253: Opioid-free vs Opioid Anesthesia and analgesia on QoR-15 after TKA: A Non-inferiority RCT

Topic: Clinical Science
Subtopic: Non-specific to any diagnosis, Pharmacological treatments, Drug development

Background and Aims: Opioid-based anesthesia-analgesia remains the standard for total knee arthroplasty under general anesthesia but is associated with adverse effects that may impair postoperative recovery. Opioid-free anesthesia (OFA) has been proposed to reduce these complications, yet its impact on patient-centered recovery quality, as measured by the QoR-15 score, has not been established. We hypothesized that an OFA-analgesia regimen would be non-inferior to a conventional opioid-based regimen in terms of the QoR-15 score 24 hours after total knee arthroplasty.

Methods: In this single-center, prospective, randomized, controlled, double-blind, non-inferiority trial, patients (ASA I-III, BMI 18.5-30 kg/m²) scheduled for elective unilateral total knee arthroplasty under general anesthesia were randomly assigned to either the OFA group or the opioids group. Both groups received a femoral nerve block before induction. The OFA group then received a multimodal intraoperative regimen including dexmedetomidine, esketamine, intravenous lidocaine, and esmolol, with tramadol-based patient-controlled intravenous analgesia (PCIA) postoperatively. The opioids group received a conventional opioid-based intraoperative regimen (including sufentanil and remifentanil), with sufentanil-based PCIA postoperatively. Anesthesia depth and nociception were guided by IoC monitoring. The primary outcome was the QoR-15 score at 24 hours postoperatively, assessed in a modified intention-to-treat and per-protocol analysis. A non-inferiority margin (δ) of 15 points was pre-specified. Secondary outcomes included QoR-15 scores at 3, 7, and 14 days; intraoperative hemodynamics; inflammatory markers, anxiety/depression scores, length of stay, and adverse events et al.

Results: A total of 300 patients were randomized, and 283 were included in the intention-to-treat analysis. The mean (SD) QoR-15 score at 24 hours was 111.3 ± 9.2 in the OFA group and 112.5 ± 9.3 in the opioids group (mean difference, 1.186; 95% CI, –0.872 to 3.245). Because the lower limit of the 95% CI for the difference was greater than the pre-specified non-inferiority margin of -15, non-inferiority of OFA was established. Key secondary outcomes, including QoR-15 scores at 3, 7, and 14 days, showed no statistically significant differences. The overall incidence of adverse events was similar between groups, although the duration of constipation was shorter in the OFA group (P < 0.001). Some intraoperative hemodynamic parameters (at osteotomy) showed statistically significant but clinically unimportant differences, and the incidence of chronic pain did not differ between groups.

Conclusions: These findings suggest that OFA is a viable opioid-sparing strategy for TKA, although no additional clinical benefits from opioid sparing were demonstrated. Future studies should explore OFA with other postoperative opioid-free analgesia modalities, in broader populations, and with long-term functional outcomes, reinforcing its role within ERAS pathways. This trial provides evidence supporting the adoption of OFA to mitigate perioperative opioid risks without sacrificing recovery quality in TKA patients under general anesthesia.

References: Opioid-free versus Opioid-based Anesthesia-Analgesia on Quality of Recovery after Total Knee Arthroplasty: A Randomized Controlled Non-inferiority Trial
Abstract
Background: Opioid-based anesthesia-analgesia remains the standard for total knee arthroplasty under general anesthesia but is associated with adverse effects that may impair postoperative recovery. Opioid-free anesthesia (OFA) has been proposed to reduce these complications, yet its impact on patient-centered recovery quality, as measured by the QoR-15 score, has not been established. We hypothesized that an OFA-analgesia regimen would be non-inferior to a conventional opioid-based regimen in terms of the QoR-15 score 24 hours after total knee arthroplasty.
Methods: In this single-center, prospective, randomized, controlled, double-blind, non-inferiority trial, patients (ASA I-III, BMI 18.5-30 kg/m²) scheduled for elective unilateral total knee arthroplasty under general anesthesia were randomly assigned to either the OFA group or the opioids group. Both groups received a femoral nerve block before induction. The OFA group then received a multimodal intraoperative regimen including dexmedetomidine, esketamine, intravenous lidocaine, and esmolol, with tramadol-based patient-controlled intravenous analgesia (PCIA) postoperatively. The opioids group received a conventional opioid-based intraoperative regimen (including sufentanil and remifentanil), with sufentanil-based PCIA postoperatively. Anesthesia depth and nociception were guided by IoC monitoring. The primary outcome was the QoR-15 score at 24 hours postoperatively, assessed in a modified intention-to-treat and per-protocol analysis. A non-inferiority margin (δ) of 15 points was pre-specified. Secondary outcomes included QoR-15 scores at 3, 7, and 14 days; intraoperative hemodynamics; inflammatory markers, anxiety/depression scores, length of stay, and adverse events et al.
Results: A total of 300 patients were randomized, and 283 were included in the intention-to-treat analysis. The mean (SD) QoR-15 score at 24 hours was 111.3 ± 9.2 in the OFA group and 112.5 ± 9.3 in the opioids group (mean difference, 1.186; 95% CI, –0.872 to 3.245). Because the lower limit of the 95% CI for the difference was greater than the pre-specified non-inferiority margin of -15, non-inferiority of OFA was established. Key secondary outcomes, including QoR-15 scores at 3, 7, and 14 days, showed no statistically significant differences. The overall incidence of adverse events was similar between groups, although the duration of constipation was shorter in the OFA group (P < 0.001). Some intraoperative hemodynamic parameters (at osteotomy) showed statistically significant but clinically unimportant differences, and the incidence of chronic pain did not differ between groups.
Conclusions: These findings suggest that OFA is a viable opioid-sparing strategy for TKA, although no additional clinical benefits from opioid sparing were demonstrated. Future studies should explore OFA with other postoperative opioid-free analgesia modalities, in broader populations, and with long-term functional outcomes, reinforcing its role within ERAS pathways. This trial provides evidence supporting the adoption of OFA to mitigate perioperative opioid risks without sacrificing recovery quality in TKA patients under general anesthesia.
Key words
Opioid-free anesthesia, Total knee arthroplasty, General anesthesia, Analgesia, QoR-15 score
 
Introduction
The current paradigm of perioperative pain management remains heavily reliant on opioid analgesics, particularly in patients undergoing surgery under general anesthesia1,2. While effective, opioids carry a well-documented spectrum of dose-dependent adverse effects, including respiratory depression, postoperative nausea and vomiting (PONV), ileus, sedation, and delirium3-6. More critically, perioperative opioid exposure has emerged as a significant contributor to the ongoing public health crisis of opioid misuse, dependence, and overdose, and has been epidemiologically linked to persistent postoperative opioid use and potentially increased long-term morbidity6-8. This precarious balance between effective nociceptive control and mitigation of serious individual and societal risks underscores the urgent need to validate opioid-sparing or opioid-free anesthetic strategies.
In response to this challenge, the concept of opioid-free anesthesia (OFA) has evolved9-12. OFA relies on a multimodal combination of non-opioid agents—such as alpha-2 agonists, NMDA receptor antagonists, sodium channel blockers, and regional techniques—to blunt the surgical stress response and provide analgesia without activating opioid receptors10,11,13-16. A growing body of evidence from less invasive surgical models, including bariatric, laparoscopic, and sinus procedures17-23, suggests that OFA can reduce postoperative opioid consumption and lower the incidence of opioid-related side effects, notably PONV. However, these data are predominantly from surgeries associated with moderate pain, and the impact of an opioid-free multimodal strategy on patient-centered recovery has not been rigorously assessed in procedures that impose a substantially higher nociceptive load, such as total knee arthroplasty (TKA).
TKA stands as a prototypical high-pain procedure that exerts a profound physical and psychological stress on patients. Although neuraxial anesthesia is often preferred, a significant proportion of patients require or receive general anesthesia24. Under these circumstances, opioids remain central for intraoperative stress attenuation and postoperative analgesia, yet their use directly competes with the goals of early mobilization, minimal nausea, and clear sensorium—core components of enhanced recovery pathways25,26. It is precisely in this context that the theoretical promise of OFA becomes most compelling: by circumventing the opioid receptor, an OFA approach could preserve high-quality recovery across its multiple dimensions—physical comfort, emotional state, and functional independence—without sacrificing analgesic efficacy. Despite this rationale, high-level evidence confirming whether OFA truly improves or simply maintains the quality of recovery after TKA is absent.
To address this knowledge gap, we conducted a prospective, single-center, randomized, double-blind, non-inferiority trial comparing a multimodal OFA regimen with a conventional opioid-based technique in patients undergoing elective unilateral TKA under general anesthesia. The primary endpoint was the 24-hour QoR-15 score, a validated multidimensional measure of patient-centered recovery 27-29. We hypothesized that OFA would be non-inferior to the opioid-based strategy in postoperative recovery quality. This trial was designed to determine whether OFA can be safely incorporated into ERAS pathways for TKA, providing an opioid-sparing strategy that preserves the quality of recovery.

 
Method
This was a single-center, parallel-group, randomized, double-blind, non-inferiority trial. The study protocol was initially designed as a multicenter trial and received ethical approval from the Ethics Committee of Shanghai Sixth People’s Hospital on December 25, 2023 (Approval No. 2023-163-[1]). Because of logistical constraints, the trial was conducted only at the principal investigator’s site from the outset. Accordingly, the protocol was formally amended to a single-center design, and this amendment was approved by the same ethics committee on December 12, 2024 (Approval No. 2023-163- [2]). The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all patients prior to enrollment.
The first patient was enrolled on June 17, 2024, and enrollment was completed on November 28, 2025. The final follow-up assessment was completed on February 28, 2026.

Statistical analysis
For comparisons of medians using the Mann Whitney U test, the non-standardized effect size was the Hodges Lehmann median difference with its 95% confidence interval. The standardized effect size r was calculated as r = Z / √N, where Z is the standardized test statistic from the Mann Whitney U test and N is the total sample size. For comparisons of means, Cohen's d was calculated using the pooled standard deviation. For comparisons of proportions, Cohen's h was calculated as the difference between the arcsine transformed proportions. Standardized effect sizes were interpreted using Cohen's conventions: 0.2 indicates a small effect, 0.5 a moderate effect, and 0.8 a large effect. All statistical analyses were performed using SPSS version 27 (IBM Corp, Armonk, NY, USA).

 
 
 
Reference
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Presenting Author: Junde Han
Submitting Author: Junde Han

Senior Author: Aizhong Wang, Tao Xu

IASP 2026 Global Year theme of Neuropathic Pain: No

• Junde Han: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Shuli Ge: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Qingyu Teng: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Zheng Chen: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Qiang Wu: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Qi Li: MD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Tao Xu: MD, PhD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
• Aizhong Wang: MD, PhD - Department of Anesthesiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine