Personalized Multimodal and Opioid-Sparing Analgesia for Postoperative Pain Management: Enhancing Recovery and Addressing the Post-Discharge Gap

Abstract: Postoperative pain remains a persistent clinical challenge affecting more than 80% of surgical patients, driving prolonged hospitalization, delayed recovery, and progression to chronic postsurgical pain. Opioid-centered analgesia, despite its historical primacy, is constrained by dependence, tolerance, opioid-induced hyperalgesia, and a critical post-discharge prescribing gap in which prescribed quantities consistently exceed actual patient consumption, perpetuating avoidable harm without proportional improvement in outcomes. Enhanced Recovery After Surgery protocols emphasize multimodal, opioid-sparing strategies combining pharmacologic agents including NSAIDs, acetaminophen, gabapentinoids, ketamine, dexmedetomidine, and intravenous lidocaine with neuraxial and peripheral nerve blocks and non-pharmacologic interventions including cognitive-behavioral therapy, physical rehabilitation, acupuncture, and digital therapeutics. Current evidence identifies NSAIDs combined with dexamethasone or regional anesthesia as delivering the greatest opioid-sparing efficacy, while emerging precision-based approaches incorporating pharmacogenomic-guided prescribing, machine learning–based pain prediction, and wearable monitoring platforms offer transformative opportunities for individualized perioperative analgesic optimization. Significant gaps persist including heterogeneity in multimodal regimen combinations, inconsistent outcome measures, limited post-discharge standardization, and insufficient long-term data on chronic postsurgical pain prevention and functional recovery across diverse surgical populations. Future research must prioritize procedure-specific, standardized, and pharmacogenomically informed multimodal protocols integrating technological innovations to optimize recovery, minimize opioid-related risks, and ensure sustainable, patient-centered perioperative pain management. Keywords: postoperative pain, multimodal analgesia, opioid sparing, chronic postsurgical pain, regional anesthesia, pharmacogenomics, enhanced recovery after surgery, perioperative pain management, opioids exposure