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

7.项目总结 这是一项概念验证先导研究，一项双盲随机对照试验(RCT)，以测试 小剂量二甲双胍改善纤维肌痛综合征(FMS)患者的疼痛等症状。 FMS是一种常见的慢性疼痛障碍，无法治愈。目前的治疗方法只对大约 50%的患者。因此，迫切需要确定有效的治疗方法来减轻痛苦。 FMS患者所经历的。二甲双胍是一个耐人寻味的候选药物，因为临床前研究表明 治疗痛觉过敏，还可以减少焦虑、抑郁和认知功能障碍的症状。二甲双胍 导致AMP激活的蛋白激酶(AMPK)的磷酸化，AMPK充当主开关激酶 调节几种关键酶和转录因子。这项研究的目的是确定 二甲双胍治疗FMS症状的疗效观察。我们在FMS大鼠模型中的初步证据 证明了二甲双胍显著减少了痛觉过敏。我们还展示了重要的酶 AMPK下游，即哺乳动物雷帕霉素复合体1(MTORC1)的靶点和NOD样蛋白 受体3(NLRP3)炎症体，当它们被拮抗时也会产生抗伤害感觉。此数据 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，以及 二甲双胍将恢复AMPK活性，并改善这些停用症状。我们的目标将是 在两个目标上实现。目的1评价小剂量二甲双胍对FMS患者症状严重程度的影响 患者通过随机、双盲、两个平行给药臂的RCT来比较安慰剂的效果 每日1次500 mg二甲双胍可改善72例FMS患者的疼痛等症状。目标2将 确定AMPK下游导致FMS患者症状严重程度降低的途径。 将使用实时定量聚合酶链式反应收集、处理和分析血液 用标准LAB法检测白细胞AMPK、mTORC1和NLRP3基因表达 代谢测试，以测试胰岛素抵抗的迹象。该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性感觉的机制可以在未来的R01/U01中进行更详细的研究 学习。我们期望我们的研究将确定二甲双胍对疼痛和共病的FMS的有效性。 并描述了AMPK及其下游靶点在这些表型中所起的作用。我们预计 这些结果将证明一种目前未用于临床治疗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的关键一步 并拥有巨大的潜力来减少1000万患有FMS的美国人的残疾。

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.