The relationship between functional sciatic nerve block duration and the rate of release of lidocaine from a controlled-release matrix.
BACKGROUND
Nerve blocks of long duration are often desirable in perioperative and postoperative situations. The relationship between the duration of such blocks and the rate at which a local anesthetic is released is important to know for developing a localized drug delivery system that will optimize block duration.


METHODS
Lidocaine concentration was varied in 1 series of formulations (OSB-L) containing a constant amount of release rate modifier. In another series (OST-R), the release rate modifier was varied while the lidocaine content was held constant. Release kinetics were measured in vitro and correlated to the in vivo duration of antinociceptive and motor block effects when the formulation was implanted next to the rat sciatic nerve. In parallel studies, rats receiving different formulations of slow-release lidocaine were fixed by intracardiac perfusion with 4% paraformaldehyde and nerve-muscle tissue taken for histopathological analysis.


RESULTS
In this study, we have demonstrated that the most important variable for effecting functional nerve block, i.e., the blockade of impulses in the relevant fibers of the sciatic nerve, is the rate of lidocaine release at that time. For the OSB-L formulations (lidocaine concentrations of 1.875%, 3.75%, 7.5%, and 15% at a constant release rate modifier of 5%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 0.91 +/- 0.28 and 1.75 +/- 0.61 mg/h, respectively. For the OST-R formulations (16% lidocaine with release rate modifier concentrations of 1.875%, 3.75%, 7.5%, and 15%), the average in vitro release rates at 50% recovery of motor block and nociceptive block were 2.33 +/- 1.39 and 4.34 +/- 1.09 mg/h, respectively. The OSB-L formulations showed a dose-dependent increase in block duration proportional to an increase in initial lidocaine concentration, whereas the OST-R formulations showed a nonmonotonic relationship between release rate modifier concentration and block duration. The histopathological studies at 24 hours, 3, 5, or 7 days, and 4 weeks after the implantation revealed inflammatory reactions with degrees correlated with lidocaine content, but limited to the connective tissue and muscle immediately surrounding the implanted material. Despite these observed inflammatory reactions, nociceptive and motor block function returned to normal, preimplantation values in all animals.


CONCLUSIONS
Increasing initial lidocaine content proportionately increased the duration of functional sciatic nerve block. However, decreasing the release rate per se does not give a proportional increase in block duration. Instead, there seems to be an optimal, intermediate release rate for achieving the maximum duration of block.
Brigham and Women's Hospital, MRB-611, 75 Francis St., Boston, MA 02115-6110, USA.
Peter
P
Gerner
Chi-Fei
CF
Wang
Byung-Sang
BS
Lee
Suzuko
S
Suzuki
Umberto
U
Degirolami
Ankur
A
Gandhi
David
D
Knaack
Gary
G
Strichartz
D000465:Algorithms; D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D007700:Kinetics; D008012:Lidocaine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009407:Nerve Block; D009619:Nociceptors / Q000187:drug effects; D017711:Nonlinear Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology
D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D004343:Drug Implants; D008012:Lidocaine