Metformin as a novel, mechanistic treatment of fibromyalgia; a proof of concept RCT

7.项目摘要 这是一项概念验证性初步研究，是一项双盲、随机对照试验（RCT），旨在测试 低剂量二甲双胍改善纤维肌痛综合征（FMS）患者的疼痛和其他症状。 FMS是一种常见的慢性疼痛疾病，无法治愈。目前的治疗方法仅在约100例患者中部分有效。 50%的患者。因此，迫切需要确定有效的治疗方法，以减轻痛苦 FMS患者的经验。美托洛尔是一个有趣的候选者，因为临床前研究表明， 治疗痛觉过敏，还可以减轻焦虑、抑郁和认知功能障碍的症状。二甲双 引起AMP活化蛋白激酶（AMPK）的磷酸化，AMPK作为主开关激酶 调节几种关键酶和转录因子。本研究的目的是确定 二甲双胍治疗FMS症状的有效性。我们在FMS大鼠模型中的初步证据 表明二甲双胍显著降低痛觉过敏。我们还发现重要的酶 AMPK的下游，即雷帕霉素复合物1的哺乳动物靶蛋白（mTORC 1）和AMPK样蛋白。 受体3（NLRP 3）炎性体，当它们被拮抗时也导致抗伤害感受。该数据 为二甲双胍的止痛作用提供了一种可能的机制。我们假设AMPK降低 激活导致FMS患者经历的痛觉过敏、认知和情绪障碍， 二甲双胍将恢复AMPK活性并改善这些致残症状。我们的目标是 实现了两个目标。目的1将评价低剂量二甲双胍对FMS症状严重程度的影响 通过随机化、双盲RCT（2个平行给药组，比较安慰剂的作用）对患者进行研究 二甲双胍500 mg每日1次对72例FMS患者的疼痛和其他症状的改善。目标2将 确定有助于FMS患者症状严重程度降低的AMPK下游途径。 将采集、处理血液，并使用真实的时间定量聚合酶链反应进行分析， 测定AMPK、mTORC 1和NLRP 3的白细胞mRNA基因表达，以及使用标准实验室 代谢测试来检测胰岛素抵抗的迹象。这些数据将提供有关以下方面的初步信息： 二甲双胍诱导的抗伤害作用机制可在未来的R 01/U 01中更详细地探讨 study.我们希望我们的研究能够确定二甲双胍对疼痛和共病FMS的有效性 症状和描绘的作用，AMPK及其下游目标发挥这些表型。我们预计 这些结果将证明目前临床上未用于治疗FMS的干预措施的有效性。 了解这些途径是开发非成瘾性疼痛治疗方法的关键一步 并具有巨大的潜力，以减少残疾的1000万美国人与FMS。

7. PROJECT SUMMARY This is a proof of concept pilot study, a double-blinded, randomized controlled trial (RCT) to test the effect of low dose metformin on improving pain and other symptoms in patients with the fibromyalgia syndrome (FMS). FMS is a common chronic pain disorder with no cure. Current treatments are only partially effective in about 50% of patients. There is therefore a critical need to identify effective therapies to lessen the suffering experienced by patients with FMS. Metformin is an intriguing candidate, as preclinical studies indicate that it treats hyperalgesia and can also reduce symptoms of anxiety, depression and cognitive dysfunction. Metformin causes the phosphorylation of AMP-activated protein kinase (AMPK) which acts as a master switch kinase modulating several key enzymes and transcription factors. The objective of this study is to determine the effectiveness of metformin in treating symptoms of FMS. Our preliminary evidence in a rat model of FMS demonstrates that metformin dramatically reduces hyperalgesia. We also show that important enzymes downstream of AMPK, namely the mammalian target of rapamycin complex 1 (mTORC1) and the nod-like receptor 3 (NLRP3) inflammasome, also result in antinociception when they are antagonized. This data provides a possible mechanism for metformin’s pain-relieving effects. We hypothesize that reduced AMPK activation contributes to the hyperalgesia, cognitive and mood disturbances experienced by FMS patients, and metformin will restore AMPK activity and ameliorate these disabling symptoms. Our objective will be accomplished in two aims. Aim 1 will evaluate the effect of low dose metformin on symptom severity in FMS patients via a randomized, double-blinded RCT with 2 parallel dosing arms comparing the effects of placebo and 500mg of once a day metformin on improving pain and other symptoms in 72 patients with FMS. Aim 2 will determine the pathways downstream of AMPK that contribute to decreased symptom severity in FMS patients. Blood will be collected, processed, and analyzed using real time quantitative polymerase chain reaction to determine leukocyte mRNA gene expression of AMPK, mTORC1 and NLRP3 as well as using standard lab metabolic tests to test for signs of insulin resistance. This data will provide preliminary information regarding the mechanism of metformin induced anti-nociception that can be pursued in more detail in a future R01/U01 study. We expect that our studies will determine the effectiveness of metformin on pain and comorbid FMS symptoms and delineate the role that AMPK and its downstream targets play on these phenotypes. We expect that these results will demonstrate the efficacy of an intervention not currently used clinically to treat FMS. Understanding these pathways represents a critical step in the development of non-addictive pain treatments and holds enormous potential to reduce disability in the 10 million Americans with FMS.