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Potentiation of Local Anesthetic Activity of Neosaxitoxin with Bupivacaine or Epinephrine: Development of a Long-Acting Pain Blocker

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Abstract

Local anesthetics effectively block and relieve pain, but with a relatively short duration of action, limiting its analgesic effectiveness. Therefore, a long-acting local anesthetic would improve the management of pain, but no such agent is yet available for clinical use. The aim of this study is to evaluate the potentiation of the anesthetic effect of neosaxitoxin, with bupivacaine or epinephrine in a randomized double-blind clinical trial. Ten healthy males were subcutaneously injected into the left and right forearms with a randomized pair of the following treatments: (i) bupivacaine (5 mg); (ii) neosaxitoxin (10 μg); (iii) neosaxitoxin (10 μg) plus bupivacaine (5 mg), and (iv) neosaxitoxin (10 μg) plus epinephrine (1:100.000), but all participant received all four formulations (in 2 ml; s.c.), with 1 month elapsing between the two round of experiments. A validated sensory and pain paradigm was used for evaluating the effect of the treatment 0–72 h after the injections, measuring sensory, pain, and mechanical touch perception threshold. The duration of the effect produced by combined treatments was longer than that by the single drugs. In conclusion, bupivacaine and epinephrine potentiate the local anesthetic effect of neosaxitoxin in humans when co-injected subcutaneously. The present results support the idea that neosaxitoxin is a new long-acting local pain blocker, with highly potential clinical use.

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Abbreviations

AUC:

Area under the curve

Neo–Bupi:

Neosaxitoxin plus bupivacaine

Neo–Epi:

Neosaxitoxin plus epinephrine

TTX:

Tetrodotoxin

WS:

Warm sensation

HP:

Heat pain

CS:

Cold sensation

CP:

Cold pain

MT:

Mechanical touch

References

  • Adams HJ, Blair MR, Takman BH (1976) The local anesthetic activity of tetrodotoxin alone and in combination with vasoconstrictors and local anesthetics. Anesth Analg 55:568–573

    PubMed  CAS  Google Scholar 

  • Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical review. Brain Res 1000:40–56

    Article  PubMed  CAS  Google Scholar 

  • Andrinolo D, Iglesias V, García C, Lagos N (2002) Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats. Toxicon 40:699–709

    Article  PubMed  CAS  Google Scholar 

  • Ballantyne JC (2007) Opioid analgesia: perspectives on right use and utility. Pain Physician 10:479–491

    PubMed  Google Scholar 

  • Bernards CM, Kopacz DJ (1999) Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans. Anesthesiology 91:962–968

    Article  PubMed  CAS  Google Scholar 

  • Bisgaard T (2006) Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 104:835–846

    Article  PubMed  Google Scholar 

  • Brennan F, Carr DB, Cousins M (2007a) Pain management: a fundamental human right. Anesth Analg 105:205–221

    Article  PubMed  Google Scholar 

  • Brennan F, Carr DB, Cousins M (2007b) The role of opioids in pain management. Anesth Analg 105:1865–1866

    Article  PubMed  Google Scholar 

  • Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP (1995) Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg 81:321–328

    Article  PubMed  CAS  Google Scholar 

  • Carr DB, Goudas LC (1999) Acute pain. Lancet 353:2051–2058

    Article  PubMed  CAS  Google Scholar 

  • Catterall WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13–25

    Article  PubMed  CAS  Google Scholar 

  • CIOMS/WHO (2002) International ethical guidelines for biomedical research involving human subjects. CIOMS, Geneva

  • Cohen MJ, Schecter WP (2005) Perioperative pain control: a strategy for management. Surg Clin North Am 85:1243–1257

    Article  PubMed  Google Scholar 

  • Covino BG (1986) Pharmacology of local anesthetic agents. Br J Anaesth 58:701–716

    Article  PubMed  CAS  Google Scholar 

  • Evans MH (1968) Topical application of saxitoxin and tetrodotoxin to peripheral nerves and spinal roots in cat. Toxicon 5:289–294

    Article  PubMed  CAS  Google Scholar 

  • Förster JG, Rosenberg PH (2003) Clinically useful adjuvants in regional anaesthesia. Curr Opin Anaesthesiol 16:477–486

    Article  PubMed  Google Scholar 

  • Fukuda K, Nakajima T, Viswanathan PC, Balser JR (2005) Compound-specific Na+ channel pore conformational changes induced by local anaesthetics. J Physiol 564(1):21–31

    Article  PubMed  CAS  Google Scholar 

  • García C, Lagos M, Truan D, Lattes K, Véjar O, Chamorro B, Iglesias V, Andrinolo D, Lagos N (2005) Human intoxication with paralytic shellfish toxins: clinical parameters and toxin analysis in plasma and urine. Biol Res 38:197–205

    Article  PubMed  Google Scholar 

  • Garrido R (2005) New toxin treatment for anal fissures. Nat Clin Pract Gastroenterol Hepatol 2:126–127

    Google Scholar 

  • Garrido R, Lagos N, Lattes K, Azolas CG, Bocic G, Cuneo A, Chiong H, Jensen C, Henríquez AI, Fernández C (2004) The gonyautoxin 2/3 epimers reduces anal tone when injected in the anal sphincter of healthy adults. Biol Res 37:395–403

    Article  PubMed  CAS  Google Scholar 

  • Garrido R, Lagos N, Lattes K, Abedrapo M, Bocic G, Cuneo A, Chiong H, Jensen C, Azolas R, Henriquez A, Garcia C (2005) Gonyautoxin: new treatment for healing acute and chronic anal fissures. Dis Colon Rectum 48:335–340

    Article  PubMed  Google Scholar 

  • Grant SA (2002) The Holy Grail: long-acting local anaesthetics and liposomes. Best Pract Res Clin Anaesthesiol 16:345–352

    Article  PubMed  CAS  Google Scholar 

  • Grant GJ, Barenholz Y, Bolotin EM, Bansinath M, Turndorf H, Piskoun B, Davidson EM (2004) A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia. Anesthesiology 101:133–137

    Article  PubMed  CAS  Google Scholar 

  • Gupta A (2005) Local anaesthesia for pain relief after laparoscopic cholecystectomy—a systematic review. Best Pract Res Clin Anaesthesiol 19:275–292

    Article  PubMed  CAS  Google Scholar 

  • Hutchison RW (2007) Challenges in acute post-operative pain management. Am J Health Syst Pharm 64:S2–S5

    Article  PubMed  Google Scholar 

  • Isbister GK, Kiernan MC (2005) Neurotoxic marine poisoning. Lancet Neurol 4:219–228

    Article  PubMed  CAS  Google Scholar 

  • Kao CY (1972) Pharmacology of tetrodotoxin and saxitoxin. Fed Proc 31:1117–1123

    PubMed  CAS  Google Scholar 

  • Kehlet H, Dahl JB (1993) The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77:1048–1056

    Article  PubMed  CAS  Google Scholar 

  • Kohane DS, Yieh J, Lu NT, Langer R, Strichartz G, Berde CB (1998) A reexamination of tetrodotoxin for prolonged anesthesia. Anesthesiology 89:119–131

    Article  PubMed  CAS  Google Scholar 

  • Kohane DS, Lu NT, Gökgöl-Kline AC, Shubina M, Kuang Y, Hall S, Strichartz GR, Berde CB  (2000) The local anesthetic properties and toxicity of saxitonin homologues for rat sciatic nerve block in vivo. Reg Anesth Pain Med 25:52–59

    PubMed  CAS  Google Scholar 

  • Kohane DS, Smith SE, Louis DN, Colombo G, Ghoroghchian P, Hunfeld NG, Berde CB, Langer R  (2003) Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain 104:415–421

    Article  PubMed  CAS  Google Scholar 

  • Lagos N (1998) Microalgal bloom: a global issue with negative impact in Chile. Biol Res 31:375–386

    PubMed  CAS  Google Scholar 

  • Lagos N, Andrinolo D (2000) Paralytic shellfish poisoning (PSP): toxicology and kinetics. In: Botana LM (ed) Seafood and freshwater toxins: mode of action, pharmacology and physiology. Marcel Dekker, New York

    Google Scholar 

  • Møiniche S, Mikkelsen S, Wetterslev J, Dahl JB (1998) A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth 81:377–383

    PubMed  Google Scholar 

  • Møiniche S, Dahl A, Dahl JB (2000) Subcutaneous infiltration with ammonium sulphate 10% does not prolong the local anaesthetic duration of lidocaine in humans. Acta Anaesthesiol Scand 44:878–883

    Article  PubMed  Google Scholar 

  • Myers RR, Kalichman MW, Reisner LS, Powell HC (1986) Neurotoxicity of local anesthetics: altered perineural permeability, edema, and nerve fiber injury. Anesthesiology 64:29–35

    Article  PubMed  CAS  Google Scholar 

  • Narahashi T (1972) Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes. Fed Proc 31:1124–1132

    PubMed  CAS  Google Scholar 

  • Nordin P, Zetterström H, Gunnarsson U, Nilsson E (2003) Local, regional, or general anaesthesia in groin hernia repair: multicentre randomised trial. Lancet 362:853–858

    Article  PubMed  Google Scholar 

  • Padera RF, Tse JY, Bellas E, Kohane DS (2006) Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity. Muscle Nerve 34:747–753

    Article  PubMed  CAS  Google Scholar 

  • Pedersen JL, Lillesø J, Hammer NA, Werner MU, Holte K, Lacouture PG, Kehlet H (2004) Bupivacaine in microcapsules prolongs analgesia after subcutaneous infiltration in humans: a dose-finding study. Anesth Analg 99:912–918

    Article  PubMed  CAS  Google Scholar 

  • Reinikainen M, Hedman A, Pelkonen O, Ruokonen E (2003) Cardiac arrest after interscalene brachial plexus block with ropivacaine and lidocaine. Acta Anaesthesiol Scand 47:904–906

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Navarro AJ, Lagos N, Lagos M, Braghetto I, Csendes A, Hamilton J, Berger Z, Wiedmaier G, Henriquez A (2006) Intrasphincteric neosaxitoxin injection evidence of lower esophageal sphincter relaxation in achalasia. Am J Gastroenterol 101:2667–2668

    PubMed  Google Scholar 

  • Rodriguez-Navarro AJ, Lagos N, Lagos M, Braghetto I, Csendes A, Hamilton J, Figueroa C, Truan D, Garcia C, Rojas A, Iglesias V, Brunet L, Alvarez F (2007) Neosaxitoxin as a local anesthetic: preliminary observations from a first human trial. Anesthesiology 106:339–345

    Article  PubMed  CAS  Google Scholar 

  • Sakura S, Bollen AW, Ciriales R, Drasner K (1995) Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 81:338–346

    Article  PubMed  CAS  Google Scholar 

  • Scholz A, Vogel W (2000) Tetrodotoxin-resistant action potentials in dorsal root ganglion neurons are blocked by local anesthetics. Pain 89:47–52

    Article  PubMed  CAS  Google Scholar 

  • Sinnott CJ, Cogswell LP, Johnson A, Strichartz GR (2003) On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology 98:181–188

    Article  PubMed  CAS  Google Scholar 

  • Stevens MF, Hoppe M, Holthusen H, Lipfert P (2004) Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaine. Acta Anaesthesiol Scand 48:128–134

    Article  Google Scholar 

  • Strichartz G, Rando T, Hall S, Gitschier J, Hall L, Magnani B, Bay CH (1986) On the mechanism by which saxitoxin binds to and blocks sodium channels. Ann NY Acad Sci 479:96–112

    Article  PubMed  CAS  Google Scholar 

  • Wagner HH, Ulbricht W (1976) Saxitoxin and procaine act independently on separate sites of the sodium channel. Pflugers Arch 364:65–70

    Article  PubMed  CAS  Google Scholar 

  • Wong K, Strichartz GR, Raymond SA (1993) On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure-activity studies on isolated peripheral nerve. Anesth Analg 76:131–143

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the support of the Henry Mayer Center, Clinical Hospital University of Chile. Thanks to Mr. Daniel Holt for the final revision of the manuscript. This study was supported by Grant # 162, Research Office, Clinical Hospital, University of Chile and FONDECYT Grants 1070706 and 11080242.

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Correspondence to Nestor Lagos.

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Rodriguez-Navarro, A.J., Lagos, M., Figueroa, C. et al. Potentiation of Local Anesthetic Activity of Neosaxitoxin with Bupivacaine or Epinephrine: Development of a Long-Acting Pain Blocker. Neurotox Res 16, 408–415 (2009). https://doi.org/10.1007/s12640-009-9092-3

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  • DOI: https://doi.org/10.1007/s12640-009-9092-3

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