Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder: A Randomized Clinical Trial.

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities. Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Personal Control Over Decisions to Participate in Research by Persons With Histories of Both Substance Use Disorders and Criminal Justice Supervision.

Individuals must feel free to exert personal control over decisions regarding research participation. We present an examination of participants' perceived personal control over, as well as reported pressures and threats from others, influencing their decision to join a study assessing the effectiveness of extended-release naltrexone in preventing opioid dependence relapse. Most participants endorsed a strong sense of control over the decision; few reported pressures or threats. Although few in number, participants' brief narrative descriptions of the pressures and threats are illuminating and provide context for their perceptions of personal control. Based on this work, we propose a useful set of tools to help ascertain participants' sense of personal control in joining research.

Relapse to opioid use disorder after inpatient treatment: Protective effect of injection naltrexone.

BACKGROUND: Opioid use disorder is often treated with short term hospitalization and medically supervised withdrawal from opioids followed by counseling alone without medication assisted treatment (MAT). More evidence is needed to confirm the expectation that the rate of relapse would be high after short term inpatient treatment and withdrawal from opioids without follow-up MAT. OBJECTIVE/METHODS: To examine relapse to opioid use disorder in a randomized, multi-site effectiveness trial of extended-release injection naltrexone (XR-NTX) vs community-based treatment as usual (TAU) without medication, as a function of the type of clinical service where treatment was initiated-short-term inpatient (N=59), long-term inpatient (N=48), or outpatient (N=201). Inpatients typically were admitted to treatment actively using opioids and had completed withdrawal from opioids before study entry. Outpatients typically presented already abstinent for varying periods of time. RESULTS: One month after randomization, relapse rates on TAU by setting were: short-term inpatient: 63%; long term inpatient: 14%; outpatient: 28%. On XR-NTX relapse rates after one month were low (<12%) across all three settings. At the end of the 6 month trial, relapse rates on TAU were high across all treatment-initiation settings (short term inpatient 77%; long term inpatient 59%; outpatient 61%), while XR-NTX exerted a modest protective effect against relapse across settings (short term inpatient: 59%; long term inpatient 46%; outpatient 38%). CONCLUSIONS: Short term inpatient treatment is associated with a high rate of relapse among patients with opioid use disorder. These findings support the recommendation that medically supervised withdrawal from opioids should be followed by medication assisted treatment.

Do patient characteristics moderate the effect of extended-release naltrexone (XR-NTX) for opioid use disorder?

BACKGROUND: Extended release naltrexone (XR-NTX) injected intramuscularly monthly has been shown to reduce relapse in persons with opioid use disorder. Baseline factors, including patients' demographics, comorbidities and lifestyle, may help identify patients who will benefit most or least from XR-NTX treatment. METHODS: Potential moderators of XR-NTX's effect were examined in the largest North American randomized open-label effectiveness trial of XR-NTX. Relapse status (Yes/No) at 6-month follow-up was regressed on treatment group (XR-NTX, N=153; or Treatment-as-Usual [TAU], N=155), baseline covariates, and their two-way interaction to identify moderator effects. Baseline covariates included age, gender, summary scores for depression, suicidal thoughts, drug abuse risk, substance use, medical, psychiatric and employment status, socialization, legal and family/social issues, history of abuse and quality of life measures. RESULTS: Alcohol use to intoxication in the 30days before randomization was a significant moderator: during the treatment phase, those who reported being recently intoxicated before randomization to XR-NTX relapsed to opioids at a rate (56%) similar to TAU (58%), while those without alcohol intoxication in the prior 30days had a lower rate of opioid relapse (41% vs. 65%, respectively, P<0.04). CONCLUSIONS: XR-NTX appeared to work equally well across subgroups with diverse demographic, addiction, mental health and environmental characteristics, with the possible exception of working better among those without recent alcohol intoxication. These findings should be reassuring to practitioners increasingly using XR-NTX as medical addiction therapy in diverse and often vulnerable populations.

Assessing informed consent in an opioid relapse prevention study with adults under current or recent criminal justice supervision.

Concerns persist that individuals with substance use disorders who are under community criminal justice supervision experience circumstances that might compromise their provision of valid, informed consent for research participation. These concerns include the possibilities that desire to obtain access to treatment might lead individuals to ignore important information about research participation, including information about risks, or that cognitive impairment associated with substance use might interfere with attending to important information. We report results from a consent quiz (CQ) administered in a multisite randomized clinical trial of long-acting naltrexone to prevent relapse to opioid use disorder among adults under community criminal justice supervision-a treatment option difficult to access by this population of individuals. Participants were required to answer all 11 items correctly before randomization. On average, participants answered 9.8 items correctly (89%) at baseline first attempt (n=306). At week 21 (n=212), participants scored 87% (9.5 items correct) without review. Performance was equivalent to, or better than, published results from other populations on a basic consent quiz instrument across multiple content domains. The consent quiz is an efficient method to screen for adequate knowledge of consent information as part of the informed consent process. Clinical researchers who are concerned about these issues should consider using a consent quiz with corrected feedback to enhance the informed consent process. Overall, while primarily useful as an educational tool, employing a CQ as part of the gateway to participation in research may be particularly important as the field continues to advance and tests novel experimental treatments with significant risks and uncertain potential for benefit.

Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.

BACKGROUND AND AIMS: Criminal justice-involved individuals are highly susceptible to opioid relapse and overdose-related deaths. In a recent randomized trial, we demonstrated the effectiveness of extended-release naltrexone (XR-NTX; Vivitrol® ) in preventing opioid relapse among criminal justice-involved US adults with a history of opioid use disorder. The cost of XR-NTX may be a significant barrier to adoption. Thus, it is important to account for improved quality of life and downstream cost-offsets. Our aims were to (1) estimate the incremental cost per quality-adjusted life-year (QALY) gained for XR-NTX versus treatment as usual (TAU) and evaluate it relative to generally accepted value thresholds; and (2) estimate the incremental cost per additional year of opioid abstinence. DESIGN: Economic evaluation of the aforementioned trial from the taxpayer perspective. Participants were randomized to 25 weeks of XR-NTX injections or TAU; follow-up occurred at 52 and 78 weeks. SETTING: Five study sites in the US Northeast corridor. PARTICIPANTS: A total of 308 participants were randomized to XR-NTX (n = 153) or TAU (n = 155). MEASUREMENTS: Incremental costs relative to incremental economic and clinical effectiveness measures, QALYs and abstinent years, respectively. FINDINGS: The 25-week cost per QALY and abstinent-year figures were $162 150 and $46 329, respectively. The 78-week figures were $76 400/QALY and $16 371/abstinent year. At 25 weeks, we can be 10% certain that XR-NTX is cost-effective at a value threshold of $100 000/QALY and 62% certain at $200 000/QALY. At 78 weeks, the cost-effectiveness probabilities are 59% at $100 000/QALY and 76% at $200 000/QALY. We can be 95% confident that the intervention would be considered 'good value' at $90 000/abstinent year at 25 weeks and $500/abstinent year at 78 weeks. CONCLUSIONS: While extended-release naltrexone appears to be effective in increasing both quality-adjusted life-years (QALYs) and abstinence, it does not appear to be cost-effective using generally accepted value thresholds for QALYs, due to the high price of the injection.

Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders.

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.).

Extended-release naltrexone to prevent relapse among opioid dependent, criminal justice system involved adults: rationale and design of a randomized controlled effectiveness trial.

BACKGROUND: Extended-release naltrexone (XR-NTX, Vivitrol; Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. METHODS: This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. RESULTS: We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. CONCLUSIONS: XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. ClinicalTrials.gov: NCT00781898.

A multisite pilot study of extended-release injectable naltrexone treatment for previously opioid-dependent parolees and probationers.

A feasibility study was conducted to pilot test the ability of 5 sites to recruit, treat, and retain opioid-dependent offenders in a trial of extended-release injectable naltrexone (XR-NTX). The participants, 61 previously opioid-dependent individuals under legal supervision in the community, received up to 6 monthly injections of Depotrex brand naltrexone and completed a 6-month follow-up interview. Six-month outcomes showed that those who completed treatment had significantly fewer opioid-positive urines and were less likely to have been incarcerated than those who had not completed treatment. The findings indicate that XR-NTX holds promise as a feasible, effective treatment option for opioid-dependent offenders.