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Surgical trauma is known to induce hyperalgesia, and if pain management is insufficient, it contributes to persistent pain in the postoperative period.In this study, our primary aims were to compare the effect of pregabalin and duloxetine on postoperative pain scores and cognitive functions. Our secondary aim was to determine drug-related side effects.This was a prospective, randomized, double-blind, placebo-controlled study.The study was carried out in the setting of the operating room and the surgical ward.Ninety-four patients, 18 to 65 years of age, ASA status I-II, scheduled for elective repair of lumbar disc herniation were enrolled in the study.The patients were randomly divided into 3 groups: the first group received pregabalin 75 mg orally 1 hour before the surgery and at the postoperative 12th and 24th hours. The second group received duloxetine 60 mg orally 1 hour before the surgery. At the postoperative 12th hour, they received a placebo capsule, and, at the 24th hour, they received duloxetine 60 mg again. The third group received placebo capsules orally at all timepoints.Postoperative pain evaluation was conducted using a Visual Analogue Scale at the postoperative first minute, 30th minute, first hour, and the 12th, 24th, and 48th hours. The preoperative and postoperative sixth hour cognitive functions were evaluated with Montreal Cognitive Assessment (MoCA) test.There was a significant reduction in mean MoCA scores postoperatively in all groups (P<0.01). The highest MoCA score reduction was in the pregabalin group (1.83±1.31 point), then in the duloxetine group (1.16±0.82), and the least decrease was in the control group (0.49±0.61). At all timepoints, the mean Visual Analogue Scale scores of the pregabalin and duloxetine groups were similar to each other, and they were lower than that of the control group (P<0.05).Preoperative use of duloxetine 60 mg can be an useful alternative to pregabalin 75 mg, as it has a similar analgesic effect on postoperative pain, with fewer incidences of drug-related negative effects on cognitive function.