Background: Post-operative pain is a frequent observation in patients undergoing knee arthroscopic surgeries and remains a challenge to anaesthesiologist. The current armamentarium of drugs as multimodal analgesia for post-operative pain utilizes many new medications with different complementary mechanism of action and remains the recommended intervention for the management of post arthroscopic knee pain. Aim: We compare the efficacy of preoperative duloxetine, melatonin and tapentadol for post spinal analgesia and sedation in knee arthroscopic surgeries. Setting and design: Randomised prospective double blind study. Methods: 124 American Society of Anaesthesiologist 1and II patients undergoing knee arthroscopic surgery requiring spinal anaesthesia were allocated randomly to four groups of 30 each to receive oral Placebo Group 1, 20 mg Duloxetine Group 2, 3 mg Melatonin Group 3, 100 mg Tapentadol Group 4, 90 minutes before surgery. We assessed block characteristics, intraoperative sedation using BIS scores, postoperative pain scores using Numeric Rating Score, time to use of first analgesic, 24 hour analgesic consumption, additional analgesic consumption and any adverse effects. Results: Mean duration of post-operativeanalgesia was 477.96±97.85 minutes in Tapentodol Group (P value<0.001). Total 24 hours diclofenac consumption is minimum in Tapentodol Group (P 0.04). No statistical significant differences were present in the onset of the spinal block, BIS and Ramsay Sedation Score among the Groups. Conclusion: Preoperative administration of oral tapentadol provides prolonged analgesia with reduced 24 hour analgesic consumption.