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Cited by 315Opioid Use Disorder TreatmentSubstance Abuse Treatment and OutcomesPain Management and Opioid Use

Extended-release naltrexone to prevent opioid relapse in criminal justice offenders

Open access
Lee, Joshua D., Friedmann, Peter D., Kinlock, Timothy W., Nunes, Edward V., Boney, Tamara Y., Hoskinson, Randall A., Wilson, Donna, McDonald, Ryan +9 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1505409PMC PMC5454800
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Abstract

BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

AI snapshot

Written from the paper’s full text.

TL;DR

In a five-site, open-label randomized trial involving 308 criminal justice offenders with opioid dependence and opioid abstinence at baseline, extended-release naltrexone reduced opioid relapse during a 24-week treatment phase compared with usual treatment. The relapse-prevention effect waned after treatment discontinuation, with opioid-negative urine rates equal at week 78.

Key findings

  • During the 24-week treatment phase, extended-release naltrexone produced a longer median time to relapse than usual treatment (10.5 vs. 5.0 weeks; P<0.001; hazard ratio, 0.49; 95% CI, 0.36 to 0.68) and a lower relapse rate (43% vs. 64%; P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65).
  • Opioid-negative urine samples were more frequent with extended-release naltrexone than usual treatment during treatment (74% vs. 56%; P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54).
  • At week 78, rates of opioid-negative urine samples were equal (46% in each group, P=0.91), and secondary outcomes including cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration were not significantly lower with extended-release naltrexone.
  • Over 78 weeks, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02).

Methods

  • Five-site, open-label, randomized controlled effectiveness trial comparing six monthly injections of extended-release naltrexone (380 mg) with usual treatment consisting of brief counseling and referrals for community treatment programs.
  • A total of 308 adult criminal justice offenders with a history of opioid dependence, a preference for opioid-free treatment, and confirmed opioid abstinence before randomization were assigned: 153 to extended-release naltrexone and 155 to usual treatment; follow-up occurred at weeks 27, 52, and 78.
  • The primary outcome was time to an opioid-relapse event during the 24-week treatment phase, defined as 10 or more days of opioid use in a 28-day period by self-report or urine testing every 2 weeks, with a positive or missing sample computed as 5 days of opioid use; analyses used Cox proportional-hazards and mixed-effects models, with missing urine data counted as positive.

Limitations

  • The trial was not blinded; the authors note that an open-label effectiveness design may increase attention, recall, and assessment biases.
  • Sites were in the U.S. Northeast corridor, participants were former or current heroin users, and implications for other U.S. regions and prescription-opioid disorders are unclear; eligibility criteria also did not distinguish among levels of previous opioid use or grades of severity, and most participants had not used opioids in the previous 30 days and did not require detoxification.
  • Intensity and methods of community supervision varied by state and site, and the trial did not directly compare extended-release naltrexone with opioid-agonist maintenance treatment; the text also makes evident that long-term follow-up used only three visits, so the primary relapse outcome was not available after treatment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1056/nejmoa1505409

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 24 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Among adult criminal justice offenders with opioid dependence and confirmed opioid abstinence at randomization, extended-release naltrexone was associated with a lower rate of opioid relapse than usual treatment during the 24-week treatment phase.

    “a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65)”
    • Also stated in: § CONCLUSIONS · plain
      “extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment.”
    • Also stated in: § DISCUSSION · plain
      “showed that extended-release naltrexone resulted in a lower rate of opioid relapse than the rate with usual treatment in a predominantly male and minority population of outpatient, voluntary participants with criminal justice involvement and opioid abstinence at baseline.”
    Quote in the paperSubstantial claim
  • Findingown data

    At week 52, opioid-negative urine samples were found in similar proportions of the naltrexone and usual-care groups (49% vs. 46%, P=0.61).

    “The percentage of participants with opioid-negative urine samples was similar in the two groups after completion of the treatment phase: 49% in the extended-release naltrexone group and 46% in the usual-treatment group at week 52 (P = 0.61), and 46% in both groups at week 78 (P = 0.91).”
    Quote in the paperSubstantial claim
  • Findingown data

    Adverse events, including those related to medication, occurred more often in the naltrexone group than in the usual-care group.

    “Adverse events, including medication-related adverse events, were more common among participants assigned to extended-release naltrexone than among those assigned to usual treatment (Table 4); however, significantly more serious adverse events occurred in the usual-treatment group than in the extended-release naltrexone group.”
    Quote in the paperNot a substantial claim
  • Findingown data

    During the trial, opioid-agonist treatment was sought by more usual-care participants than naltrexone participants (37% vs. 11%, P<0.001).

    “More participants in the usual-treatment group than in the extended-release naltrexone group pursued opioid-agonist treatments during the trial (37% vs. 11%, P<0.001), primarily after resumed illicit opioid use and relapse.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Serious adverse events were significantly more frequent in the usual-care group than in the naltrexone group.

    “Adverse events, including medication-related adverse events, were more common among participants assigned to extended-release naltrexone than among those assigned to usual treatment (Table 4); however, significantly more serious adverse events occurred in the usual-treatment group than in the extended-release naltrexone group.”
    Quote in the paperSubstantial claim
  • May combine two claims. 14
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    Self-reported cocaine use, alcohol use, intravenous drug use, unsafe sex, and reincarceration did not occur at significantly lower rates in the naltrexone group than in the usual-care group.

    “The rates of other prespecified secondary outcome measures — self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration — were not significantly lower with extended-release naltrexone than with usual treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Across the full 78 weeks, no overdoses occurred in the naltrexone group, whereas seven occurred in the usual-care group (P=0.02).

    “Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P = 0.02).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 24-week treatment phase, median time to relapse was longer for the naltrexone group than for the usual-care group (10.5 vs. 5.0 weeks; hazard ratio, 0.49; 95% CI, 0.36 to 0.68; P<0.001).

    “During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Most participants reported no opioid use in the prior 30 days and needed no detoxification.

    “The majority of participants enrolled in this trial had not used opioids in the previous 30 days and did not require detoxification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Opioid dependence is disproportionately common among people in the U.S. criminal justice system.

    “Opioid dependence disproportionately affects U.S. criminal justice system populations, and relapse and overdose deaths occur at high rates after release from incarceration.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] 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 159 592 600 24189594 PMC5242316

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After release from incarceration, relapse and overdose deaths occur at high rates.

    “Opioid dependence disproportionately affects U.S. criminal justice system populations, and relapse and overdose deaths occur at high rates after release from incarceration.1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] 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 159 592 600 24189594 PMC5242316

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Every site received approval for the shared protocol from its local institutional review board and from the U.S. Office for Human Research Protections.

    “All sites obtained approval from the local institutional review board and the U.S. Office for Human Research Protections for the common trial protocol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Community supervision differed in intensity and method across states and sites, although treatment effects did not vary by site.

    “Fourth, intensity and methods of community supervision varied according to state and site (e.g., parolees in home confinement vs. mandated residential treatment), though the main effects did not vary according to site.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Randomization used an urn procedure to balance site, sex, and whether detoxification was needed.

    “An urn randomization procedure ensured balance with respect to trial site, sex, and status regarding the need for opioid detoxification.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Stout RL Wirtz PW Carbonari JP Del Boca FK Ensuring balanced distribution of prognostic factors in treatment outcome research J Stud Alcohol Suppl 1994 12 70 5 7723001 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Both groups underwent identical follow-up and assessment procedures.

    “Follow-up and assessment procedures were the same in the two groups.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To reduce possible coercion, recruitment avoided direct referrals from correctional, probation, parole, drug-court, or diversion authorities.

    “in an effort to minimize potential coercion, we did not recruit through direct referrals from criminal justice authorities, including departments of corrections, probation, or parole and drug courts or other diversion programs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Treatment assignments were made by a centralized automated telephone system that was independent, after eligibility had been confirmed.

    “An independent, centralized, automated telephone system made the treatment assignments after eligibility of the participants was confirmed.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] U.S. Department of Veterans Affairs Office of Research and Development CSP Coordinating Center — Perry Point, MD (http://www.research.va.gov/programs/csp/perrypoint.cfm)

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    The planned sample was 164 per group; with about 5% monthly attrition, this gave 80% power to detect a hazard ratio of at least 1.53 for relapse with usual care, corresponding to a 15 percentage point difference (45% vs. 30%).

    “We calculated that a sample size of 164 participants per group, with an assumed loss to attrition of approximately 5% per month, would provide the trial with 80% power to detect a hazard ratio for relapse with usual treatment of 1.53 or higher, equivalent to an estimated difference in relapse rates of 15 percentage points (45% vs. 30%).9,13”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Comer SD Collins ED Kleber HD Nuwayser ES Kerrigan JH Fischman MW Depot naltrexone: long-lasting antagonism of the effects of heroin in humans Psychopharmacology (Berl) 2002 159 351 60 11823887 PMC4079470

      Not checked in the free run.

    • cites [13] Coviello DM Cornish JW Lynch KG A multisite pilot study of extended-release injectable naltrexone treatment for previously opioid-dependent parolees and probationers Subst Abus 2012 33 48 59 22263713 PMC3365863

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Neither the sponsor nor the drug manufacturer had access to trial data or editorial control.

    “The sponsor (National Institute on Drug Abuse) and the manufacturer of extended-release naltrexone (Alkermes) did not have editorial control or access to trial data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The eligibility rules did not separate participants by amount of prior opioid use or by severity grade of opioid-use disorder.

    “Third, eligibility criteria did not distinguish among levels of previous opioid use or grades of severity of opioiduse disorder; randomization was stratified according to whether or not detoxification was required before randomization.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The primary relapse measure could not be used in long-term follow-up, since only weeks 52 and 78 were visited.

    “The primary relapse outcome used during the treatment phase, defined by assessments performed every 2 weeks, self-report, and testing of urine samples, was not available during long-term follow-up because visits were scheduled only at weeks 52 and 78.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Missing visits and urine samples were treated as positive for opioid use, meaning dropouts counted toward relapse.

    “Missed visits and missing data on urine samples were counted as positive for opioid use; thus, dropouts contributed to a relapse event.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Seventy-five percent of participants completed the end-of-treatment-phase visit at week 27.

    “A total of 75% of the participants completed an end-of-treatment-phase visit at week 27.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The trial's findings may not generalize to other U.S. regions or to prescription-opioid disorders.

    “Second, sites were in the U.S. Northeast corridor, and participants were former or current heroin users; implications for other U.S. regions and prescription-opioid disorders are unclear.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    To show they understood the consent information, participants had to pass a quiz.

    “participants were required to establish their comprehension of consent information by passing an informed-consent quiz.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Attendance at the biweekly visits was 77% overall (3096 of 4004), 79% in the naltrexone group and 75% in the usual-care group.

    “Most of the visits that were scheduled every 2 weeks (3096 of 4004, 77%) were attended; participants assigned to extended-release naltrexone attended 79% of the scheduled visits, and those assigned to usual treatment attended 75%.”
    Quote in the paperNot a substantial claim
21 of 21

  • The paper relies on this without support.

    Data on the effectiveness of extended-release naltrexone in U.S. criminal justice populations are limited.

    “Data supporting its effectiveness in U.S. criminal justice populations are limited.”

  • The paper relies on this without support.

    Extended-release naltrexone has gained increasing acceptance in the criminal justice system despite limited data on its effectiveness.

    “As a noncontrolled substance with no known abuse or diversion potential, extended-release naltrexone has gained increasing acceptance in the criminal justice system despite limited data on effectiveness.”

  • The paper relies on this without support.

    Extended-release naltrexone is a noncontrolled substance with no known abuse or diversion potential.

    “As a noncontrolled substance with no known abuse or diversion potential, extended-release naltrexone has gained increasing acceptance in the criminal justice system despite limited data on effectiveness.”
3 of 3

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Authors
Lee, J. D., Friedmann, P. D., Kinlock, T. W., Nunes, E. V., Boney, T. Y., Hoskinson, R. A., Wilson, D., McDonald, R., Rotrosen, J., Gourevitch, M. N., Gordon, M., Fishman, M., Chen, D. T., Bonnie, R. J., Cornish, J. W., Murphy, S. M., & O’Brien, C. P.
Affiliations
  • Brown University (US)
  • Washington State University Spokane (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-03-31
Volume
374
Issue
13
Pages
1232-1242
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1505409
PMC
PMC5454800
OpenAlex
W2327042539
Semantic Scholar
53967c744edcb98b04eba5969d284ac81f438a76
Cited by
315
References
23
Citations by year
2026: 9 · 2025: 18 · 2024: 24 · 2023: 22 · 2022: 27 · 2021: 30 · 2020: 42 · 2019: 44 · 2018: 41 · 2017: 39 · 2016: 15 · 2015: 3
FWCI
45.94
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Drug Abuse (K24DA022412, R01DA024555, R01DA024550, R01DA024554, R01DA024553, R01DA024549, P30DA040500)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords
extended-release naltrexone, Vivitrol, opioid use disorder, mu-opioid receptor antagonist, injectable naltrexone, urine drug testing, cocaine use, alcohol consumption, intravenous drug use, unprotected sex, reincarceration, opioid maintenance treatment, brief counseling, community-based treatment, opioid use disorder treatment
MeSH terms
Adult, Community Health Services, Counseling, Delayed-Action Preparations, Female, Humans, Male, Middle Aged, Naltrexone, Narcotic Antagonists, Opioid-Related Disorders, Substance Abuse, Intravenous, Kaplan-Meier Estimate, Secondary Prevention, Criminals, Drug Overdose

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