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

Abstract

BackgroundCurrent 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/DesignIn 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.DiscussionDespite minor implementation problems, the protocol appears sufficiently robust to generate results of high interest to patients, clinicians and policy makers.Trial registrationClinicaltrials.gov # NCT01717963, first registered: Oct 28, 2012. Protocol version # 3C, June 12th 2012.

Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial

“…These findings align with results of non-inferiority from the concurrent Norwegian study, 25 which was also a randomised comparison of XR-NTX to BUP-NX treatment after a longer detoxification run-in, which minimised induction failure. Few participants in the Norwegian trial 26 were not able to induct onto either XR-NTX or BUP-NX treatment, and retention, opioid use, or adverse event outcomes did not differ between treatment groups, similar to what was observed in our per-protocol population.…”

Effectiveness, safety and feasibility of extended‐release naltrexone for opioid dependence: a 9‐month follow‐up to a 3‐month randomized trial

“…This 9‐month prospective cohort study was conducted following the 3‐month RCT . Participants consented to participate in the follow‐up at conclusion of the RCT.…”

“…Outcomes were: retention in treatment, measured in numbers of weeks in treatment and the number of participants completing the study; the number of participants abstinent from opioids during the study; the use of heroin and other illicit opioids, the use of cannabis, amphetamines and benzodiazepines; heavy alcohol use; injection use; acquisitive crime and work, measured in number of days within the 4 weeks preceding each study attendance; money spent on drugs and alcohol within the 4 weeks preceding each study attendance, measured in Norwegian crowns (NOK); craving for heroin and treatment satisfaction within the 4 weeks preceding each study attendance measured by a visual analogue scale (VAS) with scores from 0–10; and the number of reported adverse events .…”

“…A small number of participants chose to discontinue opioid agonists without any tapering. After a minimum of 72 hours without any intake of opioids and if passing an injection of a 0.4 mg naloxone test dose, participants were given an intramuscular injection of 380 mg XR‐NTX (Vivitrol ® ) in the buttock . To relieve withdrawal symptoms such as vomiting, chills and insomnia in the detoxification phase, participants were prescribed pharmacological treatment such as benzodiazepines, metoclopramide, valproate, quetiapine, clonidine and pregabalin, adapted individually according to clinical assessment.…”

Antagonistas periféricos de los receptores opioides Mu en el tratamiento del estreñimiento inducido por opioides: revisión.

“…Respecto a la combinación buprenorfina-naloxona utilizada en el tratamiento de deshabituación de la adicción opioide (18), existen comunicaciones respecto a su beneficio en el alivio del dolor en pacientes con dolor y adicción (19,20), y un potencial beneficio en el EIO (21).…”