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

阿片成瘾是当今英国面临的主要健康挑战之一，与阿片类药物相关的死亡人数上升到创纪录的水平。使用阿片类替代药物(如美沙酮)和心理社会支持治疗的危害最小化方法在改善健康和社会功能方面非常有效，但现在越来越重视实现戒毒。事实上，禁欲可能对整体健康更好，特别是在年迈的阿片成瘾人群中，他们的健康和社会护理需求日益复杂。许多瘾君子渴望禁欲，但发现很难实现和维持。唯一获得许可的预防复发的药物纳曲酮的有效性有限，而且接受率很低，因此我们需要新的治疗方法。我们相信，更好地了解大脑过程，如奖励、情绪处理和对药物相关线索的反应，将有助于最好地改进阿片类药物戒毒和预防复发的治疗。为此，我们建立了一个实验平台，使用基于实验室的任务和功能磁共振成像(FMRI)来测量与复发相关的任务期间大脑反应的变化。在长期戒毒者中，我们发现Shoen减少了纹状体的反应，这是一个负责调节奖赏的大脑区域，而在杏仁核(大脑的一个参与情绪处理的部分)，对负面图像(例如车祸)的反应增加。这种反应模式与吸毒者描述的难以体验快乐、感到焦虑和“有压力”是一致的。此外，对奖励反应迟钝与复发风险较高有关。我们还表明，APRAPANT是一种阻断大脑中的靶点(NK1受体)的药物，它可以减少阿片成瘾者对负面图像的杏仁核高反应性。与临床前证据一起，这表明阿普利特具有治疗阿片成瘾的潜力。我们现在将使用这种实验方法来进行一项随机的、安慰剂对照的研究，在阿片依赖者的社区美沙酮戒毒结束时，以及戒断后的几周内，对单剂量的阿片依赖者进行安慰剂的研究。每个参与者都将参加我们的临床研究单位进行为期几天的研究，其中将包括功能磁共振成像扫描，以评估大脑对奖励预期的反应，处理负面图像，以及考虑到他们参与复发的阿片类药物相关线索。我们将评估基于实验室的任务的主观(他们的感觉如何)和客观(他们如何执行)的影响，这些任务涉及奖励和积极和消极情绪刺激的处理。在一天的研究开始时，参与者将服用他们每天的美沙酮，然后被随机分配到服用安慰剂或安慰剂，然后完成MR方案和认知任务。在至少一周后的第二次访问中，他们将服用其他药物，并完成相同的研究任务。我们还将衡量安非他明是否缓解了他们剂量美沙酮的任何主观(如喜好)或客观(如呼吸)影响。在他们戒烟的前几周，他们将再次完成两个研究日，尽管不服用美沙酮；服用安慰剂和阿片类药物的顺序将被随机分配。我们的提案将提供证据，证明NK1拮抗剂阿片类药物是否为临床试验的可信靶点，以改善目前阿片成瘾在戒毒和早期戒断方面的糟糕结果。我们已经知道安非他明是一种安全且耐受性良好的药物，因为它已经获得了另一种适应症的许可。此外，我们将通过表征任务表现和大脑对复发过程的反应来表征阿片类药物从美沙酮和早期戒断中脱毒的大脑过程：奖励、情绪处理和线索反应。

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.