Full length articleTrajectory classes of opioid use among individuals in a randomized controlled trial comparing extended-release naltrexone and buprenorphine-naloxone★
Introduction
More than 2.1 million people in the U.S. have an opioid use disorder (OUD), a chronic condition with 65%–84% of individuals relapsing within a month after completing inpatient or outpatient detoxification (Bailey et al., 2013; Day and Strang, 2011). Opioid overdose deaths have steadily increased over the last 15 years with 47,600 reported in 2017 (Center for Disease Control and Prevention, 2019). Synthetic opioids (other than methadone) such as the highly potent fentanyl, fentanyl analogs, and tramadol are responsible for more than half (29,000) of opioid-related overdose deaths (National Institute on Drug Abuse (NIDA), 2018); between 2002 and 2017 there was a 22-fold increase in the total number of overdose deaths attributable to synthetic opioids. Thus, there is a dire need to identify more effective and targeted methods of treating OUD.
Three pharmacologically distinct FDA-approved medications for OUD (MOUD) have been found to be effective, the full opioid agonist methadone, the partial agonist buprenorphine-naloxone [BUP-NX], and the antagonist naltrexone formulated as an extended-release injection [XR-NTX]. These are considered front-line treatments (Volkow, 2018) and traditionally combined with psychosocial interventions to provide comprehensive care. Methadone in the U.S. is only available in regulated specialty settings (i.e., Opioid Treatment Programs), while BUP-NX and XR-NTX can be prescribed across a range of healthcare settings, and have the potential to increase the accessibility of MOUD. BUP-NX and XR-NTX each have unique induction requirements portending distinct challenges in initiation and maintenance of treatment among patients. This is particularly true of XR-NTX which requires patients to be fully detoxified from opioids (e.g., no opioids for approximately 7–10 days; Jarvis et al., 2018); however, once induction hurdles are overcome, XR-NTX appear to be as effective as BUP-NX (Lee et al., 2018; Tanum et al., 2017). For example, a multi-site randomized controlled trial (RCT) comparing daily oral BUP-NX with flexible dosing (from 4 to 24 mg/day) to monthly intramuscular XR-NTX (380 mg) revealed no differences between the medications in reducing opioid and other illicit drug use in the short-term (i.e., 12 weeks; Tanum et al., 2017). A multi-site RCT in the United States, compared BUP-NX (administered sublingually via film) to XR-NTX (administered monthly via intramuscular injection), in a sample of individuals with OUD, over 24 weeks (Lee et al., 2018). Although significantly fewer participants successfully initiated XR-NTX, among those who were fully inducted on either XR-NTX or BUP-NX (per protocol treatment groups), there were no significant differences between the two treatments in weeks to relapse, opioid-negative urines, and self-reported opioid abstinent days. Thus, although XR-NTX may present unique induction challenges, studies support its efficacy as an additional treatment for OUD.
While the aforementioned trials provided important information on mean-level differences in rates of opioid use and relapse, there is scarce information on the variability in how individuals’ opioid use changes over time while receiving MOUD. Identifying differential use patterns and treatment response and the characteristics that predict them is critical in understanding how MOUD work among subgroups of individuals, and can inform the timing and targeting of intervention efforts (Grella and Lovinger, 2011; Hser et al., 2017; Teesson et al., 2017). The limited research to date has demonstrated heterogeneity in opioid use trajectories for people on MOUD. In a sample of 795 people who use opioids and participated in a RCT of methadone or BUP-NX, Hser et al. (2017) identified 4 opioid use trajectories over time (up to 55 months posttreatment): low use, high use, decreasing use, and increasing use. More than 40% of the participants were in the low use group (demonstrating consistently low opioid use over time) after MOUD treatment. Eastwood and colleagues (2018) examined opioid use trajectories in a sample of 7719 individuals continuously enrolled in community based MOUD (methadone or buprenorphine) for at least five years and followed posttreatment for another two years. They found five heroin use trajectory classes: gradual decreasing, decreasing then increasing, continued low-level, rapid decreasing, and continued high-level (Eastwood et al., 2018). Variables that predicted non-response to treatment included current injection drug use, previous treatment, and higher social deprivation. These studies demonstrated variability in MOUD treatment response and highlight the benefit of adherence to treatment. Overall, studies show the strongest predictor of abstinence over follow-up was being on MOUD (Weiss et al., 2015). Findings underscore the need to identify treatment response early in the course of treatment to modify and optimize treatment interventions. Notably, no studies have examined patterns of treatment response during the first 24 weeks of treatment and in particular among patients randomized to XR-NTX.
The aim of this secondary analysis was to examine trajectories of opioid use for patients with OUD who were randomized to receive 24 weeks of treatment with either BUP-NX or XR-NTX, and to identify characteristics associated with each trajectory class. In particular, we were interested in exploring opioid use trajectories among individuals randomized to XR-NTX since this analysis had not previously been conducted.
Section snippets
Study design and participants
This is a secondary data analysis of a multi-site 24-week open-label randomized effectiveness and safety trial comparing XR-NTX and BUP-NX for OUD. The detailed protocol (Lee et al., 2016; Nunes et al., 2016) and primary outcome analysis (Lee et al., 2018) have been previously published.
Descriptive statistics
Table 1 presents demographic characteristics for the intent-to-treat (ITT; N = 570) sample and the retained subsample (RS) of 535 participants who had at least one time point for the outcome observation. ITT participants were predominantly white men, with a mean age of 33.9 (SD = 9.6), single, unemployed, and Medicaid-insured. Approximately 17% self-identified as Hispanic. Sixty-eight percent used drugs intravenously, and overall had been using opioids, on average, for 12.5 years (SD = 9.0).
Discussion
To advance our understanding of MOUD treatment response, the identification of distinct subgroups and factors associated with differential treatment response is critical to inform intervention efforts in terms of optimal targets and intervention leverage points. This secondary analysis identified four distinct opioid use trajectories for BUP-NX and three distinct opioid use trajectories for XR-NTX. Overall, the trajectory classes for XR-NTX and BUP-NX were quite similar (i.e., both had “near
Role of funding source
This research was supported by grants from the NIDA National Drug Abuse Treatment Clinical Trials Network (U10DA013046, UG1/ U10DA013035, UG1/U10DA013034, U10DA013045, UG1/U10DA013720, UG1/U10DA013732, UG1/U10DA013714, UG1/U10DA015831, U10DA015833, HHSN271201200017C, and HHSN271201500065C) and K24DA022412 (EVN Jr). The NIDA did not have a role in the study design, collection, analysis, and interpretation of data; nor in the writing of the report, or the decision to submit the article for
Contributors
LMR conceptualized and designed the research question. JS and MP conducted the statistical analyses. All authors drafted the initial manuscript, interpreted results, and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted.
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgments
We thank the reviewers on the NIDA National Drug Abuse Treatment Clinical Trials Network Publication Committee for their review and feedback on this manuscript.
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This research was supported by grants from the NIDA National Drug Abuse Treatment Clinical Trials Network (U10DA013046, UG1/ U10DA013035, UG1/U10DA013034, U10DA013045, UG1/U10DA013720, UG1/U10DA013732, UG1/U10DA013714, UG1/U10DA015831, U10DA015833, HHSN271201200017C, and HHSN271201500065C) and K24DA022412 (EVN Jr).