Opioid use disorder (OUD) is a national health crisis. In 2018, an average of 128 people in the US died each day of opioid overdose.1 There is clear evidence, including a recent report by the National Academies of Science, Engineering, and Medicine (NASEM), that people with OUD who receive medications for opioid use disorder (MOUD) are less likely to die from overdose,2,3 engage in less illicit opioid use, and experience improved quality of life.4 Three medications—methadone, buprenorphine, and naltrexone—are approved by the US Food and Drug Administration for the treatment of OUD.5 Although remission from opioid use may be most protective against overdose and morbidity, remission is not always achievable due to treatment gaps along the OUD cascade of care continuum (ie, diagnosis, engagement, initiation of MOUD, retention, and remission).4 Longer retention on MOUD is associated with improved mortality; however, retention rates are low and variable, with 30% to 50% reported in most settings.5–7 Possible explanations for poor retention rates include barriers to treatment access, particularly in rural settings8 or among vulnerable populations (eg, people who experience incarceration),9 stigma toward individuals with OUD and MOUD,10 fragmented care (eg, separate addiction treatment systems and medical or psychiatric care systems),4 cost of MOUD,11 and logistical challenges associated with MOUD prescribing (eg, frequent visits and diversion surveillance).4,8,9
Multiple interventions attempt to address these barriers but their impact on retention is unknown.12 Identifying which interventions are effective at improving retention is of high priority for policy makers and researchers. Therefore, the Agency for Healthcare Research and Quality (AHRQ) commissioned this rapid evidence review on interventions to improve MOUD retention to assist the Office of the Assistant Secretary for Health, Department of Health and Human Services and other federal agency stakeholders in their decision-making and current work. Rapid evidence reviews “accelerate or streamline traditional [systematic review] processes” to meet the needs and timelines of the end-users (eg, “government policymakers, health care institutions, health professionals, and patient associations”)13 The following key questions and analytic framework (Fig. 1) guided our review:
Key Question 1: What is the effectiveness and comparative effectiveness of strategies to improve retention in MOUD among nonpregnant adults with OUD?
Key Question 2: What are the harms of retention strategies for MOUD?
Key Question 3: Does the effectiveness of the MOUD retention strategy vary by participant characteristics (eg, age, gender, socioeconomic status, geographic region, polysubstance use)?
The protocol was registered in the PROSPERO database (CRD42019134739).10 The draft report was posted on the AHRQ website for public comment. The detailed methods including search strategies are available in the full report at https://effectivehealthcare.ahrq.gov/.11 We followed rapid review methods published by the World Health Organization (WHO)12 and PRISMA reporting guidance.13
Data Sources and Searches
We searched OVID MEDLINE and the Cochrane Database of Systematic Reviews from February 12, 2009 to June 16, 2019. We conducted an additional gap search through August 20, 2019.
One investigator reviewed abstracts and full-text articles for inclusion with 25% independent review by a second investigator. Appendix Table 1, https://links.lww.com/JAM/A213 details study inclusion criteria. We included existing systematic reviews (SRs) if they searched more than 2 databases; performed quality assessment; used predetermined inclusion/exclusion criteria; and described the search strategy.
We included randomized controlled trials (RCT) that compared MOUD retention strategies against each other or against treatment as usual (TAU) if TAU included the use of, or access to MOUD (ie, we excluded placebo-controlled studies or trials of abstinence based interventions). In the absence of an established definition, we defined retention as continued treatment or medication engagement for at least 3 months, which our stakeholders considered the minimum clinically-relevant treatment duration. We were purposefully inclusive in how retention was assessed (eg, by self-report, medication adherence, or documented visits). We included observational studies when there were no RCTs for a particular intervention. We included studies of interventions conducted internationally if they had potential for implementation in US, but excluded studies of interventions that used non-Food and Drug Administration-approved MOUD formulations.
With input from our stakeholders, we assessed the effectiveness of the following categories of interventions: (1) provision of MOUD in novel care settings or with integrated medical, psychiatric, or social services, or evaluations of changes in current prescribing practices in traditional care settings; (2) contingency management; (3) MOUD coupled with psychosocial counseling; (4) use of health information technology (IT); (5) extended-release (XR) MOUD formulations; and (6) financial support interventions (eg, transportation).4,14–16 No studies of financial interventions met our inclusion criteria.
Data Extraction and Quality Assessment
One investigator abstracted details on study design, setting, population, intervention, outcomes, and harms. Two reviewers independently rated study quality using criteria developed by the US Preventive Services Task Force.17 We did not downgrade studies for high attrition because it related to the primary outcome of MOUD retention.
We evaluated the quality of individual studies. We relied on high-quality published SRs and, when those existed, we used the quality ratings provided by the SR, which meant that quality assessment tools could differ. We did not conduct formal grading of the body of evidence for outcomes.
Data Synthesis and Analysis
We reported retention outcomes of intention-to-treat (ITT) analyses; if studies did not report retention using ITT, we calculated this if data were available. We synthesized findings across interventions qualitatively. Due to the small number of studies in each category, variation in types of interventions, populations, or settings, as well as methodological differences among studies, we did not perform quantitative analyses.
Role of Funding Source
AHRQ commissioned this rapid evidence review on behalf of HHS. Investigators worked with AHRQ and HHS to develop the scope and key questions. AHRQ staff provided project oversight and reviewed and made comments on drafts of the report and distributed the draft for peer review and public comment.
Of 1580 titles and abstracts retrieved, we reviewed 258 full text articles and included two SRs and 39 primary studies (Fig. 2). Duration of follow-up ranged from 3 to 24 months. Thirty-eight percent of the included studies reported retention as the primary outcome. Table 1 summarizes the included studies organized by intervention category and provides retention outcomes. Appendix Tables 7 to 11, https://links.lww.com/JAM/A213 report risk of bias assessments.
TABLE 1 -
Summary of Included Studies for Strategies to Improve Retention
||Number of Studies
||Number of Participants
||Quality of Evidence
||Summary of Retention Results
|Care settings, services, logistical support:
| MAT for soon-to-be-released incarcerated populations
||No MOUD in prison
||1 SR18 + 2 additional RCTs20,29
||SR: n = 834 (range: 32–446)
||Benefit with prerelease MOUD in all studies
||2 RCTs: n = 228 (15 and 213)
||1 fair; 1 poor
| Psychiatric & primary care (PC) services
||Specialty outpatient setting
||n = 631 (range: 94–316)
||Inconsistent (2 psychiatric studies, benefit in one and no difference than traditional setting in other; 1 study in PC, no difference from traditional setting)
| Emergency department (ED) / hospital setting
||Treatment as usual
||n = 429 (139 and 290)
||ED no worse than traditional (1 study with no difference; 1 study with benefit for hospital-initiated MOUD)
| Logistical support
||Treatment as usual
||n = 709 (range:97–300)
||1 good: 3 fair
| Opioid receptor antagonist MOUD
||Non-contingent access to a reward
||n = 140 (range:35–67)
||Benefit for contingency management in all studies
| Opioid receptor agonist/partial agonist MOUD
||Non-contingent access to a reward
,14 + 4 additional RCTs26,33–35
||SR: n = 1616
||4 RCTs: n = 698 (range:98–252)
||1 good; 3 fair
||Treatment as usual
||3 cohort studies41–43
||n = 3965 (range:55–3733)
||Telehealth no worse than in-person (2 studies with no difference, 1 study with benefit for telehealth)
| Computer-based education &/or support
||Treatment as usual
||n = 262 (range:20–160)
||2 fair: 1 poor
| Multicomponent mobile and computer-based program
||Treatment as usual
||n = 1426
|Extended-release medication based treatments:
| Naltrexone extended-release 1-month injection
||n = 60
||Benefit for XR injection
| Buprenorphine extended-release 1-month injection
||Daily SL-buprenorphine/ naloxone
||n = 428
| Buprenorphine extended-release 6-month implant
||n = 177
| Naltrexone extended-release 1-month injection
||Daily SL-buprenorphine/ naloxone
||n = 729 (159 and 570)
||1 good; 1 fair
||Inconsistent (1 study no difference, 1 study with benefit for SL buprenorphine/naloxone)
| Including behavioral, psychoanalytic and counseling interventions
||Treatment as usual
,14 + 9 additional RCTs50–58
||SR: n = 3124 (range: 14–542)
||No difference in all but one poor quality study. Many of the studies reviewed included some form of counseling in the control groups.
||9 RCTs: n = 2483 (range:49–653)
||2 good; 4 fair; 3 poor
∗SR applicable to 2 intervention types.IT, information technology; MOUD, medications for opioid use disorder; RCT, randomized controlled trial; SL, sublingual; SR, systematic review; XR, Extended-release.
Care Settings, Services, and Logistical Support
One good-quality SR18 and 11 primary studies, 1 good-19; 9 fair-20–28; and 1 poor-quality29; evaluated the effect of care setting/logistical support interventions on retention (Appendix Table 2, https://links.lww.com/JAM/A213).
MOUD for Soon-to-be-released Incarcerated Populations
The existing SR18 of 21 studies (6 RCTs and 15 observational studies) and 2 additional RCTs20,29 examined interventions that initiated MOUD in soon-to-be-released incarcerated people with OUD. The SR reported that initiating MOUD in prison was associated with higher rates of postrelease treatment retention compared with TAU controls (50% [range 27%–75%] vs 5% [range 0%–9%]).18 Two additional RCTs similarly reported improved retention with prerelease initiation of MOUD. One was a small poor-quality study (n = 15) that randomized inmates to XR-naltrexone monthly injection versus TAU and found that more than 20% of prerelease participants continued receiving treatment at 6 months versus none in the postrelease group.29 The second was a fair-quality study (n = 213) that assessed the effectiveness of prerelease initiation of buprenorphine compared with referral to begin an office-based buprenorphine treatment program after release and found higher retention in the prerelease group, measured as mean number of days in treatment at 12 months (65.9 days vs 21.8 days, P = 0.005).20
Care Setting: Integration of MOUD With Psychiatric and Primary Care Services
Three small (n range = 94–316) fair-quality RCTs provide conflicting evidence on the effectiveness of integrating primary or psychiatric services with OUD treatment to improve retention on MOUD.21–23 Two studies conducted in the US integrated methadone and buprenorphine treatment, respectively, with psychiatric care. The larger study (n = 316) found no difference in retention at 12 months (41% vs 41%, P = 0.96).22 The smaller study (n = 94), which included a third experimental arm involving MOUD treatment integrated with psychosocial therapy, reported improved retention at 20 weeks for both treatment groups compared with TAU alone (33.3% vs 51.5% vs. 21.4%, P = 0.05).23 The third study was a French trial of methadone treatment integrated within primary care, a practice not currently available in the US, versus TAU and found no statistically significant difference in retention at 12 months (n = 195, 88% vs 69%, P = 0.13).21
MOUD Initiation in Emergency Department (ED)/Hospital Settings
Two fair-quality RCTs examined retention after initiating MOUD in ED or hospital settings.24,27 One study, conducted at a US safety-net hospital (n = 139), compared an intervention that started patients on buprenorphine while inpatients, with linkage to outpatient treatment within 7 days of discharge versus TAU (medically supervised opioid withdrawal followed by referral to a community-based treatment program). Both groups experienced low retention rates but, at 6-month follow-up, the intervention group had higher retention compared to TAU (16.7% vs 3.0%, P = 0.007).24 The second study was a follow-up of a US-based, three-arm RCT (n = 290) that randomized participants to either buprenorphine treatment initiated during an ED visit with linkage to primary care (PC) within 72 hours, brief counseling intervention in ED, or referral to outpatient treatment (TAU). The study found no difference in retention, defined as self-reported engagement in OUD treatment, between the 3 groups at 6 months (53% vs 51% vs 60%, P = 0.55) or at 12 months (49% vs. 63% vs 49%, P = 0.14).27
Logistical Support Interventions
We identified one good- and 3 fair-quality RCTs that assessed interventions that either streamlined the initiation of MOUD treatment, (“low-threshold” MOUD), expedited enrollment in MOUD (“Script in a Day”), or combined OUD treatment with housing assistance and social care services.19,25,26,28 One trial (n = 300) of a low-threshold, patient-centered methadone treatment delivery intervention that allowed for nonmandatory counseling and did not discharge from treatment for administrative violations, found no differences in retention between the experimental and control groups at 12 months (48.6% vs 46.3%, P = not reported (NR)).19 Similarly, another trial (n = 212) that assessed the effectiveness of a low-threshold MOUD initiation with reduced counseling frequency found no statistically significant differences in retention at 90 (35% vs 31%, P = not significant (NS)), and 180 days of treatment (37% vs 29%, P = NS).26 A UK based study (n = 100) of an intervention offering immediate initiation of methadone treatment through a syringe exchange program followed by facilitated enrollment into office-based methadone treatment similarly found no difference in retention at 3 months compared to TAU (51% vs 47%, P = NR).28 Finally, in a Canadian trial (n = 97) of a Housing First intervention, patients with OUD experiencing homelessness were randomized to an intervention that provided housing combined with various healthcare and social services or TAU, which included referrals to housing assistance combined with outpatient specialty treatment programs. Treatment retention, measured using medication possession ratio (MPR) over a 2-year study period, did not differ between groups (MPR 0.52 vs 0.57, P = 0.60).25
Harms and Patient Characteristics
Only 4 trials reported serious harms or adverse events, 2 without specifying in which arm the events occurred. The low-threshold, patient-centered methadone treatment intervention reported 67 nonstudy-related hospitalizations and two nonstudy-related deaths, including one from methadone overdose among 149 intervention participants compared with 59 hospitalizations and four nonstudy-related deaths (2 from overdose) among 151 TAU participants.19 In the study of prerelease initiation of XR-naltrexone, 6 patients in the prerelease MOUD arm reported adverse events (2 serious, not specified) compared with 2 (none serious) in the control arm.29
The majority of studies did not examine population characteristics that affected retention outcomes. One study of prerelease MOUD initiation with linkage to office-based buprenorphine found no gender differences in retention outcomes.20
One SR14 that included 14 relevant RCTs, and 7 additional fair-26,30–34 to good-quality35 RCTs, with one follow-up analysis36 assessed the effectiveness of contingency management interventions on MOUD retention (Appendix Table 3, https://links.lww.com/JAM/A213).
All RCTs included in the SR implemented a contingency management intervention that rewarded abstinence from illicit opioids in participants receiving either full agonist (methadone or levo-alpha acetyl methadol [LAAM]) or partial agonist (buprenorphine)) forms of MOUD. Rewards for abstinence ranged from nonmonetary vouchers to take-home medication privileges. Meta-analysis of these trials showed no differences in retention (RR 1.02, 95% CI 0.96–1.08).14
Among the additional 7 RCTs we included, 4 assessed contingency management with full or partial agonist forms of MOUD and, similar to the SR findings, found no differences in retention between groups.26,33–35 The remaining 3 studies assessed contingency management with antagonist MOUD.30–32 Two of these studies (total n = 73) provided access to a workplace where study participants could earn vouchers to exchange for goods and services contingent upon receipt of XR-naltrexone monthly injections, and found that nearly twice as many intervention group participants received all scheduled monthly injections compared to controls who had noncontingent access to the workplace (66% vs 35%, P = 0.02630; and 74% vs 26%, P = 0.00431). The third study (n = 67) also provided access to the workplace contingent upon acceptance of daily naltrexone formulation, and similarly showed improved retention in the intervention group at 26 weeks (54% vs 16%, P < 0.01).32 A follow-up analysis conducted 6 month after completion of the study found no difference in medication adherence between the 2 groups (31% noncontingent vs 17% contingent, P = 0.66).32
Health Information Technology
Four RCTs (3 fair-quality37–39 and 1 poor40) and 3 fair-quality retrospective cohort studies41–43 assessed the effectiveness of Health IT (IT) interventions to improve retention on MOUD (Appendix Table 4, https://links.lww.com/JAM/A213). Figure 3 presents a graphic framework for how IT may help increase MOUD retention and summarizes the details of included studies.
All RCTs found IT interventions to be no less effective than in-person delivered TAU. The largest study was a fair-quality industry-sponsored RCT (n = 1426) that enrolled all patients into office-based buprenorphine treatment and randomized them to receive “Here-To-Help” (HTH) patient phone support intervention that provided coaching for medication adherence and access to online educational materials compared to office-based buprenorphine treatment alone (TAU). At 12 months, ITT analysis found no differences in retention between groups (55.5% HTH vs 56.1% TAU, P = NR). However, planned posthoc analyses reported that intervention participants who completed more phone coaching sessions had higher treatment retention compared to TAU (64.4% vs 56.1%, P < 0.025).38
A retrospective cohort study conducted in Ontario, Canada (n = 3733) tested the effectiveness of a telemedicine intervention on MOUD retention in areas with limited treatment access. The intervention allowed methadone-stabilized patients to receive care with an off-site physician via video-conference, while on-site nurses delivered guideline-concordant care. Just under half (47%) of patients received >75% of services in-person, 42% received >75% of services through IT, and 11% through a mix, with 25% to 75% of the therapy delivered via telemedicine. Compared to the mostly in-person group (39% retention), patients receiving mostly IT visits and patients who received a mix of IT visits were more likely to be retained in MOUD at 1 year (50% retention, aOR 1.27; 95% CI 1.14 to 1.41; 47% retention, aOR 1.27; 95% CI 1.08 to 1.47, respectively).42
Few studies reported harms associated with IT interventions. One RCT that assessed the effectiveness of combining methadone treatment with an adjunct phone-based cognitive behavioral therapy intervention reported 12 adverse events among 82 study participants (17% in the intervention group and 12% in TAU, P = NR). None were related to the intervention.37
None of the studies assessed whether the effectiveness of IT interventions varied by patient characteristics. Findings of a secondary analysis within an RCT that compared in-person counseling versus a combination of in-person and computer-based counseling (Therapeutic Educational System), found that counseling delivered using this combination may improve treatment retention among patients who are employed, highly anxious, ambivalent about opioid abstinence, and who have a history of crack cocaine use in the past 30 days.44
Extended-release Compared With Daily MOUD Formulations
Five RCTs (3 fair45–47; 2 good quality48,49) compared XR-MOUD formulations (buprenorphine injection/implant, naltrexone injection) head-to-head against daily MOUD formulations (naltrexone, buprenorphine/naloxone, buprenorphine, and methadone) (Appendix Table 5, https://links.lww.com/JAM/A213).
One (n = 60) fair-quality study compared treatment retention between XR-naltrexone monthly injections and daily naltrexone. Retention was assessed by documented clinical contact at 6 months and favored XR-naltrexone (57.1% vs 28.1%, HR = 2.18, 95% CI 1.07–4.43).46
Two studies compared retention between XR and daily buprenorphine formulations.47,49 One multi-site trial (n = 177) randomized patients who were clinically stable on daily buprenorphine before enrollment to either XR-buprenorphine 6-month implant or continued daily buprenorphine and found similar high rates of retention at 6 months (93.1% vs 94.3%, P = NR).49 Another trial (n = 428) randomized treatment-seeking patients to weekly, followed by monthly, XR-buprenorphine monthly injection versus daily buprenorphine/naloxone and also reported similar retention between groups at 24 weeks (56.8% vs 58.1%, P = NR).47
Two studies comparing XR-naltrexone monthly injection with daily buprenorphine/naloxone reported conflicting results.45,48 One good-quality Norwegian trial (n = 159) recruited patients from outpatient and inpatient settings, randomized them following completion of medically-supervised opioid withdrawal, and reported no difference in retention measured as mean days on study medication (mean [SD]: 69.3 [25.9] vs 63.7 [29.9] days, P = 0.33).48 Another multisite fair-quality US trial (n = 570) recruited patients from inpatient detox programs, randomized them before completing medically-supervised opioid withdrawal, and found lower retention rates in the XR-naltrexone group at 3 months (33.9% vs 40.0%, P = NR), in part due to decreased treatment initiation in the XR-NTX group.45
All studies of XR versus daily MOUD formulations reported adverse events. One study (n = 60) reported 2 severe drug related adverse events (hives and increased anxiety and alcohol use) which resulted in removing two XR-naltrexone group participants from the study.46 Another trial (n = 570) of XR-naltrexone injection versus daily buprenorphine/naloxone reported a total of 28 elicit opioid-related overdose events among 23 participants. Eighteen overdoses (64%) were in the XR-naltrexone arm and included 8 participants who failed treatment induction and never received an injection. Five overdose events were fatal (2 in the XR-naltrexone group and three in the daily buprenorphine/naloxone group).45 None of the studies assessed whether the effectiveness of XR-MOUD formulations to improve retention varied by participant characteristics.
One good-quality SR14 (26 relevant RCTs) and nine additional RCTs50–58 (n = 4957–65358), 2 of good quality,51,57 4 of fair quality,53,55,56,58 and 3 of poor quality,50,52,54 examined psychosocial interventions (eg, psychiatric care, psychotherapy, counseling, social work services)14 to improve MOUD retention (Appendix Table 6, https://links.lww.com/JAM/A213).
The existing SR meta-analysis found combining MOUD treatment with psychosocial interventions did not improve retention (n = 3124, RR 1.03, 95% CI 0.98–1.07).14 Of the 9 additional RCTs we identified, 8 also found no difference in MOUD retention.39,51–55,57,58 The 1 positive study was a poor-quality (n = 170) study of a community reinforcement approach (CRA+) that utilized participants’ social networks to increase MOUD program retention plus contingency management, versus contingency management alone, and reported increased retention in the CRA+ group (80% vs 64%; OR 2.3, CI 1.15–4.60).50
Few studies reported significant harms of psychosocial interventions. One study (n = 542) of pharmacist-delivered motivational interviewing versus standard methadone treatment found that intervention group participants reported poorer physical health.52
Few studies assessed which patient subgroups were most likely to benefit from the addition of psychosocial interventions. A study (n = 125) of XR-naltrexone coupled with a Behavioral Naltrexone Therapy compared to XR-naltrexone coupled with Compliance Enhancement intervention reported higher retention at 6-months in the Behavioral Naltrexone Therapy group among patients with low-severity OUD (<6 bags of heroin/day; 60% vs 24%, P = 0.03).56
It is clear that longer retention on MOUD reduces morbidity and mortality,59–61 but improving retention is difficult.6 This review summarized recent evidence on interventions to improve retention on MOUD and found limited evidence regarding which interventions are effective. We found that prerelease initiation of MOUD in incarcerated individuals with OUD, and contingency management interventions using antagonist, but not agonist, forms of MOUD, improved retention. Combining OUD treatment with medical, psychiatric, or social services, decreasing prescribing barriers to MOUD treatment, IT interventions, and XR formulations of MOUD did not worsen retention compared to TAU approaches but requires further study. Few studies reported intervention-related harms, the exception being studies of XR formulations that reported similar rates of adverse events between groups. Fewer studies assessed whether the effectiveness of different interventions to improve MOUD retention varied by patient subpopulation.
Many interventions reviewed attempt to improve retention on MOUD by expanding access to OUD treatment among novel settings. Our findings suggest that interventions initiating MOUD in soon-to-be-released incarcerated people with OUD improved retention. Given the rates of OUD in criminal justice populations and high overdose risk within the first few weeks of reentry into the community,62,63 these interventions have potential for high impact. Interventions initiating MOUD in hospital and emergency settings prior to discharge had comparable retention post-discharge as TAU; although one of the included studies and other nonrandomized evaluations found improved rates of short-term follow-up from these programs,27,64,65 our findings suggest that more efforts may be necessary postdischarge to support longer-term retention.
Another approach to improving retention may be addressing care fragmentation and delivery of patient-centered care through integrating MOUD treatment with outpatient medical, mental health, or social service settings. One potential reason that these studies did not demonstrate improved retention over TAU may be sub-optimal implementation of the integrated services and low-uptake of interventions66—future studies are needed that report aspects of implementation fidelity and specify the level of psychiatric or medical comorbidity of participants.
Our finding that contingency management interventions improved retention when combined with antagonist MOUD, but not with agonist MOUD suggests different interventions may have varying levels of effectiveness depending on MOUD type. Prior reviews have shown improved retention with methadone compared to buprenorphine.15 Several reasons for this include the effects of full-agonist compared to partial-agonist, sub-therapeutic levels of MOUD, differences in withdrawal syndromes, and past patient experience with MOUD.16 The lack of self-reinforcing properties of antagonist MOUD may be a reason why contingency management interventions improved retention only when paired with naltrexone. Although it was beyond the scope of this review to compare differential effects of interventions by MOUD, future studies could include additional treatment arms that utilize different MOUD formulations and doses.
Recognizing that there are few addiction providers and that most are concentrated in urban areas,17 IT-based interventions may be attractive for those in underserved and rural areas. The few studies we found showed similar retention rates with in-person approaches. Future studies of these interventions should be designed to assess long-term outcomes, be powered to demonstrate true equivalence, assess harms as well as benefits, and consider potential implementation challenges (eg, connectivity or software compatibility) to patients, clinicians, and systems.
Although XR-MOUD formulations are a conceptually-attractive intervention because of their ease of use, we found few studies comparing the effectiveness of XR versus daily MOUD formulations. Our synthesis extends prior reviews15 by including studies comparing XR and daily buprenorphine formulations 47,49 which showed comparable treatment retention. On the other hand, there were conflicting results in retention with XR-naltrexone monthly injection compared with daily buprenorphine. Potential reasons for this include between-study differences in the comorbidity burden of study populations, in dosing of comparator buprenorphine, and in study design (randomization before medically-supervised withdrawal versus postwithdrawal). Further comparative effectiveness trials are necessary and are underway, including a Helping to End Addiction Long-term (HEAL) Initiative trial that will assess retention at 6 months and can provide much-needed evidence in this area.67
Our review of psychosocial support interventions (excluding contingency management) found no differences in retention, consistent with a prior systematic review.68 The lack of effect may due to heterogeneity of the interventions studied, difficulties assessing fidelity of such interventions, as well as inclusion of elements of psychosocial support in the control groups, as is standard of care.18 Given these limitations, RCTs may not be the optimal study design to assess effectiveness and other evaluation methods may better assess the impact of these interventions on retention.
This review highlights a need to develop a consensus definition of retention for future research. Fewer than half of the studies included in this review reported retention as a primary outcome and were underpowered. We purposely defined retention broadly to include as many interventions as possible but this made comparisons and drawing conclusions difficult. Additionally, the wide differences in retention rates seen likely reflect enrollment of disparate populations and settings – future studies might use study designs that reflect “real-world” conditions to increase generalizability to the OUD population. Several on-going pragmatic trials, including the NIH NIDA Clinical Trials Network (CTN) “Retention-Duration-Discontinuation” trial (CTN-100 RDD Study)69 may help answer the question of whether XR formulations can improve retention in MOUD.
This review focused on MOUD interventions that are legal, available in the US, and of highest priority for stakeholders. Other interventions to address potential barriers to improved retention not addressed by our review include patient and system-level stigma towards use of MOUD4—educational interventions to overcome stigma may be effective. Athough financial barriers to MOUD are thought to affect MOUD retention, we did not identify any studies that assessed the impact of insurance or financial support and retention. Finally, our review was narrowly focused on the outcome of retention. When making healthcare or policy decisions, other outcomes (such as access to treatment, overdose, and quality of life, etc) are also important to consider.
Few studies of interventions to support MOUD retention assess retention as a primary outcome and even fewer assess intervention harms and patient characteristics associated with effectiveness. We found that retention in MOUD may be improved through several avenues, including use of integrated care settings with criminal justice populations, and use of contingency management interventions for patients on antagonist MOUD. Preliminary studies suggest that alternative means of care delivery (IT) and integration of medical, psychiatric, and social services with MOUD may yield similar retention outcomes to TAU. Although the few comparative effectiveness studies to date show no difference in retention between XR formulations and daily formulations, this evidence is evolving. Continued research on defining standard measures for retention and determining why low MOUD retention rates persist should guide future intervention development and testing.
The authors gratefully acknowledge the following individuals for their contributions to this project: Linda Humphrey, MD, MPH; Ed Reid, MS, MAT, MFA; Allison Schmidt, MS; Mark Helfand, MD, MS, MPH.
1. Substance Abuse and Mental Health Services Administration. TIP 63: Medications for Opioid Use Disorder 2018.
2. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and opioid-involved overdose deaths—United States, 2013–2017. MMWR Morb Mortal Wkly Rep
2019; 67 (5152):1419.
3. Van Handel MM, Rose CE, Hallisey EJ, et al. County-level vulnerability assessment for rapid dissemination of HIV or HCV infections among persons who inject drugs, United States. J Acquir Immune Defic Syndr
2016; 73 (3):323.
4. National Academies of Sciences Engineering, Medicine. Medications for Opioid Use Disorder Save Lives. Washington, DC: The National Academies Press; 2019.
5. Volkow ND, Jones EB, Einstein EB, Wargo EM. Prevention and treatment of opioid misuse and addiction: a review. JAMA Psychiatry
2019; 76 (2):208–216.
6. Timko C, Schultz NR, Cucciare MA, Vittorio L, Garrison-Diehn C. Retention
in medication-assisted treatment for opiate dependence: a systematic review. J of Addict Dis
2016; 35 (1):22–35.
7. NIDA. Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition)
. Bethesda, MD: NIDA; 2018.
8. Kourounis G, Richards BD, Kyprianou E, Symeonidou E, Malliori MM, Samartzis L. Opioid substitution therapy: lowering the treatment thresholds. Drug Alcohol Depend
9. Lin LA, Lofwall MR, Walsh SL, Gordon AJ, Knudsen HK. Perceptions and practices addressing diversion among US buprenorphine prescribers. Drug Alcohol Depend
10. Chan B, Gilbert J, Gean E, et al. A rapid evidence review of retention
strategies for medications for addiction treatment (MAT) in adults with opioid use disorder. PROSPERO
11. Chan B, Gean E, Arkhipova-Jenkins I, et al. Protocol: A rapid evidence review of retention
strategies for medications for addiction treatment (MAT) in adults with opioid use disorder. A research protocol. AHRQ Effective Health Care Program https://effectivehealthcare.ahrq.gov/products/retention-strategies-opioid-use-disorder/rapid-protocol
. Published 2019. Accessed October 9, 2019.
12. Tricco AC, Langlois E, Straus SE, Organization WH. Rapid Reviews to Strengthen Health Policy and Systems: a Practical Guide. Geneva, Switzerland: World Health Organization; 2017.
13. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol
2009; 62 (10):1006–1012.
14. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence. Cochrane Database Syst Rev
15. Jarvis BP, Holtyn AF, Subramaniam S, et al. Extended-release injectable naltrexone for opioid use disorder: a systematic review. Addiction
2018; 113 (7):1188–1209.
16. Office of the National Coordinator for Health IT. Section 4: Opioid epidemic and health IT. In. Health IT playbook
17. Viswanathan M, Patnode CD, Berkman ND, et al. Assessing the risk of bias in systematic reviews of health care interventions. In: Methods guide for effectiveness and comparative effectiveness reviews [Internet].
Agency for Healthcare Research and Quality (US); 2017.
18. Hedrich D, Alves P, Farrell M, Stover H, Moller L, Mayet S. The effectiveness of opioid maintenance treatment in prison settings: a systematic review. Addiction
2012; 107 (3):501–517.
19. Schwartz RP, Kelly SM, Mitchell SG, et al. Patient-centered methadone treatment: a randomized clinical trial. Addiction
2017; 112 (3):454–464.
20. Gordon MS, Kinlock TW, Schwartz RP, O’Grady KE, Fitzgerald TT, Vocci FJ. A randomized clinical trial of buprenorphine for prisoners: findings at 12-months post-release. Drug Alcohol Depend
21. Carrieri PM, Michel L, Lions C, et al. Methadone induction in primary care for opioid dependence: a pragmatic randomized trial (ANRS Methaville). PLoS ONE [Electronic Resource]
2014; 9 (11):e112328.
22. Brooner RK, Kidorf MS, King VL, et al. Managing psychiatric comorbidity within versus outside of methadone treatment settings: a randomized and controlled evaluation. Addiction
2013; 108 (11):1942–1951.
23. Miotto K, Hillhouse M, Donovick R, et al. Comparison of buprenorphine treatment for opioid dependence in 3 settings. J Addict Med
2012; 6 (1):68–76.
24. Liebschutz JM, Crooks D, Herman D, et al. Buprenorphine treatment for hospitalized, opioid-dependent patients: a randomized clinical trial. JAMA Intern Med
2014; 174 (8):1369–1376.
25. Parpouchi M, Moniruzzaman A, Rezansoff SN, Russolillo A, Somers JM. The effect of Housing First on adherence to methadone maintenance treatment. Int J Drug Policy
26. Kidorf M, Brooner RK, Leoutsakos JM, Peirce J. Treatment initiation strategies for syringe exchange referrals to methadone maintenance: a randomized clinical trial. Drug Alcohol Depend
27. D’Onofrio G, Chawarski MC, O’Connor PG, et al. Emergency department-initiated buprenorphine for opioid dependence with continuation in primary care: outcomes during and after intervention. J Gen Intern Med
2017; 32 (6):660–666.
28. Beattie A, Marques EM, Barber M, et al. Script in a Day intervention for individuals who are injecting opioids: a feasibility randomized control trial. J Public Health (Oxf)
2015; 38 (4):712–721.
29. Friedmann PD, Wilson D, Hoskinson R Jr, Poshkus M, Clarke JG. Initiation of extended release naltrexone (XR-NTX) for opioid use disorder prior to release from prison. J Subst Abuse Treat
30. Everly JJ, DeFulio A, Koffarnus MN, et al. Employment-based reinforcement of adherence to depot naltrexone in unemployed opioid-dependent adults: a randomized controlled trial. Addiction
2011; 106 (7):1309–1318.
31. DeFulio A, Everly JJ, Leoutsakos JM, et al. Employment-based reinforcement of adherence to an FDA approved extended release formulation of naltrexone in opioid-dependent adults: a randomized controlled trial. Drug Alcohol Depend
2012; 120 (1–3):48–54.
32. Dunn KE, Defulio A, Everly JJ, et al. Employment-based reinforcement of adherence to oral naltrexone treatment in unemployed injection drug users. Exp Clin Psychopharmacol
2013; 21 (1):74–83.
33. Holtyn AF, Koffarnus MN, DeFulio A, et al. The therapeutic workplace to promote treatment engagement and drug abstinence in out-of-treatment injection drug users: a randomized controlled trial. Prev Med
34. Specka M, Boning A, Kluwig J, et al. Can reinforcement-based interventions to reduce drug use successfully be adapted to routine opioid maintenance treatment? Ann Ist Super Sanita
2013; 49 (4):358–364.
35. Epstein DH, Schmittner J, Umbricht A, Schroeder JR, Moolchan ET, Preston KL. Promoting abstinence from cocaine and heroin with a methadone dose increase and a novel contingency. Drug Alcohol Depend
2009; 101 (1–2):92–100.
36. Dunn K, DeFulio A, Everly JJ, et al. Employment-based reinforcement of adherence to oral naltrexone in unemployed injection drug users: 12-month outcomes. Psychol Addict Behav
2015; 29 (2):270–276.
37. Moore BA, Buono FD, Lloyd DP, Printz DMB, Fiellin DA, Barry DT. A randomized clinical trial of the Recovery Line among methadone treatment patients with ongoing illicit drug use. J Subst Abuse Treat
38. Ruetsch C, Tkacz J, McPherson TL, Cacciola J. The effect of telephonic patient support on treatment for opioid dependence: outcomes at one year follow-up. Addict Behav
2012; 37 (5):686–689.
39. Shi JM, Henry SP, Dwy SL, Orazietti SA, Carroll KM. Randomized pilot trial of Web-based cognitive-behavioral therapy adapted for use in office-based buprenorphine maintenance. Subst Abuse
40. Marsch LA, Guarino H, Acosta M, et al. Web-based behavioral treatment for substance use disorders as a partial replacement of standard methadone maintenance treatment. J Subst Abuse Treat
2014; 46 (1):43–51.
41. Weintraub E, Greenblatt AD, Chang J, Himelhoch S, Welsh C. Expanding access to buprenorphine treatment in rural areas with the use of telemedicine. Am J Addict
2018; 27 (8):612–617.
42. Eibl JK, Gauthier G, Pellegrini D, et al. The effectiveness of telemedicine-delivered opioid agonist therapy in a supervised clinical setting. Drug Alcohol Depend
43. Zheng W, Nickasch M, Lander L, et al. Treatment outcome comparison between telepsychiatry and face-to-face buprenorphine medication-assisted treatment for opioid use disorder: a 2-year retrospective data analysis. J Addict Med
2017; 11 (2):138–144.
44. Kim SJ, Marsch LA, Guarino H, Acosta MC, Aponte-Melendez Y. Predictors of outcome from computer-based treatment for substance use disorders: Results from a randomized clinical trial. Drug Alcohol Depend
45. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet
2018; 391 (10118):309–318.
46. Sullivan MA, Bisaga A, Pavlicova M, et al. A randomized trial comparing extended-release injectable suspension and oral naltrexone, both combined with behavioral therapy, for the treatment of opioid use disorder. Am J Psychiatry
2019; 176 (2):129–137.
47. Lofwall MR, Walsh SL, Nunes EV, et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern Med
2018; 178 (6):764–773.
48. Tanum L, Solli KK, Latif ZE, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry
2017; 74 (12):1197–1205.
49. Rosenthal RN, Lofwall MR, Kim S, et al. Effect of buprenorphine implants on illicit opioid use among abstinent adults with opioid dependence treated with sublingual buprenorphine: a randomized clinical trial. JAMA
2016; 316 (3):282–290.
50. Christensen DR, Landes RD, Jackson L, et al. Adding an internet-delivered treatment to an efficacious treatment package for opioid dependence. J Consult Clin Psychol
2014; 82 (6):964–972.
51. Fiellin DA, Barry DT, Sullivan LE, et al. A randomized trial of cognitive behavioral therapy in primary care-based buprenorphine. Am J Med
2013; 126 (1):74e11–74e77.
52. Jaffray M, Matheson C, Bond CM, et al. Does training in motivational interviewing for community pharmacists improve outcomes for methadone patients? A cluster randomised controlled trial. Int J Pharm Pract
2014; 22 (1):4–12.
53. Marsden J, Stillwell G, James K, et al. Efficacy and cost-effectiveness of an adjunctive personalised psychosocial intervention in treatment-resistant maintenance opioid agonist therapy: a pragmatic, open-label, randomised controlled trial. Lancet Psychiatry
2019; 6 (5):391–402.
54. Mitchell SG, Gryczynski J, Schwartz RP, O’Grady KE, Olsen YK, Jaffe JH. A randomized trial of intensive outpatient (IOP) vs. standard outpatient (OP) buprenorphine treatment for African Americans. Drug Alcohol Depend
2013; 128 (3):222–229.
55. Schwartz RP, Kelly SM, O’Grady KE, Gandhi D, Jaffe JH. Randomized trial of standard methadone treatment compared to initiating methadone without counseling: 12-month findings. Addiction
2012; 107 (5):943–952.
56. Sullivan MA, Bisaga A, Glass A, et al. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone. Drug Alcohol Depend
57. Stein MD, Herman DS, Moitra E, et al. A preliminary randomized controlled trial of a distress tolerance treatment for opioid dependent persons initiating buprenorphine. Drug Alcohol Depend
58. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry
2011; 68 (12):1238–1246.
59. Fiellin DA, Schottenfeld RS, Cutter CJ, Moore BA, Barry DT, O’Connor PG. Primary care-based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. JAMA Intern Med
2014; 174 (12):1947–1954.
60. Larochelle MR, Bernson D, Land T, et al. Medication for opioid use disorder after nonfatal opioid overdose and association with mortality: a cohort study. Ann Intern Med
2018; 169 (3):137–145.
61. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative effectiveness of different treatment pathways for opioid use disorder. JAMA Netw Open
2020; 3 (2):e1920622.
62. Chandler RK, Fletcher BW, Volkow ND. Treating drug abuse and addiction in the criminal justice system: improving public health and safety. Jama
2009; 301 (2):183–190.
63. Binswanger IA, Blatchford PJ, Mueller SR, Stern MF. Mortality after prison release: opioid overdose and other causes of death, risk factors, and time trends from 1999 to 2009. Ann Intern Med
2013; 159 (9):592–600.
64. Wakeman SE, Chang Y, Regan S, et al. Impact of Fentanyl Use on Buprenorphine Treatment Retention
and Opioid Abstinence. J Addict Med
65. Englander H, Dobbertin K, Lind BK, et al. Inpatient addiction medicine consultation and post-hospital substance use disorder treatment engagement: a propensity-matched analysis. J Gen Intern Med
66. Ling W, Mooney L, Wu LT. Advances in opioid antagonist treatment for opioid addiction. Psychiatric Clin N Am
2012; 35 (2):297–308.
67. National Institute of Health. NIH funds study in four states to reduce opioid related deaths by 40 percent over three years. Published 2019 Accessed.
68. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev
69. National Institute of Health. Optimizing Retention
, Duration, and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (NIH HEAL Initiative); 2019. Available at: https://www.drugabuse.gov/about-nida/organization/cctn/ctn/research-studies/optimizing-retention-duration-discontinuation-strategies-opioid-use-disorder-pharmacotherapy-nih
. Accessed June 2020.