by Andrew I Spielman

How to cite this page: Spielman, AI. History of Dental Anesthesia. In: Illustrated Encyclopedia of the History of Dentistry. 2023. https://historyofdentistryandmedicine.com/

Local anesthesia

The history of local anesthesia involves three separate inventions: the pharmacological agent, the local anesthetic, the syringe, and the hollow needle. Each evolved separately and has its history. They were assembled for the first time in 1853 as a syringe with a needle and in 1880 in combination with cocaine as the first anesthetic injected locally.

Before injectable local anesthetics, throughout history, they were used as topically applied anesthetics. Applied onto the skin, the mucosal surface, or the tooth itself, they achieved some degree of anesthesia. Almost all of them were naturally occurring herbal products.

Herbal remedies

Dental pain has been in our consciousness ever since we were aware that we have teeth. Literature reflects a constant preoccupation with dental pain. St. Augustin, in his Confessions, laments that dental pain prevented him from being able to speak. Shakespeare’s Leonato in Much Ado About Nothing states, “For there was never yet philosopher, that could endure the toothache patiently”, and George Bernard Shaw makes clear that “to the person with a toothache, even if the world is tottering, there is nothing more important than a visit to a dentist.” (1)

Treatment of dental pain found solutions in superstition, prayers, and anointing saints (St. Appolonia) on the one hand and in herbal medicine and in chemicals that were ingested, applied locally, injected, or inhaled on the other. This section will focus on the natural (herbal) and chemical mitigation of dental pain throughout history.

One describes the same story by discussing the history of herbal anesthetics or toothache. Ever since one had a toothache, one tried to find a medicinal solution to blunt it. Chance observation led to the more targeted use of natural products, and if one considers alcohol as an agent to dull one’s agony, pain may have contributed to the dawn of agriculture (2).

Traditional herbal medicine such as Chinese, Ayurvedic, and Unani (India), Kampo (Japanese), Korean and Sasang (Korean constitutional medicine), Aboriginal (Australia), traditional medicine in Africa, or Russian herbal medicine all have preparations for pain. (3,4).

Scribonius Largus (1 CE? -50 CE?), personal physician to Emperor Claudius, compiled a list of herbal medicine, De Compositione Medicamentorum Liber that includes remedies for toothache such as

potentilla (cinquefoils) extraction mixed with wine. Cinquefoils have an astringent, anti-hemorrhagic, anti-ulcer, and pain-killing effect. (5).

Figure. Timeline of herbal remedies as anesthetics. ©Spielman

Dioscorides (40-90 A.D.), a Greek army surgeon, suggested a mouthwash with a mixture of medicinal components boiled in vinegar containing a mix of henbane roots (hyoscyamine), Jerusalem oak, marshmallow, pellitory, nutmeg-flower, plantain, capers among others. The medicinal use of plants was well known to Dioscorides (6), who published a 5-volume Materia medica containing detailed descriptions of 1000 drugs of plant, animal, and mineral origin (7). Many of the subsequently published herbal medicine books of Galen, Oribasisus, Celsus, Rhazes, Albucasis, Avicenna, and Mesue all were based on Dioscorides (7).

In the mid15c. Bartholomæus Montagnana of Padua (1400-1460) recommends a mouthwash solution of camphor boiled in vinegar and kept in the mouth to reduce toothache (“Camphoræ modicum, in aceto bulliat parum: deinde teneat æger in os, valet ad omnem dentis dolorem”) (8).

The search for better and more complex mixtures as remedies was not unusual for Peter Forestus (1521-1597), the Dutch Hippocrates. His concoction included a spoonful of long pepper, chrysanthemum, and staphisagria (larkspur), crushed in honey and alcohol, mixed over hot ashes, and placed into the tooth (9). Forestus still believed that an ear infusion with hot castor seed oil on the affected tooth was helpful. (10). This method was steeped in the humoral theory of Hippocrates and applied using opposites. The infusion of the hot castor oil was supposed to induce a discharge of mucus which would get rid of the excess cold humor causing the dental pain. (11)

In 1557, for toothache in children, Benedicti Leonello Victtori Faventini recommended the local application of opium on a semi-cooked and cooled egg yolk. (12) Egg yolk also appears in a recipe for dressing of the arquebus (musket) gunshot wounds on the battlefield. It was made by Ambroise Paré (1510-1590), the barber-surgeon to four French kings, when he ran out of hot oil, the recommended treatment to remove the “toxic effect” of gunpowder. He improvised a recipe containing turpentine oil (oleo teribinthini) mixed with rose oil and egg yolk. Paré was a practicing barber-surgeon, and when not on the battlefield, he applied this mixture as a filler and disinfectant of dental cavity. Turpentine oil was made of oleoresin from pine trees and had the semisolid consistency of a resin-like substance. When placed into a dental cavity, it sealed the pulp, had antiseptic properties, and reduced dental pain (13).

By the late 1500s, Martin Ruland the Elder (1532-1602), a German physician, applied camphor oil directly onto the open pulp chamber (14), a remedy that Roderigo de Fonseca, a Portuguese physician highly praised for dental pain (15). Fonseca added his mixture of oil of boxwood and oil of camphor, a drop placed into the opening of the tooth, repeated as needed; it removed pain to the “point of a miracle” (16).

One of the most enduring preparations for dental pain was clove oil mixed with oil of camphor and dropped into an opening of the dental cavity. Nutmeg, which contains clove oil among many herbal medicines, was considered powerful enough to ward off the plague. It was highly prized as a spice and source of herbal remedies. As part of the Treaty of Breda in 1667 between the Dutch and the British, the Dutch, who dominated the spice trade in the 17th century, gave up the claim of the island of Manhattan to the British in return for the spice island of Run. In essence, nutmeg is the reason Manhattan speaks English today and not Dutch.

Clove and camphor oils were part of the pain-relieving mixture Johannis Hartmann, a German physician, recommended in 1632 (17). A century later, Lorenz Heister (1683-1758), another celebrated German anatomist, botanist, and surgeon, suggested both extractions and herbal medicine for toothache. These include pepper, clove oil, guaiacum tree extract either internally or applied with a brush onto the tooth, or opium and camphor pills placed inside the dental cavity (18,19).

The painkilling effect of opium was well known from antiquity, but their related refined chemicals, such as morphine and cocaine, were only discovered in the 19th century. In 1806 Friedrich Wilhelm Sertuerner isolated an alkaloid of opium and, because of the dreamy state it could induce, named it “morphium” for the Greek god Morpheus. The name was subsequently modified to morphine. Cocaine was isolated from poppy seeds in 1855 by Friedrich Gaedcke and in a more purified form in 1860 by German chemist Albert Niemann. This was followed by its first use in 1884 by Carl Koller, a Viennese ophthalmologist. Until restricted by the Harrison Act of 1914, cocaine was very popular and used as a topical anesthetic or placed into drinks like Coca-Cola. Cocaine hydrochloride mixed with equal parts menthol and phenol was a highly effective solution for a painful tooth. This mixture was initially formulated in 1898 by Jules-Aristide Bonain, a French physician, as a topical anesthetic for the external auditory canal (20). Sold under Bonain’s Liquid, it found immediate dental application for acute pulpitis. Currently, topical anesthetics used in dentistry contain 20% benzocaine gel and 5% lidocaine cream.

Hyson
Wadley
Yuan
Zheng
Scribonius p.40
Dioscorides p.551
Prinz
Burnet p.274
Forestus p.217
Burnet (b) p.274
Birk p.37
Faventini p.78
Burnet (c) p.274
ibid (d) p.275
Fonseca p.165D
Burnet (e) p.275
Hartmann p.120
Heister p.174-175
Shklar and Chernin p.73
Bonain

Injectable anesthetics

The first breakthrough in injectable anesthesia came in 1656 when Sir Christopher Wren (1632-1723), a British architect, scientist, and physician, and the Honorable Robert Boyle (1627-1691), the chemist, injected wine and ale into the vein of a large dog. They used a syringe made of animal bladder, attached to a goose quill as a needle. The outcome was that the dogs became drunk, demonstrating the effect of alcohol and how blood circulation, freshly described by William Harvey, worked in practice. (1).

Just over a decade later, in 1667, Johann Sigismund Elsholtz (1623-1688), a physician in Berlin and an ardent supporter of William Harvey, described intravenous injection with a syringe (a form of enema) and reported the feasibility of blood transfusion from animals to humans (2-6). That same year, Jean Baptist Denys, the court physician to Louis XIV, performed transfusions, from animals, calves, and sheep, to humans in the hope of conferring the calm characteristics of the donor animal to the recipient. Denys subscribed to the theory of “vitalism” that purported that blood carried personal characteristics from a meek animal to a human needing calming. Denys could not have known about blood groups, a discovery awaiting Karl Landsteiner in 1900. The death of one of Denys’ patients and the subsequent high-profile trial that eventually acquitted him led to a ban on blood transfusions and set back transfusions for centuries. The tools for transfusion, a primitive form of a syringe, however, survived.

Although a precursor of the modern syringe was known since Ancient Egypt and used for tissue irrigation, the syringe as a pressing device behind the principle of hydraulic lifting in a confined space (Pascal’s Law) was invented by the French polymath Blaise Pascal in 1650. The modern (stiletto) syringe using Pascal’s Law was created in 1827 by A. von Neuner, chief physician of Darmstadt, Germany (7). This was perfected by the Luer German instrument maker, that became the dominant force in the 19th c. market. In 1906, Guido Fischer, a German dentist, created a new design, the “Fischer syringe,” with a better seal. The “cartridge” syringe we use today was developed by Harvey Samuel Cook, an army surgeon, in 1917.

With the syringe developed, what was still missing was the hollow needle. The first subcutaneous injection of morphine was made by Francis Rynd (1801-1861), an Irish physician who developed a hollow steel needle. Up to that point, drugs were delivered orally or topically. He published using his invention on March 12, 1845, in the Dublin Medical Press, but the article only states that supraorbital neuralgia was treated by “four punctures of an instrument made for the purpose” (8). Eight years later, in 1853, Charles Gabriel Parvaz (1791-1853), a French surgeon, and Alexander Wood (1817-1884) of Scotland, independently came up with the idea of a fine bore needle attached to a syringe to deliver small amounts of morphine (9,10). This was the first proper hypodermic syringe as we know it today.

With both syringes and needles available, the first use of cocaine as a local anesthetic (anecdotally) was used in 1864 during the American Civil War(10). Officially, on November 26, 1884. Charles Nash, a dentist, was the first to anesthetize the infraorbital nerve of Richard J. Hall, a surgeon at Roosevelt Hospital in New York, while working painlessly on an upper incisor. That same year, in November 1884, William S. Halsted (1852-1922), a surgeon at Johns Hopkins University Hospital in Baltimore, performed the first mandibular nerve block using a 4% solution of cocaine.

Figure. Timeline of local anesthetic, syringe and needle. ©Spielman

One of the first local anesthetics was Amylocaine (Stovaine), synthesized in 1903 by Ernest Fourneau (1872-1949) (fourneau = stove in English) at the Pasteur Institute. It was first used in 1904 for local anesthesia and epidural injections. The very next year, it was replaced by Procaine (Novocaine), a better anesthetic used for both local and regional anesthesia.

The effect of the local anesthetics was short-lived, though, and it diminished as blood circulation diluted and removed the active ingredient from the operation site. To increase the anesthesia time at the injected site, Heinrich Braun, a surgeon in Leipzig, 1903, came up with the idea of mixing the anesthetic with the newly isolated suprarenal hormone, adrenalin which caused vasoconstriction (11). When the synthetic version of adrenalin was synthesized by Frederich Stolz at Farbwerke Hoechst, the longer-lasting local anesthetic was born. Epinephrine (Suprarenin) isolated in 1901 by the Japanese scientist Jokichi Takamine (12), became marketed in 1906 as a vasoconstrictor by the German pharmaceutical company Hoechst.

A more widely used local anesthetic, Procaine (Novocaine), an aminobenzoic ester, was synthesized by German chemists Alfred Einhorn (1856-1917) in 1905 (13). It was the only local-regional anesthetic used until 1943 when Lignocaine (Lidocaine) was synthesized by the Swedish chemist Nils Löfgren (1913-1967) and clinically tested by Thorsten Gordh (1907-2010) as a substitute to avoid allergic reactions Novocaine induced in about 8% of the population (14). That same year, Novocaine was first used by Heinrich Braun (1862-1934), a German surgeon. It was safer and non-addictive, unlike cocaine. Recent additions to local anesthetics include bupivacaine (1963) and ropivacaine (1993).

1. Jardine p.122
2. Elsholtz p.21
3. Gladstone (a) p.432,
4. ibid (b) p.45
5. ibid (c) p.119
6. ibid (d) p.190
7. Neuner p.480
8. Rynd p.29-30
9. Wood p.266-7.
10. Bennion p.106
11. Braun
12. Takamine
13. Einhorn
14 Gordh

General anesthesia

Throughout the history of surgical interventions, a variety of compounds, topical, local, or inhalation anesthetics were used to reduce pain, including dental pain, but the most evident division of its timeline is before and after 1846, when the first ether anesthesia was publicly demonstrated at Mass General Hospital on a patient undergoing surgery to remove a lump from his neck. Before October 16, 1846, various techniques, solutions, and agents were used, including alcohol, hemlock, carbon dioxide, nitrous oxide, chloroform, and even compression.

One of the earliest forms of general anesthesia was performed by Egyptians. To reduce pain, they burnt cannabis and inhaled the fumes. The Greek military physician Dioscorides (AD 40-90) used drinks prepared from mandragora root (mandrake) to reduce pain during surgery. He was the first to use the word anaesthesia.

The Romans used a chemical reaction between calcium carbonate and acetic acid to generate carbon dioxide, which caused anesthesia if inhaled. In practice, the Romans took powdered Memphis marble and poured vinegar onto it, reaching the same end (1). Romans also used opium containing poppy juice, alcohol, and hellebore.

Hua Tao (Tuo), a physician during the Eastern Han Dynasty in the 3rd century CE, is credited to have been the first to use general anesthesia before surgery by administering a combination of wine and mafesian, a selection of herbs that made patients unconscious. (2).

Three individuals should get credit for the launch of general anesthesia in surgery: Horace Wells, a Connecticut dentist for nitrous oxide; William Thomas Green Morton, another dentist from Boston for ether anesthesia; and James Young Simpson of Scotland for chloroform.

Nitrous oxide (NO) was synthesized in 1776 by Joseph Priestley, an English chemist who isolated oxygen and carbon monoxide and was the inventor of the pencil eraser. During the first half of the 19th century, nitrous oxide, also known as laughing gas, was widely used for frolicking parties and public demonstrations where audience members were prancing around on stage while under the influence of NO.

In 1844, Horace Wells, a Connecticut dentist, observed such a public demonstration by Gardner Coulton. During the show, one spectator inflicted a large leg wound while on stage without any sign of distress. Convinced of his intuition that NO dulled the senses of the afflicted spectator, Wells invited Gardner Coulton to appear the next day at his office. There, with Coulton administering NO, Dr. Wells asked his colleague Dr. Riggs to extract one of his (Wells’) teeth. The extraction of the upper right molar went without any pain.

Emboldened by the outcome, Horace Wells approached the head surgeon of the Mass—General Hospital in Boston, Dr. John Collins Warren, for a public demonstration. Unfortunately, for unknown reasons, the operation did not go well. The outcry of the patient during surgery doomed the success of nitrous oxide for a while. There to observe the failure was William Thomas Green Morton, a part-time dentist, former medical student, and entrepreneur who decided to further explore using other general anesthetics. However, it took another two years before a new demonstration, this time with ether, could occur.

Ether Day – October 17, 1846. The administration of Letheon (Ether) by William Morton Green (standing with bottle in the foreground). John Warren, a surgeon at Mass General Hospital operating. Painting by Thomas Eakins.

Ether was known then as the sweet oil of vitriol (oleum vitrioli dulce verum. It was first introduced in 1540 by Valerius Cordus (1515-1544), a German physician. He synthesized ether by mixing sulfuric acid (vitriol) and pure ethyl alcohol (3). He describes the process as follows: “Equal parts of thrice rectified spirit of wine (ethanol) and oil of vitriol are allowed to remain in contact for two months, and then the mixture is distilled from a water or sand bath. The distillate consists of two layers of liquid, of which the upper one is oleum vitrioli dulce verum.” (4).

Not until 1842 was ether tested as an anesthetic in a surgical setting. Crawford William Long, a physician from Georgia, successfully performed surgical removal of a neck tumor under ether anesthesia. The same year, Elijah Pope, a dentist, removes a tooth painlessly using ether anesthesia. None of these interventions were recorded or published until after the public demonstration of using ether at Mass General Hospital on October 16, 1846, by William T.G. Morton. Morton decided to use ether based on a suggestion of his former professor at Harvard, Charles Jackson. Morton was looking to cash in on the invention. Ether, however, was already known. Deceptively, he masked ether with perfume, termed it Letheon, and devised a unique contraption for its administration. The head of the Mass General Hospital, Dr. Warren, agreed to a new demonstration that went flawlessly, unlike the Wells’ nitrous oxide incident. After surgery, Professor John Collins Warren declared, “Gentlemen, this is no humbug!” The successful operation opened a new era of painless surgery.

In 1849 Morton requested $100,000 from the US Congress for his discovery of ether anesthesia. A Congressional report on the subsequent investigation published in 1849 achieved three resolutions: 1. It was Dr. Jackson of Harvard, Morton’s previous teacher, who suggested to Mr. Morton that pure sulphuric ether may be inhaled with safety and that the effect of such inhalation is to produce insensibility to pain in the human body. 2. Morton (gets) the credit of having made the first practical application of sulphuric ether as an anesthetic agent. 3. (Congress) declines to recommend an appropriation of money (for Morton). (5)

Like a Greek tragedy, the three main protagonists in this discovery: Horace Wells, William T.G. Morton, and Charles T. Jackson, all had sad endings. Wells committed suicide in 1848, severing his artery under chloroform anesthesia. William Morton, mentally unstable, drowned in Central Park in 1868 after jumping in a pond, while Jackson ended up in an insane asylum and died in 1878.

In the decades after the ether demonstration, ether was also used as a topical anesthetic in dentistry. Sprayed onto the gingival mucosa, it achieved limited anesthesia during extraction. A small spray device was designed in 1866 by Benjamin W. Richardson (6), but the technique never took off.

The discovery of chloroform’s third primary anesthetic agent in 1831 is attributed independently to Samuel Guthrie (1780-1848) of New York and Eugene Soubeiron (1797-1858) of France. Just sixteen years later, James Young Simpson of Scotland demonstrated its use on himself. Chloroform was readily accepted in England, especially after Queen Victoria used it to ease childbirth pain in 1853 and 1857 when she delivered her eighth and ninths child, Prince Leopold and Princess Beatrice.

General anesthetics were not without controversies. For instance, in 1863, there were at least 163 death in England directly related to using chloroform (7). The dispute led to some hesitation. Some surgeons during the American Civil War operated without anesthesia. They allowed, however, the patient to have a bottle of brandy and bite on a lead bullet, hence the term “to bite the bullet” (8).

The next significant development in general anesthesia occurred in 1871 when Frederich Trendelenburg of Leipzig performed endotracheal (intubation) anesthesia. That step removed the danger of explosion and the imprecise nature of administering the anesthetic, but it required an incision through the trachea. Oral intubation became feasible only in 1903 as Franz Kuhn from Kassel developed a flexible tube that could be inserted through the oral cavity or nose. Robert Macintosh of Oxford, UK, added the curved laryngoscope blade in 1943.

As general anesthesia became widely used, the need to specialize in anesthesiology emerged, with the first residency programs appearing in 1927 at the University of Wisconsin in Madison.

The next breakthrough in the 1940s was the supplementation of inhalation anesthesia with intravenous sedation with injectable anesthetics. Curare was added as a muscle relaxant in 1942 by Lewis H. Right, who worked at Squibb Company. One of the more recent inhalation anesthetics is halothane, introduced in 1956 by the British Michael Johnstone.

Using general anesthetics in dentistry is limited to a subset of cases where local anesthetics would prove difficult to administer, the extent of the treatment would require excessive amounts of local anesthetic, or for patients with certain disabilities. The Society of Dental Anesthesiologists in the US was formed in 1953, while in the UK, in 1977. A certificate in general anesthesia in the US was launched in 1956 and a recognized specialty in 2004 (UK) and 2005 (US).

1. Buxton
2. Chen
3. Cordi p.229
4. Roscoe p.323
5. US Congress
6. Richardson
7. Florence p.10
8. Hyson p. 119

Dentin hypersensitivity

Dental pain related to hypersensitivity is a unique category in itself. Medieval texts advocate painkillers sometimes placed onto the tooth surface, presumably to reduce hypersensitivity. For instance, Lorenz Heister (1683-1758), a celebrated German anatomist, botanist, and surgeon, suggests herbal medicine for toothache. It included pepper, clove oils, and guaiacum tree extract applied with a brush onto the tooth (1). When dental pain and dentin hypersensitivity were delineated in the middle of the 19th century, the term used was “exalted sensibility,” which was re-coined twenty years later as “inflamed dentin”. Jonathan Taft, the namesake of Taft University, 1859 suggested the topical application of four categories of medications: tonics (Peruvian bark and gum myrrh), stimulants (tincture of capsicum), sedatives (opiates), and astringents (tannin). (2). Astringents, stimulants, and sedatives were considered anti-inflammatory. Among the topically applied solutions, Taft included tannin and tannic acid, an astringent solution known to precipitate in saliva due to salivary proline-rich proteins. Today, we know that the precipitate creates a plug of the exposed dentinal tubules reducing hypersensitivity.

Another solution used at the end of the 19th century was creosote and carbolic acid, the disinfectant subsequently Joseph Lister suggested for antiseptic surgery in 1867. Nitrate of silver was first proposed in 1859, along with zinc chloride, tetrachloride of gold, arsenious acid, and alkaline caustics. As a last resort, “the sensitiveness of dentine may be obtunded by thorough friction on the affected part with a smooth burnisher,” says Taft (2).

A better understanding of the ultrastructure of the dentin by John Tomes of London in the mid-19th century led to a separation of pulp sensitivity due to pulp inflammation from dentin hypersensitivity.

The more recent dentin desensitizing agents prevent sensory fiber depolarization in dentinal tubules or block dentinal tubules and pain transmission.

Introduced initially as a pulp-capping agent, calcium hydroxide (3,4,5) was thought to become a calming agent for inflamed pulp. But their mechanism of action was too slow for immediate clinical effect. Another development came in 1961 when the desensitizing agents, potassium nitrate and strontium chloride were included in toothpaste. These worked by preventing depolarization of nerve terminals located in the dentinal tubules (6) and had a much faster effect, usually within days of application. Oral care products containing 8% arginine, amorphous calcium, and the bicarbonate/carbonate anions, pioneered at Stony Brook University in the mid-1990 by Israel Kleinberg and his group, were commercialized a decade later as part of a new type of toothpaste (7)—these work by blocking dentinal tubules. Because desensitization was short-lived, it required constant reapplication, hence the need to include it in toothpaste for daily use.

The last 10-15 years have seen a flourishing of oral care products for demineralization, tartar pigmentation, sensitivity, gingivitis, etc., usually all included in toothpaste. A typical leading toothpaste contains 5,000 ppm fluoride or 2% neutral sodium fluoride varnish, potassium oxalates, 5% glutaraldehyde, and desensitizing agents.

Shklar and Chernin p.70
Taft p.210
Pashley
Suge
Ritter
Orchardson
Acevedo

References and notes on anesthesia.

Acevedo AM, Machedo C, Rivera LE, Wolff M, Kleinberg I. The inhibitory effect of an arginine bicarbonate/calcium carbonate Cavistat-containing dentifrice on the development of dental caries in Venezuelan school children. J Clin Dent. 2005;16:63-70.

Birk, Rukinder, K (2006). The history of pain management. p.38. The History of Anesthesia Society Proceedings, vol 36: p. 37-45.

Bonain, A. (1899). Sur un nouveau procede d’anesthesie locale pour operer sur la membrane et la caisse du tympan. Bulletin et Mémoires de la Société Française d’otologie, de laryngologie et de Rhinologie, 14:559-562.

Braun, Heinrich Frederich Wilhelm (1904). Cocaine und Adrenalin (Suprarenin). Berlin, H. Kornfeld, 32pp. (Using adrenalin for local anesthetic to prolong its action).

Burnet, Thomas (1697). Thesaurus medicinæ practicæ. Ex præstantissimorum medicorum observationibus … summâ diligentiâ collectus … Subsectio tertia. Pro Dentium Dolores, p.274-275. J. Ant. Chouet & Davidis Ritteri, Geneva. [the same page, 274 contains multiple recipes for toothache: (a). recipe by Bartholomeo Montagnana, (b). for Peter Foreest for ear infusion with castor oil. The original Latin text is: Auri instillari justi castorei exiguum cum nardo in oleo coctum; (c) for Ambroise Pare – use of egg yolk, turpentine oil, and camphor. The original Latin text is: Nil præstantius oleo terebiathinæ chimico cum pulvere Camphoræ; cujus etiam oleum chimicè paratum ett efficacissimum. Item vitellum ovi assi applicatum prodest, ut et theriaca illita. (d). p. 275. Martin Rulandus. The original Latin text is: Guttas aliquot olei Camphoræ gossipio parvo excipio, ac dentis cavernæ applicari jubeo. Martinus Rulandus Curationum empiricarum et historicarum Centuria.], (e). p. 275. Roderick Fonseca. The original Latin text is: Omnium præstantissimum est oleum buxi, quod tanquam incantamen tum, illicò dolores sedat, ad miraculum usque; et pro maximo secreto habetur, ita ut hoc solo ditari aliquis possit, in foramen dentis gutta una vel altera injiciatur: illicò dolorem tollit; ideo nihil præstantius repetiri potest: Aliud remedium ad hoc sit ex oleo Camphoræ, cujus gutta si intra foveam dentis instilletur, mirisieè dolores fedabit. Recipe of Rodericus (Rodrigo da) A Fonseca, 1619.

Buxton, DW. (1892). Anaesthetics; their uses and administration, Ch. 1. 2nd Ed. London: HK Lewis. (The Romans used marble powder and vinegar to generate carbon dioxide).

Cheng B, Hung CT, Chiu W (2002). Herbal medicine and anesthesia. Hong Kong Med. J. 8(2):123-130. (Hua Tao uses wine and mefaisan in the 3d c. before surgery to knock patients unconscious).

Cordi, Valerii (pseud. V. Eberwein) (1561). De artificiosis extractionibus Liber. In: In hoc volumine continentur Valerii Cordi Simesusij Annotationes in Pedacii Dioscoridis Anazarbei De medica materia libros V. p.225-229.

(link: https://archive.org/details/mobot31753000817848/page/n471/mode/2up/search/Ex+austero

The Latin text on page 229 states: Ex Austero quomodo Dulce fiat. Antea dictum est austerum vitrioli oleum, duplici constare mixtura, videlicet multo alumine et pauce sulphure. Quare cu ex austero oleo dulce extrahitur nihil aliud sit, quam quod sulphur ab alumine segregatur. Est itaqæ dulce vitrioli oleum nihil aliud, quom oleum sulphuris aut ipsum sulphur in liquidam substantiam redactum. Which translates: How tasteless is turned into sweet. At the start the oil of vitriol consists of a mixture of two, alum and a little sulfur. The sweet (component) is extracted from the tasteless oil; therefore, the outcome is non-other than the sulfur separated from the alum.

Discoroides, Pedanius et Cornarius, Janus (1557). Pedaci Discoridae Anazarbensis de Materia Medica Libri V. Basilae. p 551-552. (mandrake for pain).

Einhorn, A. Fiedler, K. Ladisch, C. et al. (1909). Ueber p‐Aminobenzoësäurealkaminester. Justus Liebig’s Annalen der Chemie. 371 (2):142-161. https://doi.org/10.1002/jlac.19093710204 (Synthesis of procaine-novocaine). The associated patent application is: Alfred Einhorn, Höchst Ag, U.S. Patent 812,554, DE 179627, DE 194748

Elsholtius,(Elsholtz) Johann Sigismund (1667). Clysmatica nova: sive ratio, qua in venam sectam medicamenta immitti possint. Coloniae Brandenburgicae (Berlin). (first use of a syringe (Figure II, p. 21, Infusio simplex in Homine), describes transfusion, Figure IV)

Faventini, Leonello Victtori Benedicti (1557). De aegritudinibus infantium, p. 78. (The original Latin text states: Si dolor dentium nimis invaluerit, superponatur externe Opium, cum Vitello Ovi semicocti distemperatum. = semi-cooked egg yolk, opium for toothache).

Fonseca, Roderici A. (1619). Consultationes Medicae, Venetiis, p.165D. The original Latin text is: Oleo camphoræ, cuius guttae si intra foveam dentis instillentur mirifici solet sedare dolores.

Forestus, Peter (1606). Observationum et curationum medicinalium. p.217) {Original text is: Piperis longis, pyrethri, staphisagria, subtilissime pulverizentur, melis, aqua vitae, misce supra cineres calidos, et applica dentibus.}

Gladstone, Ethel (1933). Clysmatica Nova (1665). Elsholtz’ Neglected Work on Intravenous Injection: Part I. Cal West Med. 1933; 38(6):432-434.

Gladstone, Ethel (1933). (a). Clysmatica Nova (1665). Elsholtz’ Neglected Work on Intravenous Injection: Part II. Cal West Med. 1933; 39(1):45-47.

Gladstone, Ethel (1933). (b). Clysmatica Nova (1665). Elsholtz’ Neglected Work on Intravenous Injection: Part III. Cal West Med. 1933; 39(2):119-123.

Gladstone, Ethel (1933). (c). Clysmatica Nova (1665). Elsholtz’ Neglected Work on Intravenous Injection: Part IV. Cal West Med. 1933; 39(3):190-193.

Gordh, T. (1949). Xylocain, a new local analgesic. Anaesthesia, 4:4–9. https://doi.org/10.1111/j.1365-2044.1949.tb05802.x (the discovery of xylocaine by Niels Lofgren).

Hartmann, Johannis (1632). Praxis Chymiatrica. Published in Geneva by Leonardo Chouet.

p. 120, Odontalgia Cap. LXXIII. Paragraph 4. – a recipe for dental pain. The original Latin text is: Si dentes sunt cavi & dolent, vel etiam citra cavitatem in dentibus dolentibus præstans est oleum cariophyllorum in cuius ʒ j.(1 grain) camphoræ. Solutus fuerit, hujus compositi gutta una vel altera in gossipio (præfertim moschum redolente) cavo denti immissa. Also, using Zedoary powder, powder made of the rhizome of the Curcuma zedoaria, an Indian plant of the ginger family). Applied onto the painful tooth. (see also Lazarus Rivierius, 1595-1655), Practix Medica, Liber I, Cap 16). Similarly, Hartmann used Boxwood oil – oleo buxi.

p. 138. The original Latin text

is: Si, qui dolent, dentes cavi sunt, praestans est oleum caryophyllorum, in cujus drachma solutus est camphorae semiscrupulus.( Free translation: For painful cavitated teeth, place a mixture of 60 gm of camphor oil and clove oil.) Use of a combination of clove oil and camphor oil droplets placed on a cotton ball and inserted into the tooth, with severe pain. It is probably the first description of using this mixture in case of severe decay/dental pain.

Hyson, John M. (2001). Man and Pain: Eternal Partners, J Hist Dent, Vol. 49(3):115-121. (bite the bullet).

Heister, Lorenz (1762). Compendium medicinæ practicæ. Sumptibus Societatis, Amstelædami, Ch. XIII, Odontalgia, p.174-175. The original Latin text is: …in cavum dentis erosi, vel olei piperis, caryophyllorum, aut ligni guaiaci, vel per se ope penicilli immissi, vel cum opio et camphora in forma pilulae denti cavo intrusi, et subinde, si dolor non credit, repetiti. (use of pepper and clove oil, guaiacum tree, either taken internally or applied with a brush, or opium and camphor pills placed inside the cavity, and then, if pain does not subside, repeat).

Jardine L: On a grander scale, The outstanding life of Sir Christopher Wren. New York, Harper Collins, 2002, pp 122-123. (on Ch. Wren and first injection of anesthetic).

Neuner, Adam (1827) Ueber die künstliche Erzeugung von Cataracten in todten Augen zum Behuf der leichteren Erlernung der Staaroperationen. Journal der Chirurgie und Augen-Heilkunde, 10 (3):480-492. CF Gräfe & Ph v. Walther eds., Berlin, im Verlag von G. Reimer. (description of the modern syringe). https://www.google.com/books/edition/Journal_der_Chirurgie_und_Augenheilkunde/nRU_AAAAcAAJ?hl=en&gbpv=1&dq=Hessischen+Oberarzte+zu+Darmstadt&pg=PA480&printsec=frontcover

Orchardson R, Gillam DG. The efficacy of potassium salts as agents for treating dentin hypersensitivity. J Orofac Pain. 2000;14(1):9-19.

Pashley DH, Kalathoor S, Burnham D. (1986). The effects of calcium hydroxide on dentin permeability. J Dent Res. 1986;65(3):417-420.

Prinz, Hermann (1915) The dental medicines of Pedanios Dioscorides. Dental Cosmos, 639-645.

Richardson, Benjamin Ward (1866). A new method of producing local anesthesia applicable to dental surgery. Trans. Odont. Soc. Great Britain 5:45-68. (spray of ether onto oral mucosa).

Ritter AV, de L Dias W, Miguez P, et al. (2006). Treating cervical dentin hypersensitivity with fluoride varnish: a randomized clinical study. J Am Dent Assoc. 2006;137(7):1013-1020.

Roscoe, Henry Enfield and Schorlemmer, Carl (1884). Treatise on Chemistry, Vol. III, Pt. I, pg. 323.

Rynd, Francis (1845). Treatment of neuralgia by narcotic inoculation applied to the nerve. Dublin Medical Press, March 12, 1845. Abstracted in The Half-Yearly Abstract of the Medical Sciences, Vol I, January-June 1845. p.29-30, Ed. W.H. Ranking. (using a steel hollow needle – although the needle is not described).

Scribonius Largus (1529). De Compositione Medicamentorum Liber. Cratandrus, Basileae 1529. p.40-43. (cinquefoils extraction mixed with wine as toothache remedy).

Severinus, Marcus Aurelius (1646). De Efficaci Medicina. Chapter 10-11, p.18-19. (Using cold to induce analgesia).

Shklar, G. and Chernin, D. (2007). Lorenz Heister and Oral Disease with the Original Text from His Papers. J. Hist. Dent. 55(2):68-74. (on Heister and his recommendation to use pepper and clove oil, guaiacum tree extract for toothache, based on a translation of Heister).

Suge T, Ishikowa K, Kawasaki A, et al. (1995). Effects of fluoride on the calcium phosphate precipitation method for dentinal tubule occlusion. J Dent Res. 1995;74(4):1079-1085.

Taft, Jonathan (1859). A Practical treatise on operative dentistry. United States: Lindsay & Blakiston. 1st ed., p. 278-280.

Takamine, J. (1901). Adrenalin, the active principle of the suprarenal glands, and its mode of preparation. American Journal of Pharmacy, 73: 523–31.

United States Congress (1849). Thirtieth Congress – Second Session . Report No 144. House of Representatives. William T. G. Morton – Sulfuric Ether. 146 p. https://www.woodlibrarymuseum.org/library/pdf/S_ABZV.pdf

Wadely, Greg and Hayden, Brian (2015). Pharmacological Influences on the Neolithic Transition. J. of Ethnobiology (35(3):566-584. DOI: 10.2993/etbi-35-03-566-584.1 (argues that beer-making contributed to the dawn of agriculture).

Weaver, Joel M (2019). The history of the specialty of dental anesthesiology. Anesth Prog 66:61–68 2019 j DOI 10.2344/anpr-66-02-12

Wood, Alexander (1855). New Method of Treating Neuralgia by the direct application of Opiates to the Painful Points. Edinburgh Medical Surgical Journal. 82(203): 265-281.

Yuan, H., Ma, Q., Ye, L., & Piao, G. (2016). The Traditional Medicine and Modern Medicine from Natural Products. Molecules (Basel, Switzerland), 21(5), 559. https://doi.org/10.3390/molecules21050559).

Zheng, L.W., Hua, H, Cheung, LK (2011) Traditional Chinese medicine and oral diseases: today and tomorrow. Oral Diseases, 17:7-12. doi:10.1111/j.1601-0825.2010.01706.x