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: 8806766
• 负责人: JIANREN MAO
• 金额: $ 4.4万
• 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/8806766
• 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; Health; 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; response; subcutaneous; therapy development; tizanidine

DESCRIPTION (provided by applicant): 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 ar 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.

描述（由申请方提供）：阿片类药物是治疗中度至重度疼痛的强效镇痛药。然而，矛盾阿片样物质诱导的痛觉过敏（OIH）已成为一个重要的临床问题，降低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。尽管在定义临床特征方面取得了重大进展， 由于OIH是一种重要的疾病（标志物），目前没有有效的药物疗法可用于预防和逆转OIH。多年来，一直建议在监督下减少阿片类药物剂量或阿片类药物轮换来管理疑似OIH。然而，实施该策略的主要临床挑战是需要在阿片类药物剂量减少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类药物耐受性和依赖性。最近，α 2-AR激动剂也被认为可用于改善OIH。在FDA批准的α 2-AR激动剂中（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，以单次每日剂量方案使用，并已用于（标签外）治疗注意力缺陷多动障碍。我们的初步数据表明，α-2AR激动剂在临床前模型中有效地减少了OIH，并在慢性疼痛患者中保持了阿片类镇痛作用。在本申请中，我们建议进行两项双盲、随机和安慰剂对照的临床研究，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治疗疼痛缓解不满意的慢性疼痛受试者，以评估胍法辛是否可以在他们开始阿片类药物治疗时预防OIH的发展。在第二项研究（目标2）中，我们将招募尽管服用阿片类药物至少三个月但仍经历中度至重度疼痛并表现出OIH体征的慢性疼痛受试者，以评估胍法辛是否可以逆转OIH。在方法学上，我们将使用定量感觉测试（QST，包括时间总和和弥漫性伤害抑制控制的评估）和临床（疼痛强度和影响的视觉模拟量表;皮下针刺试验）标记物 OIH评估胍法辛的有效性。我们希望，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会降低阿片类药物治疗的总体有效性，因此开发这种用于OIH治疗的新型药物疗法将有助于减少不必要的阿片类药物剂量增加，改善阿片类药物治疗的临床结果，并减少与慢性疼痛管理相关的处方阿片类药物成瘾和滥用的可能性。