Rebound pain following peripheral nerve block in extremity fracture surgery: pathophysiological mechanisms based on the “Triple-Hit” model and multimodal preventive strategies

Extremity fracture surgery is the standard surgical intervention for traumatic musculoskeletal injuries. The maturation of ultrasound-guided visualization techniques has facilitated the widespread application of peripheral nerve block (PNB) in perioperative anesthesia and analgesia. However, rebound pain (RP)—defined as the phenomenon wherein previously suppressed nociceptive signals exhibit abrupt intensification exceeding baseline levels following the termination of regional analgesic effects—has emerged as a significant clinical challenge. RP interferes with early postoperative functional mobilization, compromises patient satisfaction, and increases healthcare resource utilization. The pathogenesis of RP involves a multifactorial pathophysiological process: hyperexcitability of nerve fibers following block resolution; compensatory neurophysiological responses subsequent to local anesthetic pharmacodynamic decline; iatrogenic neural effects attributable to needle instrumentation or surgical manipulation; localized inflammatory cascade activation triggered by tissue trauma; and interindividual variability in genetic susceptibility and psychological resilience. The cornerstone of RP prevention lies in the multimodal analgesic concept, integrating pharmacological agents and techniques with divergent mechanisms of action. This review proposes a conceptual “Triple-Hit Model of RP,” hypothesizing that RP arises from the dynamic interplay of three interrelated risk elements: the first element is the magnitude of initial peripheral nociceptive input, predominantly determined by surgical trauma severity; the second element is individual central nervous system modulation capacity and pain tolerance thresholds, influenced by chronological age, anxiety states, and related factors; the third element is the withdrawal pattern of regional analgesic protection, encompassing block duration and offset velocity. The synergistic convergence of these three hits substantially amplifies the risk of severe RP manifestation.