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

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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.