Inhibition by local bupivacaine-releasing microspheres of acute postoperative pain from hairy skin incision.
BACKGROUND
Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here.


METHODS
We subcutaneously injected a new formulation of poly-lactic-co-glycolic acid polymer microspheres, which provides steady drug release for 96+ hours into rats at the dorsal region 2 hours before surgery. A single 1.2-cm-long skin incision was followed by blunt dissection of skin away from the underlying fascia, and closed by 2 sutures, followed by 14 days of testing. Microspheres containing 5, 10, 20, and 40 mg bupivacaine were injected locally 2 hours before surgery; bupivacaine-free microspheres were the vehicle control, and bupivacaine HCl solution (0.5%), the positive control. Mechanical sensitivity was determined by the frequency of local muscle contractions to repeated pokes with nylon monofilaments (von Frey hairs) exerting 4 and 15 g forces, testing, respectively, allodynia and hyperalgesia, and by pinprick.


RESULTS
Injection of bupivacaine microspheres (40 mg drug) into intact skin reduced responses to 15 g von Frey hairs for 6 hours and to pinprick for 36 hours. Respective reductions from bupivacaine HCl lasted for 3 and 2 hours. Skin incision and dissection alone caused mechanical allodynia and hyperalgesia for 14 days. Microspheres containing 20 or 40 mg bupivacaine suppressed postoperative hypersensitivity for up to 3 days, reduced integrated allodynia (area under curve of response versus time) over postoperative days 1 to 5 by 51% ± 20% (mean ± SE) and 78% ± 12%, and reduced integrated hyperalgesia by 55% ± 13% and 64% ± 11%, for the respective doses. Five and ten milligrams bupivacaine in microspheres and the 0.5% bupivacaine solution were ineffective in reducing postoperative hypersensitivity, as were 40 mg bupivacaine microspheres injected contralateral to the incision.


CONCLUSIONS
Significant suppression of postoperative pain by the slow-release bupivacaine preparation outlasts its anesthetic action on intact skin. These findings demonstrate preventive analgesia and indicate the importance of acute processes in the development of chronic postoperative pain.
From Covidien Research and Development; and Department of Anesthesiology, Perioperative and Pain Medicine, Pain Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Rachit
R
Ohri
Jeffrey Chi-Fei
JC
Wang
Phillip D
PD
Blaskovich
Lan N
LN
Pham
Daniel S
DS
Costa
Gary A
GA
Nichols
William P
WP
Hildebrand
Nelson L
NL
Scarborough
Clifford J
CJ
Herman
Gary R
GR
Strichartz
D000772:Anesthesia, Local; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002045:Bupivacaine / Q000008:administration & dosage*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006197:Hair; D006930:Hyperalgesia / Q000517:prevention & control; D008297:Male; D008863:Microspheres; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects*; D013059:Spectrum Analysis, Raman
D000779:Anesthetics, Local; D002045:Bupivacaine