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.

阿片类药物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至创纪录水平。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，但现在越来越关注实现禁欲。事实上，禁欲可能对整体健康更好，特别是在老年阿片类药物成瘾人群中，他们的健康和社会护理需求日益复杂。许多成瘾者渴望禁欲，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洛酮的有效性有限，而且服用率很低，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，例如奖励、情感处理和对药物相关线索的反应，将有助于了解如何最好地改善阿片类药物戒毒和预防复吸的治疗。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性磁共振成像（fMRI）来测量与复发相关的任务期间大脑反应的变化。在长期戒断的成瘾者中，我们发现纹状体（一个调节奖赏的大脑区域）的反应减少，而杏仁核（一个参与情绪处理的大脑区域）对负面图像（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”是一致的。此外，对奖励的迟钝反应与复发的风险较高有关。我们还发现，阿瑞匹坦，一种阻断大脑中靶点（NK 1受体）的药物，可以降低阿片类药物成瘾者对负面图像的杏仁核高反应性。沿着临床前证据，这表明阿瑞匹坦具有治疗阿片类药物成瘾的治疗潜力。我们现在将使用这种实验方法进行一项随机、安慰剂对照研究，在阿片类药物依赖者中进行单剂量阿瑞匹坦的研究，这些人将在社区美沙酮脱毒结束时和戒断后几周内再次进行。每个参与者将参加我们的临床研究单位的研究日，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，负面图像的处理以及阿片类药物相关的线索，因为他们参与复发。我们将评估基于实验室的任务的主观（他们的感受）和客观（他们的表现）影响，这些任务涉及奖励和积极和消极的情绪刺激的处理。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。在至少一周后的第二次访视时，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缓和美沙酮剂量的任何主观（例如喜好）或客观（例如呼吸）效应。在他们的前几个星期的禁欲，他们将返回完成两个研究日再次，虽然没有服用美沙酮;服用安慰剂和阿瑞匹坦的顺序将随机分配。我们的建议将提供证据，是否NK 1拮抗剂，阿瑞匹坦，是一个可靠的目标，临床试验，以改善目前的不良结果在戒毒和早期戒断阿片类药物成瘾。我们已经知道阿瑞匹坦是一种安全且耐受性良好的药物，因为它已经被许可用于另一种适应症。此外，我们还将通过表征任务表现和大脑对复吸过程的反应来表征美沙酮和早期戒断的阿片类药物脱毒过程中的大脑过程：奖励，情绪处理和线索反应。

项目成果

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

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