The substantial adverse effects associated with opioid-based analgesia and its contribution to postoperative dependence have prompted a shift toward multimodal, opioid-sparing perioperative strategies. Non-opioid analgesics now form the cornerstone of contemporary perioperative management and Enhanced Recovery After Surgery (ERAS) pathways. This review synthesizes current evidence on the efficacy, safety, and clinical utility of major non-opioid analgesic classes, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, N-methyl-D-aspartate (NMDA) antagonists, intravenous lidocaine, gabapentinoids, α2-agonists, regional anesthesia techniques, and glucocorticoids, for postoperative pain management. Evidence from randomized controlled trials, systematic reviews, and meta-analyses was evaluated with emphasis on analgesic effectiveness, opioid-sparing capacity, recovery outcomes, and adverse effects. The efficacy of non-opioid multimodal analgesia (MMA) stems from the synergistic targeting of distinct pain pathways. Across drug classes, non-opioid agents demonstrate clinically meaningful opioid-sparing effects while providing analgesia that is comparable to opioid-based regimens. Acetaminophen and NSAIDs are cornerstones of MMA, supported by extensive high-quality evidence. NMDA antagonists such as ketamine show particular benefit in major surgical procedures for modulating central sensitization and preventing chronic pain, whereas intravenous lidocaine has unique advantages in accelerating gastrointestinal recovery and may reduce hospital length of stay. Gabapentinoids may serve as adjuncts but exhibit heterogeneous efficacy and a side-effect profile (e.g., sedation) that necessitates selective use. Preoperative α2-agonists consistently prolong analgesia and reduce perioperative opioid requirements. As a core component of MMA, regional anesthesia techniques demonstrate robust reductions in both prolonged postoperative opioid use and the incidence of chronic postsurgical pain, and perioperative glucocorticoids such as dexamethasone contribute potent dual analgesic and antiemetic effects. The collective evidence indicates that MMA, integrating agents with complementary mechanisms, provides superior pain control, enhanced functional recovery, and meaningful reductions in opioid exposure. Broader implementation of standardized, procedure-specific multimodal protocols may further decrease opioid-related harms and strengthen alignment with ERAS principles. Future research should prioritize long-term outcomes and optimization of multimodal combinations to advance the transition toward a post-opioid paradigm in surgical care.
