The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome

描述（由申请人提供）：紫杉醇是最常用的抗癌药之一，在多种恶性肿瘤的治疗中起重要作用。紫杉醇引起的急性疼痛综合征（PIAPS）发生在紫杉醇给药后。其主要特点是难以治愈的疼痛。甚至阿片类药物也是无效的。虽然PIAPS通常在第7天缓解，但患者在化疗期间有三分之一的时间遭受难治性疼痛。我们的小组是第一个从临床角度对该综合征进行前瞻性表征的小组，但该综合征的病理生理学仍然未知，而且研究明显不足。我们假设非典型蛋白激酶C （PKC）同工酶PKC iota和zeta是PIAPS的关键介质，而金化合物金嘌呤是PKC iota和zeta的抑制剂，可以预防或缓解这种综合征。事实上，1)PKC家族与许多其他肌肉骨骼疼痛综合征有关；2)我们的临床前数据表明紫杉醇导致PKC iota活化；3)我们的临床前和临床数据也表明，用于治疗自身免疫性关节炎的药物金糠蛋白可以抑制PKC iota和zeta。因此，我们提出以下具体目的：1)定量测量紫杉醇给药前后患者肌肉中PKC iota和zeta mRNA表达，确定PKC iota或zeta过表达是否与PIAPS的发展相关（通过患者完成简短疼痛量表评估）。2)开展一项试点、随机对照试验，检验金糠蛋白是否能预防或缓解PIAPS。30名患者（每组15名）将在紫杉醇和安慰剂治疗后的第二天随机分配到auranofin（一次6毫克剂量）组。每日疼痛评分（简短疼痛量表）将在暴露于奥诺芬和安慰剂组之间进行比较。这两个独立但综合的目标（每个目标包括两个独立的患者组）将为PIAPS的病理生理学提供期待已久的见解，并有可能使我们在未来进行一项明确的随机对照试验，用auranofin预防或缓解PIAPS。

DESCRIPTION (provided by applicant): Paclitaxel is one of the most commonly prescribed cancer drugs and serves an important role in the treatment of a variety of malignancies. The paclitaxel-induced acute pain syndrome (PIAPS) occurs after paclitaxel administration. Its seminal feature is refractory, untreatable pain. Even opioids are ineffective. Although PIAPS typically remits by day 7, patients suffer from refractory pain one-third of their time on chemotherapy. Our group was the first to prospectively characterize this syndrome from a clinical standpoint, but the pathophysiology of this syndrome remains unknown and remarkably understudied. We hypothesize that the atypical protein kinase C (PKC) isoenzymes, PKC iota and zeta, are key mediators of the PIAPS and that the gold compound auranofin, an inhibitor of of PKC iotal and zeta, prevents or palliates this syndrome. Indeed, 1) the PKC family has been implicated in a host of other musculoskeletal pain syndromes; 2) our preclinical data demonstrate that paclitaxel results in PKC iota activation; and 3) our preclinical and clinical dat also show that auranofin, a drug used to treat autoimmune arthritis, inhibits PKC iota and zeta. Hence, we propose the following specific aims: 1) To measure quantitatively the mRNA expression of PKC iota and zeta in the muscle of patients before and after paclitaxel administration and to determine whether PKC iota or zeta overexpression are associated with the development of the PIAPS (as assessed by patients' completion of the Brief Pain Inventory). 2) To conduct a pilot, randomized controlled trial to test whether auranofin prevents or palliates the PIAPS. Thirty patients (15 per arm) will be randomly assigned to either auranofin (one 6 mg dose) the day after paclitaxel versus placebo. Daily pain scores (Brief Pain Inventory) will be compared between auranofin- and placebo-exposed arms. These two independent but integrated aims -- which include two independent groups of patients for each aim -- will provide long-overdue insight into the pathophysiology of the PIAPS and will potentially position us to mount a future, definitive randomized controlled trial with auranofin to prevent or palliate the PIAPS.