Nikolaj Kunøe

Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial

BACKGROUND Naltrexone has considerable potential in helping to prevent relapse in heroin dependency. A longer-lasting formulation for naltrexone treatment is desirable to further reduce non-adherence and relapse during treatment of opiate dependence. AIMS To evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment. METHOD A group of 56 abstinence-oriented patients who completed in-patient treatment for opioid dependence were randomly and openly assigned to receive either a 6-month naltrexone implant or their usual aftercare. Drug use and other outcomes were assessed at 6-month follow-up. RESULTS Patients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (both P<0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months. Two patients died, neither of whom had received an implant. CONCLUSIONS Naltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.

Naltrexone Implants Compared to Methadone: Outcomes Six Months after Prison Release

Background:After prison release, offenders with heroin use problems are at high risk of relapse and overdose death. There is a particular need for treatments that can be initiated in prison and continued after release into the community. Methadone maintenance treatment has been shown to reduce heroin use, criminality and mortality. Naltrexone implant treatment has not previously been evaluated in prison settings. Methods:This study compares the effects of naltrexone implants and methadone treatment on heroin and other illicit drug use, and criminality among heroin-dependent inmates after release from prison. Results:Forty-six volunteers were randomly allocated to naltrexone implants or methadone before release. Intention-to-treat analyses showed reductions in both groups in frequency of use of heroin and benzodiazepines, as well as criminality, 6 months after prison release. Conclusions:Naltrexone implants may be a valuable treatment option in prison settings.

Naltrexone Depot Formulations for Opioid and Alcohol Dependence: A Systematic Review

Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid‐dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option.

Effectiveness of Injectable Extended-Release Naltrexone vs Daily Buprenorphine-Naloxone for Opioid Dependence: A Randomized Clinical Noninferiority Trial

Importance To date, extended-release naltrexone hydrochloride has not previously been compared directly with opioid medication treatment (OMT), currently the most commonly prescribed treatment for opioid dependence. Objective To determine whether treatment with extended-release naltrexone will be as effective as daily buprenorphine hydrochloride with naloxone hydrochloride in maintaining abstinence from heroin and other illicit substances in newly detoxified individuals. Design, Setting and Participants A 12-week, multicenter, outpatient, open-label randomized clinical trial was conducted at 5 urban addiction clinics in Norway between November 1, 2012, and December 23, 2015; the last follow-up was performed on October 23, 2015. A total of 232 adult opioid-dependent (per DSM-IV criteria) individuals were recruited from outpatient addiction clinics and detoxification units and assessed for eligibility. Intention-to-treat analyses of efficacy end points were performed with all randomized participants. Interventions Randomization to either daily oral flexible dose buprenorphine-naloxone, 4 to 24 mg/d, or extended-release naltrexone hydrochloride, 380 mg, administered intramuscularly every fourth week for 12 weeks. Main Outcomes and Measures Primary end points (protocol) were the randomized clinical trial completion rate, the proportion of opioid-negative urine drug tests, and number of days of use of heroin and other illicit opioids. Secondary end points included number of days of use of other illicit substances. Safety was assessed by adverse event reporting. Results Of 159 participants, mean (SD) age was 36 (8.6) years and 44 (27.7%) were women. Eighty individuals were randomized to extended-release naltrexone and 79 to buprenorphine-naloxone; 105 (66.0%) completed the trial. Retention in the extended-release naltrexone group was noninferior to the buprenorphine-naloxone group (difference, −0.1; with 95% CI, −0.2 to 0.1; P = .04), with mean (SD) time of 69.3 (25.9) and 63.7 (29.9) days, correspondingly (P = .33, log-rank test). Treatment with extended-release naltrexone showed noninferiority to buprenorphine-naloxone on group proportion of total number of opioid-negative urine drug tests (mean [SD], 0.9 [0.3] and 0.8 [0.4], respectively, difference, 0.1 with 95% CI, −0.04 to 0.2; P < .001) and use of heroin (mean difference, −3.2 with 95% CI, −4.9 to −1.5; P < .001) and other illicit opioids (mean difference, −2.7 with 95% CI, −4.6 to −0.9; P < .001). Superiority analysis showed significantly lower use of heroin and other illicit opioids in the extended-release naltrexone group. No significant differences were found between the treatment groups regarding most other illicit substance use. Conclusions and Relevance Extended-release naltrexone was as effective as buprenorphine-naloxone in maintaining short-term abstinence from heroin and other illicit substances and should be considered as a treatment option for opioid-dependent individuals. Trial Registration clinicaltrials.gov Identifier: NCT01717963

Retention in naltrexone implant treatment for opioid dependence

BACKGROUND Naltrexones usefulness in the treatment of opioid dependence stems from its ability to block the action of heroin and other opioids. However, many patients are ambivalent towards naltrexone and often drop out of treatment with orally administered naltrexone. Sustained release naltrexone seems promising in reducing opioid use, but the extent to which patients remain in treatment beyond the first dosage of naltrexone is not clear. METHODS Patients (n=61) receving treatment with sustained release naltrexone implants were offered a second naltrexone implant after 6 months. Patients who remained in treatment were compared to those who did not, on drug use, mental health, and social problems before and during naltrexone implant treatment. Information was obtained on other treatments sought by patients who discontinued naltrexone. Blood samples were used to verify naltrexone release, and hair samples to confirm opioid intake. RESULTS Of the patients who received the first naltrexone implant, 51% (n=31) remained in naltrexone implant treatment. Among those who discontinued treatment, 21% expressed a wish to reimplant but failed to attend for reimplantation and 28% declined reimplantation: 6 non-retained patients initiated maintenance or residential treatment. Remaining in naltrexone treatment was related to pre-study length of employment, illicit drug use, and concern for family problems. Higher levels of substance misuse and criminal activity during naltrexone treatment were negatively related to subsequent retention. CONCLUSION Rates of retention among opioid-dependent patients receiving naltrexone implant treatment are encouraging and support this as a feasible long-term treatment option.

Injectable and implantable sustained release naltrexone in the treatment of opioid addiction

Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid‐addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1–7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood‐borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at‐risk groups such as prison inmates or opioid‐addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction.

Treatment research in prison: Problems and solutions in a randomized trial

Opioid-dependent individuals are frequently incarcerated and relapse rates following their release are high. Evidence of the effectiveness of prison-based treatments and community aftercare is limited. We report the preliminary findings of a randomized controlled trial that encountered specific challenges inherent in prison research. Naltrexone implants were compared with methadone maintenance treatment among pre-release inmates. Naltrexone implants have not previously been evaluated in prison settings. Approximately 41% of eligible inmates volunteered to participate; 27 of the total 46 participants commenced treatment according to the protocol. Although most inmates intended to remain abstinent from heroin after their release, the relapse rates among individuals who had not commenced treatment were high. Naltrexone implants were regarded as a valuable treatment option. During the study, several problems were encountered regarding enrollment, treatment initiation and aftercare. These findings have important implications for future prison research. Random allocation to the fixed interventions was inefficient in limiting the risk of selection bias. Alternative approaches should be considered, such as sequential multiple assignment randomized trials.

The Norwegian Offender Mental Health and Addiction Study – Design and Implementation of a National Survey and Prospective Cohort Study

The Norwegian prison inmates are burdened by problems before they enter prison. Few studies have managed to assess this burden and relate it to what occurs for the inmates once they leave the prison. The Norwegian Offender Mental Health and Addiction (NorMA) study is a large-scale longitudinal cohort study that combines national survey and registry data in order to understand mental health, substance use, and criminal activity before, during, and after custody among prisoners in Norway. The main goal of the study is to describe the criminal and health-related trajectories based on both survey and registry linkage information. Data were collected from 1,499 inmates in Norwegian prison facilities during 2013–2014. Of these, 741 inmates provided a valid personal identification number and constitute a cohort that will be examined retrospectively and prospectively, along with data from nationwide Norwegian registries. This study describes the design, procedures, and implementation of the ongoing NorMA study and provides an outline of the initial data.