Identifying Virtual Reality Analgesia Mechanisms by Pharmacologic Manipulation

描述（由申请人提供）：本提案涉及PA-07-282（疼痛研究中的机制、模型、测量和管理）中确定的研究目标，并特别针对生物行为疼痛、疼痛管理和转化疼痛研究的主题。我们提出了一系列的研究，在实验室疼痛设置（热和/或电疼痛的健康志愿者），旨在测试三个具体的和相关的假设，探索神经生理机制，沉浸式虚拟现实（VR）作为一种非药物疼痛管理技术。在这些研究中，VR镇痛的同时药理学操作可能会产生机制上的见解，这将改善VR暴露的未来临床应用，并使沉浸式VR成为更多患者更有效的镇痛工具。VR的理想临床应用可能是作为“多模式镇痛”方案的一个组成部分，与药理学镇痛药联合给药。然而，这些技术的相加和潜在的协同镇痛作用还有待研究。该提案的重点是同时使用VR暴露和已知会影响疼痛感知的全身性镇痛激动剂或拮抗剂，并建立在我们小组以前的工作基础上，该工作比较了沉浸式VR和全身阿片类药物治疗镇痛的并发主观和神经影像学证据。该提案有两个广泛的目标：（1）使用伴随的主观和功能性脑成像（fMRI）评估疼痛体验来测试关于VR镇痛的神经生理学机制的特定假设，以及（2）确定沉浸式VR和药物镇痛联合给药的潜在累加和/或协同镇痛作用。这些目标将通过三个具体目标来实现：（1）确定纳洛酮阿片受体拮抗剂对VR镇痛的主观镇痛作用的抑制程度（或不抑制）;（2）确定沉浸VR和N-甲基-D-天冬氨酸（NMDA）拮抗作用与小剂量氯胺酮的比较和相加效应。（在亚麻醉剂量下，没有幻觉效应，但与镇痛、情绪膨胀和感知增强有关）;（3）确定沉浸式VR和NMDA拮抗作用与低剂量氯胺酮对“疼痛基质”的标准脑区域中疼痛相关脑活动的比较作用，以及在与疼痛体验的调节相关的脑结构中，并将观察到的脑活动与疼痛体验的主观报告相关联。从拟议的研究中获得的信息将指导（1）未来的研究，定义沉浸式VR的具体镇痛机制，（2）在“多模式镇痛”方法中VR暴露和药理学镇痛药的深思熟虑的临床组合，以减少手术疼痛，及（3）日后的费用评估─ VR系统的有效应用，旨在最大限度地提高沉浸式VR在各种临床疼痛环境中的镇痛效果。公共卫生相关性：为患者提供舒适度，特别是在对所有年龄段的患者越来越频繁地执行的痛苦的诊断和治疗医疗程序的情况下，是对卫生保健提供者的持续挑战。缓解疼痛的药物和镇静剂在满足这种需要方面是部分有效的，但是与令人不快或危险的副作用有关;因此，这种药物疗法通常与非药物（即，心理）治疗，也减少疼痛，同时，减少这种副作用的风险。在这个项目中，我们将探索这种有前途的治疗方法-沉浸式虚拟现实-如何缓解疼痛，以及如何将其与标准药物治疗相结合，以便它可以发展成为更多人更有效的止痛工具。

DESCRIPTION (provided by applicant): This proposal addresses the research objectives identified in PA-07-282 (Mechanisms, Models, Measurement, and Management in Pain Research) and specifically targets the topics of Biobehavioral Pain, Pain Management, and Translational Pain Research. We propose a series of studies in the laboratory pain setting (thermal and/or electrical pain in healthy volunteers) designed to test three specific and related hypotheses exploring the neurophysiologic mechanisms that underlie immersive Virtual Reality (VR) as a non- pharmacologic pain management technique. The concurrent pharmacologic manipulation of VR analgesia in these studies will likely yield mechanistic insights that will improve future clinical application of VR exposure, and make immersive VR a more effective analgesic tool for more patients. The ideal clinical use of VR will likely be as one component of a "multimodal analgesia" regimen, administered in combination with pharmacologic analgesics. However, the additive and potential synergistic analgesic effects of these techniques have yet to be examined. This proposal focuses on the concomitant use of VR exposure and systemic analgesic agonists or antagonists known to affect pain perception, and builds on previous work by our group that has compared concurrent subjective and neuroimaging evidence of analgesia with immersive VR and systemic opioid therapy. This proposal has two broad goals: (1) to test specific hypotheses concerning the neurophysiologic mechanisms of VR analgesia, using concomitant subjective and functional brain imaging (fMRI) assessments of the pain experience, and (2) to determine the potential additive and/or synergistic analgesic effects of combined immersive VR and pharmacologic analgesic administration. These goals will be met through three Specific Aims: (1) To determine the extent to which subjective analgesic effects of VR analgesia are inhibited (or not) by opioid receptor antagonism with naloxone; (2) To determine the comparative and additive effects of immersive VR and N-methyl-D-aspartate (NMDA) antagonism with low- dose ketamine (at a sub-anesthetic dose devoid of hallucinatory effects, but associated with analgesia, expansive mood, and heightened perception); (3) To determine the comparative effects of immersive VR and NMDA antagonism with low-dose ketamine on pain-related brain activity in standard brain regions of the "pain matrix", as well as in brain structures associated with modulation of the pain experience, and to correlate observed brain activity with subjective reports of the pain experience. Information gained from the proposed studies will guide (1) future investigations that define specific analgesic mechanisms of immersive VR, (2) the thoughtful clinical combination of VR exposure and pharmacologic analgesics in a "multimodal analgesia" approach to reducing procedural pain, and (3) future assessments of the cost-effective application of VR systems designed to maximize the analgesic effect of immersive VR in various clinical pain settings. PUBLIC HEALTH RELEVANCE: Providing for patient comfort, particularly in the setting of painful diagnostic and therapeutic medical procedures that are performed with increasing frequency on patients of all ages, is a continuing challenge to health care providers. Pain relieving drugs and sedatives are partially effective in meeting this need, but are associated with unpleasant or dangerous side effects; thus, such drug therapy is often combined with non- drug (i.e., psychological) treatments that also reduce pain and, at the same time, reduce the risk for such side effects. In this project we will explore how one such promising treatment - immersive virtual reality - causes pain relief, as well as how it can be thoughtfully combined with standard drug therapies, so that it can be developed into a more effective analgesic tool for more people.