Authors: Ostertag-Hill, Claire A. et al.
Anesthesiology, September 17, 2025. DOI: 10.1097/ALN.0000000000005679
This experimental study explored a promising development in pain medicine — a metabolite of amino-amide local anesthetics called 2′,6′-pipecoloxylidide (PPX). Researchers sought to determine whether PPX could provide sensory-selective anesthesia (blocking pain and sensation without causing motor paralysis) and to evaluate its safety profile compared to ropivacaine.
Rats received sciatic or intrathecal injections of PPX or ropivacaine, followed by sensory and motor testing. PPX achieved substantial sensory blockade with no motor impairment, while ropivacaine affected both. The sensory block duration for PPX was shorter (around 67 minutes vs 150 minutes for ropivacaine), but its selectivity was a significant advantage. Interestingly, adding permeation enhancers eliminated PPX’s sensory selectivity, suggesting the mechanism depends on the compound’s physicochemical balance. Toxicity testing showed PPX was markedly safer, with no severe systemic effects even at nearly double the toxic dose of ropivacaine. Histologic studies revealed benign tissue reactions comparable to conventional local anesthetics.
Overall, PPX demonstrates true sensory selectivity — the ability to relieve pain while preserving movement — and an excellent safety margin. This property could have profound implications for both acute and chronic pain management if confirmed in future human trials.
What You Should Know:
PPX could represent the next step toward the ideal local anesthetic — effective pain relief without motor blockade. Its favorable safety and sensory specificity may make it especially useful for postoperative analgesia and chronic pain therapies, pending further translational research.
Thank you to Anesthesiology for publishing this forward-looking study on the future of sensory-selective local anesthesia.