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Background: Postoperative analgesia with the use of parenteral opioids or epidural analgesia can be associated with troublesome side effects. Good perioperative analgesia facilitates rehabilitation, improves patient satisfaction, and may reduce the hospital stay. We investigated the analgesic effect of locally injected drugs around a total knee prosthesis.Methods: Sixty-four patients undergoing total knee arthroplasty were randomized either to receive a periarticular intraoperative injection containing ropivacaine, ketorolac, epimorphine, and epinephrine or to receive no injection. The perioperative analgesic regimen was standardized. All patients in both groups received patient-controlled analgesia for twenty-four hours after the surgery, and this was followed by standard analgesia. Visual analog scores for pain, during activity and at rest, and for patient satisfaction were recorded preoperatively and postoperatively and at the six-week follow-up examination. The consumption of patient-controlled analgesia at specific postoperative time-points and the overall analgesic requirement were measured.Results: The patients who had received the injection used significantly less patient-controlled analgesia at six hours, at twelve hours, and over the first twenty-four hours after the surgery. In addition, they had higher visual analog scores for patient satisfaction and lower visual analog scores for pain during activity in the post-anesthetic-care unit and four hours after the operation. No cardiac or central nervous system toxicity was observed.Conclusions: Intraoperative periarticular injection with multimodal drugs can significantly reduce the requirements for patient-controlled analgesia and improve patient satisfaction, with no apparent risks, following total knee arthroplasty.Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.