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Background: Direct stimulation of the afferent nerve endings in the venous endothelium is one explanation of propofol injection pain. Previous studies found that ondansetron can also block sodium channels. This effect is similar to that of lidocaine., Objective: The primary outcome was the efficacy of ondansetron compared to lidocaine and placebo for the reduction of propofol injection pain., Method: This trial was conducted in 240 patients, American Society of Anesthesiologists classification I-III and aged between 18-65 years old, undergoing elective surgery, and having a 20-gauge intravenous catheter at the hand dorsum. Each group of 80 patients received 8 mg. of ondansetron in the O Group, 40 mg. of lidocaine in the L Group and normal saline in the C Group. The study medications were blindly administered to the patients through a 20-gauge intravenous catheter placed on the hand dorsum, and then 1 min later, the small dose of propofol (50 mg.) was infused via the syringe pump at a rate of 600 ml/hr. for 30 s. Following that, the syringe pump of propofol was temporarily stopped, and the patients were asked to rate their pain at the injection site., Result: The incidence of pain was lowest in the L group (66.2%) compared with the O (82.5%) and the C groups (85.0%) (P < 0.01). The median pain score in the L, O, and C groups were 2 (0-4), 4 (2-5), and 4.5 (2-6), respectively (P < 0.01). The incidences of no pain, mild, moderate, and severe pain were also significantly different in the L group (33.8%, 37.5%, 21.2%, and 7.5%, respectively) compared with those in the O group (17.5%, 31.2%, 31.2%, and 20.0%, respectively) and the C groups (15.0%, 22.5%, 40.0%, and 22.5%, respectively) (P < 0.01)., Conclusion: Pretreatment with intravenous lidocaine, rather than ondansetron, can reduce the incidence and intensity of propofol-induced pain., (© 2022. The Author(s).)