Opioid-based versus opioid-sparing patient-controlled analgesia using ketorolac and nefopam after total knee arthroplasty: a randomized, double-blind, non-inferiority trial

Jiwon Han; Haesun Jung; Min Kyoung Kim; Yong-Beom Park; Seihee Min

doi:10.4097/kja.25695

Korean J Anesthesiol > Epub ahead of print

Clinical Research Article

DOI: https://doi.org/10.4097/kja.25695 [Epub ahead of print]
Published online February 3, 2026.

Opioid-based versus opioid-sparing patient-controlled analgesia using ketorolac and nefopam after total knee arthroplasty: a randomized, double-blind, non-inferiority trial

Jiwon Han¹

¹Department of Anesthesiology and Pain Medicine, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Korea
²Department of Orthopedic Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Gwangmyeong, Korea
³Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Corresponding author: Seihee Min, Tel: +82-2-3010-3868, Fax: +82-2-540-4892,
Email: seiheemin@gmail.com

Received: 10 August 2025 • Revised: 29 December 2025 • Accepted: 1 January 2026

Abstract

Background
Opioids remain widely used for postoperative pain control after total knee arthroplasty (TKA); however, concerns about adverse effects and dependency drive interest in opioid-sparing alternatives. This study evaluated the efficacy and safety of opioid-sparing patient-controlled analgesia (PCA) after TKA.
Methods
In this prospective, randomized, double-blind, non-inferiority study, 98 patients undergoing TKA under spinal anesthesia received either opioid-based PCA (continuous infusion of 1200 μg fentanyl, n = 49) or opioid-sparing PCA (continuous infusion of 150 mg ketorolac tromethamine and 100 mg nefopam hydrochloride, n = 49). Both groups received patient-controlled boluses of 300 μg fentanyl. The primary endpoint was the visual analog scale (VAS) pain score at rest on postoperative day (POD) 1, assessed using a 1.5-point non-inferiority margin. Secondary endpoints included additional analgesics, mobility, postoperative pain at rest and during ambulation, and adverse effects on PODs 1 and 2.
Results
The mean VAS score at rest on POD 1 was 5.45 ± 2.48 in the opioid-based PCA group and 5.90 ± 2.31 in the opioid-sparing PCA group. The mean difference was 0.45 points (95% CI, −0.36 to 1.25), within the prespecified non-inferiority margin. Pain scores at each time point were non-inferior in the opioid-sparing group, whereas rescue analgesic requirements were significantly reduced on POD 2 (P = 0.006). Nausea and vomiting on POD 1 were more frequent with opioid-based group (34.7% vs. 12.2%, P = 0.009).
Conclusions
Opioid-sparing PCA with ketorolac and nefopam provides non-inferior analgesia to opioid-based PCA, while reducing opioid consumption and drug-related adverse effects after TKA.

Key Words: Analgesics, non-narcotic; Analgesics, opioid; Analgesia, patient-controlled; Arthroplasty, replacement, knee; Opiate substitution treatment; Opioid analgesics; Pain, postoperative; Total knee arthroplasty.