Risk of relapse to non-opioid addictive substances among opioid dependent patients treated with an opioid receptor antagonist or a partial agonist: A randomized clinical trial.

BACKGROUND AND OBJECTIVE: First study to assess any compensatory increase in use of non-opioid illicit substances and alcohol in opioid dependent patients randomized to treatment with extended-release naltrexone (XR-NTX) or buprenorphine-naloxone (BP-NLX) and in longer term treatment with extended-release naltrexone. METHOD: A multicenter, outpatient, open-label randomized clinical trial where patients received intramuscular extended-release naltrexone hydrochloride, 380 mg/month, or daily sublingual buprenorphine-naloxone 8-24/2-6 mg for 12 weeks, and an option to continue with extended-release naltrexone for an additional 36 week follow-up. The study was conducted at five urban addiction clinics and detoxification units in Norway between November 2012, and July 2016. RESULTS: Among the 143 patients, 106 men and 37 women, there were no significant differences between those randomized to XR-NTX or BP-NLX in the risk of first relapse to alcohol (HR 1.31; 0.68-2.53), amphetamines (HR 0.88; 0.43-1.80), benzodiazepines (HR 1.24; 0.74-2.09) or cannabis (HR 1.55; 0.83-2.89). Also in the 36-week (12-48 weeks) follow-up period we found no significant differences between patients continuing with XR-NTX compared to those switching to XR-NTX after the randomized period in risk of first relapse to any non-opioid substance. In both study periods, the mean time in the study were longer among those relapsing to non-opioid addictive substances than those who did not. There was no significant association between first relapse to illicit opioids and first relapse to non-opioid addictive substances. CONCLUSION: There was no increase in the risk of relapse to non-opioid addictive substances neither in short term nor longer-term treatment with extended-release naltrexone. Trial registrationclinicaltrials.gov Identifier: NCT01717963.

The Predictive Value of Degree of Preference for Extended-Release Naltrexone for Treatment Adherence, Opioid Use, and Relapse.

BACKGROUND: Extended-release naltrexone (XR-NTX) is effective for illicit opioid abstinence as an opioid maintenance treatment. To improve treatment outcomes, patient's preference for the modality of treatment is an important factor. OBJECTIVES: We aimed to test the relationship between baseline preference for XR-NTX and adherence to treatment, use of illicit opioids, and risk of relapse. METHODS: In an open-label, Norwegian clinical trial participants with opioid use disorder were randomized to either monthly injections with XR-NTX or daily sublingual buprenorphine-naloxone (BP-NLX) for 12 weeks. Subsequently, participants could continue with their preferred medication in a 36-week follow-up and in a prolonged period of 104 weeks. RESULTS: Of 153 participants who completed detoxification, 72% were men, with a mean age of 36 years. Preference levels were similar across the randomized groups, with no significant associations between preference and adherence to treatment, opioid use, or relapse. The BP-NLX group had a significantly higher risk of first relapse to opioids than the XR-NTX group for all levels of preference (p < 0.001) and a significantly higher number of days of illicit opioid use. In the follow-up period, the adherence rate was twice as high among participants with the highest preference compared to participants with the lowest preference, both among those who switched to XR-NTX and those who continued (hazard ratio 2.2; 1.2-4.0, p = 0.013). Opioid use was significantly higher among participants who switched to XR-NTX with the lowest preference than the medium (p = 0.003) or the highest (p = 0.001) preference. The risk of relapse to opioids, however, was significantly higher among XR-NTX continuing participants with the lowest (p = 0.002) or the medium (p = 0.043) preference than those with the highest preference. CONCLUSIONS: Individuals who matched with their preferred treatment used less illicit opioids than those who did not during short-term treatment. However, baseline preference for XR-NTX treatment primarily influenced longer term opioid use and treatment adherence.

Life satisfaction among individuals with opioid use disorder receiving extended-release naltrexone: A 12-week randomized controlled trial and a 36-week follow-up.

INTRODUCTION: Life satisfaction (LS) in opioid-dependent individuals is lower than in the general population. This study aimed to explore changes in LS during short- and long-term treatment with extended-release naltrexone (XR-NTX). METHODS: This open-label 12-week clinical trial randomized 159 participants to either monthly XR-NTX or daily buprenorphine-naloxone (BP-NLX). In a subsequent 36-week follow-up study on XR-NTX, participants either continued or switched to XR-NTX. The study collected data on the Temporary Satisfaction with Life (TSWL) and illicit opioid use every fourth week. The research team assessed changes in TSWL by a linear mixed model and growth mixture model. The study assessed relationship between opioid use and TSWL by a linear mixed model. RESULTS: Change in LS differed significantly between the groups in both study periods. TSWL scores were significantly higher in the XR-NTX group at week 4 (p = 0.013) and week 8 (p = 0.002). In the follow-up period, the groups were significantly different only at week 16 (p = 0.031) and week 48 (p = 0.025), with the higher TSWL scores in the XR-NTX continued group. Increase in opioid use by one day was associated with a 0.12 point lower mean TSWL score. Both study periods identified groups with low and high LS levels. In the trial period, the TSWL scores exhibited a significant increase from baseline to week 12 in both groups, p < 0.001 and p = 0.011 in the low and high LS group, respectively. In the follow-up period, the TSWL scores exhibited a significant increase from week 16 to week 48 (p = 0.003) in the high LS group, while the low LS group showed persistently lower values throughout that period. CONCLUSIONS: XR-NTX treatment given once monthly is associated with higher LS, as measured by TSWL, compared to daily use of BP-NLX. The majority of the participants had relatively low TSWL scores and did not report any change in TSWL during longer-term treatment. The study found a significant association between more frequent illicit opioid use and a low or decreased LS during follow-up.

Risk of Relapse Among Opioid-Dependent Patients Treated With Extended-Release Naltrexone or Buprenorphine-Naloxone: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Compare the risk of relapse to heroin and other illicit opioids among opioid-dependent patients receiving treatment with extended-release naltrexone (XR-NTX) or buprenorphine-naloxone (BP-NLX). METHODS: Re-analyzed data from a 12-week multicenter, open-label, randomized treatment study with a subsequent 36-week open-label follow-up study. All patients, N = 143, had completed detoxification and received at least one dose of study medication. RESULTS: Of 143 patients (72% men), mean age 36 years, 71 received XR-NTX and 72 BP-NLX. The risk of first relapse and the risk of any relapse to heroin and other illicit opioids were both significantly lower in the XR-NTX group compared with the BP-NLX group (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.28-0.76; P = .002, and HR, 0.11; 95% CI, 0.04-0.29; P < .001, respectively) and (HR, 0.15; 95% CI, 0.09-0.27; P < .001 and HR, 0.05; 95% CI, 0.03-0.09; P < .001, respectively). There was a stable low risk of relapse among participants receiving XR-NTX in the follow-up. DISCUSSION AND CONCLUSIONS: Compared to BP-NLX, patients on XR-NTX had a substantially reduced risk of relapse to illicit opioids and showed a stable low risk of relapse over time in longer-term treatment. SCIENTIFIC SIGNIFICANCE: Our data support XR-NTX as a first-line treatment option for patients with opioid addiction both in short and longer-term treatment. This is the first European study showing that XR-NTX significantly reduces the risk of first and any relapse to heroin use in opioid-dependent patients compared to BP-NLX. Our data contradict previous data from the X:BOT study, showing no significant difference in relapse risk between the groups in a 6-month randomised controlled trial. (© 2021 Authors. The American Journal on Addictions published by Wiley Periodicals LLC on behalf of The American Academy of Addiction Psychiatry). (Am J Addict 2021;30:451-458).

Availability of Extended-Release Naltrexone May Increase the Number of Opioid-Dependent Individuals in Treatment: Extension of a Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Opioid maintenance treatment (OMT) is highly available in Norway, but only 50% of opioid-dependent individuals are enrolled in such programs. This study was aimed at examining if availability of extended-release naltrexone (XR-NTX) could attract individuals who for different reasons were not enrolled in an OMT program. METHODS: In a Norwegian clinical study, n = 117 opioid-dependent adults volunteered to receive XR-NTX in a 9-month period, as an extension of a previous randomized clinical trial. RESULTS: Before study inclusion, 40.2% (n = 47) of the study participants were not enrolled in OMT while the remainder were recruited from OMT. Participants not enrolled in OMT displayed more ongoing severe addiction-related problems such as heroin use (p = 0.002), but displayed a higher retention in treatment in the 9-month extension study (p = 0.048 for log-rank test) than participants enrolled in OMT. CONCLUSION: Availability of XR-NTX attracted opioid-dependent individuals not previously enrolled in OMT. While OMT may be perceived as a burden with regard to daily intake and control measures, one-monthly injections with XR-NTX may be perceived favourable, offering more freedom to the patients, not having addictive properties, and potentially reducing heroin craving. We suggest that an introduction of XR-NTX in Europe may increase the number of opioid-dependent individuals in treatment.

Interest in Extended Release Naltrexone among Opioid Users.

BACKGROUND/AIMS: Treatment for addiction to illicit opioids has, thus far, been limited to 2 main approaches: maintaining physical dependence by administering opioids medically and medication-free abstinence with psychosocial support. Assisted abstinence by taking daily tablets with the opioid antagonist naltrexone is rarely practiced, but it is unclear whether this is due to the limited efficacy of this method or because of user opposition to antagonist medication. Therefore, we wanted to investigate opioid users' interest in antagonist treatment with naltrexone, administered as extended release injection, which supports abstinence by blocking illicit opioids for 4-5 weeks per administration. METHOD: A one-page questionnaire was distributed among opiate users at a broad range of outreach facilities and a total of 731 answered surveys were analysed. RESULTS: More than half of the opioid users in our study were 'very' or 'quite' interested in receiving a 4-weekly opioid-blocking medication for a year (n = 421), while less than a quarter (n = 164) were 'not interested' at all. CONCLUSION: We discovered a high user interest for naltrexone treatment, suggesting that the interest for such treatment was not a barrier to the implementation of extended release naltrexone treatment.

Design of a randomized controlled trial of extended-release naltrexone versus daily buprenorphine-naloxone for opioid dependence in Norway (NTX-SBX).

BACKGROUND: Current guidelines for opioid dependence recommend daily maintenance of physical dependence with methadone or buprenorphine, and discourage abstinence due to the high risk of relapse and overdose. Extended-release formulations of the opioid antagonist naltrexone (XR-NTX) block heroin and other opioid agonists competitively for around 4 weeks per administration. XR-NTX thus enables opioid users to experience abstinence from opioid agonists with greatly reduced risk of overdose compared to medication-free abstinence. While XR-NTX has shown promise compared to placebo and daily naltrexone tablets, there is limited information on long-term safety and its performance compared to daily maintenance treatment. METHODS/DESIGN: In this five-hospital RCT with long-term follow-up, we aim to recruit n = 180 patients in treatment for opioid dependence and allocate them in an open, randomized manner (1:1) to receive either 4-week XR-NTX or daily buprenorphine-naloxone (BP-NLX) for the duration of 12 weeks. Allocation is open-label due to the risk of overdose during attempts to self-unmask allocation using heroin. Urine drug tests are scheduled every week with follow-up visits & assessment every 4 weeks. Primary outcomes are abstinence from illicit opioids in urine drug tests and self-report, as well as retention in treatment. Secondary outcomes include other substance use, injecting behavior, drug craving, mental health, quality of life, treatment satisfaction, abstinence motivation, opioid agonist effect rating, insomnia, and pain. Observation is continued for another 36 weeks in order to assess longer-term safety, adherence and effectiveness. The study is an investigator-initiated trial, funded by public grants and approved by an Independent Ethical Committee (the Regional Ethical Committee for Research South-East B # 2011/1320) and the Norwegian Medicines Agency. DISCUSSION: Despite minor implementation problems, the protocol appears sufficiently robust to generate results of high interest to patients, clinicians and policy makers. TRIAL REGISTRATION: Clinicaltrials.gov # NCT01717963 , first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012.