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

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到创纪录的水平。用阿片剂替代药物（如美沙酮）和社会心理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，但现在越来越注重实现戒断。的确，戒断可能对整体健康更有利，特别是对那些有日益复杂的健康和社会护理需求的老年鸦片成瘾人群而言。许多上瘾者渴望禁欲，但发现很难实现和维持。唯一获得许可的预防复发药物纳曲酮的效果有限，而且使用率很低，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，如奖励、情绪处理和对药物相关线索的反应，将告知如何最好地改善阿片解毒治疗和预防复发。为此，我们建立了一个实验平台，使用实验室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。在长期戒断成瘾者中，我们发现纹状体（大脑中负责调节奖励的区域）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”的情况是一致的。此外，对奖励的迟钝反应与更高的复发风险有关。我们还发现阿瑞匹坦，一种阻断大脑靶点（NK1受体）的药物，可以减少阿片类药物成瘾者对负面图像的杏仁核过度反应。与临床前证据一起，这表明阿瑞吡坦具有治疗阿片成瘾的治疗潜力。现在，我们将使用这种实验方法进行随机、安慰剂对照研究，对阿片类药物依赖个体进行单剂量阿瑞吡坦的研究，这些个体即将结束以社区为基础的美沙酮解毒，并在几周内再次戒断。每位参与者都将参加我们的临床研究单元的学习日，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，对负面图像的处理，以及与阿片类药物相关的线索，因为它们与复发有关。我们将评估主观（他们的感受）和客观（他们的表现）对实验室任务的影响，这些任务包括处理奖励和积极和消极的情绪刺激。在研究日开始时，参与者将服用每日美沙酮，然后在完成MR协议和认知任务之前随机分配服用安慰剂或阿瑞吡坦。在至少一周后的第二次访问中，他们将服用另一种药物并完成相同的研究任务。我们还将测量阿瑞吡坦是否能缓解美沙酮剂量对患者的主观（如喜好）或客观（如呼吸）影响。在禁欲的前几周，他们将再次返回完成两天的研究，但不服用美沙酮；随机分配安慰剂和阿瑞吡坦的服用顺序。我们的建议将提供证据，证明NK1拮抗剂阿瑞吡坦是否可以作为临床试验的可靠靶点，以改善目前阿片成瘾患者在解毒和早期戒断方面的不良结果。我们已经知道阿瑞吡坦是一种安全且耐受性良好的药物，因为它已经被许可用于另一种适应症。此外，我们将通过描述任务表现和大脑对复发过程的反应来描述美沙酮和早期戒断期间的大脑过程：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.