title: Local toxicity from local anesthetic polymeric microparticles.
abstract: BACKGROUND
  Local tissue injury from sustained-release formulations for local anesthetics can be severe. There is considerable variability in reporting of that injury. We investigated the influence of the intrinsic myotoxicity of the encapsulated local anesthetic (lidocaine, low; bupivacaine, high) on tissue reaction in rats.
  
  
  METHODS
  Cytotoxicity from a range of lidocaine and bupivacaine concentrations was measured in C2C12 myotubes over 6 days. Rats were given sciatic nerve blocks with 4 microparticulate formulations of lidocaine and bupivacaine: 10% (w/w) lidocaine poly(lactic-co-glycolic) acid (PLGA), 10% (w/w) bupivacaine PLGA, 50% (w/w) lidocaine PLGA, and 50% (w/w) bupivacaine PLGA. Effectiveness of nerve blockade was assessed by a modified hotplate test and weightbearing measurements. Myotoxicity was scored in histologic sections of injection sites. Bupivacaine and lidocaine release kinetics from the particles were measured.
  
  
  RESULTS
  Median sensory blockade duration for 50% (w/w) lidocaine was 255 (90-540) minutes versus 840 (277-1215) minutes for 50% (w/w) bupivacaine (P = 0.056). All microparticulate formulations resulted in myotoxicity. The choice of local anesthetic did not influence the severity of myotoxicity. Median myotoxicity scores for 50% (w/w) lidocaine compared with 50% (w/w) bupivacaine at 4 days were 3.4 (2.1-4.2) vs 3.3 (2.9-3.5) (P = 0.44) and at 14 days 1.9 (1.8-2.4) vs 1.7 (1.3-1.9) (P = 0.23), respectively.
  
  
  CONCLUSIONS
  Lidocaine and bupivacaine PLGA microspheres resulted in similar degrees of myotoxicity, irrespective of drug loading. Intrinsic myotoxicity did not predict tissue injury from sustained release of these anesthetics. Caution is warranted in the use of such devices near muscle and nerve.
authors: Department of Medicine, Medicine Critical Care Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors: J Brian
authors: JB
authors: McAlvin
authors: Gally
authors: G
authors: Reznor
authors: Sahadev A
authors: SA
authors: Shankarappa
authors: Cristina F
authors: CF
authors: Stefanescu
authors: Daniel S
authors: DS
authors: Kohane
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002045:Bupivacaine / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D007267:Injections; D019344:Lactic Acid; D008012:Lidocaine / Q000633:toxicity; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D053758:Nanoparticles / Q000008:administration & dosage / Q000633:toxicity*; D009407:Nerve Block; D010316:Particle Size; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve
chemical_list: D000779:Anesthetics, Local; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008012:Lidocaine; D002045:Bupivacaine