title: Local pathology and systemic serum bupivacaine after subcutaneous delivery of slow-releasing bupivacaine microspheres.
abstract: BACKGROUND
  Prolonged local anesthesia, particularly desirable to minimize acute and chronic postoperative pain, has been provided by microspheres that slowly release bupivacaine (MS-Bup). In this study, we report on the systemic drug concentrations and the local dermatopathology that occur after subcutaneous injection of MS-Bup.
  
  
  METHODS
  Rats (approximately 300 g) were injected under the dorsolumbar skin with MS-Bup containing 40 mg of bupivacaine (base) or with 0.4 mL of 0.5% bupivacaine-HCl (BupHCl; 1.78 mg bupivacaine). Blood was drawn, under sevoflurane anesthesia, at 10 minutes to 144 hours, and the serum analyzed for total bupivacaine by liquid chromatography-tandem mass spectrometry. In different animals, skin punch biopsies (4 mm) were taken at 1, 3, 7, 14, and 30 days after the same drug injections, sectioned at 5 μm, and stained with hematoxylin-eosin. Samples from skin injected with BupHCl, with MS-Bup suspended in carboxymethyl cellulose (MS-Bup.CMC), or in methyl cellulose (MS-Bup.MC) were compared with their respective drug-free controls (placebos).
  
  
  RESULTS
  Serum bupivacaine reached a maximal average value (n = 8) of 194.9 ng/mL at 8 hours after injection of MS-Bup (95% upper prediction limit = 230.2 ng/mL), compared with the maximal average (n = 6) serum level of 374.9 ng/mL (95% prediction limit = 470.6 ng/mL) at 30 minutes after injection of BupHCl. Serum bupivacaine decreased to undetectable levels (<3.23 ng/mL) at 8 hours after BupHCl and was detectable at approximately 20% of the maximal value at 144 hours after MS-Bup injection. BupHCl injection resulted in moderate lymphocytic infiltration of skeletal muscle at 1 and 3 days. MS-Bup.CMC and placebo-CMC caused extensive infiltration of macrophages, lymphocytes, and some neutrophils at 1 to 7 days, whereas MS-Bup.MC and placebo-MC caused only mild inflammation.
  
  
  CONCLUSIONS
  Subcutaneous administration of microspheres releasing bupivacaine results in lower blood levels lasting for much longer times than those from bupivacaine solution.
authors.affiliation: From the Division of Dermatopathology, Department of Pathology, Children's Hospital, Boston, Massachusetts; Covidien Surgical Solutions, Bedford, Massachusetts; Pain Research Center, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; EKG Life Science Solutions, St. Louis, Missouri; and Mallinckrodt Pharmaceuticals, St. Louis, Missouri.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Schmidt
authors.forename: Rachit
authors.initials: R
authors.lastname: Ohri
authors.forename: Jeffrey Chi-Fei
authors.initials: JC
authors.lastname: Wang
authors.forename: Phillip
authors.initials: P
authors.lastname: Blaskovich
authors.forename: Allen
authors.initials: A
authors.lastname: Kesselring
authors.forename: Nelson
authors.initials: N
authors.lastname: Scarborough
authors.forename: Clifford
authors.initials: C
authors.lastname: Herman
authors.forename: Gary
authors.initials: G
authors.lastname: Strichartz
mesh_terms: D000772:Anesthesia, Local / Q000009:adverse effects*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D003692:Delayed-Action Preparations; D007279:Injections, Subcutaneous / Q000009:adverse effects; D008297:Male; D008863:Microspheres; D011183:Postoperative Complications / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000293:injuries* / Q000473:pathology
chemical_list: D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D002045:Bupivacaine