Synergistic Analgesic Effect of Low Doses of Fluoxetine and Mefenamic Acid Combination: In Silico and In Vivo Studies

Fluoxetine drug comes under the category of selective serotonin reuptake inhibitor (SSRI). It is used in the treatment of depression but in elderly population cannot be use due to more occurrence of gastrointestinal (GI) adverse event compared to younger population. A non-steroidal anti-inflammatory drug (NSAIDS) mefenamic acid, used frequently to treat mild to severe pain but cannot be used for more than one week due to the risk of heart attack and stomach or intestinal bleeding. Drug combination therapy in case of analgesics is frequently used to increase the clinical utility. The administration of two drugs in combination may achieve analgesia at lower doses than those required for individual drug alone, resulting in enhanced pain relief and reduction of adverse drug reaction. Probable interaction between fluoxetine and mefenamic acid on pain was examined in mice using in silico and in vivo experiments. Molecular docking studies indicated that the main residues responsible for the synergistic analgesic action against COX-2 are Tyr385 and Ser530. In first experiment, fluoxetine (5, 10, and 15mg/kg) a SSRI and mefenamic acid (50, 100. and 150 mg/kg) a NSAID were administered intraperitoneally (i.p.) in their respective groups (n = 6) to assess analgesic effect in mice using hot plate test (HPT). On the basis of these results, we selected an effective dose of fluoxetine i.e. 15 mg/kg and mefenamic acid i.e. 50 mg/kg, for the second experiment. remarkably, we observed a synergistic effect between half of the effective doses of fluoxetine (7.5 mg/kg) along with mefenamic acid (25 mg/kg). It can be concluded from these results that the co-administration of drug fluoxetine (as an adjuvant) increases the effectiveness of mefenamic acid for modulation of pain.