OBJECTIVE: The purpose of this study is to compare the pain scores, opioid consumption, and range of motion of the operated knee after total knee replacement (TKR) in the 10-day follow-up period between a traditional opioid-containing pain management protocol and a multimodal opioid-sparing treatment protocol. METHODS: This prospective, randomized, single-center study included 90 patients (24 men and 66 women; mean age 69.7±7.2 years) undergoing TKR for osteoarthritis between October 2019 and October 2020. Patients were randomized into 3 cohorts for comparison: traditional opioid-containing pain management protocol (n=30), multimodal opioid-sparing pain management protocol (n = 30), and traditional opioidcontaining pain management protocol with additional local infi ltration analgesia (LIA). Changes in visual analog scale for pain (VAS), range of motion (ROM), and opioid consumption were compared between groups. RESULTS: A lower mean postoperative VAS score was observed in the opioid-sparing cohort, which was statistically signifi cant at all time points compared with the traditional cohorts. Mean total morphine consumption was signifi cantly lower in the opioid-sparing cohort (2.7 ± 5.8 MMEs) compared to the traditional (14.0±14.8 MMEs) and traditional with LIA cohorts (8.3 ± 9.5 MMEs; p < 0.05). The mean degree of fl exion of the operated knee of patients was signifi cantly greater in patients in the opioid-sparing group than in the other groups on the postoperative day 3 (opioid-sparing: 87.0 ± 11.2°; traditional: 74.1 ± 11.6°; traditional with LIA: 84.7±8.9°; p<0.05), as well as on day 10 (opioid-sparing: 99.3 ± 10.8°; traditional: 87.3 ± 12.4°; traditional with LIA: 92.5±9.7°; p < 0.05). The rate of adverse events after TKR did not differ between the groups. CONCLUSION: The results of this study suggest that a multimodal opioid-sparing pain protocol after TKR, which includes oral non-opioid medications and periarticular injection with bupivacaine, provides better pain relief and early functional gains with fewer rescue opioids compared to traditional opioid-based protocols (Tab. 4, Fig. 2, Ref. 22).