Opioid-free anesthesia (OFA) is used in surgery to avoid opioid-related side effects. However, uncertainty exists in the balance between OFA benefits and risks. We searched for randomized controlled trials (RCTs) comparing OFA to opioid-based anesthesia (OBA) in five international databases. The co-primary outcomes were postoperative acute pain and morphine consumption at 2, 24, and 48 h. The secondary outcomes were the incidence of postoperative chronic pain, hemodynamic tolerance, severe adverse effects, opioid-related adverse effects, and specific adverse effects related to substitution drugs. Overall, 33 RCTs including 2209 participants were assessed. At 2 h, the OFA groups had lower pain scores at rest MD (0.75 (-1.18; -0.32)), which did not definitively reach MCID. Less morphine was required in the OFA groups at 2 and 24 h, but with very small reductions: 1.61 mg (-2.69; -0.53) and -1.73 mg (p < 0.05), respectively, both not reaching MCID. The reduction in PONV in the OFA group in the PACU presented an RR of 0.46 (0.38, 0.56) and an RR of 0.34 (0.21; 0.56), respectively. Less sedation and shivering were observed in the OFA groups with an SMD of -0.81 (-1.05; -0.58) and an RR of 0.48 (0.33; 0.70), respectively. Quantitative analysis did not reveal differences between the hemodynamic outcomes, although severe side effects have been identified in the literature. No clinically significant benefits were observed with OFA in terms of pain and opioid use after surgery. A clear benefit of OFA use was observed with respect to a reduction in PONV. However, more data on the safe use of OFAs should be collected and caution should be taken in the development of OFA.
Keywords: adverse effect; analgesia; anesthesia; opioid-free anesthesia; systematic review.