Multivesicular liposomal bupivacaine at the sciatic nerve

Abstract

Clinical translation of sustained release formulations for local anesthetics has been limited by adverse tissue reaction. Exparel™ (DepoFoam bupivacaine) is a new liposomal local anesthetic formulation whose biocompatibility near nerve tissue is not well characterized. Exparel™ injection caused sciatic nerve blockade in rats lasting 240 min compared to 120 min for 0.5% (w/v) bupivacaine HCl and 210 min for 1.31% (w/v) bupivacaine HCl (same bupivacaine content as Exparel™). On histologic sections four days after injection, median inflammation scores in the Exparel™ group (2.5 of 4) were slightly higher than in groups treated with bupivacaine solutions (score 2). Myotoxicity scores in the Exparel™ group (2.5 of 6) were similar to in the 0.5% (w/v) bupivacaine HCl group (3), but significantly less than in the 1.31% (w/v) bupivacaine HCl group (5). After two weeks, inflammation from Exparel™ (score 2 of 6) was greater than from 0.5% (w/v) bupivacaine HCl (1) and similar to that from 1.31% (w/v) bupivacaine HCl (1). Myotoxicity in all three groups was not statistically significantly different. No neurotoxicity was detected in any group. Tissue reaction to Exparel™ was similar to that of 0.5% (w/v) bupivacaine HCl. Surveillance for local tissue injury will be important during future clinical evaluation.

Keywords: Bupivacaine; DepoFoam; Exparel™; Inflammation; Myotoxicity; Neurotoxicity.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Phase contrast photomicrograph of Exparel™. Scale bar = 30 µm.

Figure 2

Cumulative release of bupivacaine from Exparel™. Also shown is the release of unencapsulated 1.31% (w/v) and 0.5% (w/v) bupivacaine HCl. Data are means ± standard deviations, n=4.

Figure 3

Representative photographs 4 days and 14 days after injection at the sciatic nerve with Exparel™, 0.5% (w/v) bupivacaine HCl or 1.31% (w/v) bupivacaine HCl.

Figure 4

Representative light microscopy of hematoxylin/eosin-stained sections of adjacent muscle (M) 4 and 14 days after injection at the sciatic nerve with Exparel™, 0.5% (w/v) bupivacaine HCl or 1.31% (w/v) bupivacaine HCl. 4 days after injection with (A and B) Exparel™ or 0.5% (w/v) bupivacaine HCl, myotoxicity (Mtox) and inflammation (Infl) were predominantly perifascicular; for (C) 1.31% (w/v) bupivacaine HCl, only the deepest layers were spared. (D–F) At 4 days myotoxicity and inflammation, regardless of treatment group, were characterized by regenerating myocytes (Regen) surrounded by macrophages and occasional polymorphonuclear cells and lymphocytes. (D) For Exparel™, foamy macrophages (FM) with ingested particulate matter could be seen. 14 days after injection with (H and I) Exparel™ or 0.5% (w/v) bupivacaine HCl, tissue injury was limited to the periphery of the fascicle and was characterized by (K and L) myocytes with centralized nuclei surrounded by occasional lymphocytes; for (J) 1.31% (w/v) bupivacaine HCl, perifasicular myotoxicity and holofasicular inlmammation were observed and was characterized by (M) regenerating myocytes surrounded by vacoulated macrophages and lymphocytes. Scale bars represent 100 µm (A–C, H–J) or 20 µm (D–F, K–M).

Figure 5

Toludine blue stained sciatic nerve samples harvested from rats 4 days after injection with either (A) Exparel™, (B) 0.5% (w/v) bupivacaine HCl or (C) 1.31% (w/v) bupivacaine HCl demonstrated normal findings. No significant changes in axonal density or myelin structure were observed. The perineural tissue appeared normal. (D) Normal, uninjected sciatic nerve. Scale bars represent 100 µm.