Alleviating Opioid-Induced Hyperalgesia with Novel Pharmacotherapy

用新型药物疗法减轻阿片类药物引起的痛觉过敏

• 批准号: 8610607
• 负责人: JIANREN MAO
• 金额: $ 43.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610607
• 关键词: Absence of pain sensation; Adverse effects; Affect; Agonist; Analgesics; Attention deficit hyperactivity disorder; Biological Availability; Cardiovascular system; Clinical; Clinical Data; Clinical Research; Clonidine; Data; Dependence; Development; Dexmedetomidine; Dose; Double-Blind Method; Drug Formulations; Effectiveness; FDA approved; Guanfacine; Half-Life; Hour; Human; Hyperalgesia; Hypertension; Label; Morphine; Muscle relaxants; Needlestick Injuries; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Rotation; Oral; Outcome; Outcome Study; Pain; Pain intensity; Pain management; Patients; Pharmacotherapy; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Prevention; Randomized; Recruitment Activity; Regimen; Sensory; Study Subject; Testing; Visual; analog; capsule; chronic pain; compliance behavior; diffuse noxious inhibitory control; experience; improved; novel; novel therapeutic intervention; opioid abuse; prescription opioid; prevent; prospective; public health relevance; response; subcutaneous; therapy development; tizanidine

Abstract Opioids are strong analgesics for the treatment of moderate to severe pain. However, paradoxical opioid-induced hyperalgesia (OIH) has become a significant clinical issue that reduces the effectiveness of opioid therapy and contributes to prescription opioid addiction and abuse. Despite significant progress in defining clinical features (markers) of OIH, no effective pharmacotherapies are currently available to prevent and reverse OIH. For years, supervised opioid dose reduction or opioid rotation has been proposed to manage suspected OIH. However, a major clinical challenge in implementing this strategy is the need to maintain adequate pain relief while opioid dose is reduced. Centrally acting alpha2-adrenoreceptor (alpha2-AR) agonists have long been known to improve opioid tolerance and dependence. Recently, alpha2-AR agonists also have been suggested to be useful to improve OIH. Among FDA-approved alpha2-AR agonists (e.g., clonidine, dexmedetomidine, tizanidine), guanfacine possesses a stable cardiovascular side effect profile, is used in a single daily dose regimen, and has been used (off-label) for the treatment of attention deficit hyperactivity disorder. Our preliminary data has shown that alpha-2AR agonist effectively reduces OIH in a preclinical model and maintains the opioid analgesic effect in chronic pain patients. In this application, we propose to conduct two double-blind, randomized, and placebo-controlled clinical studies in order to examine the effectiveness of guanfacine in the prevention and reversal of OIH. In the first study (Aim 1), we will recruit chronic pain subjects who currently are experiencing unsatisfactory pain relief with non-opioid treatment to assess whether guanfacine can prevent the development of OIH as they commence opioid therapy. In the second study (Aim 2), we will recruit chronic pain subjects who experience moderate to severe pain despite having taken opioid for at least three months and demonstrate signs of OIH to assess whether guanfacine can reverse OIH. Methodologically, we will use both quantitative sensory testing (QST including assessment of temporal summation and diffuse noxious inhibitory control) and clinical (visual analog scale of pain intensity and affect; subcutaneous needle stick test) markers of OIH to assess the effectiveness of guanfacine. We expect that the proposed prospective human studies will yield important and timely clinical data regarding a novel and practical approach to managing OIH. Since OIH decreases the overall effectiveness of opioid therapy, developing this novel pharmacotherapy for OIH treatment will help reduce unnecessary opioid dose escalation, improve clinical outcome of opioid therapy, and diminish the liability of prescription opioid addiction and abuse related to chronic pain management.

摘要 阿片类药物是治疗中度至重度疼痛的强效镇痛剂。然而，矛盾的是， 阿片类药物诱导的痛觉过敏（OIH）已成为一个重要的临床问题，它可以减少疼痛。 阿片类药物治疗的有效性，并有助于处方阿片类药物成瘾和滥用。尽管 虽然在定义OIH的临床特征（标志物）方面取得了重大进展，但目前还没有有效的药物治疗， 目前可用于预防和逆转OIH。多年来，监督阿片类药物剂量减少或阿片类药物 已提议轮调，以管理被怀疑的海地问题办公室。然而，一个主要的临床挑战是， 实施这一策略需要在减少阿片类药物剂量的同时保持足够的疼痛缓解。 中枢作用的α 2-肾上腺素受体（α 2-AR）激动剂长期以来被认为可以改善阿片样物质 宽容和依赖。最近，也已经提出α 2-AR激动剂可用于治疗癌症。 改善OIH。在FDA批准的α 2-AR激动剂（例如，可乐定，右美托咪定， 替扎尼定），胍法辛具有稳定的心血管副作用特征， 剂量方案，并已用于（标签外）治疗注意缺陷多动障碍。 我们的初步数据表明，α-2AR激动剂在临床前模型中有效降低OIH 并维持阿片类药物对慢性疼痛患者的镇痛作用。在本申请中，我们建议 进行两项双盲、随机和安慰剂对照临床研究，以检查 胍法辛预防和逆转OIH的有效性。在第一项研究（目标1）中，我们将 招募目前非阿片类药物疼痛缓解不满意的慢性疼痛受试者 治疗，以评估胍法辛是否可以防止OIH的发展，因为他们开始阿片类药物 疗法在第二项研究（目标2）中，我们将招募经历中度至中度疼痛的慢性疼痛受试者。 严重疼痛，尽管服用阿片类药物至少三个月，并表现出OIH的迹象， 评估胍法辛是否能逆转OIH。在方法论上，我们将使用定量的感官 测试（QST，包括时间总和和弥漫性伤害抑制控制的评估）和 OIH的临床（疼痛强度和情感的视觉模拟量表;皮下针刺试验）标志物 来评估胍法辛的有效性我们预计，拟议的前瞻性人体研究将 产生重要和及时的临床数据，关于一种新的和实用的方法来管理OIH。 由于OIH降低了阿片类药物治疗的整体有效性，因此开发这种新的 OIH治疗的药物治疗将有助于减少不必要的阿片类药物剂量递增， 阿片类药物治疗的临床结果，并减少处方阿片类药物成瘾和滥用的可能性 与慢性疼痛管理有关。