Introduction

Epidural analgesia provides excellent pain relief during labor but is commonly limited by motor block and sympathectomy. A long-standing goal has been to achieve nociceptor-specific local anesthesia without other side effects. TRPV1 channels are expressed exclusively on nociceptors and have been exploited to selectively deliver polarized local anesthetics into nociceptors. In mice, co-administration of capsaicin (TRPV1 agonist) with QX-314 (polarized lidocaine derivative) produced profound nociceptor-selective anesthesia without motor or sympathetic block.However, burning injection pain from capsaicin and QX-314 neurotoxicity prevented clinical translation. Here we use lidocaine as the TRPV1 agonist² and chloroprocaine as the most polarized local anesthetic in clinical use. We hypothesize that this co-administration will be synergistic.

Methods

We designed an isobolographic study design to assess synergism between epidural chloroprocaine and lidocaine. 1st stage: We determined success of epidural lidocaine and chloroprocaine at 20min using a 5-point Likert scale and used this to determine ED50 by the Dixon–Massey up–down sequential method, with probit regression. 2nd stage: We used individual ED50s to assess the ED50 of drug combinations (ED50 of lidocaine co-administered with ½ED50 chloroprocaine; ED50 of chloroprocaine co-administered with ½ED50 lidocaine, and the ED50 of a 1:1 fixed dose ratio). We determined synergy using the interaction index3, where γ=(a/A)+(b/B). If γ< 1 the combination is synergistic; if y=1 the combination is additive. Women were eligible if they were in active labor, VAS ≥30mm, dilation ≤5cm, ≤4 previous deliveries, no prior cesarean.

Results

Conclusions
This is the first clinical study to attempt combining a TRPV1agonist with a polarized local anesthetic with the aim of attaining nociceptor-selective anesthesia without motor block. If the TRPV1 agonist interaction with polarized local anesthetic would be as hypothesized, we would have expected synergism between chloroprocaine and lidocaine; this was not observed.