Ling, Walter MD; Nadipelli, Vijay R. MS; Aldridge, Arnie P. PhD; Ronquest, Naoko A. PhD; Solem, Caitlyn T. PhD; Chilcoat, Howard ScD; Albright, Victoria MA; Johnson, Courtney MPH; Learned, Susan M. PhD; Mehra, Vishaal MD; Heidbreder, Christian PhD

Author Information

UCLA Department of Family Medicine, Center for Behavioral & Addiction Medicine, Los Angeles, CA (WL); Indivior Inc, Richmond, VA (VRN, HC, SML, CH); RTI International, Research Triangle Park, NC (APA, NAR, VA); Pharmerit International, Bethesda, MD (CTS, CJ); John Hopkins Bloomberg School of Public Health, Baltimore, MD (HC); CamBright Research LLC, Dursay đắm, NC (VA); Artemis Institute for Clinical Retìm kiếm, San Diego, CA (VM).

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Sover correspondence lớn Dr. Walter Ling, MD, UCLA Department of Family Medicine, Center for Behavioral và Addiction Medicine, 16556 Park Lane Circle, Los Angeles, CA 90049. E-mail: .

Received 11 September, 2019

Accepted 6 February, 2020

WL is a consultant for Indivior Inc, Alkermes, Camurus/Braeburn, Opiant, and Tichảy Pharmaceuticals. VM is a clinical investigator for BUP-XR clinical trials và a consultant for Indivior Inc. VRN, SML, HC, & CH are employees and own stochồng in Indivior Inc. NAR was an employee of Indivior Inc when this work was developed. APA is an employee of RTI International và consultant for Indivior Inc. VA was an employee of RTI International and consultant for Indivior Inc when this work was developed. CTS và CJ are employees of Pharmerit International & consultants for Indivior Inc. The RECOVER study was sponsored by Indivior Inc.

Supplemental digital nội dung is available for this article. Direct URL citation appears in the printed text & is provided in the HTML và PDF versions of this article on the journal"s Web site (

This is an open access article distributed under the terms of the Creative sầu Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to tải về and nội dung the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Journal of Addiction Medicine: September/October 2020 - Volume 14 - Issue 5 - p e233-e240
doi: 10.1097/ADM.0000000000000647
mở cửa Metrics



While evidence has mounted regarding the short-term effectiveness of pharmacotherapy for opioid use disorder (OUD), little is known about longer-term psychosocial, economic, và health outcomes. We report herein 12-month outcomes for an observational study enrolling participants who had previously taken part in a long-acting buprenorphine subcutaneous injection (BUP-XR) trial for moderate to lớn severe OUD.


The RECOVER (Remission from Chronic Opioid Use: Studying Environmental and SocioEconomic Factors on Recovery; NCT03604861) study enrolled participants from 35 US community-based sites. Self-reported sustained opioid abstinence over 12 months & self-reported past-week abstinence at 3-, 6-, 9-, and 12-month visits were assessed. Multiple regression models assessed the association of BUP-XR duration with abstinence, controlling for potential confounders. Withdrawal, pain, health-related unique of life, depression, & employment at RECOVER baseline & 12-month visits were also compared to values collected before treatment in the BUP-XR trial.


Of 533 RECOVER participants, 425 completed the 12-month visit (average age 42 years; 66% male); 50.8% self-reported sustained 12-month và 68.0% past-week opioid abstinence. In multiple regressions, participants receiving 12-month versus ≤2-month BUP-XR treatment duration had significantly higher likelihood of sustained opioid abstinence (75.3% vs 24.1%; P = 0.001), with similar results for past-week self-reported abstinence over time. During RECOVER, participants had fewer withdrawal symptoms, lower pain, positive sầu health-related unique of life, minimal depression, & higher employment versus pre-trial visit.


RECOVER participants reported positive sầu outcomes over the 12-month observational period, including high opioid abstinence & stable or improved humanistic outcomes. These findings provide insights inlớn the long-term impact of pharmacotherapy in OUD recovery.

In 2017, the United States (US) Department of Health và Human Services (HHS) declared the opioid epidemic a public health emergency. The first strategy recommended for fighting the opioid crisis by the HHS was improving access to lớn treatment and recovery services (US Department of Health and Human Services, 2018). However, efforts khổng lồ combat this emergency appear to lớn focus more on the promotion of overdose-reversing medications & provision of tools to healthcare providers to limit unnecessary use of opioids for pain relief (Sharfstein & Olsen, 2019). Although these efforts may decrease the number of opioid-related overdoses and potentially avoid future cases of opioid use disorder (OUD), effective sầu treatment of patients with OUD is paramount to lớn saving patient lives (Sharfstein & Olsen, 2019).

The clinical efficacy of buprenorphine, methadone, and naltrexone for the treatment of OUD has been well characterized (Mattick et al., 2009; Schwartz et al., 2013; Mattiông chồng et al., 2014). More recently, buprenorphine extended-release subcutaneous injection (BUP-XR a.k.a. RBP-6000 or SUBLOCADE, Indivior Inc, North Chesterfield, VA) was shown to be a safe and effective OUD treatment option (Haight et al., 2019) that could improve sầu the chất lượng of life (Ling et al., 2019b) of treatment-seeking individuals with moderate or severe OUD.

Pharmacotherapy for OUD is underutilized (Leshner & Dzau, 2019) with estimates from the year 2019 suggesting that fewer than 35% of adults with OUD received OUD treatment in the past year (National Academies of Sciences, 2019). Although the beneficial effects of pharmacotherapy, including decreased opioid use, decreased opioid-related overdose deaths, decreased criminal activity, decreased infectious disease transmission, và increased social functioning, are clearly demonstrated (Mattichồng et al., 2009; Schwartz et al., 2013; Mattiông chồng et al., 2014), little is known about patient recovery following pharmacolô ghích treatment of OUD. The objectives of this analysis were lớn describe 12-month outcomes from an observational study enrolling individuals who had previously taken part in a BUP-XR trial.


Study Design and Setting

The RECOVER study (Remission from Chronic Opioid Use: Studying Environmental & SocioEconomic Factors on Recovery; NCT03604861)(Ling et al., 2019a) was a 24-month, observational study that assessed life changes in patients with OUD who had received up khổng lồ 12 monthly BUP-XR injections as part of either a separate randomized clinical efficacy trial (NCT02357901) (Haight et al., 2019; Ling et al., 2019b) and/or a separate open-label safety (NCT02510014) study before entering RECOVER. Additional details of the study thiết kế và characteristics of patients enrolled in the RECOVER study have sầu been previously published (Ling et al., 2019a). Data reported herein represent analyses through the 12-month visit, which was completed in March 2018.

As part of the RECOVER study, participants completed detailed self-administered assessments concerning illicit substance use, treatment for substance use disorder, và psychosocial measures at RECOVER enrollment và at 6 & 12 months post-enrollment. RECOVER study enrollment occurred at least 28 days after completing or discontinuing participation in the aforementioned BUP-XR trials. A shorter battery of assessments was conducted at 3 & 9 months after enrollment. Ten panel urine drug screens (UDS; T-cup Multi-Drug Urine Test) were conducted at all visits. An attempt to contact all actively enrolled RECOVER participants was made for all visits, regardless of whether participants had missed an earlier visit.

The RECOVER study was conducted in accordance with all applicable ethical và regulatory requirements. In accordance with national và local regulations, Institutional Đánh Giá Board or Ethical Committee approval was obtained. Additionally, a Certificate of Confidentiality from the US government was granted khổng lồ the RECOVER study to protect participants’ right lớn refuse requests for disclosure of assessment data. All participants provided informed consent before study participation. This study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines (von Elm et al., 2007).

Treatment During RECOVER

As RECOVER was a prospective sầu observational study, any treatment that participants received, including those for OUD, were not provided as part of the RECOVER study. Participants were asked khổng lồ self-report whether they were receiving substance use disorder treatment at the 6- and 12-month visits. Some RECOVER participants (n = 146) elected khổng lồ extend their BUP-XR treatment by 6 months after leaving the open-label safety study through participation in a BUP-XR open-label extension study (NCT02896296) that ran concurrently with RECOVER. Participants self-reporting OUD treatment at either the 6- or 12-month visit or enrolled in the open-label extension study concurrent with RECOVER were noted as receiving OUD treatment during RECOVER.

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Study Outcomes

RECOVER 12-month analysis operationalized opioid abstinence as (1) self-reported sustained abstinence over the entire 12-month reporting period và (2) self-reported past week abstinence at each visit over 12 months.

Sustained 12-month abstinence was defined as no days of opioid use self-reported for the past 6 months (collected at 6 và 12 months) among those participants who had completed the 12-month visit. If the 6-month visit was missing, only self-report at 12 months was used. Self-reported opioid use included any misuse of prescription painkillers, methadone, or buprenorphine, or use of heroin, goofball (heroin + methamphetamine), or speedball (heroin + cocaine). While bioxúc tích assays such as UDS are useful for capturing drug use over short time spans (eg, 2–3 days for opioids), self-reported abstinence was used for the main definition in order to lớn capture opioid use over longer time spans. In order to lớn thử nghiệm the robustness of this definition, 2 sensitivity analyses were conducted. The first sensitivity analysis defined a participant as abstinent over the 12-month period if there was no opioid use on any self-reported measure (ie, past-week, past-month, & past 6 months) at 3, 6, 9, and 12 months. The second sensitivity analysis required participants to lớn have a UDS that was negative sầu for opioids in addition to no self-reported opioid use, as described in the first sensitivity analysis. If a positive UDS result was indicated for either opiates or oxycodone, the UDS was considered to lớn indicate opioid use. In the case where the UDS result for any substance indicated that the thử nghiệm was invalid, the UDS was treated as missing.

Past-week, self-reported abstinence at each quarterly visit was defined as no self-reported opioid use in the past week. As a sensitivity analysis, participants were only considered abstinent if there were no days of self-reported opioid use và UDS results were negative for opioids. To underst& the impact of missing data on observed results, sensitivity analyses were run in which the last observation was carried forward for all future missing visits, & a second analysis considered all missing visits as non-abstinent (ie, worst case imputation).

In addition to lớn the aforementioned abstinence-related outcomes, outcomes collected at both the initial visit within the BUP-XR clinical trials (ie, before receiving treatment in the randomized efficacy or open-label safety studies) and within RECOVER were described. These included past-month self-reported abstinence, opiate abstinence according to UDS results, withdrawal symptoms (Subjective sầu Opiate Withdrawal Scale ), pain intensity (Brief Pain Inventory ), quality of life (36-Item Short Form Survey in efficacy và safety trials, 12-Item Short Form Survey in RECOVER), depression severity (Beck Depression Inventory ), và employment status.

Statistical Analysis

Primary abstinence outcomes were measured within the overall cohort & compared between BUP-XR treatment duration groups based on injections received within the randomized efficacy và open-label safety studies: 0- lớn 2-month BUP-XR (0–2m; ie, placebo or 1 or 2 BUP-XR injections), 3- lớn 5-month BUP-XR (3–5m; ie, 3–5 BUP-XR injections), 6- lớn 11-month BUP-XR (6–11m; ie, 6–11 BUP-XR injections), and 12-month BUP-XR (12m; ie, 12 BUP-XR injections).

To control for differences between duration groups, weighted and adjusted models were applied. Inverse probability weights were calculated for the 3–5m, 6–11m, and 12m BUP-XR groups relative sầu to the 0–2m BUP-XR group to lớn balance pre-trial characteristics. Pre-trial characteristics used in the weighted analysis included: insurance status, BDI-II score ≥20, opiate UDS results, mean-weighted average BPI score, và mean-weighted total SOWS scores.

Multiple logistic regression models, including inverse probability weights, were used to lớn assess the association of key patient treatment and demographic characteristics with abstinence outcomes including BUP-XR treatment duration, sex, age at baseline, race, education, marital status & housing stability at baseline, age of first nonmedical use of opioids, types of opioids used over lifetime (ie, heroin only, prescription opioid only, or heroin & prescription opioid use), OUD pharmacotherapy (ie, buprenorphine or methadone) use prior khổng lồ enrollment in BUP-XR trial, community-level OUD treatment availability (ie, năm 2016 state-level naloxone composite score obtained through the 2016 to 2017 Prescription Drug Abuse Policy System , % of treatment centers in the state offering any outpatient pharmacotherapy per năm 2016 National Survey of Substance Abuse Treatment Service ), & number of weeks between last BUP-XR injection during the randomized efficacy or open-label safety study and baseline RECOVER visit. To assess whether the association of BUP-XR treatment duration varied over the follow-up period, past-week abstinence models additionally included variables for the period of data collection (ie, 3, 6, 9, or 12 months) & the interaction between BUP-XR duration and survey collection period.

Patient-centered recovery outcomes were reported at the randomized efficacy and open-label safety trial screening visit, at RECOVER baseline, and at the RECOVER 12-month visit within the entire cohort khổng lồ understand how these outcomes changed over time. For participants enrolled in both the randomized efficacy & open-label safety trials, the value obtained from the screening visit prior lớn the randomized efficacy trial was used, as this was prior to any BUP-XR exposure.

The data analysis for this paper was generated using SAS/STAT software, version 9.4, of the SAS System for Windows (SAS Institute Inc, Cary, NC).


Of the 533 RECOVER participants, 5trăng tròn (98%) were eligible for survey completion (ie, not deceased or incarcerated) at 3 months, 518 (97%) at 6 months, 508 (95%) at 9 months, & 506 (95%) at 12 months. Assessment completion rates at each visit out of eligible participants were above sầu 80% (82% <427/520> at 3 months, 86% <444/518> at 6 months, 81% <414/508> at 9 months, 84% <425/506> at 12 months), & UDS completion rates were almost as high (78% <407/520> at 3 months, 82% <425/518> at 6 months, 79% <402/508> at 9 months, 82% <416/506> at 12 months). A total of 339 participants completed all visits (64% of the entire sample). In total, there were 116 (22%) participants in the 0–2m BUP-XR duration group, 61 (11%) in the 3–5m BUP-XR duration group, 96 (18%) in the 6–11m BUP-XR duration group, và 260 (49%) in the 12m BUP-XR duration group based on BUP-XR use in the randomized efficacy and open-label safety studies.

Participant Characteristics

RECOVER participants were predominately male (66%), had a mean age at baseline of 42 years, và most had graduated from high school or had a general education diploma (67%; Table 1). Although the sample form size completing the 12-month visit decreased to 425 participants, there was no evidence of systematic dropout based on observed participant characteristics at baseline.

RECOVER Baseline Sociodemographic Characteristics

Treatment During RECOVER

A total of 254 (47.7%) participants either self-reported receiving treatment for a substance use disorder or were participating in the open-label extension study (Table 2). The majority of these participants were receiving pharmacotherapy (207/254 <81%>), and nearly all who received pharmacotherapy (196/207 <95%>) were treated with buprenorphine. Approximately three-quarters of those treated with buprenorphine received BUP-XR through enrollment in the BUP-XR open-label extension study concurrent with RECOVER. Counseling, reported by approximately 10% of study participants (Table 2), was the most commonly reported non-pharmacoxúc tích và ngắn gọn treatment modality.

Treatments Received for Substance Use Disorder Between RECOVER Baseline & 12-month Visit

Among muốn the 279 participants who did not receive any substance use disorder treatment (pharmacotherapy or other) during the entire 12-month follow-up period, 193 (69.2%) participants reported that they did not need further treatment (Table 2).

Primary Abstinence Outcomes

Half (50.8%) of participants who completed the 12-month RECOVER visit had sustained abstinence over the entire 12-month observational period based on no self-reported opioid use within the past 6 months reported at both the 6- & 12-month visits. In sensitivity analyses when all self-reported evidence was used (i.e., no past-week, past-month, or past 6-month self-reported days of use at quarterly visits), the sustained abstinence rate was 45.2%. When additionally requiring all measured UDS results to lớn be opioid negative, the sustained abstinence rate was 32.0%.

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Within multiple regression analysis, longer BUP-XR treatment duration (6–11 m and 12 m BUP-XR groups) and female sex were associated with sustained 12-month abstinence, whereas previous use of pharmacotherapy for OUD and age 30 years and older were associated with non-abstinence (Table 3). After adjustment and weighting in multiple regression analyses, the likelihood of abstinence for the full 12 months of RECOVER was 75% for participants who had received 12m of BUP-XR treatment compared with 24% for participants who had received 0–2m of BUP-XR treatment (Fig. 1A).

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