The Effect of Liposomal Bupivacaine on Rebound Pain After Peripheral Nerve Block.

Liposomal Bupivacaine Combined With Plain Bupivacaine for Peripheral Nerve Block to Reduce Rebound Pain After Orthopedic Extremity Surgery: A Multicenter Randomized Controlled Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Pain; Orthopaedic Surgery
• Intervention / Treatment: Drug: liposomal bupivacaine; Drug: Normal Saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 668
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200233
      • Shanghai Sixth People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

18-80 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: liposomal bupivacaine; 10 ml of plain bupivacaine 0.75% will be mixed with 10 ml liposomal bupivacaine (133mg)	Drug: liposomal bupivacaine; Prepare a local anesthetic by combining liposomal bupivacaine (133 mg/10 mL) and bupivacaine hydrochloride (75 mg/10 mL) in a 1:1 volume ratio.
Placebo Comparator: normal saline; 10 ml of plain bupivacaine 0.75% will be combined with 10 ml of normal saline	Drug: Normal Saline; placebo (normal saline)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of rebound pain	Rebound pain was defined as initial mild pain (<4/ 10) when the patient left the recovery room, progressing to severe pain (>7/10) (NRS, 0-10) occurring within the first 24 hours after the procedure.	the first 24 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Return of Sensation	Sensory recovery time is defined as the time (in hours) until ≥75% of the initially blocked test locations regain cold and pinprick sensation. Sensory recovery will be assessed using a combined patient-reported and investigator-verified approach. Every 2 hours, patients will self-report their sensory status using a three-point scale: 0 = completely numb, 1 = abnormal sensation, 2 = normal sensation. Investigators will verify patient reports twice daily (at 7:00 and 19:00) using ice and pinprick testing. This outcome, time to sensory recovery, will be defined as the first hour at which the patient reports a score of 2 (normal sensation).	72 hours
Area under the pain intensity-time curve	Area under the pain intensity-time curve (0-72 hours) at rest / with movement	up to 72 hours
Total postoperative opioid consumption	Total postoperative opioid consumption (IV morphine mg equivalents) at 24, 48, and 72 hours	24, 48, 72 hours

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: May 19, 2026
• First Submitted That Met QC Criteria: May 19, 2026
• First Posted (Actual): May 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Acute Pain; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution
• Other Study ID Numbers: in process; Grant No. 20240814 (Other Grant/Funding Number: the Shanghai Jiao Tong University School of Medicine Double Hundred Talent Program); Grant No. 82525022 (Other Grant/Funding Number: National Natural Science Foundation of China (NSFC) Project)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No