Alleviating Opioid-Induced Hyperalgesia with Novel Pharmacotherapy

描述(申请人提供)：阿片类药物是治疗中度至重度疼痛的强效止痛药。然而，矛盾阿片诱导的痛觉过敏(OIH)已经成为一个重要的临床问题，它降低了阿片类药物治疗的有效性，并导致处方阿片成瘾和滥用。尽管在定义临床特征方面取得了重大进展 (标记物)，目前还没有有效的药物疗法来预防和逆转OIH。多年来，有人建议在监督下减少阿片类药物剂量或阿片类药物轮换，以管理可疑的OIH。然而，实施这一策略的一个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止痛效果。中枢作用的α2-肾上腺素受体(α2-AR)激动剂长期以来一直被认为可以改善阿片类药物的耐受和依赖。最近，α2-AR激动剂也被认为是改善OIH的有用药物。在FDA批准的α2-AR激动剂(如可乐定、右旋美托咪定、替扎尼定)中，胍法辛具有稳定的心血管副作用，用于单一的每日给药方案，并已被用于(标签外)治疗注意缺陷多动障碍。我们的初步数据显示，在临床前模型中，α-2AR激动剂有效地减少了OIH，并在慢性疼痛患者中保持了阿片类止痛效果。在这项应用中，我们建议进行两项双盲、随机和安慰剂对照的临床研究，以检验瓜那法辛在预防和逆转OIH方面的有效性。在第一项研究中(目标1)，我们将招募目前在非阿片类药物治疗中疼痛缓解不满意的慢性疼痛受试者，以评估当他们开始阿片类药物治疗时，金刚烷是否可以防止OIH的发展。在第二项研究中(目标2)，我们将招募慢性疼痛受试者，这些受试者在服用阿片类药物至少三个月后仍有中到重度疼痛，并表现出OIH的迹象，以评估瓜那法辛是否可以逆转OIH。在方法上，我们将同时使用定量感觉测试(QST包括时间总和和弥漫性有害物质抑制控制的评估)和临床(疼痛强度和影响的视觉模拟评分；皮下针刺试验)标记物。 以评估鸟嘌呤的疗效。我们期望拟议的前瞻性人体研究将产生重要和及时的临床数据，为OIH的治疗提供一种新的、实用的方法。由于OIH降低了阿片类药物治疗的整体疗效，开发这一治疗OIH的新药物疗法将有助于减少不必要的阿片类药物剂量上升，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成瘾和滥用的风险。

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.