An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade.
BACKGROUND
Functional blockade of peripheral nerves is the primary objective of local anesthesia, and it is often desirable to have a persistent blockade, sustained throughout and beyond a surgical procedure. Current local anesthetics give effective analgesia for <8-12 h after a single bolus injection. We report on an implantable, controlled-release drug delivery system intended for use in bone and consisting of a Food and Drug Administration-approved matrix containing lidocaine that is capable of local delivery for several days.


METHODS
Xybrex, an absorbable, controlled-release delivery system containing 16% (w/w) lidocaine, was implanted next to the sciatic nerve of male rats (300-350 gm), at lidocaine doses of 5.3, 10.6, 16, and 32 mg lidocaine per rat. For comparison, a lidocaine HCl solution (0.2 mL, 2% = 4 mg) was injected in close proximity to the sciatic nerve. Rats were assessed behaviorally for analgesia by a forceps pinch of the lateral digits, and for motor block by quantifying the extensor postural thrust. Potential neurotoxicity of sciatic nerves was evaluated histologically at 24 h, 4 days, and 4 wk after implantation. The kinetics of lidocaine's release from the matrix was measured in vitro by ultraviolet detection of lidocaine in samples collected at 2.5, 6.5, 20, and 24.25 h.


RESULTS
Xybrex at the highest doses (300 and 600 mg/kg, containing 16 and 32 mg of lidocaine free base, respectively) provided complete analgesia to an intense pinch for 7.0 +/- 2.0 h, 6.9 +/- 1.7 h and partial analgesia for 60.0 +/- 5.4 h, 58.8 +/- 4.2 h, respectively, compared to 0.61 +/- 0.03 h of complete analgesia and 0.96 +/- 0.03 h of partial analgesia by sciatic block from the 2% lidocaine solution (containing 4 mg lidocaine). These same high doses of Xybrex produced complete motor block for 17.0 +/- 3.3 h, 17.6 +/- 3.3 h with full recovery in 352.0 +/- 55.7 h (14.7 +/- 2.3 days), 579.0 +/- 36.1 h (24.1 +/- 1.5 days) respectively. Data are reported as mean +/- SE. P < 0.001 for all Xybrex groups compared to the 2% lidocaine group. Minor local tissue inflammation/pathology, primarily in the connective tissue and muscle 0.1 mm adjacent to the nerve, was observed equally in animals treated with Xybrex and 2% lidocaine solution. There were no behavioral signs of systemic toxicity. The in vitro release followed exponential kinetics and its comparison to the time-course of functional nociceptive deficit implied that the duration of nociception represented the local, immediate interaction of lidocaine between the nerve and the matrix and not a cumulative effect of previously released drug.


CONCLUSIONS
Xybrex is an absorbable, controlled-release drug delivery system that provides several days of analgesia for rat peripheral nerves without apparent significant local neurotoxicity or systemic toxicity.
Wang
Chi-Fei
CF
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Djalali
Alimorad G
AG
Gandhi
Ankur
A
Knaack
David
D
De Girolami
Umberto
U
Strichartz
Gary
G
Gerner
Peter
P
D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004343:Drug Implants; D008012:Lidocaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009407:Nerve Block; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D012995:Solubility
D000779:Anesthetics, Local; D004343:Drug Implants; D008012:Lidocaine