Metformin: A Prospective Alternative for the Treatment of Chronic Pain

Abstract

Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/ calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

Migraine, Brain Glucose Metabolism and the “Neuroenergetic” Hypothesis: A Scoping Review

“…Interestingly, research data confirmed the efficacy of metformin in obtaining chronic pain relief [8].…”

A Novel Microcrystalline BAY-876 Formulation Achieves Long-Acting Antitumor Activity Against Aerobic Glycolysis and Proliferation of Hepatocellular Carcinoma

“…The liver is the center of human material and energy metabolism and the most important organ for glucose metabolism. For glucose metabolism, the liver is the center of hepatic glycogen synthesis and gluconeogenesis, and glucose uptake mediated by GLUT1 is essential for this process (82)(83)(84)(85)(86)(87)(88)(89). At the same time, HCC is derived from normal liver cells, and HCC not only has more vigorous material and energy metabolism, but also has the characteristics of aerobic glycolysis and Warburg (47).…”

Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain

“…Given that this drug is a disease-modifying agent in type II diabetes mellitus, it is possible that it has similar properties for reducing pain and its comorbidities 11 . Metformin has been shown to alleviate pain-like behaviors by activating the AMP-activated protein kinase (AMPK) and opioidergic pathways 6 , 12 . In rodent models of pain, metformin was found to inhibit peripheral and central inflammation, major contributing factors of pain progression, along with reflexive and non-reflexive pain behaviors 13 , 14 .…”