287) or extended-release naltrexone injection (XR-NTX, n=283). The HAM-D score was completed at baseline and follow-up visit up to 36 weeks. A linear mixed model analysis was performed for log transformed HAM-D score and the generalized linear mixed model analysis was conducted for depression status.

Compared with BUP-NX, subjects randomized to XR-NTX had higher HAM-D scores at weeks 1 and 3 (p<0.05). There were significant interactions between treatment and visit on HAM-D score and depression status during the first four weeks of treatments in individuals without lifetime major depressive disorder (MDD). Past year cocaine use was associated with HAM-D score and depression status just in individuals without MDD, whereas past year cannabis use was associated with HAM-D score and depression status just in individuals with MDD. Past year amphetamine use was associated with HAM-D score just in individuals without MDD, however, lifetime anxiety was associated with HAM-D scores regardless of MDD.

Conclusion: When prescribing XR-NTX, particularly in the first month of treatment, it is essential to monitor for depressive symptoms. Screening for depression and multiple substance uses may help clinicians identify appropriate treatment.

Related protocols: CTN-0051