Effect of Adjuvant Drugs on the Action of Local Anesthetics in Isolated Rat Sciatic Nerves

Abstract

Background and Objectives There is increasing clinical use of adjuvant drugs to prolong the duration of local anesthetic-induced block of peripheral nerves. However, the mechanistic understanding regarding drug interactions between these compounds in the periphery is quite limited. Accordingly, we undertook this study to determine whether selected adjuvants are efficacious in blocking action potential propagation in peripheral nerves at concentrations used clinically, and whether these drugs influence peripheral nerve block produced by local anesthetics. Methods Isolated rat sciatic nerves were used to assess (1) the efficacy of buprenorphine, clonidine, dexamethasone, or midazolam, alone and in combination, on action potential propagation; and (2) their influence on the blocking actions of local anesthetics ropivacaine and lidocaine. Compound action potentials (CAPs) from A- and C-fibers were studied before and after drug application. Results At estimated clinical concentrations, neither buprenorphine nor dexamethasone affected either A- or C-waves of the CAP. Clonidine produced a small, but significant attenuation of the C-wave amplitude. Midazolam attenuated both A- and C-wave amplitudes, but with greater potency on the C-wave. The combination of clonidine, buprenorphine, and dexamethasone had no influence on the potency or duration of local anesthetic- or midazolam-induced block of A-and C-waves of the CAP. Conclusions These results suggest that the reported clinical efficacy of clonidine, buprenorphine, and dexamethasone influence the actions of local anesthetics via indirect mechanisms. Further identification of these indirect mechanisms may enable the development of novel approaches to achieve longer duration, modality-specific peripheral nerve block.

A randomised controlled trial of perineural vs intravenous dexamethasone for foot surgery

“…Dexamethasone may decrease the redistribution of local anaesthetics through an anti-inflammatory action [30]. The 8 mg intravenous dose of dexamethasone may be sufficient to reduce local anaesthetic washout from nerves throughout the body.…”

The effect of continuous interscalene brachial plexus block with 0.125% bupivacaine vs 0.2% ropivacaine on pain relief, diaphragmatic motility, and ventilatory function

“…Other adjuvants have been evaluated in single-injection peripheral nerve blocks, showing various degrees of efficacy in prolonging the effects of local anesthetics. In an in vitro study on rat sciatic nerve, continuous infusions of clonidine, buprenorphine, and dexamethasone had no direct effect on blocking the propagation of action potentials, suggesting that they do not have a direct effect on peripheral nerves [33]. Ideally, an adjuvant (or a combination of adjuvants) would allow for a lower local anesthetic concentration or a lower infusion rate, while causing equivalent pain relief with preserved phrenic nerve function.…”

Mechanisms Underlying Midazolam-Induced Peripheral Nerve Block and Neurotoxicity

“…7 Briefly, rats were anesthetized with a subcutaneous injection of 1 mL/kg of a mixture of ketamine (55 mg/mL)/xylazine (5.5 mg/mL)/acepromazine (1.1 mg/mL). Sciatic nerves (~30 mm) were quickly dissected and transferred to a dish containing ice-cold Locke solution of the following composition (in mM): 136 NaCl, 5.6 KCl, 14.3 NaHCO 3 , 1.2 NaH 2 PO 4 , 2.2 CaCl 2 , 1.2 MgCl 2 , and 11 dextrose, equilibrated continuously with 95% O 2 and 5% CO 2 , to pH 7.2 to 7.4.…”

“…In addition, using the same stimulus intensity to evoke both A and C waves enabled simultaneous monitoring of changes in both waveforms. 7 Compound action potential data were filtered at 2 kHz (low-pass) and sampled at 20 kHz via a CED 1401 Micro A/D converter and acquired and analyzed using CED Spike 2 version 5 for MS Windows (CED, Cambridge, England). Compound action potential data were rectified, and the average of 6 consecutive CAPs was integrated to quantify A-and C-fiber components of the CAP as area under the curve (AUC).…”

“…6 Consistent with a direct action on the peripheral nerve, we recently showed that midazolam can produce a small but significant block of compound action potential (CAP) propagation in an isolated sciatic nerve preparation. 7 Importantly, we focused on relatively low concentrations in this nerve block study because we had previously demonstrated that higher concentrations of midazolam are neurotoxic. 8 Together, these observations suggest that midazolam-induced nerve block is due to an action at site(s) other than the benzodiazepine site on the GABA A receptor, raising the intriguing possibility that identification of this target may suggest a way to maximize the therapeutic utility of midazolam, or better yet, a more effective way to achieve the same therapeutic action while minimizing the potential for neurotoxicity.…”