Local Myotoxicity from Sustained Release of Bupivacaine from Microparticles

Abstract

Background: Sustained release of local anesthetics is frequently associated with myotoxicity. The authors investigated the role of particulate delivery systems and of the pattern of drug release in causing myotoxicity.Methods: Rats were given sciatic nerve blocks with bupivacaine solutions, two types of bupivacaine-containing microparticles (polymeric microspheres and lipid-protein-sugar particles), or blank particles with or without bupivacaine in the carrier fluid. Myotoxicity was scored in histologic sections of the injection sites. Bupivacaine release kinetics from the particles were measured. Myotoxicity of a range of bupivacaine concentrations from exposures up to 3 weeks was assessed in C2C12 myotubes, with or without microparticles.Results: Both types of bupivacaine-loaded microparticles, but not blank particles, were associated with myotoxicity. Whereas 0.5% bupivacaine solution caused little myotoxicity, a concentration of bupivacaine that mimicked the amount of bupivacaine released initially from particles caused myotoxicity. Local anesthetics showed both concentration and time-dependent myotoxicity in C2C12s. Importantly, even very low concentrations that were nontoxic over brief exposures became highly toxic after days or weeks of exposure. The presence of particles did not increase bupivacaine myotoxicity in vitro but did in vivo. Findings applied to both particle types.Conclusions: Whereas the release vehicles themselves were not myotoxic, both burst and extended release of bupivacaine were. A possible implication of the latter finding is that myotoxicity is an inevitable concomitant of sustained release of local anesthetics. Particles, and perhaps other vehicles, may enhance local toxicity through indirect mechanisms.

Prolonged duration local anesthesia with minimal toxicity

“…Although the reason for this improvement is not clear, it confirms the observation that the presence of particles per se (and by inference their nature) has a large impact on local injury (3).…”

“…Myotoxicity of bupivacaine solution increased with concentration and duration of exposure ( Fig. 2A) (3). In contrast, free STX (0.005-0.05 mg/mL) was not myotoxic at any of the concentrations or any durations of exposure tested (e.g., P Ͻ 0.001, 0.01 vs. 0.05 mg/mL at 48 h, and P Ͻ 0.001 at 0.1 mg/mL at 6 vs. 24 h; Fig.…”

“…Conventional local anesthetics are also neurotoxic (6,7). The presence of particles themselves enhances local anesthetic myotoxicity in vivo (3), and can cause inflammatory responses at the nerve that may considerably outlast the duration of blockade (2,3,8). In contrast, site 1 sodium-channel blockers do not cause myo-or neurotoxicity (9,10), which would make them desirable for an extended release formulation.…”

“…However, tissue reaction to such formulations has been problematic. Conventional local anesthetics are intrinsically myotoxic (3,4). They are also myotoxic when released from a wide range of delivery systems (3,5), even when the delivery systems themselves are minimally toxic.…”

“…Conventional local anesthetics are intrinsically myotoxic (3,4). They are also myotoxic when released from a wide range of delivery systems (3,5), even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure (3), suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds.…”