An absorbable local anesthetic matrix provides several days of functional sciatic nerve blockade

Abstract

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.