Lumbar Intrathecal Administration of the Quaternary Lidocaine Derivative, QX-314, Produces Irritation and Death in Mice

Abstract

Lumbar intrathecal QX-314 concentration-dependently produced irritation and death in mice, at lower concentrations than those associated with robust motor blockade. Although QX-314 did produce long-lasting neural blockade, these findings indicate that QX-314 is unlikely to be a suitable candidate for spinal anesthesia in humans.

The Quaternary Lidocaine Derivative, QX-314, Exerts Biphasic Effects on Transient Receptor Potential Vanilloid Subtype 1 Channels In Vitro

“…7 This may explain why intrathecal lidocaine does not produce the sustained severe acute irritation associated with QX-314. 29 That said, lidocaine is well known to be neurotoxic, and on the basis of the current study, it would seem possible that Ca 2ϩ influx mediated by TRPV1 activation [53][54][55] contributes to LA-induced cell death by inducing necrotic and apoptotic mechanisms. 56,57 The cellular degeneration caused by QX-314 chloride (60 mM) and bromide (Ն30 mM) in this study may well relate to the adverse intrathecal effects observed in vivo.…”

“…29 In general, pain upon injection of LAs is a wellknown phenomenon and often a source of discomfort for patients undergoing local anesthesia. 49 One possible mechanism may be the low pH of some LA formulations, 50 because TRPV1 is considered the main transducing receptor system for proton-induced excitation of nociceptive sensory neurons.…”

“…28 We recently found that intrathecal administration of QX-314 at concentrations as low as 0.5 mM produced unacceptable adverse effects in mice (including death at Ն 5 mM). 29 These effects occurred at lower concentrations than those associated with robust motor blockade, suggesting a low therapeutic index for use in spinal anesthesia. The findings also suggested a distinct neurotoxic action of QX-314 compared with lidocaine 29 : whereas lidocaine neurotoxicity mainly manifests as irreversible conduction blockade, intrathecal QX-314 acutely produced marked irritable, nocifensive-type behavior in the animals.…”

“…29 These effects occurred at lower concentrations than those associated with robust motor blockade, suggesting a low therapeutic index for use in spinal anesthesia. The findings also suggested a distinct neurotoxic action of QX-314 compared with lidocaine 29 : whereas lidocaine neurotoxicity mainly manifests as irreversible conduction blockade, intrathecal QX-314 acutely produced marked irritable, nocifensive-type behavior in the animals. Although QX-314 holds promise as an LA to produce long-lasting peripheral antinociception, it is imperative on the basis of these observations that more preclinical studies be conducted to better define the mechanisms underlying the therapeutic and adverse effects of QX-314 before it is tested in humans.…”

Current and Future Issues in the development of spinal agents for the management of pain

“…However, activating membrane channels such as the TRV1 channel has been reported to allow QX314 entry into the neurons and to block the Na v channel from the interior and result in a selective block of the TRPV1 expressing primary afferent [150]. Intrathecal QX316 has been reported to produce significant pain behavior after intrathecal delivery in rodent models and this may reflect upon its ability to concurrently activate the TRPV1 channel [151]. It should be noted that while this section considers the role of sodium channel blockage in reducing axon excitability, it has been shown that conditions leading to an enhanced expression of sodium channels often lead to a reduction in the expression of potassium channels which further contributes to membrane excitability [152].…”