title: Mitigation of experimental, chronic post-thoracotomy pain by preoperative infiltration of local slow-release bupivacaine microspheres.
abstract: BACKGROUND
  Postoperative pain is treated incompletely and ineffectively in many circumstances, and chronic postoperative pain causes suffering and diminishes productivity. The objective of this project is to determine whether a recently developed slow-release formulation of bupivacaine was effective in reducing the experimental chronic postoperative pain.
  
  
  METHODS
  In male Sprague-Dawley rats (250-300 g body weight), bupivacaine-releasing microspheres (MS-Bupi), containing 60 mg of bupivacaine base, were locally injected (MS-Bupi-L) 2 hours preoperatively into the subcutaneous compartment at the locus for experimental thoracotomy. Hypersensitivity to tactile stimulation was assessed by reductions in the threshold force required to induce a response to von Frey filaments (VFH) applied to the hairy back near the incision/retraction site. Pain behavior was assessed using a Qualitative Hyperalgesia Profile. Control groups included rats receiving the same dose of MS-Bupi but at a distant site on the back (MS-Bupi-D, testing for systemic drug actions) and rats receiving the same mass of microspheres with no drug (MS-Placebo) at the wound site. Rats were tested for 3 days before and 28 days (postoperative days [PODs]) after the procedure. Withdrawal threshold differences, which were the primary outcome measure, among all treatment groups were assessed by the Kruskal-Wallis test, after which pairwise comparisons were made by determining Wilcoxon-Mann-Whitney odds (WMWodds), with Bonferroni correction of the confidence intervals.
  
  
  RESULTS
  Microsphere bupivacaine released near the incision reduced the chronic tactile allodynia after thoracotomy. The threshold values during PODs 14 to 28 were different among the 3 treatment groups when examined on PODs 14, 16, 18, 23, 25, and 28 but not on POD21 (P = 0.0603). WMWodds showed that threshold of the MS-Bupi-L group differed from those of the MS-Bupi-D and the MS-Placebo groups for all the tested PODs, whereas the thresholds of the MS-Bupi-D group never differed from those of the MS-Placebo group. Area-under-curve analysis for threshold reductions below baseline, using WMWodds, also showed a reduction during the entire 28 PODs that was greater for the MS-Bupi-L group compared with the MS-Placebo or MS-Bupi-D group. The incidence of intense pain scores by the Qualitative Hyperalgesia Profile analysis was observed in 7 of 8 rats in the MS-Placebo group and in 5 of 8 rats in the MS-Bupi-L group.
  
  
  CONCLUSIONS
  Local slow release of bupivacaine subcutaneously from the MS-Bupi formulation suppresses postoperative mechanical hypersensitivity for ≥4 weeks after experimental thoracotomy. Systemic bupivacaine from this treatment has no effect on this hypersensitivity.
authors.affiliation: From the *Pain Research Center, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts; †Department of Anesthesiology, National Cheng Kung University Medical College and Hospital, Tainan City, Taiwan; and ‡Covidien Surgical Solutions, Bedford, Massachusetts.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Strichartz
authors.forename: Jeffrey Chi-Fei
authors.initials: JC
authors.lastname: Wang
authors.forename: Phillip
authors.initials: P
authors.lastname: Blaskovich
authors.forename: Rachit
authors.initials: R
authors.lastname: Ohri
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage*; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D006930:Hyperalgesia / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008863:Microspheres; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D011300:Preoperative Care; D017207:Rats, Sprague-Dawley; D013908:Thoracotomy / Q000009:adverse effects*; D013997:Time Factors; D014110:Touch
chemical_list: D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D002045:Bupivacaine