Neurotoxicity Research

, 16:408 | Cite as

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

  • Alberto J. Rodriguez-Navarro
  • Marcelo Lagos
  • Cristian Figueroa
  • Carlos Garcia
  • Pedro Recabal
  • Pamela Silva
  • Veronica Iglesias
  • Nestor Lagos
Article

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.

Keywords

Neosaxitoxin Local anesthetic Long-acting pain blocker Clinical trial 

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

Notes

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.

References

  1. Adams HJ, Blair MR, Takman BH (1976) The local anesthetic activity of tetrodotoxin alone and in combination with vasoconstrictors and local anesthetics. Anesth Analg 55:568–573PubMedGoogle Scholar
  2. Almeida TF, Roizenblatt S, Tufik S (2004) Afferent pain pathways: a neuroanatomical review. Brain Res 1000:40–56CrossRefPubMedGoogle Scholar
  3. Andrinolo D, Iglesias V, García C, Lagos N (2002) Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats. Toxicon 40:699–709CrossRefPubMedGoogle Scholar
  4. Ballantyne JC (2007) Opioid analgesia: perspectives on right use and utility. Pain Physician 10:479–491PubMedGoogle Scholar
  5. Bernards CM, Kopacz DJ (1999) Effect of epinephrine on lidocaine clearance in vivo: a microdialysis study in humans. Anesthesiology 91:962–968CrossRefPubMedGoogle Scholar
  6. Bisgaard T (2006) Analgesic treatment after laparoscopic cholecystectomy: a critical assessment of the evidence. Anesthesiology 104:835–846CrossRefPubMedGoogle Scholar
  7. Brennan F, Carr DB, Cousins M (2007a) Pain management: a fundamental human right. Anesth Analg 105:205–221CrossRefPubMedGoogle Scholar
  8. Brennan F, Carr DB, Cousins M (2007b) The role of opioids in pain management. Anesth Analg 105:1865–1866CrossRefPubMedGoogle Scholar
  9. 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 81:321–328CrossRefPubMedGoogle Scholar
  10. Carr DB, Goudas LC (1999) Acute pain. Lancet 353:2051–2058CrossRefPubMedGoogle Scholar
  11. Catterall WA (2000) From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26:13–25CrossRefPubMedGoogle Scholar
  12. CIOMS/WHO (2002) International ethical guidelines for biomedical research involving human subjects. CIOMS, GenevaGoogle Scholar
  13. Cohen MJ, Schecter WP (2005) Perioperative pain control: a strategy for management. Surg Clin North Am 85:1243–1257CrossRefPubMedGoogle Scholar
  14. Covino BG (1986) Pharmacology of local anesthetic agents. Br J Anaesth 58:701–716CrossRefPubMedGoogle Scholar
  15. Evans MH (1968) Topical application of saxitoxin and tetrodotoxin to peripheral nerves and spinal roots in cat. Toxicon 5:289–294CrossRefPubMedGoogle Scholar
  16. Förster JG, Rosenberg PH (2003) Clinically useful adjuvants in regional anaesthesia. Curr Opin Anaesthesiol 16:477–486CrossRefPubMedGoogle Scholar
  17. Fukuda K, Nakajima T, Viswanathan PC, Balser JR (2005) Compound-specific Na+ channel pore conformational changes induced by local anaesthetics. J Physiol 564(1):21–31CrossRefPubMedGoogle Scholar
  18. 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 38:197–205CrossRefPubMedGoogle Scholar
  19. Garrido R (2005) New toxin treatment for anal fissures. Nat Clin Pract Gastroenterol Hepatol 2:126–127Google Scholar
  20. 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 37:395–403CrossRefPubMedGoogle Scholar
  21. 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 48:335–340CrossRefPubMedGoogle Scholar
  22. Grant SA (2002) The Holy Grail: long-acting local anaesthetics and liposomes. Best Pract Res Clin Anaesthesiol 16:345–352CrossRefPubMedGoogle Scholar
  23. 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 101:133–137CrossRefPubMedGoogle Scholar
  24. Gupta A (2005) Local anaesthesia for pain relief after laparoscopic cholecystectomy—a systematic review. Best Pract Res Clin Anaesthesiol 19:275–292CrossRefPubMedGoogle Scholar
  25. Hutchison RW (2007) Challenges in acute post-operative pain management. Am J Health Syst Pharm 64:S2–S5CrossRefPubMedGoogle Scholar
  26. Isbister GK, Kiernan MC (2005) Neurotoxic marine poisoning. Lancet Neurol 4:219–228CrossRefPubMedGoogle Scholar
  27. Kao CY (1972) Pharmacology of tetrodotoxin and saxitoxin. Fed Proc 31:1117–1123PubMedGoogle Scholar
  28. Kehlet H, Dahl JB (1993) The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 77:1048–1056CrossRefPubMedGoogle Scholar
  29. Kohane DS, Yieh J, Lu NT, Langer R, Strichartz G, Berde CB (1998) A reexamination of tetrodotoxin for prolonged anesthesia. Anesthesiology 89:119–131CrossRefPubMedGoogle Scholar
  30. 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 25:52–59PubMedGoogle Scholar
  31. 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 104:415–421CrossRefPubMedGoogle Scholar
  32. Lagos N (1998) Microalgal bloom: a global issue with negative impact in Chile. Biol Res 31:375–386PubMedGoogle Scholar
  33. 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 YorkGoogle Scholar
  34. 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 81:377–383PubMedGoogle Scholar
  35. 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 44:878–883CrossRefPubMedGoogle Scholar
  36. Myers RR, Kalichman MW, Reisner LS, Powell HC (1986) Neurotoxicity of local anesthetics: altered perineural permeability, edema, and nerve fiber injury. Anesthesiology 64:29–35CrossRefPubMedGoogle Scholar
  37. Narahashi T (1972) Mechanism of action of tetrodotoxin and saxitoxin on excitable membranes. Fed Proc 31:1124–1132PubMedGoogle Scholar
  38. Nordin P, Zetterström H, Gunnarsson U, Nilsson E (2003) Local, regional, or general anaesthesia in groin hernia repair: multicentre randomised trial. Lancet 362:853–858CrossRefPubMedGoogle Scholar
  39. Padera RF, Tse JY, Bellas E, Kohane DS (2006) Tetrodotoxin for prolonged local anesthesia with minimal myotoxicity. Muscle Nerve 34:747–753CrossRefPubMedGoogle Scholar
  40. 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 99:912–918CrossRefPubMedGoogle Scholar
  41. Reinikainen M, Hedman A, Pelkonen O, Ruokonen E (2003) Cardiac arrest after interscalene brachial plexus block with ropivacaine and lidocaine. Acta Anaesthesiol Scand 47:904–906CrossRefPubMedGoogle Scholar
  42. 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 101:2667–2668PubMedGoogle Scholar
  43. 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 106:339–345CrossRefPubMedGoogle Scholar
  44. Sakura S, Bollen AW, Ciriales R, Drasner K (1995) Local anesthetic neurotoxicity does not result from blockade of voltage-gated sodium channels. Anesth Analg 81:338–346CrossRefPubMedGoogle Scholar
  45. Scholz A, Vogel W (2000) Tetrodotoxin-resistant action potentials in dorsal root ganglion neurons are blocked by local anesthetics. Pain 89:47–52CrossRefPubMedGoogle Scholar
  46. Sinnott CJ, Cogswell LP, Johnson A, Strichartz GR (2003) On the mechanism by which epinephrine potentiates lidocaine’s peripheral nerve block. Anesthesiology 98:181–188CrossRefPubMedGoogle Scholar
  47. 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 48:128–134CrossRefGoogle Scholar
  48. 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 479:96–112CrossRefPubMedGoogle Scholar
  49. Wagner HH, Ulbricht W (1976) Saxitoxin and procaine act independently on separate sites of the sodium channel. Pflugers Arch 364:65–70CrossRefPubMedGoogle Scholar
  50. 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 76:131–143CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Alberto J. Rodriguez-Navarro
    • 1
    • 2
  • Marcelo Lagos
    • 1
  • Cristian Figueroa
    • 1
  • Carlos Garcia
    • 1
  • Pedro Recabal
    • 1
  • Pamela Silva
    • 1
  • Veronica Iglesias
    • 3
  • Nestor Lagos
    • 1
  1. 1.Membrane Biochemistry Laboratory, Programme of Physiology and Biophysics, ICBM, Faculty of MedicineUniversity of ChileSantiago 7Chile
  2. 2.Padre Alberto Hurtado HospitalSantiagoChile
  3. 3.Public Health School, Faculty of MedicineUniversity of ChileSantiagoChile

Personalised recommendations