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Sensory-selective Peripheral and Neuraxial Nerve Blockade with 2',6'-Pipecoloxylidide. BACKGROUND: Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. This articles describes the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics, 2',6'-pipecoloxylidide (PPX). METHODS: PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. RESULTS: In male rats, sciatic sensory and motor block from 15 mM ROP lasted approximately 150 min; sensory nerve block from 30 mM PPX lasted 67.4 ± 17.4 min without motor block. The addition of chemical permeation enhancers to 30 mM PPX abolished sensory selectivity. Intrathecal 15 mM ROP produced sensory and motor block lasting approximately 15 min; sensory block from 30 mM PPX lasted 24.8 ± 8.7 min without motor block; repeated injection caused continuous sensory-selective block. In female rats, sciatic nerve blocks with ROP were similar to blocks in males, while blocks with PPX were sensory-selective, but higher PPX concentrations were required. Ex vivo , 1.5 mM ROP caused reversible block of Aδ and C-fibers; 15 mM PPX blocked Aδ-fibers but not C-fibers. Systemic 39.0 ± 1.8 mg/kg ROP caused severe clinical toxicity; 75.3 ± 3.2 mg/kg PPX caused none. Tissue reaction to PPX was benign, comparable to that of ROP. CONCLUSIONS: PPX provides sensory-selective local and neuraxial anesthesia with a good safety profile. The sensory selectivity may be attributable to the particular hydrophilic-hydrophobic balance of PPX.