Anesthesiology, V 120 • No 4 976 April 2014 E FFECTIVE management of acute postoperative pain is important for promoting recovery of patients after surgery and for improving postoperative outcomes. Regional anesthesia, especially peripheral nerve blockade, is enjoying wider popularity, thanks in large part to the use of ultra- sound guidance. Some studies suggest that major morbid- ity, including persistent pain after surgery, as well as patient mortality, is reduced by the use of regional anesthesia peri- operatively. Key problems in regional anesthesia include the relatively brief duration of action of clinically available local anesthetics, necessitating cumbersome and expensive cath- eter infusions, and nonselective blockade, leading to numb- ness, motor weakness, and hypotension. As a result, sustained release preparations and other approaches are under develop- ment to produce prolonged nociceptor-selective nerve block. A recent strategy is to open membrane channels selectively expressed on nociceptors to allow entry of local anesthet- ics. 1–4 Te transient receptor potential vanilloid 1 (TRPV1) channel, important in the transduction of nociceptive or painful stimuli, 5 is such a large pore channel and is expressed not only on terminals of C and Aδ sensory fbers but also on their axons, the site of perineural injection. Initial stud- ies by Binshtok et al. 1 used perisciatic administration of the What We Already Know about This Topic • The transient receptor potential vanilloid 1 channel on noci- ceptive neurons provides a route of intracellular entry for local anesthetics • The combination of capsaicin, which opens the transient re- ceptor potential vanilloid 1 channel, and local anesthetics re- sults in prolonged nociceptor-selective nerve blockade in rats What This Article Tells Us That Is New • After incisional hind paw surgery in rats, administration of li- docaine and QX-314 followed by capsaicin initially attenuated mechanical hypersensitivity, but led to a delayed onset of me- chanical hypersensitivity and neurotoxicity Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2014; 120:976-86 ABSTRACT Background: Long-lasting, sensory-specifc peripheral nerve blockade would advance perioperative analgesia. Perineural injection of a combination of transient receptor potential vanilloid 1 channel agonists and lidocaine or its hydrophilic deriva- tive, QX-314, produces prolonged sensory or nociceptor-selective nerve block in rodents. In this study, the authors tested the efcacy of these combinations in peripheral nerve block after incisional surgery in rats. Methods: Te authors administered perisciatic lidocaine (2%), QX-314 (0.2%) followed by dilute capsaicin (0.05%, 10 min later), or vehicle in rats and the duration of motor and sensory block to thermal and mechanical stimuli assessed in normal animals and those after incisional surgery to the hind paw. Other animals receiving these injections were evaluated 7 weeks later by behavior and histology for potential neurotoxicity. Results: Perineural injection of the combination not only attenuated mechanical hypersensitivity for 72 h after incision but also resulted in delayed onset mechanical hypersensitivity several weeks later, accompanied by degeneration of central termi- nals of isolectin B4 (nonpeptidergic) and calcitonin gene–related peptide–containing (peptidergic) aferents in the ipsilateral spinal cord. Dorsal root ganglia ipsilateral to injection of the combination showed increased expression of activating transcrip- tion factor-3 and satellite cell activation. Conclusions: Combined administration of local anesthetics with the transient receptor potential vanilloid 1 agonist capsaicin induced a near complete blockade of incision-induced hypersensitivity for several days. However, the same combination induced delayed mechanical hypersensitivity and neurotoxicity in naïve rats. Combination of these drugs in these concentrations is likely to result in neurotoxicity, and the safety of other concentrations warrants further study. (ANESTHESIOLOGY 2014; 120:976-86) Portions of this research were previously presented at Neuroscience 2011 on November 15, 2011, in Washington, D.C. Steven L. Shafer, M.D., served as Handling Editor for this article. Submitted for publication May 6, 2013. Accepted for publication October 23, 2013. From the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (C.M.P., T.T.H., and C.A.A.); Department of Anesthesiology-Pediatric Anesthe- sia, Wake Forest University School of Medicine, Winston-Salem, North Carolina (D.R.); and Department of Anesthesiology and Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (J.C.E.). Nociceptor-selective Peripheral Nerve Block Induces Delayed Mechanical Hypersensitivity and Neurotoxicity in Rats Christopher M. Peters, Ph.D., Douglas Ririe, M.D., Ph.D., Timothy T. Houle, Ph.D., Carol A. Aschenbrenner, M.A., James C. Eisenach, M.D. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/120/4/976/264012/20140400_0-00033.pdf by guest on 25 June 2022