Opioid-free anesthesia is increasingly being adopted to reduce opioid consumption, but its impact on early postoperative recovery after major surgery has not been evaluated in comparative trials. The hypothesis was that an opioid-free anesthesia protocol would enhance the early quality of recovery for patients undergoing scheduled major surgery under general anesthesia.


The SOFA study was a monocentric, randomized, controlled, assessor- and patient-blinded clinical trial conducted from July 10, 2021, to February 12, 2022. The eligible population included male and female patients undergoing scheduled major surgery, excluding bone procedures, that typically require opioids for postoperative pain management. Patients in the intervention group received a combination of at least two drugs among ketamine, lidocaine, clonidine, and magnesium sulfate, without opioids for anesthesia. The standard group received opioids. The primary outcome was early postoperative quality of recovery, assessed by Quality of Recovery-15 score at 24 h after surgery. Secondary outcomes were Quality of Recovery-15 at 48 and 72 h after surgery, incidence of chronic pain, and quality of life at 3 months.


Of the 136 randomized patients, 135 were included in the primary analysis (mean age, 45.9 ± 15.7 yr; 116 females [87.2%]; 85 underwent major plastic surgery [63.9%]), with 67 patients in the opioid-free anesthesia group and 68 in the standard group. The mean Quality of Recovery-15 at 24 h was 114.9 ± 15.2 in the opioid-free anesthesia group versus 108.7 ± 18.1 in the standard group (difference, 6.2; 95% CI, 0.4 to 12.0; P = 0.026). Quality of Recovery-15 scores also differed significantly at 48 h (difference, 8.7; 95% CI, 2.9 to 14.5; P = 0.004) and at 72 h (difference, 7.3; 95% CI, 1.6 to 13.0; P = 0.013). There were no differences in other secondary outcomes. No major adverse events were noticed.


The opioid-free anesthesia protocol improved quality of recovery after major elective surgery in a statistically but not clinically significant manner when compared to standard anesthesia.

Editor’s Perspective
What We Already Know about This Topic
  • Given concerns about the risks associated with opioids, some have promoted the use of opioid-free anesthesia as a routine approach

  • Existing literature on the benefits of opioid-free anesthesia is limited

What This Article Tells Us That Is New
  • In this single-center, randomized controlled clinical trial, patients received a combination of at least two drugs including ketamine, lidocaine, clonidine, and magnesium sulfate without opioids for anesthesia or a standard approach that included opioids

  • Opioid-free anesthesia, compared to the standard approach, resulted in a small improvement in a validated measure of quality of recovery at 24, 48, and 72 h after surgery, but these differences did not completely reach the threshold for clinical significance

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