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Site-1 Sodium Channel Blockers As Local Anesthetics Will Neosaxitoxin Supplant the Need for Continuous Nerve Blocks?

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Site-1 Sodium Channel Blockers As Local Anesthetics Will Neosaxitoxin Supplant the Need for Continuous Nerve Blocks? EDITORIAL VIEWS Site-1 Sodium Channel Blockers as Local Anesthetics Will Neosaxitoxin Supplant the Need for Continuous Nerve Blocks? Laura A. Lahaye, M.D., John F. Butterworth IV, M.D. HE ideal agent for regional Therefore, it is not surprising that T anesthesia would have high animal studies have demonstrated affinity (and be highly specific) for a reduced potential for cardiotoxic- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/123/4/741/372504/20151000_0-00007.pdf by guest on 01 October 2021 the target site, have a rapid onset of ity with neosaxitoxin as compared action, have minimal local or sys- with bupivacaine.6 Humans ingest- temic toxicity, and would provide a ing large doses of these neurotoxins long duration of analgesia. Unfor- have been observed to have life- tunately, traditional local anesthet- threatening neuromuscular dys- ics incompletely fulfill these criteria. function manifesting as respiratory These compounds bind the voltage- arrest in the notable absence of car- gated sodium channels responsible diotoxicity.7 While the safety profile for producing peripheral nerve is of great concern, so too are the block with relatively low affinity block characteristics in the postop- and limited specificity.1 As a con- erative period. In many cases, the sequence, the relatively large doses ideal agent would provide excel- of local anesthetics that are often lent analgesia while allowing use required to produce regional anes- “... it appears that a neu- of the affected limb and providing thesia have an increased likelihood a barrier to injury with retention of systemic toxicity. Nerve blocks rotoxin may provide a of motor function and propriocep- produced by single injections of tion, and it remains unclear whether plain local anesthetics exhibit a nor- potential alternative to lo- neosaxitoxin alone or in combina- mal course of resolution that limits cal anesthetic infusions tion will exhibit these traits. the analgesic benefit to the immedi- Although investigational stud- ate postoperative period. Additives when prolonged analgesia ies involving human subjects are (e.g., dexamethasone) can modestly limited, we know that neosaxi- increase the duration of the more is desired.” toxin provided prolonged analge- potent, longer-persisting local anesthetics to a maximum of sia when infiltrated at port sites during laparoscopic surgery about 24 h.2 Continuous local anesthetic infusions can be used in humans.8 When given in combination with bupivacaine, to produce prolonged analgesia but increase the complexity of neosaxitoxin had a duration of action outlasting either drug the nerve block procedure. Now it appears that a neurotoxin alone when injected subcutaneously in healthy volunteer may provide a potential alternative to local anesthetic infusions subjects.9 Studying cutaneous neosaxitoxin injections in when prolonged analgesia is desired. In this issue of ANESTHESI- volunteers, Lobo et al. have described safety and adverse 3 4 OLOGY, the articles by Lobo et al. and Templin et al. provide event profiles by using rating scales and comprehensive evidence for the safety and analgesic potential of neosaxitoxin, physiologic monitoring. Although a prior clinical investi- a site-1 sodium channel blocker. gation10 supported the safety of neosaxitoxin, the current Neosaxitoxin and similar neurotoxins have low affinity for study’s use of measured negative inspiratory force, grip cardiac sodium channels (Nav1.5) relative to their affinity for strength and vital capacity measurements, correlated with the sodium channel isoforms (Nav1.7, Nav1.8, and others) detailed drug concentration data provide greater reassur- found in peripheral nerves.5 The separation in neosaxitoxin ance regarding safety. Both neuromuscular and respiratory affinities for sodium channel isoforms is at least an order of mag- function remained stable at the doses studied and symp- nitude greater than that for any conventional local anesthetic. toms were correlated with administered dose. Image: Micrograph of cyanobacteria (blue-green algae), from which neosaxitoxin is derived. From Sinclair Stammers/Science Photo Library. Corresponding articles on page 873 and page 886. Accepted for publication July 2, 2015. From the Department of Anesthesiology, Virginia Commonwealth University, Richmond, Virginia. Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 123:741-2 Anesthesiology, V 123 • No 4 741 October 2015 Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Editorial Views Given the relative potency of neosaxitoxin and its apparent Correspondence ability to provide prolonged sensory blockade with limited Address correspondence to Dr. Lahaye: llahaye@mcvh-vcu. cardiotoxicity when administered alone, one may wonder if edu its advantages are not offset with the addition of a traditional local anesthetic such as bupivacaine. Previous work has dem- References onstrated that to maximize block duration while minimizing 1. Cummins TR, Sheets PL, Waxman SG: The roles of sodium toxicity, a combination of neurotoxin, local anesthetic, and channels in nociception: Implications for mechanisms of 11 pain. Pain 2007; 131:243–57 vasoconstrictor may best be used. When either local anes- 2. Cummings KC III, Napierkowski DE, Parra-Sanchez I, Kurz A, thetic or neurotoxin is administered alone in small doses, Dalton JE, Brems JJ, Sessler DI: Effect of dexamethasone on incomplete or unreliable sensory blockade may result. How- the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth 2011; 107:446–53 ever, the combination at similarly small doses may provide Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/123/4/741/372504/20151000_0-00007.pdf by guest on 01 October 2021 3. Lobo K, Donado C, Cornelissen L, Kim J, Ortiz R, Peake excellent block characteristics. These findings suggest that in RWA, Kellog M, Alexander M, Zurakowski D, Kurgansky KE, combination, the favorable characteristics of each drug are Peyton J, Bilge A, Boretsky K, McCann ME, Berde C, Cravero enhanced while minimizing undesirable side effects. J: A phase I dose escalation, double-blind, block randomized controlled trial of safety and efficacy of neosaxitoxin alone If clinical studies have begun, why is there need for fur- and in combination with 0.2% bupivacaine, with and without ther animal investigations before regulatory approval? The epinephrine, for cutaneous anesthesia. ANESTHesiologY 2015; models of systemic toxicity used by Templin et al. provide 123:873–85 greater detail regarding the safety profile of neosaxitoxin in 4. Templin JS, Wylie MC, Kim JD, Kurgansky KE, Gorski G, Kheir J, Zurakowski D, Corfas G, Berde C: Neosaxitoxin in rodents. Specifically, there was no enhancement of neosaxi- rat sciatic block: Improved therapeutic index using combi- toxin toxic effects when it was combined with bupivacaine, nations with bupivacaine, with and without epinephrine. despite considerable prolongation of analgesia when the two ANESTHesiologY 2015; 123:886–98 5. Zimmer T: Effects of tetrodotoxin on the mammalian cardio- drugs were given together. While local anesthetic systemic vascular system. Mar Drugs 2010; 8:741–62 toxicity is of great concern, so too is localized tissue toxic- 6. Wylie MC, Johnson VM, Carpino E, Mullen K, Hauser K, ity. The histologic evaluation of rat sciatic nerves showing Nedder A, Kheir JN, Rodriguez-Navarro AJ, Zurakowski D, low injury scores after perineural injection provides another Berde CB: Respiratory, neuromuscular, and cardiovascular effects of neosaxitoxin in isoflurane-anesthetized sheep. Reg element in the mounting case for further clinical trials of Anesth Pain Med 2012; 37:152–8 neosaxitoxin (especially with bupivacaine) in humans. 7. García C, Lagos M, Truan D, Lattes K, Véjar O, Chamorro Despite these promising findings, much remains unknown B, Iglesias V, Andrinolo D, Lagos N: Human intoxication about the safety and potential clinical utility of neosaxitoxin. with paralytic shellfish toxins: Clinical parameters and toxin analysis in plasma and urine. Biol Res 2005; 38: Questions yet unanswered include the following: What is the 197–205 maximum safe dose when injected at typical regional anesthetic 8. Rodríguez-Navarro AJ, Berde CB, Wiedmaier G, Mercado A, sites? How do comorbid medical conditions influence dosing Garcia C, Iglesias V, Zurakowski D: Comparison of neosaxi- toxin versus bupivacaine via port infiltration for postopera- and safety? How closely will the reported pharmacokinetic data tive analgesia following laparoscopic cholecystectomy: A mimic the drug concentrations that would be achieved when randomized, double-blind trial. Reg Anesth Pain Med 2011; the drug is injected at typical sites for regional anesthesia? 36:103–9 In summary, the findings by Lobo et al.3 and Templin 9. Rodriguez-Navarro AJ, Lagos M, Figueroa C, Garcia C, Recabal 4 P, Silva P, Iglesias V, Lagos N: Potentiation of local anesthetic et al. provide substantial new knowledge, which should activity of neosaxitoxin with bupivacaine or epinephrine: guide further investigations of neosaxitoxin as a local anes- Development of a long-acting pain blocker. Neurotox Res thetic. We look forward to future work addressing the safety 2009; 16:408–15 of neosaxitoxin when administered for regional analgesia at a 10. Rodriguez-Navarro AJ, Lagos N, Lagos M,
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