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A History of Patient Comfort (Part III): Comfortably Numb

February 1, 2013
by Peter Nkansah, M.Sc., DDS, Dip. Anaes., FADSA, Specialist in Dental Anaes. (ON)


One of the facets of dentistry that makes it unique in the field of healthcare is the ability to anaesthetize whatever tissues we are working on. This was not always reliably true, which in addition to the fact that our jobs take place in a highly personal, sensitive area of the body, has contributed to our less-than-favourable reputation with the general public. If the discovery of general anaesthesia was the most important advance in medicine ever, which has been suggested, then the discovery of local anaesthesia is probably the most significant one in dentistry.

Cocaine in the form of coca leaves was first used by South American Indians as long as 5000 years ago.1 They chewed the coca leaf to extract the cocaine for its central nervous system effects. Erythroxylum coca is the plant that contains the highest concentration of cocaine and has historically been grown in Nicaragua, Venezuela, Bolivia and Peru.2 The effects were first described in writing by Pedro Cieza de Leon in Spain in 1532 when he discussed the habit of leaf chewing by the Peruvian Indians in order to provide exhilaration as well as the energy to work at high altitudes for long periods of time.2,3 Although the leaves were introduced to Europe shortly afterwards, interest was lukewarm, in part because the leaves would lose much of their potency when dried for transport. They had a use on their native soil though, since after the Spanish conquest of South America in 1492, workers were needed there to mine silver. While “coqueros” (coca chewers) were formerly linked to the aristocracy of the Incas, they became more common with the increased labour demands from the Old World.4

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The isolation of cocaine as a compound in 1859 by Albert Niemann and Fredrich Gaedicke in Germany added to the growing list of alkaloids to be used for therapies. Its chemistry was not simple, and in fact was not completely known until 1898. Experimentation with cocaine started in 1868 as part of doctoral thesis by Thomas Moreno y Maïz in Paris. Even though it was noted that cocaine injections could cause insensitivity in rats, guinea pigs and frogs, he did not appear to use it in his experimental surgeries on these animals. That advance was made in 1880 by Basil von Anrep at the University of Würzburg (Germany) when he injected a small amount of cocaine solutions under the skin of his arm and found that the injected area did not feel needle jabs. The same was true when he topically applied weaker solutions to his tongue. It was finally noted that cocaine could and should be used as a surgical anaesthetic.2 In 1883, Theodor Aschenbrandt, while working as a doctor in the German army gave cocaine to soldiers during maneuvers. He found that there was the beneficial effect of diminishing fatigue. Aschenbrandt and von Anrep may have known each other, as they were both working under the supervision of the highly-respected pharmacist Joseph Rossbach at the University of Würzburg in 1881 and 1882. Whether they collaborated or not, Aschenbrandt was certainly aware of von Anrep’s previous findings. All of this fascinated one Sigmund Freud.1

Sigmund Freud began experimenting himself with cocaine, initially to examine its fatigue-suppressing effects, then as a self-treatment against depression and indigestion.4 Later he used it in the treatment of a colleague suffering from morphine addiction. To say that Freud was enthusiastic about cocaine would be an understatement. He wrote a long letter to his fiancée about the virtues of this “magical drug” as well as a monograph (“Ueber Coca”) about it in 1884.1,5 Freud also shared his experiences as well as samples of this “miracle” with his friends, among them, his medical school classmate Carl Koller.

Carl Koller was hoping to gain a position in the ophthalmologic department at the Vienna Clinic of Ophthalmology. One of the most common operations of the day was the removal of cataracts for which the new discovery of general anaesthesia was not particularly applicable because of the incidence of post-operative nausea and vomiting, which would ruin the surgery as the increased pressure in the orbit would tear the sutures (if placed) out.5 Further, the anesthesia equipment of the day created a physical impediment to accessing the surgical field, so the surgeries tended to proceed without anesthesia.1 Understandably, this was not a procedure that either the patient or the surgeon would want to redo. Koller’s experimentation progressed from frogs to rats to dogs and then to himself and his colleagues. His experiments included swallowing cocaine, which numbed his tongue. This effect had been noted by others and was prescribed as a treatment for painful conditions of the pharynx and larynx. Koller sought to extend this application to the eye, and began to develop an aqueous solution for this purpose.1 On September 11, 1884, Koller performed the first ophthalmologic surgery using a local anaesthetic. Later, Dr. Koller would be called the “father of local anaesthesia”.3

Immediately following this success, Koller prepared a presentation for the German Ophthalmological Society Conference, which was to start in only 4 days. Koller did not have the money to travel to Heidelberg for the meeting, but his friend, Dr. Josef Brettauer, delivered the paper for him. A live demonstration of the described technique was also performed on a dog for the conference audience.1,2,5,6 That audience included Dr. Henry Noyes from New York who immediately reported what he had seen in an open letter to The Medical Record (also referred to as the New York Medical Record). His letter was published exactly 1 month after Koller’s successful surgery. On October 17th, Dr. Koller presented his own findings to the Medical Society of Vienna, and published his article in the Wiener Medizinische Wochenschrift on October 25th.2

News, excitement and controversy about this breakthrough quickly spread throughout the healthcare world. Cocaine’s previous uses had been mostly limited to Vin Mariani (an all-purpose tonic wine marketed by a chemist, Angelo Mariani) and the treatment of some addictions.4 Now its testing grounds included ophthalmology, urology, general surgery and dentistry.6 In a letter dated November 26, 1884 to the New York Medical Journal Dr. Richard John Hall wrote that he and his friend, Dr. William Stewart Halsted, with the aid of Hall’s dentist, Dr. Nash, injected cocaine close to the infraorbital foramen for the purpose of restoring tooth 11. This tooth had previously been very sensitive to manipulation, but after the injection there was complete anaesthesia of the tooth, as well as the upper lip and the cheek.5 As an aside, the hypodermic needle had recently been developed separately but almost simultaneously by both Dr. Charles Gabriel Pravaz in 1853 (a veterinary surgeon in Lyon, France) and Dr. Alexander Wood in 1855 (a physician in Scotland) and was consistently being improved upon.2

In 1884, Dr. W.S. Halsted was a successful surgeon in New York City. He had received an “intellectual baptism” during a medical tour through Berlin, Halle, Zurich, London and Vienna, where was exposed to Lister’s carbolic (antiseptic) sprays, Volkmann’s early attempts at new cancer surgeries and Billroth’s ground-breaking, miraculous abdominal surgeries.7 Halsted had a reputation as a daring and original surgeon, a tireless worker and an inspiring teacher.6 By December 1884, he was a member of “a body of gentlemen” who, as described in an editorial by Dr. George F. Shrady in The Medical Journal, were experimenting with the effect of injected cocaine “when applied directly to the sensory cutaneous nerves”.6

The newfound art of nerve block (regional) anaesthesia was used, taught and reported on by Hall and Halsted. While the experimental and surgical results were spectacular, no less striking was the dark side of cocaine, particularly the risk of addiction and the lure of
money for those who manufactured and distributed the drug. An editor’s comment accompanying the first report by Hall noted that the drug should not be considered innocuous, a sentiment that was certainly held to be true as the drug’s experimenters often became addicts.8,9 And so it was, through trial and error and self- and peer-experimentation that the inferior alveolar nerve block came into being. Halsted and Hall described nerve blocks of the cubital nerve, the anterosuperior alveolar nerve, the inferior alveolar nerve and the lingual nerve in an 1884 article appearing in the New York Medical Journal. The technique, also known as the Standard block or the Halsted technique is basically the same today as it was described then.

Cocaine truly represented a double-edged sword for healthcare. It was a drug that was capable of so much good and so many truly awful consequences at the same time. Cocaine addiction cost Halsted dearly. His only published report on cocaine, from September 12, 1885, was a rambling, incoherent mess presented as a rebuttal to another physician who had failed to duplicate Halsted’s success. The opening sentence read: “Neither indifferent as to which of how many possibilities may best explain, nor yet at a loss to comprehend, why surgeons have, and that so many, quite without discredit, could have exhibited scarcely any interest in what, as a local anaesthetic had been supposed, if not declared, by most so very sure to prove, especially to them, attractive…”, which takes you to about the halfway point in that sentence.10 In this letter he repeatedly referred to a more comprehensive report on cocaine that was never published. By 1889, cocaine (and morphine) had cost Halsted his practice in New York. This after several tries at rehabilitation, first with a sea voyage (widely viewed to be therapeutic for those who could afford it), then with 2 stays at the Butler sanatorium in Providence, Rhode Island (where exercise, a healthful diet, combined with alcohol, chloral hydrate and morphine were prescribed for agitation and insomnia), he joined the pathology lab at Johns Hopkins Hospital in Baltimore.7,11 It is likely that he never completely escaped his addictions to morphine and cocaine, still, under the watchful eye of his new friend and new employer, Dr. William Welch, Halsted was able to work his way up from creating new surgical techniques on dogs to surgeon-in-chief, then to (the first) Professor of Surgery at Johns Hopkins in 1892.6,11 As influential as Halsted was to dentistry, he may have had a greater impact on medicine, specifically breast cancer surgeries. This is very well described in Dr. Siddhartha Mukherjee’s fascinating book, The Emperor of All Maladies: A Biography of Cancer.

For a time in the late 1800s, cocaine was a star. It was not illegal. Sherlock Holmes used it, as did his author, Sir Arthur Conan Doyle.12 In fact, as mentioned earlier, it was the medicinal ingredient in Vin Mariani. It was also the medicinal ingredient in “the real thing”: Coca-Cola. Dr. John Styth Pemberton’s original recipe in 1886 included cocaine, which made the product medicinal. It was promoted as a “temperance” drink offering the virtues of coca without the vices of alcohol, as in the coca wines.4 However, by 1906, Coca-Cola was using decocainized leaves; the ingredients of the drink still include a nonnarcotic coca leaf extract. Elsewhere, cocaine and morphine were used to treat addictions to each other. Cocaine could be bought over the counter as a powder, in cigarettes, in tonics, toothache cures, chocolate cocaine tablets, even as an injectable, complete with its own needle.4 But between 1884 and 1891, 200 cases of systemic intoxication including 13 deaths were reported in the U.S. in healthcare.13 Part of the problem was the lack of a formula for the preparation of injectable cocaine. Concentrations of the drug varied between 1% and 10%.12 By the turn of the century, the addictive properties of cocaine were well-known, which led to its inclusion in the Harrison Narcotics Tax Act in 1914 in the U.S. which did not prohibit cocaine or opioids, but greatly reduced their general availability.4

Cocaine’s toxicity, addictive potential and tissue irritation spurred a search for a safe, effective alternative. In Germany, chemist Alfred Einhorn and others were hard at work to determine the chemical structure of cocaine in order to isolate the desirable anaesthetic properties without the adverse effects. First came the eucaines (A and B), then stovaine, then butyn and alypin, then monocaine, none of them was suitable for clinical use.14 However, in 1904, the search was rewarded as Einhorn patented 18 different para-aminobenzoic derivatives; compound number 2 was procaine hydrochloride: Novocain(e).2,12 In the first article about Novocaine by Professor Heinrich Braun in 1905, it was touted as effective, non-irritating and without “toxic side effects” (translated from German).12 This ended up not being exactly true though as it was allergenic to a noticeable portion of the population. Procaine is also a good vasodilator (as opposed to the vasoconstrictive property of cocaine) that would sometimes cause profound, even fatal decreases in blood pressure after infiltration.2,3,12 This was overcome by including epinephrine in the preparations. The early concentrations of epinephrine were 1:20,000, but the standard soon became 1:200,000. Standardization for the dose of Novocaine presented another challenge for practitioners. Originally, procaine was distributed in powder or tablet form, which had to be mixed in distilled water when needed.12 This was inconvenient, to say nothing of inaccurate but it was the only option as stock solutions degraded and became non-sterile quickly.14 Two advances created the pathway to easy practitioner acceptance. The first was the creation the anaesthetic cartridge by Dr. Harvey S. Cook in 1920. Cook was an army physician during World War I who faced the challenge of treating the troops with minimal delays. Inspired by the bullet cartridges of army rifles, Cook cut the glass tubes by hand, created stoppers out pencil erasers, filled the cartridges and loaded them into a brass syringe with a double-pointed needle in place so that he was ready to go the next day.12,14 The second advance was the creation of a stable, isotonic procaine solution that contained mineral salts by Dr. R.B. Waite. This, along with manufacturing advances, allowed mass production and distribution of effective and easy-to-use local anaesthetics to healthcare practitioners via the Antidolor Manufacturing Company.12 Its effect on society is still felt today with “novocaine” being a universally understood generic term for local anaesthetics in dentistry.

The modern, amide local anaesthetics were first settled upon in 1947, when after three years of testing by Dr. Nils Löfgren, Bengt Lundqvist and Dr. Torsten Gordh at the Institute of Chemistry at Stockholm University (Sweden), “LL30” (soon to be named lidocaine) was submitted for registration in Sweden by Astra AB.15,16 “Xylocaine” was named after the xylidine (or xylene amine) nucleus in its chemistry. The list of advantages over procaine was long: it could be sterilized; it was water-soluble; it was stable when mixed with epinephrine; it did not appear to be allergenic; it had a faster onset and produced more profound numbing.15,16 In January 1948, Xylocaine was launched in Sweden coincident with published articles on its safety and effectiveness. Later that year, Xylocaine was introduced to North America.15 Its adoption into dentistry was immediate; for a variety of reasons the medical community did not really embrace regional anaesthesia until the 1970s.

After the introduction of lidocaine to the market, other amide local anaesthetics soon followed. In 1956, mepivacaine was synthesized by Bo af Ekenstam, who also synthesized bupivacaine in 1957. Löfgren and Cläes Tegner synthesized prilocaine in 1959. The stable o
f commonly-used current local anaesthetics was rounded out when Ruschling, Muschaweck and colleagues synthesized articaine in Germany in 1969.2,3

Research goes on, as we search for faster, safer, more reliable, less-acidic local anaesthetic agents and preparations. Recent history has served us well, as we can now treat our patients without pain in most situations. Now, if we could only eliminate the element of fear … we’ve come a long way there too, but that is a story for another day.OH

Dr. Nkansah is a specialist in Dental Anaesthesia with a private practice in Toronto. He is a member of the editorial board of Oral Health and is an educator with the University of Toronto, Western University and Sunnybrook Health Sciences Centre.

Oral Health welcomes this original article.

Part II appeared in February 2012.

Part I appeared in the 100th anniversary issue of Oral Health, Fall 2011.

REFERENCES
1. Goerig M, Bacon D, van Zundert A. Carl Koller, Cocaine, and Local Anesthesia. Regional Anesthesia and Pain Medicine. 2012; 37(3):318-324.

2. Calatayud J, Gonzalez A. History of the Development and Evolution of Local Anesthesia Since the Coca Leaf. Anesthesiology. 2003; 98:1503-1508.

3. Malamed SF. Local anesthetics: Dentistry’s most important drugs. JADA. 1994; 125:1571-1576.

4. Goldstein RA, DesLauriers C, Burda AM. Cocaine: History, Social Implications, and Toxicity – A Review. Dis Mon. 2009; 55:6-38.

5. Leonard M. Carl Koller: Mankind’s Greatest Benefactor? The Story of Local Anesthesia. Journal of Dental Research. 1998; 77(4):535-538.

6. Olch PD. William S. Halsted and Local Anesthesia: Contributions and Complications. Anesthesiology. 1973; 42(4): 479-486.

7. Mukherjee, S. Part One: “Of blacke cholor, without boyling”. In: The Emperor of All Maladies: A Biography of Cancer. Toronto: Scribner; 2010. p. 9-104.

8. López-Valverde A, De Vincente J, Cutando A. The surgeons Halsted and Hall, cocaine and the discovery of dental anaesthesia by nerve blocking. British Dental Journal. 2011; 211(10): 485-487.

9. Nunn, DB. Dr. Halsted’s Addiction. Johns Hopkins Advanced Studies in Medicine. 2006; 6(3): 106-108.

10. Halsted, WS. Practical comments on the use and abuse of cocaine. New York Medical Journal. 1885; 42: 294-295.

11. Markel H. The Accidental Addict. The New England Journal of Medicine. 2005; 352(10): 966-968.

12. Ring ME. The History of Local Anesthesia. California Dental Association Journal. 2007; 35(4): 275-282.

13. Anonymous. Cocaine. British Medical Journal. 1979 April 14; 1(6169): 971-972.

14. Archer, WH. The History of Anesthesia. 1940; Proceedings of the Dental Centenary Celebration pp.334-363.

15. Holmdahl, MH. Xylocain (Lidocaine, Lignocaine), its discovery and Gordh’s contribution to its clinical use. Acta Anaesthesiologica Scandinavica. 1998; 42 (Supp. 113): 8-12.

16. Gordh T, Gordh TE, Lindqvist K. Lidocaine: The Origin of a Modern Local Anesthetic. Anesthesiology. 2010; 113: 1433-1437.


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