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Abstract: No existing model allows clinicians to predict whether patients might return to opioid use in the early stages of treatment for opioid use disorder. The goal of this study was to develop an individual-level prediction tool for risk of return to use in opioid use disorder. This decision analytical model (CTN-0094) used predictive modeling with individual-level data harmonized in June 1, 2019, to October 1, 2022, from 3 multicenter, pragmatic, randomized clinical trials of at least 12 weeks’ duration within the National Institute on Drug Abuse Clinical Trials Network (CTN) performed between 2006 and 2016 (CTN-0027 [START], CTN-0030 [POATS], and CTN-0051 [X:BOT]). The clinical trials covered a variety of treatment settings, including federally licensed treatment sites, physician practices, and inpatient treatment facilities. All 3 trials enrolled adult participants older than 18 years, with broad pragmatic inclusion and few exclusion criteria except for major medical and unstable psychiatric comorbidities. All participants received 1 of 3 medications for opioid use disorder: methadone, buprenorphine, or extended-release naltrexone. Predictive models were developed for return to use, which was defined as 4 consecutive weeks of urine drug screen (UDS) results either missing or positive for nonprescribed opioids by week 12 of treatment. The overall sample included 2199 trial participants (mean [SD] age, 35.3 [10.7] years; 728 women [33.1%] and 1471 men [66.9%]). The final model based on 4 predictors at treatment entry (heroin use days, morphine- and cocaine-positive UDS results, and heroin injection in the past 30 days) yielded an area under the receiver operating characteristic curve (AUROC) of 0.67 (95% CI, 0.62-0.71). Adding UDS in the first 3 treatment weeks improved model performance (AUROC, 0.82; 95% CI, 0.78-0.85). A simplified score (CTN-0094 OUD Return-to-Use Risk Score) provided good clinical risk stratification wherein patients with weekly opioid-negative UDS results in the 3 weeks after treatment initiation had a 13% risk of return to use compared with 85% for those with 3 weeks of opioid-positive or missing UDS results (AUROC, 0.80; 95% CI, 0.76-0.84). Conclusions: The prediction model described in this study may be a universal risk measure for return to opioid use by treatment week 3. Interventions to prevent return to regular use should focus on this critical early treatment period. Related protocols: CTN-0027, CTN-0030, CTN-0051, CTN-0094

Abstract:

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

Abstract:

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

Abstract:

Relapse rates during opioid use disorder (OUD) treatment remain unacceptably high. It is possible that optimally matching patients with medication type would reduce risk of relapse. This study’s objective was to learn a rule by which to assign type of medication for OUD to reduce risk of relapse and to estimate the extent to which risk of relapse would be reduced if such a rule were used.

This was a secondary analysis of CTN-0051 (X:BOT), an open-label randomized controlled, 24 week comparative effectiveness trial of injection extended-release naltrexone (XR-NTX) delivered approximately every 28 days, or daily sublingual buprenorphine-naloxone (BUP-NX) for treating OUD, 2014-2017 (N=570). Outcome was a binary indicator of relapse to regular opioid use during the 24 weeks of outpatient treatment.

Analysis found that applying an estimated individualized treatment rule — i.e., a rule that assigns patients with OUD to either XR-NTX or BUP-NX based on their individual characteristics in such a way that risk of relapse is minimized — would reduce risk of relapse by 24 weeks by 12% compared to randomly assigned treatment.

Conclusions: The number-needed-to-treat with the estimated treatment rule to prevent a single relapse is 14. A simpler, alternative estimated rule in which homeless participants would be treated with XR-NTX and stably housed participants would be treated with BUP-NX performed similarly. These results provide an estimate of the amount by which a relatively simple change in clinical practice could be expected to improve prevention of OUD relapse.

Related protocols: CTN-0051

Abstract:

There are a wide variety of methods for using combustible cannabis which may impact an individual’s pattern of use as well as their response to cannabis use disorder (CUD) treatment. Previous research has noted racial/ethnic differences in cannabis users’ preferred method of use.

This study examined data from a randomized placebo-controlled trial of a pharmacological intervention for adults with CUD (CTN-0053). Latent profile analysis classified participants (N=302) based on their primary method of combustible cannabis use.

A four profile solution emerged that identified participants who demonstrated 1) Primarily Joint (n=50), 2) Primary Blunt (n=106), 3) Mixed Method of Use (MoU; n=30), and 4) Primarily Pipe (i.e. pipe or bong; n=116) use. Profiles were compared on socio-demographic characteristics and racial differences were found among the four latent profiles as well as differences in their level of use. Cannabis users with a preference for joints were more likely to be White as compared to other racial groups. In contrast, a greater proportion of participants with a preference for blunts were African American. The Primarily Joint profile was found to have the highest cannabis relapse rate at 1-month follow-up (94%) which was significantly greater than the Mixed MoU (74%) and Primarily Pipe (78%) profiles. Interestingly, there was no difference in 1-month follow-up cannabis relapse rates between the Primarily Joint and Primarily Blunt profiles (87%).

Conclusions: Findings suggest that treatment-seeking individuals who primarily use joints or blunts may face unique challenges that may impact cannabis abstinence. Along with other cannabis-related characteristics, an individual’s preferred method of use may represent an important factor to consider in the treatment of CUD.

Related protocols: CTN-0053

Abstract:

The effectiveness of treatment incorporating relapse prevention medications for opioid use disorder (OUD) is typically examined in research using rigidly predefined endpoints of success versus failure, usually over a single episode of care. But this perspective may not adequately portray the nonlinear trajectories typical of real-world treatment courses in this chronic, remitting, and relapsing disorder.

This descriptive study examined 12-month treatment trajectories of 60 patients enrolled at a single site of a larger multisite randomized controlled trial examining the comparative effectiveness of buprenorphine versus extended-release naltrexone (CTN -0051, X:BOT). While the parent study provided medication treatment through the research protocol for 6 months, this study documents treatment up to 12 months, including medications, provided through standard community resources (treatment as usual) outside of the protocol.

Analysis found that some patients continued medications past the end of the study intervention, while others did not. Some patients initiated medications other than the one assigned by the study. Some patients switched from 1 medication to the other. Many patients returned to treatment after 1 or more periods of dropout and/or relapse. Patients utilized multiple episodes of bed-based care, including short-term acute residential and long-term residential treatment, and also recovery housing supports. At 12 months, while rates of continuous treatment retention were low (8%), rates of cross-sectional treatment engagement including return to treatment after drop-out were higher (35%).

Conclusions: Nonlinear trajectories are typical of treatment as usual, including multiple episodes of treatment and utilization of various support services across a continuum of care and across different providers. This description of nonlinear treatment trajectories highlights the potential benefits of flexibility and optimism in the promotion of re-engagement, despite interim outcomes that might traditionally be considered “failure” endpoints.

Related protocols: CTN-0051

Abstract:

Relapse is common in treatment for opioid use disorders (OUD). Pain and depression often co-occur during OUD treatment, but little is known about how they influence relapse among patients with a primary diagnosis of prescription opioid use disorder (POUD). Advanced statistical analyses that can simultaneously model these two conditions may lead to targeted clinical interventions.

The objective of this study was to utilize a discrete survival analysis with a growth mixture model to test time to prescription opioid relapse, predicted by parallel growth trajectories of depression and pain, in a clinical sample of patients in buprenorphine/naloxone treatment. The latent class analysis characterized heterogeneity with data collected from the NIDA Clinical Trials Network protocol CTN-0030 (Prescription Opioid Addiction Treatment Study, which compared buprenorphine/naloxone with standard medical management).

Results suggested a 4-class solution was the most conservative based on global fit indices and clinical relevance. The 4 classes identified were: 1) low relapse, 2) high depression and moderate pain, 3) high pain, and 4) high relapse. Odds ratios for time-to-first use indicated no statistically significant differences in time to relapse between the high pain and the high depression classes, but all other classes differed significantly.

Conclusions: This is the first longitudinal study to characterize the influence of pain, depression, and relapse in patients receiving buprenorphine and naloxone treatment. These results emphasize the need to monitor the influence of pain and depression during stabilization on buprenorphine and naloxone. Future work may identify appropriate interventions that can be introduced to extend time-to-first prescription opioid use among patients.

Related protocols: CTN-0030

Abstract:

Opioid use disorder (OUD) is a chronic, relapsing condition with severe negative health consequences. Previous studies have reported that 5-year abstinence is a good predictor of reduced likelihoods of relapse, but factors that shape long-term opioid abstinence are poorly understood.

The present study is based on data from a prospective study of 699 adults with OUD who had been randomized to either methadone or buprenorphine/naloxone and who were followed for at least 5 years (CTN-0050, Long Term Follow-Up of START Patients). During the 5 years prior to the participants’ last follow-up interview, 232 (33.2%) had achieved 5-year abstinence from heroin. Of those 232, 145 (20.7% of the total) had remained abstinent from both heroin and other opioids (e.g., hydrocodone, oxycodone, other opioid analgesics, excluding methadone or buprenorphine). Compared to non-abstinent individuals, those in both categories of opioid abstinence had lower problem severity in health and social functioning at the final follow-up. Logistic regression results indicated that cocaine users and injection drug users were less likely to achieve 5-year heroin abstinence, whereas Hispanics (vs. whites) and those treated in clinics on the West Coast (vs. East) were less likely to achieve 5-year abstinence from heroin and other opioids. For both abstinence category groups, abstinence was positively associated with older age at first opioid use, lower impulsivity, longer duration of treatment for OUD, and greater social support.

Conclusions: Given the current opioid crisis, this study contributes valuable information by identifying correlates of long-term opioid abstinence that are important for efforts to facilitate stable recovery. Reducing cocaine use and injection drug use and increasing social support and retention in treatment may help maintain long-term abstinence from opioids among individuals treated with agonist pharmacotherapy.

Related protocols: CTN-0050

Abstract:

Patients with prescription opioid use disorder commonly report relief of chronic pain as the chief reason for first opioid use; indeed, the prevalence of chronic pain is high in this population. Understanding the association between pain severity and subsequent opioid use is crucial for understanding how to manage these conditions simultaneously and has not been examined in this population. The aim of this analysis was to examine the proximal effect of pain severity on opioid use during 12 weeks of buprenorphine-naloxone therapy for patients with chronic pain and prescription opioid use disorder.

This study is a secondary analysis of the NIDA Clinical Trials Network’s randomized, controlled trial of buprenorphine-naloxone plus counseling for prescription opioid dependent patients (CTN-0030, Prescription Opioid Addiction Treatment Study (POATS)). The association between past-week pain severity and opioid use in the subsequent week was examined in 148 patients presenting with chronic pain at baseline. Results from a multivariable logistic regression model showed that greater pain severity in a given week was significantly associated with increased odds of opioid use in the following week over the 12-week treatment, even after adjusting for covariates associated with opioid use (aOR=1.15, p<.001).

Conclusions: This longitudinal study is the first examination of the association between pain severity and subsequent opioid use in patients with prescription opioid use disorder. Despite previous reports of no association between baseline pain and subsequent opioid use, these findings suggest that patients who experience flare-ups of pain during treatment are prone to relapse to opioid use. Understanding the mechanism by which pain flare-ups may lead to substance use would be clinically meaningful; identification of those who are at risk to use opioids may be facilitated by carefully monitoring patterns of pain intensity over time.

Related protocols: CTN-0030

Abstract:

Decision-making processes have been posited to affect treatment outcome in addiction patients. This multi-site study assessed whether two measures of decision-making predicted relapse and subsequent use in stimulant-dependent patients. A total of 160 methamphetamine- or cocaine-dependent patients participating in a multi-site clinical trial evaluating a modified 12-step facilitation intervention for stimulant-dependent patients (NIDA Clinical Trials Network protocol CTN-0031, STAGE-12) were assessed. Decision-making processes of risk and delay (Iowa Gambling Task (IGT)) and response reversal (Wisconsin Card Sorting Task (WCST)) were obtained shortly after treatment admission followed by assessment of stimulant use over the next six months. The relationships of the IGT and WCST (Perseverative Errors) with relapse (yes/no) and days of stimulant use during the period following post-randomization were evaluated.

Performance on the IGT and WCST did not significantly predict relapse status or time to relapse. Unexpectedly, worse performance on the IGT was associated with fewer number of stimulant use days (p=0.001). In contrast, worse performance on the WCST (fewer perseverative errors) was associated with a greater number of stimulant use days (p=0.0003). The predictive effects of perseverative errors on subsequent use were confined to methamphetamine-dependent and minority participants.

Conclusions: Decision-making processes, as measured in the current study, do not uniformly predict relapse or subsequent use. A decrease in the salience attribution of non-drug reinforcers may explain the positive relationship between IGT performance and post-relapse use. More comprehensive and global measures of impulsiveness may better assess relapse risk and use.

Related protocols: CTN-0031

Abstract:

This study aimed to quantify the relations between craving and withdrawal symptoms and time to first opioid use among prescription opioid (PO) abusers undergoing buprenorphine detoxification. Higher indicators of craving and withdrawal at the outset of the taper were hypothesized to predict earlier user. Data from 653 PO-dependent individuals initiating a 14-day taper from buprenorphine/naloxone, recruited for the National Drug Abuse Treatment Clinical Trials Network protocol CTN-0030, were analyzed using survival analysis to explore time to first use as a function of opioid craving and withdrawal. Participants were collapsed across condition and measurements taken at the start of the taper were used. Participants were followed for 10 weeks after the taper began. PO craving was measured by 3 items on the Visual Analog Scale (VAS; e.g. “How much do you currently crave opiates?”) and opioid withdrawal was measured by the Clinical Opiate Withdrawal Scale and 1 item on the VAS. Withdrawal significantly predicted time to first use, such that each withdrawal unit increase led to a 1.0% decrease in time to first use. Craving items significantly predicted time to first use. Each unit increase on the craving item response scales was associated with a 1.7% to 1.9% decrease in time to first use, depending on the item. Further analyses revealed differences among individuals who terminated study involvement after the first taper and those willing to take part in a second taper.

Conclusions: Higher reports of withdrawal and craving at the outset of a buprenorphine taper are important clinical indicators of earlier lapse to opioids. Novel therapies to attenuate these effects are needed.

Related protocols: CTN-0030