Pain Selective Anesthesia for Labor Mobility (PSALM Study): a Randomized Controlled Trial of Combined Lidocaine - Chlorprocaine for Labor Epidural Analgesia

The holy grail of pain management is providing highly effective pain relief without any side effects. The most common analgesic stratagems include a) systemic analgesia or b) local anesthesia using either peripheral nerve blockade or epidural/spinal anesthesia. Current approaches are not specific for pain blockade and are limited by side effects. The overall goal of the study is to achieve pain-specific local anesthesia, with selective nociceptive block, without either motor block, sensory block or sympathetic block. While the implications apply to many clinical pain states, here the team focuses on labor analgesia, where this strategy will allow mothers to feel no pain, while being able to feel the need to push, retaining the ability to push and to ambulate in labor, and avoiding hypotension. This goal is achieved by targeting nociceptors directly via a novel neural target.

The team developed a novel platform for nociceptor-selective local anesthesia. Using the transient receptor potential vanilloid receptor-1 (TRPV1 channel) expressed only by pain fibers, as an innate nociceptor-targeted drug delivery system for selectively introducing membrane-impermeable local anesthetics into nociceptors. TRPV1 is a transmembrane ion channel protein activated by noxious stimuli5 and by chemical irritants such as capsaicin. Capsaicin was used as the TRPV1 agonist and a lidocaine derivative, QX-314, as a polarized, membrane-impermeable, and hence generally ineffective local anesthetic. The preclinical co-investigator (Prof Alex Binshtok) previously showed that the activated TRPV1 channel is large enough to allow entry of QX-314 into nociceptors, so blocking their electrical activity in vitro, while not affecting the excitability of non-nociceptor neurons not expressing TRPV1 channels. Similarly, the co-injection of QX-314 and capsaicin in-vivo selectively abolished the response of animals to noxious stimuli without any detectable motor or tactile deficits, whereas the injection of either capsaicin or QX-314 alone did not produce any antinociceptive effect. Importantly, the team demonstrated that QX-314 permeates the human orthologue of TRPV1, leading to the inhibition of human sodium channel isoforms.

The team proposed that this approach for selectively shuttling sodium channel blockers to nociceptive neurons through nociceptor-specific TRPV1 channels could be exploited clinically to produce long-lasting, pain-selective, regional analgesia while preserving motor and autonomic function, for example during childbirth or after surgery. Furthermore, the team proposed that either systemic or regional administration of these combinations could also be used to treat other clinical conditions such as acute postoperative pain, intractable cancer pain, inflammatory or neuropathic pain and itch.

However, the clinical application of the "capsaicin-QX-314" approach encountered two main obstacles, both of which this current study is designed to address.

1. Capsaicin-induced pain: The activation of TRPV1 channels by capsaicin leads to severe "injection" pain before QX-314 enters nociceptors to induce analgesia. The team solves this problem by activating TRPV1 channels with lidocaine instead of capsaicin. The team and others have demonstrated that lidocaine activates human TRPV1 channels at 5mM doses (or 0.12%). The team co-applied QX-314 with lidocaine as the TRPV1 agonist instead of capsaicin and showed that lidocaine-induced activation of TRPV1 was sufficient to allow QX-314 to enter nociceptive neurons. Co-application of QX-314 and lidocaine induced a prolonged differential nociceptive block without "injection" pain.
2. QX-314 neurotoxicity: Several groups have demonstrated that QX-314 is neurotoxic in rats. Here the team avoids neurotoxicity by replacing QX-314 by standard local anesthetics with established safety records. The team's approach was based on their earlier observations showing that activation of TRPV1 channels by capsaicin prolongs the duration of nociceptive blockade by other local anesthetics, by facilitating entry for their polarized (membrane-impermeable) forms selectively into nociceptive neurons, thus leading to differential pain blockade with minimal motor block.