Effective perioperative pain management must balance timely analgesia with minimizing opioid-related harm. Pharmacologic and anesthetic strategies that deliberately reduce perioperative opioid exposure have expanded rapidly, including multimodal analgesia protocols, opioid-sparing and opioid-free anesthesia (OFA), and intravenous lidocaine or ketamine-based regimens. This systematic review synthesized randomized and comparative clinical studies evaluating opioid-sparing approaches in adult surgical patients. Electronic databases were searched to November 2025 for trials comparing multimodal or OFA strategies against conventional opioid-centered care, with outcomes including opioid consumption, pain scores, and recovery indices. Nine eligible studies were identified: eight randomized controlled trials and one retrospective cohort, spanning gynecologic laparoscopy and laparotomy, breast lumpectomy, major abdominal laparoscopy, orthopedic arthroscopy, and robotic prostatectomy. Enhanced recovery pathways and structured multimodal regimens consistently reduced postoperative opioid use while maintaining or improving pain scores and quality-of-recovery measures. OFA strategies using lidocaine, esketamine, and dexmedetomidine often achieved non-inferior analgesia with reduced intraoperative opioid requirements, though extubation time and sedative effects were sometimes increased. Intravenous lidocaine as an adjunct showed procedure- and context-dependent benefits. Overall, perioperative opioid-sparing strategies appear safe and feasible when integrated into multidisciplinary care pathways, but heterogeneity of regimens and outcomes limits firm procedural recommendations.