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).
Background: Pre-clinical and clinical studies have shown that inflammatory pain intensity is increased under diabetes condition. Open cholecystectomy (OC) is a surgical procedure with predictable postoperative pain. However, the comparison of postoperative pain due to open cholecystectomy in diabetic and non-diabetic patients remains unknown. The research question to answer was whether diabetic patients undergoing OC development greater intensity of postoperative pain than non-diabetic patients. Methods: The study was conducted between June 2016 and February 2018 at the Regional Hospital of High Specialty "Dr. Juan Graham Casasús" of Villahermosa, Tabasco, Mexico. Seventy patients in two groups of 35 patients each scheduled for OC under general anesthesia were studied. Pain was assessed using the 11-point numerical rating scale (NRS). The primary endpoint was to know NRS pain scores after awaking of general anesthesia. Secondary outcomes included the time of onset of pain and comparing NRS scores between diabetic and non-diabetic patients undergoing OC. Results: Diabetic patients reported significantly greater intensity pain than non-diabetic patients. The mean overall pain score in the diabetic and non-diabetic patients was 7.2 ± 0.3 and 5.3 ± 0.3 (P = 0.0002), respectively. Furthermore, 60% of diabetic patients had severe pain (NRS ≥ 8) compared to 20% of non-diabetics (P = 0.006). The time to onset postoperative pain was about 35 minutes in both groups (P = 0.876). Conclusions: Diabetic patients undergoing OC have greater intensity postoperative pain and also more frequency of patients with severe pain
This study was designed to characterize the type of interaction (subadditive, additive, or synergistic) after simultaneous administration by two different routes (intraperitoneal plus peripheral local) of the same nonsteroidal anti-inflammatory drugs (NSAID) ketorolac and indomethacin or paracetamol. The antinociceptive effects of locally or intraperitoneally delivery of NSAIDs or paracetamol, and the simultaneous administration by the two routes at fixed-dose ratio combination were evaluated using the formalin test. Pain-related behavior was quantified as the number of flinches of the injected paw. Isobolographic analysis was used to characterize the interaction between the two routes. ED 30 values were estimated for individual drugs, and isobolograms were constructed. Ketorolac, indomethacin, or paracetamol and fixed-dose ratio combinations produced a dose-dependent antinociceptive effect in the second but not in the first phase of the formalin test. The analysis of interaction type after simultaneous administration by the two routes the same NSAID or paracetamol (on basis of their ED 30 ), revealed that the simultaneous administration of ketorolac or paracetamol was additive and for indomethacin was synergistic. Since the mechanisms underlying the additive effect of ketorolac or paracetamol and the synergistic effect of indomethacin were not explored; it is possible that the peripheral and central mechanism is occurring at several anatomical sites. The significance of these findings for theory and pain pharmacotherapy practice indicates that the combination of one analgesic drug given simultaneously by two different administration routes could be an additive or it could lead to a synergistic interaction. Behavioural Pharmacology 33: 15-22
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