Kinetics and target engagement for a Phase II trial of RTX for cancer pain

RTX 治疗癌症疼痛的 II 期试验的动力学和靶点参与

• 批准号: 10801438
• 负责人: ROBERT M CAUDLE
• 金额: $ 10万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10801438
• 关键词: Absence of pain sensation; Acute; Acute Pain; Affect; Analgesics; Animals; Attenuated; Behavior assessment; Behavioral; Behavioral Assay; Biological Assay; Brain; Cannabidiol; Cannabinoids; Cannabis; Chronic; Clinical; Collaborations; Controlled Study; Dependence; Depressed mood; Foundations; Future; Goals; Grant; Individual; Kinetics; Lesion; Maps; National Institute of Drug Abuse; Neurosciences; Nociceptors; Opioid; Opioid Analgesics; Opioid Receptor; Oxycodone; Pain; Pain Clinics; Pain Measurement; Pain management; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Property; Psychological reinforcement; Public Health; Research; Rewards; Self Administration; Societies; TRPV1 gene; Tetrahydrocannabinol; Variant; Work; abuse liability; cancer pain; cannabinoid receptor; chronic pain; chronic pain management; cost; experimental study; heuristics; human subject; innovation; multidisciplinary; neural; neuroimaging; novel; novel strategies; opioid epidemic; opioid sparing; opioid use; pain behavior; pain model; parent grant; phase II trial; prescription opioid; programs; substance use

Abstract Chronic pain is a significant public health problem that costs society billions of dollars per year and causes great suffering in countless individuals. Opioid-based medications are among the most prescribed for various forms of chronic pain contributing to the current opioid epidemic. Recently, cannabis and cannabinoid compounds (e.g., 9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been described as having pain-alleviating properties. While these cannabinoids, particularly the less psychoactive variant, CBD, may offer alternatives to opioid treatments for pain, few well-controlled studies demonstrate analgesic efficacy, especially for CBD. While it is still unclear if cannabinoids are good stand-alone options for treating pain, cannabinoids may act as useful opioid-sparing drugs, given the substantial overlap between opioid and cannabinoid receptors in reward- and pain-related pathways. Our proposed project will focus on a heuristic approach that incorporates fundamental pharmacology, novel operant behavioral assays of pain, and functional neuroimaging. The long-term goal of this research program is to establish novel approaches to treat chronic pain by maximizing analgesic efficacy and minimizing abuse liability. The objective of this proposal, which embodies the first step toward this long- term goal, is to determine how CBD modifies the effects of oxycodone (OXY), a commonly prescribed opioid analgesic, in the contexts of chronic pain and opioid self-administration. Our overarching hypothesis is that CBD and OXY will act synergistically to yield enhanced analgesic effects, and that CBD will attenuate the effects of pain on OXY self-administration. Two major specific aims will be investigated: (1) to determine how CBD interacts with OXY to reduce chronic operant pain behaviors; and (2) to determine the interacting effects of chronic pain, OXY self-administration, and CBD on analgesia, reinforcement, and dependence. We will assess the effects of preexisting pain on OXY self-administration, as well as the effects of preexisting OXY self- administration on pain. The latter goal is a particularly innovative aspect of this proposal. CBD-modulatory effects on pain and OXY self-administration will be evaluated under both conditions. Neuroimaging will be used across experiments to map and quantify changes in neural connectivity across reward and pain centers of the brain following the various drug treatments (CBD, OXY) and pain states (acute, chronic). Further, we will use clinically important and innovative pain-depressed behavioral assessments that accurately model pain in human subjects. The rationale for completing these studies is that by determining how CBD and OXY interact to affect pain and substance use, we will establish the necessary foundation for future efforts to develop effective analgesics with reduced abuse liability. We believe we are particularly well suited to undertake this project because we have a unified (and already collaborating) multidisciplinary team with complementary expertise in behavioral neuroscience, pharmacology, and neuroimaging.

抽象的 慢性疼痛是一个重大的公共卫生问题，每年给社会造成数十亿美元的损失，并造成巨大的影响。 无数人的痛苦。以阿片类药物为基础的药物是治疗各种形式最常用的药物之一 慢性疼痛导致了当前阿片类药物的流行。最近，大麻和大麻素化合物（例如， 9-四氢大麻酚（THC）和大麻二酚（CBD））被描述为具有缓解疼痛的作用 特性。虽然这些大麻素，特别是精神活性较低的变体 CBD，可能提供替代品 阿片类药物治疗疼痛，很少有对照良好的研究证明其镇痛功效，尤其是 CBD。尽管 目前尚不清楚大麻素是否是治疗疼痛的良好独立选择，大麻素可能有用 鉴于阿片类药物和大麻素受体在奖励和治疗方面存在大量重叠，阿片类药物节省药物 疼痛相关通路。我们提出的项目将侧重于一种启发式方法，其中包含基本的 药理学、新型疼痛操作行为分析和功能神经影像学。长期目标是 该研究计划旨在通过最大限度地提高镇痛功效来建立治疗慢性疼痛的新方法 并最大限度地减少滥用责任。该提案的目标体现了朝着这一长期目标迈出的第一步 术语目标是确定 CBD 如何改变羟考酮 (OXY)（一种常用的阿片类药物）的作用 在慢性疼痛和阿片类药物自我给药的情况下镇痛。我们的总体假设是 CBD 和 OXY 将协同作用，产生增强的镇痛效果，而 CBD 会减弱该效果 OXY 自我给药时的疼痛。将研究两个主要具体目标：（1）确定 CBD 如何 与 OXY 相互作用，减少慢性操作性疼痛行为； (2) 确定相互作用的影响 慢性疼痛、OXY 自我给药以及 CBD 的镇痛、强化和依赖性。我们将 评估先前存在的疼痛对 OXY 自我给药的影响，以及先前存在的 OXY 自我给药的影响 对疼痛的管理。后一个目标是该提案特别创新的方面。 CBD 调节作用 将在两种情况下评估对疼痛和 OXY 自我给药的影响。神经影像学将用于 绘制和量化大脑奖励和疼痛中心神经连接变化的实验 遵循各种药物治疗（CBD、OXY）和疼痛状态（急性、慢性）。此外，我们将在临床上使用 重要且创新的疼痛抑制行为评估，可以准确模拟人类受试者的疼痛。 完成这些研究的基本原理是，通过确定 CBD 和 OXY 如何相互作用来影响疼痛和 物质使用，我们将为未来开发有效的镇痛药奠定必要的基础 减少滥用责任。我们相信我们特别适合承担这个项目，因为我们有 统一的（并且已经合作的）多学科团队，在行为方面具有互补的专业知识 神经科学、药理学和神经影像学。