This study will prospectively compare the preventive effect of liposomal bupivacaine combined with plain bupivacaine versus plain bupivacaine alone on rebound pain after nerve block in patients undergoing orthopedic extremity surgery. The primary aim is to assess whether the combination reduces the incidence or severity of rebound pain (i.e., more effectively covers the postoperative inflammatory peak on days 2-3 and provides a smoother regression curve of sensory blockade). Secondary aims include evaluation of upper limb functional scores, occurrence of chronic pain, and health-related quality of life. All aims will be assessed over 72 hours or the duration of hospitalization if shorter.

Rebound pain (RP) after nerve block occurs in up to 50% of patients, presenting as acute severe pain that impairs recovery and is associated with chronic pain. Risk factors include female sex, younger age, orthopedic surgery, and lack of perioperative dexamethasone use. Even with dexamethasone, approximately one-third of patients show a poor response, suggesting the limitations of a single-agent anti-inflammatory strategy.

RP is associated with an imbalance in perioperative inflammation management. The postoperative inflammatory peak occurs on days 2-3 and is accompanied by central sensitization, with pain rebounding after block resolution. Prolonged sensory blockade may reduce RP; however, continuous nerve block techniques are complex and associated with higher complication rates, which limits their clinical application.

Liposomal bupivacaine provides up to 72 hours of analgesia with a single injection, prolongs sensory blockade, and may theoretically reduce RP. Nevertheless, existing evidence is inconsistent: some studies support its efficacy, whereas others fail to demonstrate clinically important differences. Moreover, one animal study suggests that it may only delay, rather than eliminate, RP, albeit with limited evidence quality. This study aims to evaluate the preventive effect of liposomal bupivacaine combined with plain bupivacaine on RP after nerve block in orthopedic extremity surgery, thereby providing evidence to inform clinical strategies.

Inclusion Criteria:

• 18-65 years old;
• ASA Physical Status 1-3;
• Scheduled for elective unilateral orthopedic surgery of the upper or lower extremity.

Exclusion Criteria:

• Women who are pregnant or breastfeeding;
• Bupivacaine sensitivity or known allergy;
• Contraindication for nerve blocks;
• Enrollment in another clinical trial that could confound pain evaluation;
• Other conditions that preclude study participation.