Plasma and synovial fluid concentrations and cartilage toxicity of bupivacaine following intra-articular administration of a liposomal formulation to horses

Abstract

Background: The use of intra-articular (IA) local anaesthetics has proven to be an effective means to treat post-operative pain. The effects of local anaesthetics on equine chondrocytes are mixed with some studies reporting chondrodestruction and others no adverse effects. A liposomal formulation of bupivacaine is used in people and dogs by intra- and peri-articular administration to provide up to 72 h of analgesia. The potential uses, side effects including chondrotoxicity, and likelihood of abuse (long-term analgesic effects) has not been evaluated in horses.

Objectives: Describe bupivacaine concentrations following IA administration and assess biomarkers as indicators of the effects of liposomal bupivacaine on chondrocytes in vivo.

Study design: Parallel design.

Methods: Sixteen exercised horses received a single IA administration of 0.12 mg/kg liposomal bupivacaine or 0.9% saline. Blood and urine samples were collected for 96 h post-drug administration. Six horses treated with bupivacaine and those receiving saline, underwent daily arthrocentesis. Six additional bupivacaine treated horses underwent arthrocentesis at 96 h. Drug concentrations were measured using LC-MS/MS and pharmacokinetic analyses performed. Immunoassays were used to measure markers of collagen degradation (C2C, C12C) and cartilage matrix synthesis (CPII, CS846) in synovial fluid.

Results: The bupivacaine plasma elimination half-life was 17.8 ± 5.42 and 11.9 ± 5.17 h for horses from which synovial fluid was collected daily and at 96 h respectively. Bupivacaine concentrations in the joint were still detectable at 96 h. Significant increases in C12C and C2C were noted at 96 h in horses undergoing arthrocentesis at 96 h only. CPII was increased at 48 h and CS846 at 24 and 48 h in horses sampled daily.

Main limitations: Limited number of animals and absence of liposome control group.

Conclusions: Sustained concentrations of IA bupivacaine suggest viability of this medication as an intra-articular analgesic. Effects on equine chondrocytes need further study.

Keywords: bupivacaine; cartilage; horse; liposomal; synovial fluid; toxicity.