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、疼痛管理和转化性疼痛研究的主题。我们建议在实验室疼痛环境中进行一系列研究(健康志愿者的热痛和/或电痛)，旨在测试三个特定和相关的假设，探索沉浸式虚拟现实(VR)作为一种非药物疼痛管理技术的神经生理学机制。在这些研究中，VR止痛的同步药理操作可能会产生机理上的见解，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止痛工具。VR的理想临床应用可能是作为“多模式止痛”方案的一个组成部分，与药物止痛剂结合使用。然而，这些技术的相加和潜在的协同止痛效果还有待检验。这项建议的重点是同时使用VR暴露和已知的影响痛觉的全身止痛激动剂或拮抗剂，并建立在我们小组之前的工作的基础上，该小组将同时存在的主观和神经影像止痛证据与沉浸式VR和全身阿片类药物治疗进行了比较。这项建议有两个广泛的目标：(1)检验关于VR镇痛的神经生理机制的具体假设，使用伴随的主观和功能脑成像(FMRI)对疼痛体验的评估，以及(2)确定沉浸式VR和药物止痛剂联合应用的潜在相加和/或协同止痛效果。这些目标将通过三个具体目标来实现：(1)确定阿片受体拮抗纳洛酮对VR镇痛的主观镇痛效果的抑制程度；(2)确定浸入式VR和N-甲基-D-天冬氨酸(NMDA)拮抗与小剂量氯胺酮(在亚麻剂量下无幻觉作用，但伴有镇痛、扩张情绪和感觉增强)的比较和相加效应；(3)确定沉浸式VR和NMDA拮抗联合小剂量氯胺酮对“疼痛矩阵”标准脑区以及与疼痛体验调制相关的脑结构中与疼痛相关的脑活动的比较影响，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)未来确定沉浸式VR的具体止痛机制的研究，(2)在“多模式止痛”方法中将VR暴露与药物止痛剂进行深思熟虑的临床组合，以及(3)未来对旨在使沉浸式VR在各种临床疼痛环境中的止痛效果最大化的VR系统的成本效益应用进行评估。公共卫生相关性：为病人提供舒适，特别是在所有年龄段的病人越来越频繁地进行痛苦的诊断和治疗性医疗程序的情况下，这是卫生保健提供者面临的持续挑战。止痛药和镇静剂在满足这一需求方面部分有效，但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)治疗相结合，这些疗法也可以减轻疼痛，同时降低此类副作用的风险。在这个项目中，我们将探索这样一种有希望的治疗方法-沉浸式虚拟现实-如何缓解疼痛，以及如何将其与标准药物疗法进行深思熟虑的结合，以便将其开发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.