Background:Periarticular local infiltration analgesia (LIA) is largely utilized for controlling pain after total knee arthroplasty (TKA). The present work aimed to assess the efficacy of a modified LIA cocktail for patients undergoing TKA.Methods:Magnesium sulfate (MgSO4) and sodium bicarbonate (NaHCO3) were added to a conventional LIA cocktail comprising ropivacaine, epinephrine, and dexamethasone. After the safety of this modified cocktail was tested in rats, its efficacy and safety were evaluated in a prospective, double-blinded study including 100 individuals randomized to receive periarticular infiltration of the modified cocktail or a conventional cocktail. The primary outcome was postsurgical use of morphine hydrochloride for rescue analgesia. Secondary outcomes were the time until the first rescue analgesia, postsurgical pain (on a visual analog scale [VAS]), functional recovery (assessed by range of knee motion and ambulation distance), time to discharge, and complication rates.Results:Adding NaHCO3 to the local anesthetics caused some instantaneous precipitation in all cases. Administering the modified cocktail to rats did not obviously damage the injected area of the nerve or surrounding tissues. Administration of the modified cocktail to patients was associated with markedly reduced postsurgical morphine use in the initial 24 hours (4.2 ± 5.0 versus 14.6 ± 8.9 mg, p < 0.001), reduced total morphine use (9.8 ± 8.4 versus 19.6 ± 11.4 mg, p < 0.001), prolonged time to the first rescue analgesia, lower VAS pain scores at rest and during motion at 12 and 24 hours following the operation, better functional recovery on postoperative days 1 and 2, and a shorter hospital stay. The modified and conventional cocktail groups had similar rates of complications.Conclusions:The present modification of a conventional cocktail significantly prolonged analgesia and reduced opioid consumption, which may substantially improve pain control in arthroplasty.Level of Evidence:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.