Background and Objectives: The management of acute postoperative pain (APP) following major abdominal surgery implies various analgetic strategies. Opioids lie at the core of every analgesia protocol, despite their side effect profile. To limit patients' exposure to opioids, considerable effort has been made to define new opioid-sparing anesthesia techniques relying on multimodal analgesia. Our study aims to investigate the role of adjuvant multimodal analgesic agents, such as ketamine, lidocaine, and epidural analgesia in perioperative pain control, the incidence of postoperative cognitive dysfunction (POCD), and the incidence of postoperative nausea and vomiting (PONV) after major abdominal surgery. Materials and Methods: This is a clinical, observational, randomized, monocentric study, in which 80 patients were enrolled and divided into three groups: Standard group, C (n = 32), where patients received perioperative opioids combined with a fixed regimen of metamizole/acetaminophen for pain control; co-analgetic group, Co-A (n = 26), where, in addition to standard therapy, patients received perioperative systemic ketamine and lidocaine; and the epidural group, EA (n = 22), which included patients that received standard perioperative analgetic therapy combined with epidural analgesia. We considered the primary outcome, the postoperative pain intensity, assessed by the visual analogue scale (VAS) at 1 h, 6 h, and 12 h postoperatively. The secondary outcomes were the total intraoperative fentanyl dose, total postoperative morphine dose, maximal intraoperative sevoflurane concentration, confusion assessment method for intensive care units score (CAM-ICU) at 1 h, 6 h, and 12 h postoperatively, and the postoperative dose of ondansetron as a marker for postoperative nausea and vomiting (PONV) severity. Results: We observed a significant decrease in VAS score, as the primary outcome, for both multimodal analgesic regimens, as compared to the control. Moreover, the intraoperative fentanyl and postoperative morphine doses were, consequently, reduced. The maximal sevoflurane concentration and POCD were reduced by EA. No differences were observed between groups concerning PONV severity. Conclusions: Multimodal analgesia concepts should be individualized based on the patient's needs and consent. Efforts should be made to develop strategies that can aid in the reduction of opioid use in a perioperative setting and improve the standard of care.

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