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.
Opioid-use disorder is a chronic relapsing condition that has serious public health consequences. Opioid dependence disproportionately affects U.S. criminal justice system populations, and relapse and overdose deaths occur at high rates after release from incarceration.1 Evidence-based opioid-agonist maintenance therapies for opioid dependence (methadone and buprenorphine) are effective in prison, jail, and community reentry (i.e., parole) settings2–5 but have historically been unavailable or discouraged among criminal justice clients.6–8 Extended-release naltrexone (Vivitrol, Alkermes), a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, was approved by the Food and Drug Administration in 2010 for the prevention of relapse to opioid dependence. Extended-release naltrexone may be particularly appealing and beneficial to patients and providers who are unlikely to access opioid-agonist maintenance treatment or who prefer a relapse-prevention medication. 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.
Extended-release naltrexone gradually releases sufficient naltrexone to block the euphoric effects of opioids for approximately 1 month after injection and is efficacious as compared with placebo.9–12 A pilot study that was performed at the same five sites that participated in this trial used a single-group observational cohort design and showed the feasibility of using Depotrex, an alternative formulation of extended-release naltrexone, as a treatment option for outpatient parolees and probationers.13 We conducted a large, multisite, randomized trial to examine the effectiveness of extended-release naltrexone among community-dwelling criminal justice offenders who were at high risk for opioid relapse and related adverse outcomes.
METHODS
TRIAL DESIGN, SITES, AND OVERSIGHT
This open-label, randomized, controlled effectiveness trial compared six monthly injections of extended-release naltrexone (Vivitrol, Alkermes) with usual treatment (brief counseling and referrals for community treatment programs) for the prevention of opioid relapse among criminal justice offenders. We hypothesized that the likelihood of an opioid-relapse event would be lower, the time to relapse longer, and overall rates of opioid use lower with extended-release naltrexone than with usual treatment.
Five independently funded sites implemented a common collaborative protocol: University of Pennsylvania (Philadelphia), New York University School of Medicine and Bellevue Hospital Center (New York), Rhode Island Hospital and Brown University (Providence, Rhode Island), Columbia University Medical Center (New York), and Friends Research Institute (Baltimore). The University of Pennsylvania, which was the lead site, hosted the regulatory and data management cores and the data and safety monitoring board.
The rationale, protocol development, design, and methods of this trial are described in full elsewhere.14 All sites obtained approval from the local institutional review board and the U.S. Office for Human Research Protections for the common trial protocol. The authors alone designed and implemented the trial; collected, accessed, and analyzed the data; and vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol, which is available with the full text of this article at NEJM.org. The first author wrote the initial draft of the manuscript, and all the authors participated in revisions and approved the final draft. 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. The manufacturer contributed Vivitrol in kind through an investigator-initiated trial contract, which allowed for review of and comment on the manuscript before submission for publication.
PARTICIPANTS
We recruited community-dwelling adult volunteers who had been incarcerated and who had a history of opioid dependence. Eligibility criteria were current (within the previous 12 months) or lifetime (any previous) opioid dependence (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition [DSM-IV])15; a stated goal of opiate-free treatment rather than opioid-agonist or partial-agonist maintenance therapy; an opioid-free status as confirmed by negative urine toxicologic screening for all opioids before randomization; residence in the community and receipt of an adjudicated sentence that included supervision (e.g., parole, probation, outpatient drug-court programs, or other court-mandated treatment) or, in the previous 12 months, release from jail or prison, a plea-bargain arrangement, or any community supervision as above; general good health as determined by history and physical examination; an age of 18 to 60 years; and the ability to provide written informed consent.
Exclusion criteria were other drug or alcohol dependence requiring a level of care that would interfere with trial participation; pregnancy or a plan to conceive during the 24-week treatment phase, lactation, or an inability to use adequate contraceptive methods; an untreated psychiatric disorder or medical condition that might make participation hazardous, including liver-enzyme levels more than three times the upper limit of the normal range and a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 40; allergy to naltrexone, polylactide-co-glycolide, carboxymethylcellulose, or other components of the diluent; a current diagnosis of chronic pain for which opioids were prescribed; or a drug overdose in the previous 3 years requiring inpatient hospitalization.
We recruited participants by standard outreach to community-dwelling at-risk populations through print, radio, and online publicity and provider detailing (e.g., letters to clinic directors); 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. Prescreening questionnaires were used to briefly evaluate potential participants and to schedule an in-person screening visit at which written informed consent was obtained; participants were required to establish their comprehension of consent information by passing an informed-consent quiz.
RANDOMIZATION AND TRIAL TREATMENTS
Participants were randomly assigned, in a 1:1 ratio, to extended-release naltrexone or usual treatment for opioid-relapse prevention. An urn randomization procedure ensured balance with respect to trial site, sex, and status regarding the need for opioid detoxification.16 An independent, centralized, automated telephone system made the treatment assignments after eligibility of the participants was confirmed.17
Trial physicians or nurses administered extended-release naltrexone by injection and provided medication-management counseling. Extended-release naltrexone, at a dose of 380 mg, was administered by intramuscular injection once every 4 weeks during medical management visits, the first of which occurred at the time of randomization. A standard naloxone challenge (i.e., administration of >0.8 mg of naloxone intravenously, intramuscularly, or subcutaneously and assessment of opioid-withdrawal symptoms) had to be negative before the initial injection. At one site (Friends Research Institute), 12.5 mg of oral naltrexone was also administered as a low-dose challenge, followed by a 2-hour observation period, before injection of extended-release naltrexone; this additional challenge reflected the preferences of the local site and institutional review board. Medical management counseling focused on medication side effects, support for recovery and treatment participation, and counseling to reduce the risk of relapse and overdose.18 Participants in the usual-treatment group received similar counseling that was focused on adverse events, the prevention of relapse and overdose, and support for community treatment involvement from the same trial personnel.
Incentives, follow-up visit schedules and procedures, and community treatment referrals were the same in the two groups; all participants were encouraged by the same trial staff to access appropriate community treatment and relapse-prevention resources, including buprenorphine or methadone treatment if preferred or indicated during the trial and after the treatment phase (no extended-release naltrexone was provided after the end of the 24-week treatment phase). All participants were compensated for attendance at individual visits; total cash or voucher compensation across 17 visits varied according to site ($385 to $820).
CLINICAL ASSESSMENTS
Follow-up and assessment procedures were the same in the two groups. Visits occurred at screening, randomization, and then every 2 weeks for 24 weeks during the treatment phase. Post-treatment follow-up assessments occurred at weeks 27, 52, and 78 (three visits only). The visits occurring every 2 weeks and at weeks 27, 52, and 78 included urine toxicologic screening and self-report of opioid, cocaine, alcohol, and intravenous drug use with the use of the Timeline Followback calendar method for count data.19 Urine samples were tested for opiates (a level >300 ng per milliliter was considered to indicate a positive test), oxycodone, methadone, buprenorphine, and cocaine metabolites. Data on unsafe sex were captured every 6 months with the use of the Sex Risk subscale of the Risk Assessment Battery (on which scores range from 0 to 18, with higher scores indicating a greater risk of contracting and spreading human immunodeficiency virus [HIV] infection through sexual behaviors).20 Self-reported information about criminal activity, rearrests, and days of reincarceration was collected every 2 weeks with the use of the Timeline Followback method for days in controlled environments, monthly with the use of the Crime and Legal Activities Report,21 and every 6 months with the use of the legal-status items in the Addiction Severity Index Lite.22
OUTCOMES
The primary outcome was the time (in weeks) to an opioid-relapse event during the 24-week treatment phase. A relapse event was defined as 10 or more days of opioid use in a 28-day (4-week) 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. Relapse was considered to be a onetime event and corresponded to the loss of persistent opioid abstinence after randomization, when all participants had been opioid-free and had endorsed a goal of opioid abstinence. Related opioid-use outcomes were rates of opioid-negative (vs. opioid-positive or missing) urine samples, the percentage of 2-week intervals with no opioid use as assessed by self-report or by testing of urine samples (confirmed abstinence), the percentage of days with self-reported opioid use, and post-treatment rates of opioid use as assessed by self-report (percentage of 2-week intervals with any opioid use vs. no opioid use) and by testing of single urine samples at weeks 52 and 78. 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. Secondary outcomes of interest were rates of alcohol and nonopioid drug use, HIV risk behaviors, rearrests and reincarcerations, and adverse events including opioid overdose.
STATISTICAL ANALYSIS
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 The primary outcome analysis tested whether extended-release naltrexone resulted in a longer time to relapse than that with usual treatment, with the use of Cox proportional-hazards regression models. We compared overall relapse rates using intention-to-treat mixed-effects logistic-regression models and compared rates of positive urine tests and days with self-reported opioid use using a linear mixed-effects model for count data. Missed visits and missing data on urine samples were counted as positive for opioid use; thus, dropouts contributed to a relapse event. Missing data for secondary outcomes (cocaine, alcohol, and intravenous drug use; score on the Sex Risk subscale of the Risk Assessment Battery; and reincarceration) were estimated from available data only.
At the week 52 and week 78 visits, participants provided 6 months of self-reports on opioid use and a single urine sample. We analyzed the percentage of opioid-negative (vs. opioid-positive or missing) urine samples at both visits using mixed-effects logistic models. We used a logistic mixed-effects model for repeated measures to analyze self-reported opioid use from week 1 to week 78 and to test for differences in the treatment groups over time with the use of an interaction term between group and time.
RESULTS
SCREENING AND RANDOMIZATION
Recruitment began in February 2009 and continued through November 2013. The five sites obtained consent from and screened 437 persons, of whom 308 underwent randomization; 153 were assigned to extended-release naltrexone and 155 to usual treatment (Fig. 1). Common reasons for exclusion were an incomplete screening visit, incomplete detoxification or a lack of opioid abstinence before randomization, and serious medical or psychiatric coexisting conditions. Two potential participants were excluded because of a BMI of more than 40 and therefore a potentially elevated risk of a severe injection-site reaction.
Figure 1.
Screening, Randomization, and Follow-up.
PARTICIPANTS
The characteristics of the trial groups were similar at baseline. The mean age was 44 years; 85% of the participants were male, 77% were black or Hispanic, 74% were on parole or probation, and 65% had not used heroin or other opioids in the previous 30 days (Table 1). All reported a history of DSM-IV opioid dependence. A total of 88% of the participants reported heroin use and 41% reported injection-drug use during their lifetimes; 34% reported any opioid (heroin or other) use in the previous 30 days. A total of 9% of the participants required opioid detoxification to enter the trial.
Table 1.
Baseline Characteristics of the Participants.*
| Characteristic | Extended-Release Naltrexone (N = 153) | Usual Treatment (N = 155) |
|---|---|---|
| Age — yr | 44.4±9.2 | 43.2±9.4 |
| Male sex — no. (%) | 129 (84.3) | 132 (85.2) |
| Race or ethnic group — no./total no. (%)† | ||
| White | 31/152 (20.4) | 30/155 (19.4) |
| Black | 81/152 (53.3) | 74/155 (47.7) |
| Hispanic | 37/152 (24.3) | 45/155 (29.0) |
| Years of education | 11.5±2.2 | 11.5±1.8 |
| Current employment — no. (%) | 26 (17.0) | 29 (18.7) |
| Status with respect to supervision by criminal justice system — no. (%) | ||
| Current supervision‡ | 121 (79.1) | 124 (80.0) |
| Probation | 55 (35.9) | 62 (40.0) |
| Parole | 57 (37.3) | 54 (34.8) |
| Other | 9 (5.9) | 8 (5.2) |
| No supervision§ | 32 (20.9) | 31 (20.0) |
| Health insurance | ||
| Any | 109 (71.2) | 111 (71.6) |
| Medicaid | 70 (45.8) | 65 (41.9) |
| Opioid use during lifetime — no./total no. (%) | ||
| Opioid dependence¶ | 153/153 (100) | 155/155 (100) |
| Heroin use | 135/152 (88.8) | 137/155 (88.4) |
| Other, non-heroin, opioid use | 77/152 (50.7) | 74/155 (47.7) |
| Injection-drug use | 64/152 (42.1) | 62/155 (40.0) |
| Opioid use in past 30 days — no./total no. (%) | ||
| Heroin use | 32/152 (21.1) | 43/155 (27.7) |
| Other, non-heroin, opioid use | 31/152 (20.4) | 26/155 (16.8) |
| Any opioid use | 47/152 (30.9) | 59/155 (38.1) |
| Needed opioid detoxification to enter trial — no. (%) | 13 (8.5) | 14 (9.0) |
| Cocaine use in past 30 days — no./total no. (%) | 30/152 (19.7) | 29/155 (18.7) |
| Heavy alcohol use in past 30 days — no. (%) | 18 (11.8) | 19 (12.3) |
Plus–minus values are means ±SD. There were no significant differences between the two groups at baseline.
Race and ethnic group were self-reported.
Current supervision by the criminal justice system was defined as parole, probation, or other involvement (drug court, diversion, or alternative sentencing program) at baseline.
No supervision by the criminal justice system was defined as recent criminal justice involvement (i.e., arrest, incarceration, conviction, or plea bargain) 0 to 12 months before baseline, with no current supervision as above.
Opioid dependence was defined according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition.
ATTENDANCE AT SCHEDULED VISITS AND ADHERENCE TO MEDICATION
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%. A total of 75% of the participants completed an end-of-treatment-phase visit at week 27. Overall, participants assigned to extended-release naltrexone completed 711 of the 918 planned monthly injections (77%). Seven participants (5%) declined any injections after randomization; 146 (95%) completed the first injection, 132 (86%) the second injection, 119 (78%) the third injection, 111 (73%) the fourth injection, 100 (65%) the fifth injection, and 93 (61%) the sixth injection.
PRIMARY OUTCOME AND RELATED OPIOID-USE OUTCOMES
During the 24-week treatment phase, the time to relapse was significantly longer in the extended-release naltrexone group than in the usual-treatment group: 10.5 weeks versus 5.0 weeks (P<0.001; hazard ratio for relapse, 0.49; 95% confidence interval [CI], 0.36 to 0.68) (Fig. 2). A relapse event was detected in 66 participants assigned to extended-release naltrexone (43%) as compared with 99 assigned to usual treatment (64%) (P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65); this finding is consistent with the higher rate of opioid-negative urine samples, the lower percentage of days with self-reported opioid use, and the higher percentage of 2-week intervals with confirmed abstinence that we observed with extended-release naltrexone than with usual treatment (Table 2). An alternative analysis of missing urine data, in which only two consecutive confirmed positive urine screening results or self-reports of opioid use contributed to a “confirmed relapse outcome,” also favored extended-release naltrexone (rate of relapse, 15% vs. 37%; P<0.001; hazard ratio, 0.33; 95% CI, 0.21 to 0.54). The treatment effect did not differ significantly according to site.
Figure 2.
Kaplan–Meier Curves for Relapse-free Survival.
Table 2.
Opioid Relapse and Related Outcomes during the 24-Week Treatment Phase.*
| Outcome | Extended-Release Naltrexone (N = 153) | Usual Treatment (N = 155) | P Value | Hazard Ratio, Odds Ratio, or Incidence-Density Ratio (95% CI) |
|---|---|---|---|---|
| Primary outcome: median time to relapse — wk† | 10.5 | 5.0 | <0.001 | 0.49 (0.36–0.68)‡ |
| Opioid-relapse event — no. (%) | 66 (43.1) | 99 (63.9) | <0.001 | 0.43 (0.28–0.65)§ |
| Percentage of 2-wk intervals with confirmed abstinence | 71.1 | 49.5 | <0.001 | 2.50 (1.66–3.76)¶ |
| Percentage of opioid-negative urine samples | 74.1 | 55.7 | <0.001 | 2.30 (1.48–3.54)¶ |
| Percentage of days with self-reported opioid use | 4.6 | 12.7 | 0.02 | 0.35 (0.21–0.59)|| |
CI denotes confidence interval.
Shown is the median time to relapse if a relapse event occurred.
Shown is the hazard ratio for relapse, calculated with a Cox proportional-hazards model.
Shown is the odds ratio calculated with a generalized estimating equation (GEE) mixed-effects logistic-regression model, with trial site as the repeated measure.
Shown is the odds ratio calculated with a GEE mixed-effects logistic-regression model for repeated measures, with participant as the repeated measure and with adjustment for trial site and week.
Shown is the incidence-density ratio calculated with a GEE mixed-effects Poisson regression model, with trial site as the repeated measure and with adjustment for log days at risk.
SECONDARY OUTCOMES
Several important secondary outcomes did not differ significantly between the groups: rates of cocaine, alcohol, and intravenous drug use; the score on the Sex Risk subscale of the Risk Assessment Battery; and self-reported reincarceration (percentage of participants with any reincarceration and total days of incarceration) (Table 3). Participation in other, nontrial treatment in the community for opioid-use disorders did not differ significantly between the groups (62% of the participants in the extended-release naltrexone group and 65% of the participants in the usual-treatment group, P = 0.63). 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. No participants reported continuing extended-release naltrexone after the treatment phase; the drug was approved for the prevention of opioid relapse mid-trial and was not widely available in public-sector facilities during the treatment phase.
Table 3.
Secondary Outcomes.*
| Outcome | Extended-Release Naltrexone (N = 153) | Usual Treatment (N = 155) | P Value | Odds Ratio or Incidence-Density Ratio (95% CI) |
|---|---|---|---|---|
| Percentage of days with cocaine use† | 3.9 | 4.3 | 0.71 | 0.91 (0.56–1.48)‡ |
| Heavy drinking in past 30 days at wk 27 — no. (%)§ | 16 (13.9) | 17 (14.9) | 0.77 | 0.89 (0.43–1.87)¶ |
| Any intravenous drug use — %|| | 7 (5.9) | 10 (8.6) | 0.43 | 0.67 (0.25–1.82)¶ |
| Mean score on Sexual Risk subscale of RAB at wk 27** | 2.75 | 2.86 | 0.68†† | |
| Any reincarceration — no. (%) | 35 (22.9) | 45 (29.0) | 0.38 | 0.71 (0.33–1.52)‡‡ |
| Total days of reincarceration | 1651 | 2628 | 0.22 | 0.63 (0.32–1.23)‡ |
| Days incarcerated | ||||
| Among participants with any reincarceration | 47.2±41.8 | 58.4±51.4 | 0.30†† | |
| Among all participants | 11.1±28.4 | 17.6±38.9 | 0.10†† | |
Plus–minus values are means ±SD.
Data are based on self-report for weeks 1 to 25 with the use of the Timeline Followback calendar method. No Timeline Followback data were available for 4 participants in the extended-release naltrexone group and 6 participants in the usual-treatment group.
Shown is the incidence-density ratio calculated with a GEE mixed-effects Poisson regression model, with trial site as the repeated measure and adjustment for log days at risk.
Data on self-reported heavy drinking for weeks 1 to 25 were missing for 38 participants in the extended-release naltrexone group and 41 participants in the usual-treatment group.
Shown is the odds ratio calculated with a chi-square test.
Data on self-reported intravenous drug use for weeks 1 to 25 were missing for 35 participants in the extended-release naltrexone group and 39 participants in the usual-treatment group.
Scores on the Sex Risk subscale of the Risk Assessment Battery (RAB) range from 0 to 18, with higher scores indicating a greater risk of contracting and spreading HIV infection through sexual behaviors.
The P value was calculated with a t-test.
Shown is the odds ratio calculated with a GEE mixed-effects logistic-regression model, with trial site as the repeated measure and adjustment for log days at risk.
SAFETY AND LONG-TERM OPIOID-USE OUTCOMES
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. All recorded overdose events, fatal or nonfatal, occurred among participants assigned to usual treatment (0 events in the extended-release naltrexone group vs. 5 in the usual-treatment group from week 0 to 25, P = 0.10; 0 vs. 7 events from week 0 to 78, P = 0.02); no overdoses occurred in the extended-release naltrexone group after discontinuation of the agent. 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). Self-reported opioid use showed an interaction between treatment and time: participants assigned to extended-release naltrexone reported less use than those assigned to usual treatment during the active treatment phase, but the increase after the active treatment phase was greater in the extended-release naltrexone group, with the result that opioid use was similar in the two groups through week 52 and week 78. (Additional information is provided in Fig. S1A and S1B in the Supplementary Appendix, available at NEJM.org.)
Table 4.
Adverse Events and Serious Adverse Events.*
| Event | Extended-Release Naltrexone (N = 153) | Usual Treatment (N = 155) | P Value |
|---|---|---|---|
| no. of participants (%) | |||
| ≥1 Adverse event | 119 (77.8) | 90 (58.1) | <0.001 |
|
| |||
| Adverse event related to trial drug | |||
|
| |||
| Total | 59 (38.6) NA | ||
|
| |||
| Leading to discontinuation of trial drug | 5 (3.3) NA | ||
|
| |||
| Injection-site reaction | |||
|
| |||
| Mild or moderate | 42 (27.5) NA | ||
|
| |||
| Severe | 4 (2.6) NA | ||
|
| |||
| Headache | 29 (19.0) | 13 (8.4) | 0.007 |
|
| |||
| Gastrointestinal upset | 28 (18.3) | 3 (1.9) | <0.001 |
|
| |||
| Nasopharyngitis | 15 (9.8) | 17 (11.0) | 0.74 |
|
| |||
| Insomnia | 11 (7.2) | 8 (5.2) | 0.46 |
|
| |||
| Flulike symptoms | 6 (3.9) | 2 (1.3) | 0.17 |
|
| |||
| Depression | 2 (1.3) | 11 (7.1) | 0.02 |
|
| |||
| Serious adverse events† | 16 (10.5)‡ | 45 (29.0)§ | 0.006 |
|
| |||
| Depression or suicidality | 3 (2.0) | 6 (3.9) | |
|
| |||
| Death | 2 (1.3) | 5 (3.2) | |
|
| |||
| Chest pain | 2 (1.3) | 4 (2.6) | |
|
| |||
| Musculoskeletal symptom | 2 (1.3) | 4 (2.6) | |
|
| |||
| Stroke | 2 (1.3) | 0 | |
|
| |||
| COPD | 0 | 5 (3.2) | |
|
| |||
| Abscess | 0 | 4 (2.6) | |
|
| |||
| Nonfatal overdose | 0 | 4 (2.6) | |
|
| |||
| Exacerbation of preexisting condition | 0 | 3 (1.9) | |
|
| |||
| Surgery for colon cancer | 0 | 2 (1.3) | |
|
| |||
| Any overdose | 0 | 7 (4.5) | 0.02 |
|
| |||
| Weeks 1–27 | 0 | 5 (3.2) | 0.06 |
|
| |||
| Weeks 28–78 | 0 | 2 (1.3) | 0.50 |
|
| |||
| Fatal overdose | 0 | 3 (1.9) | 0.25 |
|
| |||
| Weeks 1–27 | 0 | 2 (1.3) | 0.50 |
|
| |||
| Weeks 28–78 | 0 | 1 (0.6) | 1.00 |
|
| |||
| Deaths 2 (1.3) | 5 (3.2) | 0.45 | |
|
| |||
| Weeks 1–27 | 0 | 2 (1.3) | 0.50 |
|
| |||
| Weeks 28–78 | 2 (1.3) | 3 (1.9) | 1.00 |
COPD denotes chronic obstructive pulmonary disease, and NA not applicable.
A serious adverse event was defined as an adverse event that was life-threatening or that resulted in death, hospitalization or prolongation of hospitalization, persistent or clinically significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event. Included in the table are serious adverse events that affected two or more participants in a trial group.
Serious adverse events in the extended-release naltrexone group also included one event each of abdominal pain, dehydration, acute renal failure, opioid withdrawal related to the trial drug, and hospitalization of unknown cause. Of the two deaths, one each was caused by homicide and seizure.
Serious adverse events in the usual-treatment group also included one event each of abdominal pain, asthma, cancer, influenza, hypertension, hypoglycemia, pancreatitis, and pneumonia. Of the five deaths, three were caused by overdose and one each was caused by homicide and cardiopulmonary arrest. Of the three events related to a preexisting condition (i.e., resulting from exacerbation or treatment of a preexisting condition), one each was related to deep-vein thrombosis, diabetes, and musculoskeletal injury.
DISCUSSION
This U.S. multisite, randomized, controlled trial 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. During a 24-week treatment phase, the percentage of participants with a relapse event was lower among participants assigned to extended-release naltrexone than among those assigned to usual treatment (43% vs. 64%), corresponding to an absolute difference in risk of 21 percentage points and a number needed to treat of 5. The prevention of opioid use by extended-release naltrexone did not persist through follow-up at week 52 and week 78, approximately 6 months and 12 months, respectively, after the treatment phase had ended. In addition, we did not detect a benefit of extended-release naltrexone on several important secondary outcomes, including rates of cocaine, heavy alcohol, and injection-drug use. Rates of self-reported reincarceration and days of incarceration through week 27 were also not significantly lower in the extended-release naltrexone group than in the usual-treatment group.
There was not an increased risk of overdose events during treatment with extended-release naltrexone or immediately after its discontinuation; indeed, no overdose events were observed among participants assigned to extended-release naltrexone through 78 weeks, during which time seven overdose events occurred among participants assigned to usual treatment. Product labeling and expert reviews describe an increased risk of opioid overdose among patients receiving extended-release naltrexone, both during treatment, when a patient may “super-dose” opioids to overcome the naltrexone blockade, or after therapy, when tolerance is low and resumption of opioid use is even more dangerous.23,24
The trial groups did not differ significantly at baseline in terms of demographic characteristics and criminal justice status, and results were not modified by site, missed visits, or missing data. Main relapse-prevention effects were similar to those in the placebo-controlled pivotal efficacy trial, in which the median percentage of weeks of confirmed abstinence was 90% in the extended-release naltrexone group, as compared with 35% in the placebo group.12 On the basis of self-reports and a single urine sample at week 52 and week 78, months after extended-release naltrexone therapy had ended, the relapse-prevention effects had waned. As is the case with any chronic illness, symptoms of opioid-use disorder are more likely to recur with the discontinuation of effective pharmacotherapy.25 Future research would be needed to determine whether long-term or continuous treatment with extended-release naltrexone — similar to buprenorphine or methadone maintenance therapy — could help maintain the short-term benefits observed in this trial and improve longer-term outcomes.
This trial had important limitations. First, the trial was not blinded. Although an open-label effectiveness design may increase generalizability, it may also increase attention, recall, and assessment biases. The agreement between the results of this trial and those of other recent trials is reassuring with respect to validity.12,26 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. 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. The majority of participants enrolled in this trial had not used opioids in the previous 30 days and did not require detoxification. 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. Finally, this trial did not directly compare extended-release naltrexone with the standard of opioid-agonist maintenance treatment, a comparison that is being assessed in an ongoing trial (ClinicalTrials.gov number, NCT02032433).
In summary, this U.S. multisite, open-label, randomized effectiveness trial showed that among adult offenders who had a history of opioid dependence, the rate of relapse was lower among participants assigned to extended-release naltrexone than among those assigned to usual treatment.
Supplementary Material
Acknowledgments
Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.
Supported by the National Institute on Drug Abuse (NIDA) through a collaborative clinical trial mechanism, PAR-07-232 (R01DA024549, to Dr. Friedmann; R01DA024550, to Dr. Kinlock; R01DA024553, to Dr. O’Brien; R01DA024554, to Dr. Nunes; and R01DA024555, to Dr. Lee), and additional support (K24DA022412, to Dr. Nunes). Trial medication was provided in kind from an investigator-initiated grant from Alkermes. Funding from the Dana Foundation to Dr. O’Brien supported the conduct of a five-site pilot study.
Dr. Lee reports receiving grant support and study medication from Alkermes and study medication from Indivior (formerly Reckitt Benckiser). Dr. Friedmann reports receiving fees for serving on an advisory board and travel support from Indivior and an honorarium for leading a roundtable discussion from Orexo. Dr. Kinlock reports receiving grant support and study medication from Alkermes. Dr. Nunes reports serving on an advisory board for Alkermes, receiving study medication from Reckitt Benckiser and Duramed Pharmaceuticals, being lead investigator for a NIDA-funded study of a computer-delivered behavioral intervention supplied by HealthSim, and being site principal investigator for a study funded by, and receiving travel support from, Brainsway. Dr. Rotrosen reports receiving study medication from Alkermes and Indivior. Dr. Gordon reports receiving grant support and study medication from Alkermes. Dr. Fishman reports receiving travel support from Alkermes. Dr. O’Brien reports receiving consulting fees from Alkermes. No other potential conflict of interest relevant to this article was reported.
We thank the trial participants and combined research staff across all sites.
Footnotes
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
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