Characterizing the neurobiology of detoxification and early abstinence in opiate addiction: is there a role for NK1 antagonism to improve outcomes?

点击翻译按钮获取中文摘要

Opiate addiction is one of the major health challenges facing the UK today, with the numbers of opiate-related deaths rising to record levels. The harm minimisation approach to treatment with opiate substitution medication (e.g. methadone) and psychosocial support has been highly effective in improving health and social functioning, but there is now an increasing focus on achieving abstinence. Indeed abstinence is likely to be better for overall health, particularly in the aging opiate addict population who have increasingly complex health and social care needs. Many addicts desire abstinence but find it hard to achieve and maintain. The effectiveness of the only licensed medication to prevent relapse, naltrexone, is limited and take-up is low, so we are in need of new treatments. We believe that understanding brain processes better, such as reward, emotional processing and responses to drug-related cues, will inform how best to improve treatment of opiate detoxification and relapse prevention. To do this we have established an experimental platform using lab-based tasks and functional magnetic resonance imaging (fMRI) to measure changes in brain responses during tasks that are relevant to relapse. In long-term abstinent addicts, we have shoen reduced responses in the striatum, a brain region that mediates reward and increased responses to negative images (e.g. of a car crash) in the amygdala, a part of the brain involved in emotional processing. This pattern of responses is consistent with addicts describing difficulty in experiencing pleasure, feeling anxious and 'stressed'. In addition, the blunted response to reward was associated with higher risk of relapse. We also showed that aprepitant, a medication that blocks a target in the brain (NK1 receptor) reduces the amygdalar hyper-reactivity to negative images seen in opiate addicts. Along with preclinical evidence, this suggests that aprepitant has therapeutic potential to treat opiate addiction. We will now use this experimental approach to conduct a randomised, placebo-controlled study of a single dose of aprepitant in opiate dependent individuals towards the end of their community based detoxification from methadone and again within a few weeks of abstinence. Each participant will attend our clinical research unit for study days that will include fMRI scans to assess brain responses to reward anticipation, processing of negative images and also opiate-related cues given their involvement in relapse. We will assess the subjective (how they feel) and objective (how they perform) impact of lab-based tasks that involve processing of reward and of positive and negative emotional stimuli. At the start of a study day, participants will take their daily methadone and then be randomly allocated to take either placebo or aprepitant before completing the MR protocol and cognitive tasks. On their 2nd visit at least a week later, they will take the other medication and complete the same study tasks. We will also measure whether aprepitant moderates any subjective (e.g. liking) or objective (e.g. breathing) effects of their dose of methadone. In their first few weeks of abstinence, they will return to complete the two study days again, though without taking methadone; the order of taking placebo and aprepitant will be randomly allocated.Our proposal will provide evidence about whether the NK1 antagonist, aprepitant, is a credible target for a clinical trial to improve the current poor outcomes in either or both detoxification and early abstinence in opiate addiction. We already know that aprepitant is a safe and well tolerated medication as it is already licensed for another indication. In addition we will have characterised brain processes during opiate detoxification from methadone and early abstinence by characterizing task performance and brain responses to processes involved in relapse: reward, emotional processing and cue-reactivity.