Novel Use of Ketotifen (Mast Cell Stablizier)in Fibromyalgia: A Pilot Study

描述（由申请人提供）：尽管纤维肌痛（FM）给社会和个人带来了巨大的负担，但对这种疾病的有效治疗仍然不是最佳的。在临床试验中，只有三分之一的患者至少从目前FDA批准的FM药物中获益。不良的治疗结果可能是由于缺乏针对FM病理生理学其他方面的药物。在FM皮肤活检中发现皮肤肥大细胞数量增加，肥大细胞是一种强有力的炎症细胞。肥大细胞介质（例如，趋化因子）可能是到达中枢神经系统的诱导和/或维持中枢致敏的增加的外周刺激的潜在来源。有趣的是，血液中的趋化因子水平（即，IL-8、MCP-1和嗜酸性粒细胞趋化因子）在FM患者中升高。尽管越来越多的证据表明FM的免疫学基础，但是药物试验主要集中在影响上行的中枢作用剂（例如，普瑞巴林）或下行（例如，去甲肾上腺素再摄取抑制剂）疼痛通路。也许针对炎症介质或肥大细胞的连续治疗可能会改善FM的治疗结果。因此，我们建议进行一项使用酮替芬（肥大细胞稳定剂）治疗FM的随机临床试验，并获得初步估计的治疗效果，用于设计一个更大的试验。在一周的安慰剂导入期后，38名FM患者将随机接受酮替芬或安慰剂治疗10周。基线（第0周）和第11周的结果评估将包括以下：每周平均疼痛严重程度、趋化因子水平（即，IL-8、MCP-1和嗜酸性粒细胞趋化因子）和压痛阈值。这项研究具有创新性，因为它将是第一个研究基于免疫的治疗对FM相关疼痛的影响，也是第一个评估趋化因子作为疾病严重程度生物标志物的研究。

DESCRIPTION (provided by applicant): Despite the enormous societal and personal burden of fibromyalgia (FM), effective treatment for this condition remains suboptimal. Only one-third of patients in clinical trials derive at least some benefit from currently FDA-approved drugs for FM. Poor treatment outcomes may be accounted for by the absence of drugs that target other aspects of the pathophysiology of FM. Increased number of skin mast cell, a powerful inflammatory cell, has been noted in FM skin biopsies. Mast cells mediators (e.g., chemokines) maybe a potential source of increased peripheral stimuli reaching the central nervous system that induce and/or maintain central sensitization. Interestingly, blood levels of chemokines (i.e., IL-8, MCP-1 and eotaxin) have been reported to be elevated in patients with FM. Despite growing evidence of the immunologic basis of FM however, drug trials have largely focused on centrally-acting agents that influence the ascending (e.g., pregabalin) or the descending (e.g., serotonin-norepinephrine reuptake inhibitors) pain pathways. Perhaps adjunctive therapies directed against inflammatory mediators or towards mast cells may improve the dismal treatment outcomes in FM. Therefore, we propose to conduct a randomized clinical trial using ketotifen (mast cell stabilizer) for FM, and to obtain preliminary estimates of treatment effects for use in designing a larger trial. After a one week placebo run-in phase, 38 FM patients will be randomized to receive ketotifen or placebo for 10 weeks. Outcome assessments at baseline (week 0) and week 11 will include the following: weekly average pain severity, chemokine levels (i.e., IL-8, MCP-1 and eotaxin) and pressure pain threshold. The proposed research is innovative because it will be the first to investigate the effects of an immune-based therapy on FM-related pain, and also the first to evaluate chemokines as biomarkers of disease severity.