An injectable controlled-release local anesthetic formulation of levobupivacaine based on a temperature-responsive polymer: Evaluation of analgesia, motor impairment, and histological toxicity in rats.

Abstract

Purpose: Postoperative pain management is extremely important for early recovery after surgery. However, effective and safe techniques for controlling postoperative pain are lacking. This study examined the effectiveness of controlled-release levobupivacaine for creating sciatic nerve blocks in a rat model of postoperative pain.

Methods: A novel controlled-release injectable levobupivacaine gel was produced using a triblock copolymer of poly(ε-caprolactone-co-glycolide) and polyethylene glycol (tri-PCG). Male rats were used to create the incisional pain model. A single dose of controlled-release levobupivacaine (2.25%) gel, 0.25% levobupivacaine (clinical use), or tri-PCG was injected around the sciatic nerve of each rat immediately before paw incision. The pain thresholds were assessed preoperatively and up to 48 h postoperatively using von Frey filaments. Side effects were assessed using a motor impairment test, levobupivacaine blood level measurements, and pathological assessments.

Results: The novel controlled-release levobupivacaine exhibited temperature-responsive sol-gel transition. In vitro, this formulation released 60% of its levobupivacaine content within 24 h. The withdrawal threshold was higher in the controlled-release levobupivacaine group than in the 0.25% levobupivacaine group at 6 and 12 h after paw incision. Motor impairment was not observed after controlled-release levobupivacaine injection, and the levobupivacaine blood level remained below the limit of detection throughout the assessment. On histopathology, weak signs of inflammation were detected in rat muscle and nerve tissues in the controlled-release levobupivacaine group.

Conclusion: A single injection of controlled-release levobupivacaine gel almost safely inhibited hyperalgesia for 12 h in a rat model. However, further research is needed on its effects on the surrounding tissue.