Faculty Bibliography

Chronic pain is highly prevalent among patients with opioid use disorder (OUD). However, little is known about how pharmacological treatments for OUD, for example, extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX), affect pain. To begin addressing this question, we performed a secondary analysis of pain data on a large prospective 24-week, open-label, randomized-controlled comparative effectiveness trial of XR-NTX versus BUP-NX (X:BOT trial). Participants' pain status was measured by the EuroQol (EQ-5D). Based on their responses to the pain question at baseline, participants were dichotomized into "Pain" versus "No Pain" categories. Participant's pain status was evaluated every 4 weeks. A mixed effects longitudinal logistic regression model was fitted to examine the differential effect of XR-NTX versus BUP-NX on pain, modelling pain at all available follow-up assessments, adjusted for age, sex, and baseline pain. A total of 474 individuals who were successfully inducted onto their assigned medications were included in this analysis. Among participants endorsing pain at baseline, substantial reductions in pain were observed over the course of the study in both treatment groups. Howecver reduction in pain was slightly greater in the group treated with XR-NTX than the one treated with BUP-NX (OR = 1.60 [95% CI: 1.07-2.40], P = 0.023). Future research using instruments and design specifically focused on pain could extend the present observations and evaluate their clinical significance.

BACKGROUND: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. Our 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. METHODS:This was a secondary analysis of 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. RESULTS:We 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.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X² =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X² =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

BACKGROUND:The randomized X:BOT trial 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), we 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. METHODS:Timeline follow-back recorded standard drink units consumed. Mixed-models regression examined monthly frequencies of any drinking or heavy drinking over 6 months of treatment and proportional hazard survival examined time to first drink. RESULTS: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.

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.

BACKGROUND:Smoking prevalence in individuals with opioid use disorder (OUD) is over 80%. Research suggests that opioid use significantly increases smoking, which could account for the strikingly low smoking-cessation rates observed in both methadone- and buprenorphine-maintained patients, even with the use of first-line smoking-cessation interventions. If opioids present a barrier to smoking-cessation, then better smoking outcomes should be observed in OUD patients treated with extended-release naltrexone (XR-NTX, an opioid antagonist) compared to those receiving buprenorphine (BUP-NX, a partial opioid agonist). METHODS:The current study is a secondary analysis of a 24-week, multi-site, open-label, randomized clinical trial conducted within the National Drug Abuse Treatment Clinical Trials Network comparing the effectiveness of XR-NTX vs. BUP-NX for adults with OUD. Longitudinal mixed effects models were used to determine if there was a significant reduction in cigarette use among daily smokers successfully inducted to treatment (n = 373) and a subset of those who completed treatment (n = 169). RESULTS:Among daily smokers inducted onto OUD medication, those in the XR-NTX group smoked fewer cigarettes per day (M = 11.36, SE = 0.62) relative to smokers in the BUP-NX group (M = 13.33, SE = 0.58) across all study visits, (b (SE) = -1.97 (0.55), p < .01). Results were similar for the treatment completers. CONCLUSIONS:OUD patients treated with XR-NTX reduced cigarette use more than those treated with BUP-NX, suggesting that XR-NTX in combination with other smoking cessation interventions might be a better choice for OUD smokers interested in reducing their tobacco use.

AIM/OBJECTIVE: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). DESIGN/METHODS: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 were encouraged to continue MOUD. This report examined opioid use outcomes in 428 (75%) of the 570 participants who attended the 36-week follow-up visit. SETTING AND PARTICIPANTS/METHODS:Adults with opioid use disorder recruited from 8 community treatment programs across the United States. MEASUREMENTS/METHODS: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. FINDINGS/RESULTS: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.

BACKGROUND AND AIMS/OBJECTIVE:In a US randomized-effectiveness trial comparing extended-release naltrexone (XR-NTX) with buprenorphine-naloxone (BUP-NX) for the prevention of opioid relapse among participants recruited during inpatient detoxification (CTN-0051), the requirement to complete opioid detoxification prior to initiating XR-NTX resulted in lower rates of initiation of XR-NTX (72% XR-NTX versus 94% BUP-NX). DESIGN/METHODS:This was a retrospective secondary analysis of CTN-0051 trial data, including follow-up data over 24-36 weeks. SETTING/METHODS:Eight community-based, inpatient-detoxification and follow-up outpatient treatment facilities in the United States. PARTICIPANTS/METHODS:A total of 283 participants randomized to receive XR-NTX. MEASUREMENTS/METHODS:Efficiency was estimated using a multivariable generalized structural equation model to explore simultaneous determinants of XR-NTX induction and induction duration (detoxification + residential days). Cost-effectiveness was estimated from the health-care sector perspective and included expected costs and quality-adjusted life-years (QALYs). FINDINGS/RESULTS:Treatment site was the only modifiable factor that simultaneously increased the likelihood of XR-NTX induction and decreased induction duration. Incorporating the higher predicted probability of XR-NTX induction, and fewer predicted days of detoxification and subsequent residential treatment into the cost-effectiveness framework, reduced the incremental average 24-week total cost of XR-NTX treatment from $5317 more than that of BUP-NX (P = 0.01) to a non-statistically-significant difference of $1016 (P = 0.63). QALYs gained remained similar across arms. CONCLUSION/CONCLUSIONS:Adopting an efficient model of extended-release naltrexone initiation could result in extended-release naltrexone and buprenorphine-naloxone being of comparable economic value from the health-care sector perspective over 24-36 weeks for patients seeking treatment for opioid use disorder at an inpatient detoxification facility.

BACKGROUND:Extended-release naltrexone (XR-NTX) is an effective maintenance treatment for opioid use disorder, but induction from active opioid use is a challenge as individuals must complete detoxification before induction. We aimed to determine whether use of methadone or buprenorphine, long acting agonist opioids commonly used for detoxification, were associated with decreased likelihood of induction onto XR-NTX. METHODS:We performed a secondary analysis of a large open-label randomized trial of buprenorphine versus XR-NTX for treatment of individuals with opioid use disorder recruited from eight short term residential (detoxification) units. This analysis only included individuals randomized to the XR-NTX arm of the trial (N = 283). The method of detoxification varied according to usual practices at each inpatient program. Logistic regression models estimating the log-odds of induction onto XR-NTX were fit, with detoxification regimen received as the predictor. RESULTS:In the unadjusted logistic regression model, detoxification drug received (either methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: P < 0.001); buprenorphine vs non-opioid detoxification: OR (95% CI) = 0.32 (0.15-0.67); methadone vs non-opioid detoxification: OR (95% CI) = 0.23 (0.11-0.46). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance. CONCLUSIONS:Use of agonist medication during detoxification was associated with XR-NTX induction failure. Medication choice was determined by each site's clinical practice and therefore this association could not be separated from other site level variables. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT02032433.