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

描述阿片成瘾中解毒和早期戒断的神经生物学特征：NK1 拮抗作用是否有助于改善结果？

• 批准号: MR/R024197/1
• 负责人: Anne Lingford Hughes
• 金额: $ 103.53万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR024197%2F1
• 关键词: Characterizing; neurobiology; detoxification; early; abstinence

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.

阿片成瘾是英国当今面临的主要健康挑战之一，与阿片有关的死亡人数上升至创纪录水平。使用阿片类替代药物（例如美沙酮）和社会心理支持进行危害最小化治疗方法在改善健康和社会功能方面非常有效，但现在人们越来越关注实现戒烟。事实上，戒酒可能对整体健康更好，特别是对于健康和社会护理需求日益复杂的老年鸦片成瘾人群。许多成瘾者渴望戒毒，但发现很难实现和维持。唯一获得许可的预防复发药物纳曲酮的有效性有限且使用率较低，因此我们需要新的治疗方法。我们相信，更好地理解大脑过程，例如奖励、情绪处理和对药物相关线索的反应，将有助于如何最好地改善阿片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。在长期戒瘾的成瘾者中，我们发现纹状体（负责调节奖励的大脑区域）的反应减少，而杏仁核（大脑中参与情绪处理的部分）对负面图像（例如车祸）的反应增加。这种反应模式与成瘾者描述的难以体验快乐、感到焦虑和“压力”一致。此外，对奖励的迟钝反应与较高的复发风险相关。我们还发现，阿瑞吡坦是一种阻断大脑靶标（NK1 受体）的药物，可降低阿片类成瘾者杏仁核对负面图像的过度反应。连同临床前证据，这表明阿瑞吡坦具有治疗阿片成瘾的潜力。我们现在将使用这种实验方法对阿片类药物依赖个体进行单剂量阿瑞匹坦的随机、安慰剂对照研究，该研究将在社区美沙酮戒毒结束时以及戒断几周内再次进行。每位参与者都将参加我们的临床研究单元进行研究日，其中包括功能磁共振成像扫描，以评估大脑对奖励预期的反应、负面图像的处理以及考虑到他们参与复发的阿片类药物相关线索。我们将评估实验室任务的主观（他们的感受）和客观（他们的表现）影响，这些任务涉及奖励以及积极和消极情绪刺激的处理。在研究日开始时，参与者将每天服用美沙酮，然后在完成 MR 方案和认知任务之前随机分配服用安慰剂或阿瑞匹坦。至少一周后第二次就诊时，他们将服用其他药物并完成相同的研究任务。我们还将测量阿瑞匹坦是否会调节美沙酮剂量的主观（例如喜好）或客观（例如呼吸）影响。在戒酒的最初几周，他们将再次完成两天的研究，但不服用美沙酮；安慰剂和阿瑞匹坦的服用顺序将是随机分配的。我们的提案将提供证据证明 NK1 拮抗剂阿瑞匹坦是否是临床试验的可信目标，以改善目前阿片成瘾戒毒和早期戒断中的不良结果。 。我们已经知道阿瑞吡坦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涉及复发的过程的反应（奖励、情绪处理和提示反应性）来表征美沙酮阿片戒毒和早期戒断期间的大脑过程。

项目成果

Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; an fMRI study

NK1拮抗作用对阿片依赖提示反应性的功能评估；

• DOI: http://dx.10.17605/osf.io/h3kws
• 发表时间: 2022
• 作者: Fonville L

Functional evaluation of NK1 antagonism on cue reactivity in opiate dependence; An fMRI study.

NK1拮抗作用对阿片依赖提示反应性的功能评估；

• DOI: http://dx.10.1016/j.drugalcdep.2021.108564
• 发表时间: 2021
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: Fonville L

DEFICITS IN 'HOT' COGNITION IN METHADONE-MAINTAINED OPIOID USE DISORDER

美沙酮维持的阿片类药物使用障碍的“热”认知缺陷

• 发表时间: 2022
• 作者: Hand; L
• 通讯作者: L