Background and Objectives Although 2-chloroprocaine continues to be a useful drug for epidural anesthesia in obstetrics, it has the anomalous action of decreasing the analgesic effectiveness of subsequently administered epidural fentanyl. Some investigators have suggested that 2-chloroprocaine may act at an opioid receptor site to antagonize the effects of fentanyl. The purpose of our studies was to investigate this hypothesis.

Methods Radioligiand binding assays using the mu and kappa opioid receptor-selective radioligands [³H]-DAMGO and [³H]-U69,593, respectively, were performed to determine the potencies of lidocaine, 2-chloroprocaine, and 2-chloroprocaine metabolites at the mu and kappa opioid receptor sites. Electrophysiologic experiments in in vitro hippocampal slice preparations were then used to examine the effects of 2-chloroprocaine at these opioid receptor subtypes.

Results Lidocaine caused a partial reduction of [³H]-DAMGO binding, which was dose-limited owing to the solubility of lidocaine. 2-Chloroprocaine caused complete displacement of [³H]-DAMGO binding, with a median effective concentration of 1.44 ± 0.36 mM. The EC₅₀ values for [³H]-U69,593 displacement were 177 ± 47 μM for 2-chloroprocaine and 2.53 ± 0.48 mM for lidocaine. Assuming a competitive interaction between anesthetic and opioid, the K_i value for 2-chloroprocaine was 435 μM at mu receptors and 49 μM at kappa receptors. In the mu activity bioassay, 2-chloroprocaine reversed the increased neuronal excitability caused by fentanyl, but this effect was further reduced by naloxone. In addition, 2-chloroprocaine did not reverse the afterdepolarization caused by fentanyl. In the kappa activity bioassay, 2-chloroprocaine produced effects similar to the kappa agonist U69,593, but these were not antagonized by naloxone.

Conclusions Although 2-chloroprocaine has binding affinity at mu and kappa opioid receptor sites, it does not appear to act through an opioid receptor to antagonize the physiologic effects of fentanyl.