Metformin Synergizes With Conventional and Adjuvant Analgesic Drugs to Reduce Inflammatory Hyperalgesia in Rats

BACKGROUND: Metformin is a widely used and safe antidiabetic drug that has recently been shown to possess analgesic properties in models of inflammatory pain. Because various arthritic inflammatory disorders are highly prevalent in diabetic patients, we aimed to examine the type of interaction between metformin and several conventional and adjuvant analgesic drugs (ibuprofen, aspirin, tramadol, and pregabalin) in a rat model of somatic inflammatory hyperalgesia. METHODS: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 mL, 1%). The antihyperalgesic effects of metformin (intraperitoneally), analgesics (orally or intraperitoneally), and 2-drug metformin-analgesic combinations were assessed with an electronic Von Frey anesthesiometer, by measuring the change in paw withdrawal thresholds induced by carrageenan (n = 6 rats in drug/drug combination-treated groups). First, we determined the doses of individual drugs needed to produce an antihyperalgesic effect of 50% (ED50 values). In combination experiments, drugs were coadministered in fixed-dose fractions (1/16, 1/8, 1/4, and 1/2) of their individual ED50 values and the type of interaction between components was determined by isobolographic analysis. RESULTS: Metformin (50-200 mg/kg) significantly and dose-dependently reduced carrageenan-induced hyperalgesia with a maximal antihyperalgesic effect (mean ± SEM) of 62 ± 6% (all P ≤ .024). Ibuprofen (25-150 mg/kg), aspirin (100-400 mg/kg), tramadol (0.5-5 mg/kg), and pregabalin (2.5-20 mg/kg) also produced significant and dose-dependent antihyperalgesic effects (all P ≤ .042) of similar magnitude to metformin (the maximal antihyperalgesic effects were 73 ± 4% for ibuprofen, 62 ± 4.2% for aspirin, 69 ± 5.9% for tramadol, and 56 ± 3.9% for pregabalin). In combination experiments, administration of 2-drug metformin-analgesic combinations led to a significant and dose-dependent reduction of carrageenan-induced hyperalgesia (all P ≤ .027). The isobolographic analysis revealed that metformin interacted synergistically with the examined analgesics (experimental ED50 values of 2-drug combinations were significantly lower than theoretical additive ED50 values; all P < .05) and that there was a similar, approximately 5-fold, reduction of doses of both drugs in all tested combinations. CONCLUSIONS: Our results suggest that in patients who are already receiving metformin therapy, lower doses of ibuprofen/aspirin/tramadol/pregabalin might be sufficient for achieving satisfactory pain relief. Metformin-aspirin combination might be particularly useful because it may achieve multiple therapeutic goals (glucoregulation, pain relief, and cardioprotection).