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Purpose Propofol injection pain, despite various strategies, remains common and troublesome. This study aimed to test the hypothesis that pretreatment with the combination of intravenous lidocaine and magnesium would have an additive effect on reducing propofol injection pain. Methods After institutional review board (IRB) approval and informed consent, we performed a prospective, double-blind, placebo-controlled, randomized trial. Subjects were randomly assigned to pretreatment with either lidocaine (50 mg), magnesium sulfate (0.25 mg), lidocaine (50 mg) plus magnesium sulfate (0.25 mg), or 0.9 % sodium chloride. Following pretreatment, propofol (50 mg) was administered, and subjects were questioned regarding injection site pain and observed for behavioral signs of pain. Results Two hundred subjects were enrolled and 158 subjects (39 placebo, 38 lidocaine, 44 magnesium sulfate, and 37 lidocaine plus magnesium sulfate) received their assigned pretreatment intervention. Intergroup baseline characteristics were similar. The proportion of subjects reporting propofol injection pain was highest in those pretreated with magnesium sulfate (57 %), followed by those pretreated with placebo (46 %), lidocaine plus magnesium sulfate (41 %), and then lidocaine (29 %; p = 0.011). When adjusted for age, gender, diabetes mellitus, chronic pain, tobacco use, and selective-serotonin reuptake inhibitor use, the pain response scale scores were significantly reduced by lidocaine pretreatment compared to magnesium sulfate and placebo (p = 0.031 and p = 0.0003, respectively). Conclusions In this double-blind, placebo-controlled, randomized trial, the combination of intravenous magnesium sulfate and lidocaine offered no additional benefit for the relief of propofol injection pain compared to intravenous lidocaine alone. An improved, receptor-based understanding of the mechanism of propofol injection pain is still needed., Author(s): Richard E. Galgon[sup.1] , Peter Strube[sup.1] , Jake Heier[sup.1] , Jeremy Groth[sup.1] , Sijian Wang[sup.2] , Kristopher M. Schroeder[sup.1] Author Affiliations: (1) Department of Anesthesiology, University of Wisconsin School [...]