Introduction of the First Injectable Anesthetic

Date 1905

Novocaine—the trade name for procaine—was synthesized by the German chemist Alfred Einhorn and introduced by the German surgeon Heinrich Braun. It was the first injectable synthetic anesthetic to be used safely in surgery and became the most frequently used local anesthetic in dentistry and minor surgical procedures.

Locale Germany

Key Figures

• Alfred Einhorn (1857-1917), German medicinal chemist
• Heinrich Braun (1862-1934), German surgeon
• Paul Ehrlich (1854-1915), German physician and biochemist
• Karl Koller (1857-1944), Austrian ophthalmologist
• William Stewart Halsted (1852-1922), American surgeon
• Robert Heinz (1865-1924), German pharmacologist and pathologist
• Richard Willstätter (1872-1942), German organic chemist
• Guido Fischer (1877-1959), German dental professor
• August Karl Gustav Bier (1861-1949), German professor of surgery

Summary of Event

The applied science of local anesthesia dates from its discovery by Alfred Einhorn, a chemist at the University of Munich who found that esters of 4-aminobenzoic acid exhibit anesthetic properties. (An ester is a functional group in organic chemistry that results from the combination of an alcohol with a carboxylic acid.) Einhorn synthesized numerous variations of this chemical structure, and by 1905 he had submitted a compound for clinical trials that was to become the standard against which other local anesthetics were compared for nearly fifty years. This compound, Novocaine, has had a legacy so great that many still use its name as a generic term for all local anesthetics.

During the first half of the nineteenth century, scientists developed procedures to induce unconsciousness through use of general anesthesia, in which patients inhaled volatile or gaseous anesthetics such as diethyl ether, nitrous oxide (also known as laughing gas), and the highly toxic chloroform. Not all surgical procedures required an unconscious patient, however, so scientists sometimes employed local (or regional) anesthetics to numb specific areas of the body. These types of compounds have much more complex chemical structures, and they can be injected with a hypodermic syringe or applied topically as creams, lotions, or aerosol sprays. Cocaine was used as a topical anesthetic during eye surgery in 1884 by Karl Koller, a house surgeon at the Wiener Allgemeines Krankenhaus (Vienna’s general hospital), at the suggestion of his young colleague Sigmund Freud. Later that year, William Stewart Halsted employed cocaine to produce the first nerve block by local injection. However, cocaine’s toxicity, cost, and addictive properties, in addition to the fact that the anesthesia it induced was of short duration, encouraged the search for a substitute.

Paul Ehrlich is credited as the first to relate the chemical structure of a molecule to its effectiveness as a medicine. To draw this connection, Ehrlich employed a multistep methodology common in medicinal chemistry: Isolate the active ingredient of a known herbal remedy or other medicinal of natural origin; determine its chemical structure, including stereochemistry (the three-dimensional arrangement of atoms); deduce the simplest portion of this chemical structure that retains the physiological effect; and use sequential chemical reactions to prepare derivative compounds for pharmacological testing.

In 1860, pure cocaine was isolated as the active principle in leaves of the Erythroxylon coca bush by Albert Niemann, a graduate student working in the chemistry laboratory of Friedrich Wöhler at Göttingen University. Alfred Einhorn proposed in 1890 that the portion of the cocaine molecule promoting anesthetic activity was a benzoate ester moiety, and he proceeded to prepare a series of analogs containing this anesthesiophoric unit. In 1896, Robert Heinz found one of these compounds, methyl 4-amino-3-hydroxybenzoate, to be an effective local anesthetic during clinical trials; it was subsequently marketed by the German chemical company Farbwerke Höchst under the trade name Orthoform. Unfortunately, Orthoform possessed very limited solubility in water, so it was administered as a powder into open wounds. In 1900, E. Ritsert at Farbwerke Höchst submitted another topical anesthetic for clinical trials called benzocaine (ethyl 4-aminobenzoate); this compound remains a popular ingredient of throat lozenges.

The complete chemical structure of cocaine was finally established in 1898 at the University of Munich by Richard Willstätter, a former student of Einhorn and Nobel laureate in 1915. Einhorn modified the structures of his target benzoate esters so that they more closely resembled cocaine and received a patent titled “Verfahren zur Darstellung von p-Aminobenzoësäurealkaminestern” on November 27, 1904. His patent described the synthesis of eighteen alkylamino esters of 4-aminobenzoic acid prepared for Farbwerke Höchst. These compounds were tested at the Pharmacological Institute in Breslau, Germany (now Wroclaw, Poland), and the most promising one, procaine, was sent to Heinrich Braun at Leipzig for clinical trials in 1905.

Procaine (2-diethylaminoethyl 4-aminobenzoate) becomes water-soluble when converted to a hydrochloride salt. Braun observed that procaine hydrochloride caused much less tissue irritation than existing agents, but he noted that the resulting anesthesia was brief unless very strong solutions were employed. He also discovered that procaine’s effect was greatly increased when it was mixed with the hormone epinephrine (also called adrenaline) as a vasoconstrictor, narrowing the blood vessels. Another injectable synthetic anesthetic of similar molecular structure was Stovaine, which was prepared concurrently by the French chemist Ernest Fourneau in 1904, but it was found to be less potent and considerably more irritating.

Alfred Einhorn was associated with Farbwerke Höchst (formally called Meister, Lucius, and Brüning), a chemical factory at Höchst in Hesse, central Germany, which later became the industrial district of Frankfurt. Founded in 1863, the company began producing pharmaceuticals in 1883, and it was the first to manufacture procaine hydrochloride, which it marketed under the trade name Novocaine (meaning “new cocaine” and derived from the Latin novus plus caine). The overall safety, low toxicity, lack of irritancy, and efficacy when combined with epinephrine ensured that Novocaine would dominate the field of local anesthesia for nearly half a century. It was introduced in the United States in 1907 and popularized by Guido Fischer from the Königlich Zahnärztlichen Universitäts-Instituts (now the School of Dental Medicine at the Philipps University of Marburg), in Marburg, Germany. Fischer, with support from Farbwerke Höchst, made an instructional film in 1914 for use during lectures that demonstrated injection techniques for dental surgery to large professional audiences. With Richard H. Riethmueller, Fischer published the book Local Anesthesia in Dentistry (1912) in English.

Heinrich Braun published his influential Local Anesthesia: Its Scientific Basis and Practical Use in 1905 (the book went through seven editions in Braun’s lifetime), and, in 1909, Einhorn finally published the details of his synthetic procedures as a series of papers in volume 371 of Justus Liebig’s Annalen der Chemie und Pharmacie. August Karl Gustav Bier, a professor of surgery at the University of Berlin and pioneer of spinal anesthesia, employed Novocaine in 1908 to cause a loss of feeling in an entire limb using the new technique of intravenous-regional anesthesia (now referred to as Bier’s block). Einhorn promoted surgical applications of Novocaine until his death in 1917, and he especially encouraged its use for amputations and other procedures necessitated by the wounds suffered by soldiers during World War I. He was dismayed, however, that military field surgeons were reluctant to employ Novocaine. Dentists embraced it with enthusiasm, but Einhorn felt that dental drilling and tooth extraction were mundane applications of his noble innovation. Eventually, Novocaine was displaced by Xylocaine (the trade name for lidocaine) and other anesthetics.

Significance

Prior to the introduction of anesthesia, patients had been tied down or otherwise immobilized on operating tables while surgeons rushed to perform nightmarish procedures. Only crude techniques were possible under these conditions, and barbers’ razors were as likely to be used as medical doctors’ knives. The availability of effective and reliable anesthetic agents gave relief to patients and also allowed for the development and expansion of techniques and procedures in surgery and dentistry.

The development of Novocaine also played an important role in fostering the emergence of the modern pharmaceutical industry, which originated in the synthetic-dye factories established in Germany during the 1860’s. Companies such as Farbwerke Höchst developed working relationships with research scientists at universities, and this led to several important medical advancements. Much of the credit for achievements in the field of pharmaceuticals prior to World War I is owed to collaborations with recipients of the Nobel Prize in Physiology or Medicine such as Emil von Behring (1901), Robert Koch (1905), and Paul Ehrlich (1908).

Bibliography

Burger, Alfred, ed. Medicinal Chemistry. 3d ed. New York: Wiley-Interscience, 1970. Chapter 63 extensively covers the primary literature of Einhorn’s contemporaries, unlike subsequent fourth (1981), fifth (1997), or sixth (2003) editions.

Burnham, Bruce S., Iris H. Hall, and Alex Gringauz. Introduction to Medicinal Chemistry: How Drugs Act and Why. 2d ed. New York: Wiley-Interscience, 2006. The chemistry, pharmacology, and history of anesthetics are included in this update to the 1997 edition by Alex Gringauz.

Dunsky, Joel L. “Alfred Einhorn: The Discoverer of Procaine.” Journal of the Massachusetts Dental Society 46, no. 3 (Fall, 1997): 25-26. A rare article focusing on Einhorn’s contribution to anesthesiology.

Lasslo, Andrew. Molecules, Miracles, and Medicine. St. Louis, Mo.: Warren H. Green, 2000. Procaine is one of eight common drugs whose histories are summarized.

Ruetsch, Yvan A., Thomas Böni, and Alain Borgeat. “From Cocaine to Ropivacaine: The History of Local Anesthetic Drugs.” Current Topics in Medicinal Chemistry 1, no. 3 (August, 2001): 175-182. A review article with ninety-seven references on both classic and modern anesthetics.

Sneader, Walter. Drug Prototypes and Their Exploitation. New York: John Wiley & Sons, 1996. Structure-activity relationships of local anesthetics are included in chapters 18 and 19.

Vertosick, Frank T. Why We Hurt: The Natural History of Pain. New York: Harcourt, 2000. A physician presents a broad review of the subjects of pain and pain management.