320 patients who underwent total knee arthroplasty were randomized to either receive extended-release tramadol HCl 75 mg/acetaminophen 650 mg (TA-ER) or immediate-release tramadol HCl 37.5 mg/acetaminophen 325 mg (TA-IR) for a period of 48 hours after the discontinuation of patient-controlled analgesia (PCA) postoperatively. This was done to compare the efficacy and safety of the two treatments for patients following total knee arthroplasty. Outcomes measured included the sum of pain intensity difference from time of first dose to time of final assessment at 48 hours, and adverse events. Results indicated that when a corrected non-inferiority margin was used, TA-ER was non-inferior to TA-IR in terms of efficacy. The results also indicated that, although there was a large number of adverse events, the incidence was similar between groups.