Alleviating Opioid-Induced Hyperalgesia with Novel Pharmacotherapy

摘要 阿片类药物是治疗中度至重度疼痛的强效止痛剂。然而，矛盾的是 阿片诱导的痛觉过敏(OIH)已成为一个重要的临床问题，它减少了 阿片类药物治疗的有效性，并导致处方类阿片成瘾和滥用。尽管 在确定OIH的临床特征(标志物)方面取得了重大进展，目前还没有有效的药物治疗方法 目前可用于预防和逆转OIH。多年来，受监督的阿片类药物剂量减少或阿片类药物 已提议轮换来管理疑似OIH。然而，临床上的一个主要挑战是 实施这一战略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 宽容和依赖。最近，α2-AR激动剂也被认为对 改善OIH。在FDA批准的α2-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，每天一次使用 剂量方案，并已被用于治疗注意缺陷多动障碍(标签外)。 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维持阿片类止痛效果。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 金刚烷预防和逆转OIH的疗效观察在第一项研究(目标1)中，我们将 招募目前正在经历非阿片类药物疼痛缓解不满意的慢性疼痛受试者 评估愈创法辛是否可以预防OIH的发展，因为他们开始使用阿片类药物 心理治疗。在第二项研究(目标2)中，我们将招募经历中度至 尽管服用了至少三个月的阿片类药物，但仍然剧烈疼痛，并表现出OIH的迹象 评估瓜那法辛是否能逆转OIH。在方法论上，我们将使用定量感官 测试(QST包括时间总和和弥漫性有害抑制控制的评估)和 OIH的临床(疼痛强度和影响的视觉模拟评分；皮下针刺试验)标记物 目的：评价鸟嘌呤类药物的疗效。我们预计拟议的前瞻性人体研究将 产生重要的和及时的临床数据，关于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效果，开发这一新的 OIH的药物治疗将有助于减少不必要的阿片类药物剂量升级，改善 阿片类药物治疗的临床结果，并减少处方阿片成瘾和滥用的可能性 与慢性疼痛管理相关。

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.