Background:Propofol is a most widely used intravenous anesthetic drug. One of its most common complications is the pain upon injection; therefore, different methods, with various effects, have been proposed in order to alleviate the pain.Objectives:This study investigates the effects of paracetamol, ondansetron, granisetron, magnesium sulfate and lidocaine drugs on reducing the pain of propofol injection during anesthetic induction. Also, the hemodynamic changes will be analyzed.Patients and Methods:This is an interventional study containing 336 patients underwent elective orthopedic surgeries in Educational Hospitals of Mashhad University, using systematic sampling, the patients were divided into six groups. A 20-gauge needle was inserted into a venous vessel in the back of the hand and 100 cc of Ringer serum was injected into the vein, which was applied proximal to the injection site. Afterwards, paracetamol 2 mg/kg (group p), magnesium sulfate 2 mmol (group M), ondansetron 4 mg (group O), granisetron 2 mg (group G), lidocaine 40 mg (group L) and 5 cc saline (group S) were injected into the vessel, after 60 seconds, the tourniquet was opened. One quarter of the total dose of propofol (2.5 mg/kg) was injected with a flow rate of 4 mg/sec and then the injection pain was measured. Finally, the fentanyl (2 µg/kg), atracurium 0.5 mg/kg, and the remaining dose of propofol were injected and the vital signs were recorded before the administration of propofol and 1, 3, 5 and 10 minutes after the propofol injection.Results:The six groups did not significantly differ, regarding their gender, weight or age. Propofol injection pain was less in L and G groups, in comparison with the others (P ≤ 0.001). By analyzing the hemodynamic changes, it was observed that the least amount of change in mean arterial pressure was observed in the paracetamol group.Conclusions:The reduction of propofol injection pain was observed by using medications (in comparison with normal saline), but it was more significant in groups G and L. Moreover, Hypotension was higher in groups S and G and it was lessened in group P.