Acceptability, feasibility, mechanism of action and potential side effects of extended release depot naltrexone (XRNT) in opioid dependent patients

Heroin dependence is a quintessential international health problem, with a significant prevalence in both the US and the Netherlands. In the Netherlands there are about 18.000 problematic heroin users (NDM, 2010). Of these, almost 13.000 (70%) are in regular contact with the treatment system: 11.000 in methadone maintenance treatment (MMT), 800 in heroin assisted treatment (HAT), and 1.200 in abstinence oriented treatment. Average age is 44 years, only 6% is younger than 30 years, and only 5% are new referrals with no treatment history. The vast majority are chronic polydrug dependent patients with a long treatment history. Based on anecdotal information, it seems that some of the new referrals, many of the patients in abstinence treatments, and some of the patients in MMT and HAT are interested in a life without opioids, i.e. without illegal heroin or prescribed methadone or heroin. However, drug free treatments, including pharmacologically supported interventions using oral naltrexone (NT), have not been very successful, mainly due to low compliance. The recent introduction of extended release naltrexon (XRNT) treatment, consisting of monthly injections, may create new opportunities. Injectable XRNT is an innovative treatment delivery method that blocks the rewarding effects heroin, and possibly also alcohol and stimulants for at least one month after injection. XRNT is currently awaiting FDA approval as a new treatment for heroin dependence. The primary aim of the US parent grant, “Treatment Study Using Depot Naltrexone” (R01 DA024553-01A1, 03/01/2008 - 02/28/2013), is to determine the effectiveness of longterm (6 months) XRNT for preventing opioid use in heroin addicts on parole or probation. Secondary aims are to determine the effect of XRNT on co-morbid drug and alcohol use, HIV risk behaviors and criminal behaviors leading to arrests and re-incarceration. The parent project is a multi-site, randomized clinical trial coordinated at the University of Pennsylvania (UPenn: prof. O'Brien). Planned enrollment is 380 participants, 80 of which are randomized at the UPenn coordination and data management site. The primary outcome variable is relapse to drug use and XRNT treatment compliance. The aims of the US-NL supplemental proposal are: (1) to determine acceptability of XRNT by Dutch clinicians and patients as a new treatment option; (2) to explore the feasibility of XRNT treatment in the Netherlands in terms of treatment participation and treatment retention; (3) to study the mechanism of action of XRNT using pharmacoMRI (US and NL) and SPECT (NL), and (4) to study the potential negative effect of XRNT on natural rewards (e.g. food, sex). ad (1) Acceptability The Netherlands has a well-developed and easy accessible treatment system for heroin and polydrug addicts, including abstinence oriented and substitution treatments. Based on negative experiences in the past with oral NT and the positive effects of MMT and HAT, there seems to be limited enthusiasm for new abstinence oriented treatments among clinicians and patients alike. However, no data are available on attitude towards XRNT after adequate information is provided. Therefore, the Dutch supplemental project will study attitudes towards XRNT in 200 clinicians (doctors, nurses, social workers) and 300 patients in both abstinence oriented treatment settings (n=100/150) and in substitution programs (n=100/150) in different regions in the Netherlands. ad (2) Feasibility A positive attitude towards XRNT is important, but in order to know the clinical potential of this new treatment option, we also need information on the percentage and the profile of actual starters with XRNT and their retention in treatment. Patient profiles, treatment initiation and treatment retention over a treatment period of 3 months will therefore be studied in a cohort of patients. Patients with a positive attitude towards XRNT treatment in the acceptability part of the study will be asked to start XRNT treatment until a maximum of 20 have started this treatment. ad (3) Mechanism of action Until now, very little is known about the mechanism of action of (XR)NT in human heroin addicts. In this supplemental proposal 40 heroin addicts will be studied before, during and after XRNT using functional MRI (fMRI: US n=20 and NL n=20) and dopamine transporter imaging (NL n=20). ad (4) Side effects Finally, this supplemental project examines the possible negative effects of XRNT on natural rewards, i.e. changes in reward from food and sex (anhedonia). In the US project this will be limited to self-report measures, whereas in the Dutch project these subjective experiences will also be correlated with changes in striatal dopamine transporter availability (SPECT). This international project examines the generalizability of US RCT data on XRNT and provides better insight in underlying mechanisms and possible side effects using a well-powered, imaging study using MRI and SPECT.