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

二甲双胍作为纤维肌痛的新型机械治疗方法；

• 批准号: 10655834
• 负责人: Akiko Okifuji
• 金额: $ 16.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655834
• 关键词: 5' -AMP-activated protein kinase; Affect; American; Anxiety; Biochemical Markers; Blood; Caring; Cells; Chronic; Clinical; Clinical Research; Complex; Consent; Data; Databases; Development; Diabetes Mellitus; Dose; Double-Blind Method; Enzymes; FRAP1 gene; Fatigue; Fibromyalgia; Future; Gene Expression; Genes; Genetic Transcription; Goals; Harm Reduction; Healthcare; Hyperalgesia; IL18 gene; Immune; Impaired cognition; Inflammasome; Inflammation; Inflammatory; Insulin Resistance; Interleukin-1 beta; Leukocytes; Measures; Mechanics; Medical; Mental Depression; Messenger RNA; Metabolic; Metabolism; Metformin; Methods; Modeling; Neurobehavioral Manifestations; Neuropathy; Nociception; Non-Insulin-Dependent Diabetes Mellitus; Pain; Pain intensity; Pain management; Pathway interactions; Patient Self-Report; Patients; Peripheral; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Phosphorylation; Phosphotransferases; Physical Function; Pilot Projects; Placebo Effect; Placebos; Play; Polymerase Chain Reaction; Population; Pre-Clinical Model; Process; Productivity; Public Health; Quality of life; Questionnaires; Randomized; Randomized, Controlled Trials; Rattus; Research; Resources; Role; Safety; Severities; Sleep disturbances; Spinal cord injury; Symptoms; Testing; Time; Treatment Efficacy; Work; affective disturbance; antinociception; anxiety symptoms; arm; central sensitization; chronic painful condition; chronic widespread pain; comorbidity; cost; cytokine; disability; disabling symptom; double-blind placebo controlled trial; effective therapy; effectiveness evaluation; experience; fibromyalgia patients; improved; interest; mood symptom; neuroinflammation; novel; opioid use; pain relief; pain symptom; pre-clinical; preclinical study; primary endpoint; prospective; receptor; recruit; reduce symptoms; secondary endpoint; symptom treatment; transcription factor

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.

7。项目摘要 这是概念试验研究的证明，这是一项双盲，随机对照试验（RCT），以测试 低剂量二甲双胍可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障碍，无法治愈。当前的治疗仅在大约有效 50％的患者。因此，迫切需要确定有效的疗法以减轻痛苦 由FMS患者体验。二甲双胍是一个有趣的候选人，因为临床前研究表明它 珍贵的痛觉过敏，还可以减少动画，抑郁和认知功能障碍的症状。二甲双胍 引起AMP激活蛋白激酶（AMPK）的磷酸化，该蛋白激酶充当主开关激酶 调节几种关键酶和转录因子。这项研究的目的是确定 二甲双胍在治疗FMS症状中的有效性。我们在FMS大鼠模型中的初步证据 证明二甲双胍会大大降低痛觉过敏。我们还表明了重要的酶 AMPK的下游，即雷帕霉素复合物1（MTORC1）和点头样的哺乳动物靶标 受体3（NLRP3）炎性体，在拮抗时也会引起抗伤害感受。这个数据 提供了二甲双胍疼痛舒张作用的可能机制。我们假设减少了AMPK 激活有助于FMS患者所经历的痛觉过敏，认知和情绪障碍，以及 二甲双胍将恢复AMPK活性并改善这些残疾症状。我们的目标将是 以两个目标完成。 AIM 1将评估低剂量二甲双胍对FMS症状严重程度的影响 通过随机双盲RCT和2平行剂量臂比较安慰剂的影响的患者 每天500毫克的二甲双胍用于改善72例FMS患者的疼痛和其他症状。 AIM 2意志 确定AMPK下游的途径，这导致FMS患者的症状严重程度降低。 将使用实时定量聚合酶链反应收集，处理和分析血液 确定AMPK，MTORC1和NLRP3的白细胞mRNA基因表达以及使用标准实验室 代谢测试以测试胰岛素抵抗的迹象。这些数据将提供有关有关的初步信息 二甲双胍诱导的抗吸引物的机制可以在未来的R01/U01中更详细地探讨 学习。我们预计我们的研究将决定二甲双胍对疼痛和合并FMS的有效性 症状并描述AMPK及其下游目标在这些表型中的作用。我们期望 这些结果将证明目前未在临床上用于治疗FMS的干预措施的效率。 理解这些途径是发展非疼痛治疗的关键步骤 并具有减少有FMS 1000万美国人的残疾的巨大潜力。