Journal of Anesthesia

, Volume 32, Issue 4, pp 632–636 | Cite as

The history and progress of local anesthesia: multiple approaches to elongate the action

  • Masaru TobeEmail author
  • Takashi Suto
  • Shigeru Saito
Review Article


Analgesia and temporary inhibition of motor activity without interfering with central nervous function have been the essential merits of local anesthesia. Local anesthetics originated from cocaine have played a major role in local analgesia. However, the relatively short duration of action of local anesthetics has been a concern in intra- and post-operative analgesia. From the early age of modern local anesthesia, physicians and medical scientists had been struggling to control the active duration of local anesthetics. Such approach includes: development of long-acting local anesthetics, with physical tourniquet techniques, co-administration of other medicines such as vaso-constrictive agents or analgesics, development of mechanical devices to continuously or intermittently administer local anesthetics, and utilization of pharmaceutical drug delivery systems. In this review, the historical sequence of studies that have been performed in an effort to elongate the action of local anesthetics is presented, referring to epoch-making medical and scientific studies.


Local anesthetic Cocaine Drug delivery system 



The authors thank Dr. Mitsugu Fujimori for his advice on the historical notes of local anesthetics.


  1. 1.
    Calatayud J, Gonzalez A. History of the development and evolution of local anesthesia since the coca leaf. Anesthesiology. 2003;98(6):1503–8.CrossRefGoogle Scholar
  2. 2.
    Gaedcke F. Ueber das Erythroxylin, dargestellt aus den Blattern des in Sudamerika cultivirten Strauches Erythroxylon Coca Lam. Arch Pharm 1855; 132: 141–50.CrossRefGoogle Scholar
  3. 3.
    Niemann A. Ueber eine neue organische Base in den Cocablättern. Arch Pharm 1860; 153:129–55, 291–308.Google Scholar
  4. 4.
    Niemann A. Uever eine organische Base in der Coca. Ann Chem 1860; 124: 213.Google Scholar
  5. 5.
    Lossen W. Ueber das Cocain. Ann Chem Pharm 1865; 133: 351–71.CrossRefGoogle Scholar
  6. 6.
    Anrep B von. Ueber die physiologische Wirkung des Cocaïn. E Pflüger Arch Ges Physiol 1880; 21: 38–77.CrossRefGoogle Scholar
  7. 7.
    Koller C. On the use of cocaine for producing anaesthesia on the eye. Lancet 1884; 2: 990–2.CrossRefGoogle Scholar
  8. 8.
    Löfgren N, Lundquist B. Studies on local anaesthetics: II. Svenks Kem Tidskr. 1946;58:206–17.Google Scholar
  9. 9.
    Löfgren N. Studies on Local Anesthetics: Xylocaine, a New Synthetic Drug. Worcester: Morin Press; 1948.Google Scholar
  10. 10.
    Holmdahl M. Xylocaine, its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiol Scand Suppl. 1948;113:8–12.Google Scholar
  11. 11.
    Ekenstam B, Egner B, Pettersson G. Local anaesthetics: I. N-alkyl pyrrolidine and N-alkyl piperidine carboxylic acid amides. Acta Chem Scand. 1957;11:1183–90.CrossRefGoogle Scholar
  12. 12.
    Löfgren N, Tegner C. Studies on local anesthetics: XX. Synthesis of some α-monoalkylamino-2.-methylpropionanilides: a new useful local anesthetic. Acta Chem Scand. 1960;14:486–90.CrossRefGoogle Scholar
  13. 13.
    Adams HJ, Kronberg GH, Takman BH. Local anesthetic activity and acute toxicity of (±) 2-(N-ethylpropylamino)-2′, 6′-butyroxylidide, a new long-acting agent. J Pharm Sci. 1972;61:1829–31.CrossRefGoogle Scholar
  14. 14.
    Ruetsch YA1, Böni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem. 2001;1(3):175 – 82.CrossRefGoogle Scholar
  15. 15.
    Corning JL. On the prolongation of the anaesthetic effect of the hydrochlorate of cocaine, when subcutaneously injected. An experimental study. NY Med J 1885; 42: 317–9.Google Scholar
  16. 16.
    Braun H. Ueber den Einfluss der Vitalitat der Gewebe auf die ortlichen und allgemeinen Giftwirkungen localanasthesirender Mittel und ueber die Bedeutung des Adrenalins fur die Localanasthesie. Arch Klin Chir. 1903;69:541.Google Scholar
  17. 17.
    Braun H. Ueber einige neue örtliche anaesthetica (Stovain, Alypin, Novocain). Dtsch Med Wochenschr. 1905;31:1667–71.CrossRefGoogle Scholar
  18. 18.
    Potter JK, Whitacre RJ. Pontocaine-dextrose-ephedrine for spinal anesthesia. Anesthesiology. 1946;7:499–504.CrossRefGoogle Scholar
  19. 19.
    Ruben JE, Kamsler PM, Howell WL. Jr. The spinal anaesthetic effects of ephedrine sulfate: a preliminary report. Science. 1948;107:223.CrossRefGoogle Scholar
  20. 20.
    Taylor RL. Prolonged spinal anesthesia using ephedrine sulfate intrathecally. Am J Surg. 1950;79:369 – 72.CrossRefGoogle Scholar
  21. 21.
    Penman WR. A comparative study of intrathecal ephedrine sulfate, intrathecal Pontocaine, and inhhalation anesthesia for obstetrical delivery. Am J Obstet Gynecol. 1950;59:1095–9.CrossRefGoogle Scholar
  22. 22.
    Schultz FH. The local anesthetic properties of ephedrine hydrochloride. Anesthesiology. 1940;1:69–71.CrossRefGoogle Scholar
  23. 23.
    Djalali AG, Wang JC, Perez-Valdivieso JR, et al. Anesthe Analg. 2013;116:944–8.CrossRefGoogle Scholar
  24. 24.
    Bromage PR, Robson JG. Concentrations of lignocaine in the blood after intravenous, intramuscular, epidural, and endotracheal administration. Anaesthesia. 1961;16:461 – 78.CrossRefGoogle Scholar
  25. 25.
    Gangarosa LP, Halik FJ. A clinical evaluation of local anesthetic solutions containing graded epinephrine concentrations. Arch Oral Biol. 1967;12:611–21.CrossRefGoogle Scholar
  26. 26.
    Sisk AL. Vasoconstrictors in local anesthesia for dentistry. Anesth Prog. 1992;39:187–93.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Jaboulay M. Drainage de I’espace sous-arachnoidien et injection de liquids medicamenteux dans les meninges. Lyon Med 1898: 20: 71 – 2.Google Scholar
  28. 28.
    Matsuki A. The origin and evolution of anesthesia in Japan. Hirosaki: Hirosaki University Press; 2017. pp. 99–102.Google Scholar
  29. 29.
    Sciassi B. Un procede simplifie de cocainization de la moelle. La Sem Med. 1900;20:94.Google Scholar
  30. 30.
    Matas R. Local and regional anesthesia with cocaine and other analgesic drugs, including the subarachnoid method, as applied in general surgical practice. Phila Med J. 1900;6:820 – 43.Google Scholar
  31. 31.
    Kitagawa O. On the spinal anesthesia with cocaine. J Jpn Soc Surg. 1901;3:185–91.Google Scholar
  32. 32.
    Tamsen A, Gordh T. Epidural clonidine produces analgesia. Lancet. 1984;2:231–2.CrossRefGoogle Scholar
  33. 33.
    De Kock M, Gautier P, Fanard L, Hody JL, Lavand’homme P. Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy: a dose-response study. Anesthesiology. 2001;94:574–8.CrossRefGoogle Scholar
  34. 34.
    Dobrydnjov I, Axelsson K, Thörn SE, Matthiesen P, Klockhoff H, Holmström B, Gupta A. Clonidine combined with small-dose bupivacaine during spinal anesthesia for inguinal hemiorrhaphy: a randomized double-blinded study. Anesth Analg. 2003;96:1496–503.CrossRefGoogle Scholar
  35. 35.
    Wa HH, Wang HT, Jin JJ, Cui GB, Zhou KC, Chen Y, Chen GZ, Dong YL, Wang W. Dose dexmedetomidine as a neuraxial adjuvant facilitate better anesthesia and analgesia? A systematic review and meta-analysis. PLoS One. 2014;9:e93114.CrossRefGoogle Scholar
  36. 36.
    Kopacz DJ, Lacouture PG, Wu D, Nandy P, Swanton R, Landau C. The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers. Anesth Analg. 2003;96:576–82.PubMedGoogle Scholar
  37. 37.
    Islas JA, Astorga J, Laredo M. Epidural ketamine for control of postoperative pain. Anesth Analg. 1985;64:1161–2.CrossRefGoogle Scholar
  38. 38.
    Hawksworth C, Serpell M. Intrathecal anesthesia with ketamine. Reg Anesth Pain Med. 1998;23:283–8.PubMedGoogle Scholar
  39. 39.
    Yanli Y, Eren A. The effect of extradural ketamine on onset time and sensory block in extradural anesthesia with bupivacaine. Anesthesia. 1996;51:84–6.CrossRefGoogle Scholar
  40. 40.
    Kathirvel S, Sadhasivam S, Saxena A, Kannan TR, Ganjoo P. Effects of intrathecal ketamine added to bupivacaine for spinal anesthesia. Anesthesia. 2000;55:899–904.CrossRefGoogle Scholar
  41. 41.
    Corning JL. Spinal anaesthesia and local medication of the cord. NY Med J 1885; 42: 294–5.Google Scholar
  42. 42.
    Tuffier T. Analgesie chirurgicale par I’injection sous-arachnoidenne lombaire de cocaine. CR Soc Biol 1899; 51: 882.Google Scholar
  43. 43.
    Bier A. Das zurzeit an der Berliner chirurgischen Universitatsklinik ubliche Verfahren der Ruckenmarksanasthesie. Dtsch Z Chir. 1909;95:373–85.CrossRefGoogle Scholar
  44. 44.
    Dean HP. The importance of anaesthesia by lumbar injection in operations for acute abdominal diseases. Br Med J. 1906;1:1086.CrossRefGoogle Scholar
  45. 45.
    Lemmon WT. A method for continuous spinal anesthesia: a preliminary report. Ann Surg. 1940;111:141–4.CrossRefGoogle Scholar
  46. 46.
    Edwards WB, Hingson RA. Continuous caudal anesthesia in obstetrics. Am J Surg. 1942;57:459–64.CrossRefGoogle Scholar
  47. 47.
    Hingson RA, Edwards WB. Continuous caudal anesthesia during labor and delivery. Anesth Analg. 1942;21:301–11.CrossRefGoogle Scholar
  48. 48.
    Tuohy E. Continuous spinal anesthesia: Its usefulness and technic involved. Anesthesiology. 1944;5:142–8.CrossRefGoogle Scholar
  49. 49.
    Tuohy EB. Continuous spinal anesthesia: a new method utilizing a ureteral catheter. Surg Clin North Am. 1945;25:834.Google Scholar
  50. 50.
    Curbelo MM. Continuous peridural segmental anesthesia by means of a ureteral catheter. Curr Res Anesth Analg. 1949;28:13–23.CrossRefGoogle Scholar
  51. 51.
    Denny NM, Selander DE. Continuous spinal anaesthesia. Br J Anaesth. 1998;81:590–7.CrossRefGoogle Scholar
  52. 52.
    Curelaru I, Sandu L, Eugen Bogdan Aburel. The pioneer of regional analgesia for pain relief in childbirth. Anesthesia. 1982;37:663–9.CrossRefGoogle Scholar
  53. 53.
    Martinez Curbelo M. Continuous peridural segmental anesthesia by means of ureteral catheter. Curr Res Anesth Analg. 1949;28(1):13–23.PubMedGoogle Scholar
  54. 54.
    Bucklin BA, Hawkins JL, Anderson JR, Ullrich FA. Obstetric anesthesia workforce survey: twenty-year update. Anesthesiology. 2005;103:645 – 53.CrossRefGoogle Scholar
  55. 55.
    Curley J, Castillo J, Hotz J, Uezono M, Hernandez S, Lim JO, Tigner J, Chasin M, Langer R, Berde C. Prolonged regional nerve blockade: Injectable biodegradable bupivacaine/polyester microspheres. Anesthesiology. 1996;84:1401–10.CrossRefGoogle Scholar
  56. 56.
    Haynes DH, Kirkpatrick AF. Ultra-long duration local anesthesia produced by injection of lecithin coated methoxyflurane microdroplets. Anesthesiology. 1985;63:490–9.CrossRefGoogle Scholar
  57. 57.
    Estebe JP, Ecoffey C, Dollo G, Le Corre P, Chevanne F, Le Verge R. Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-beta-cyclodextrin complex in sheep. Eur J Anesth. 2002;19(4):308 – 10.CrossRefGoogle Scholar
  58. 58.
    Mowat JJ, Mok MJ, MacLeod BA, Madden TD. Liposomal bupivacaine: Extended duration nerve blockade using large unilamellar vesicles that exhibit a proton gradient. Anesthesiology. 1996;85:635 – 43.CrossRefGoogle Scholar
  59. 59.
    Haas E, Onel E, Miller H, Ragupathi M, White PF. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 2012;78(5):574 – 81.PubMedGoogle Scholar
  60. 60.
    Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of Depofoam® bupivacaine (extended-release bupivacaine local anesthetic) in bunionectomy. Adv Ther. 2011;28(9):776 – 88.CrossRefGoogle Scholar
  61. 61.
    Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blinded, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19(5):530–6.CrossRefGoogle Scholar
  62. 62.
    Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32(1):69–76.CrossRefGoogle Scholar
  63. 63.
    Lambrechts M, O’Brien MJ, Savoie FH, You A. Liposomal extended-release bupivacaine for postsurgical analgesia. Patient Prefer Adherence. 2013;7:885 – 90.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Wang X, Xiao L, Wang Z, Zhao G, Ma J. Comparison of peri-articular liposomal bupivacaine and standard bupivacaine for postsurgical analgesia in total knee arthroplasty: a systematic review and meta-analysis. Int J Surg. 2017;39:238 – 48.CrossRefGoogle Scholar
  65. 65.
    Hamilton TW, Athanassoglow V, Mellon S, Stickland LH, Trivella M, Murray D, Pandit HG. Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. Cochrane Database Syst Rev. 2017 Feb;1:2: CD011419.Google Scholar
  66. 66.
    Aggarwal N. Local anesthetics systemic toxicity association with exparel (bupivacaine liposome) - a pharmacovigilance evaluation. Expert Opin Drug Saf. 2017;5:1–7.Google Scholar
  67. 67.
    Zhang L, Wang J, Chi H, Wang S. Local anesthetic lidocaine delivery system: chitosan and hyaluronic acid-modified layer-by-layer lipid nanoparticles. Drug Deliv. 2016;23(9):3529–37.CrossRefGoogle Scholar
  68. 68.
    Jang YJ, Lee JH, Seo TB, Oh SH. Lidocaine/multivalent ion complex as a potential strategy for prolonged local anesthesia. Eur J Pharm Biopharm. 2017;115:113 – 21.CrossRefGoogle Scholar
  69. 69.
    Suzuki T, Tobe M, Obata H, Tabata Y, Saito S. Efficacy and duration on analgesia from a sustained-release lidocaine sheet in humans. Int J Drug Deliv. 2014;6(1):75–81.Google Scholar

Copyright information

© Japanese Society of Anesthesiologists 2018

Authors and Affiliations

  1. 1.Department of AnesthesiologyGunma University Graduate School of MedicineMaebashiJapan

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