Figure 1-1. James Young Simpson.

Another distinguished British physician and president of the Medical Society of London in 1868 was Sir Benjamin Ward Richardson. He spent many years in the attempt to alleviate pain by modifying substances capable of producing general or local anesthesia. He brought into use no fewer than 14 anesthetics and invented the first double-valved mouthpiece for the administration of chloroform. He initially experimented with electricity before turning to the effects of coid as an anesthetic. Cold was known to produce a numbing effect and was used as far back as Napoleon’s time when his surgeon, Baron Larrey, used its effects to alleviate pain. He introduced a method of producing local insensibility by freezing the part with an ether spray, which became the most practical method of using local anesthesia until cocaine’s actions became apparent. The ether spray was utilized as a local agent until it was replaced by ethyl chloride in 1880² (Figure 1-3).

Figure 1-2. Nerve compression technique.

Figure 1-3. Ether spray.

Figure 1-4. Coca leaf.

COCAINE ANESTHESIA

The Origins

If local anesthesia has a Eureka moment, then it may have happened in the forests of South America. Centuries ago, an unnamed inhabitant of these climates may have been experimenting by putting leaves of various plants into his mouth and giving them a good chew. We can imagine that this would be a largely unrewarding hobby, but let us focus on the moment when he first placed a coca leaf into his mouth and masticated vigorously. Did he fall to his knees and shout in wonderment: “My lips have gone numb—surely this is the dawn of a new age of painless surgery!”. Almost certainly not—although he might have later told his friends that he felt somewhat excited, energetic, and euphoric while he chewed the leaves.

For thousands of years, South American peoples have chewed the coca leaf. It is a remarkable plant in that it contains vital nutrients as well as numerous alkaloids, most notably cocaine. The coca leaves are taken from a shrub of the genus Erythroxylon coca, named by Patrico Browne because of the reddish hue of the wood of the main species.³ Many species of this genus have been grown in Nicaragua, Venezuela, Bolivia, and Peru since pre-Columbian times. Erythroxylon coca contains the highest concentration of the alkaloid known as cocaine in its leaves^3,4 (Figure 1-4).

Traditionally, the leaves were chewed for social, mystical, medicinal, and religious purposes. The Florentine cartographer Amerigo Vespucci (1451–1512) was arguably the first European to document the human use of the coca leaf.^5,6 In his account of his voyage to America on the second expedition of Alonso de Ojeda and Juan de la Cosa from 1499 to 1500, he reported that the inhabitants of the Island of Margarita chewed certain herbs containing a white powder.⁷ Among sixteenth-century Spanish chroniclers, the appearance of coca is associated with Francisco Pizarro’s (1475–1541) conquest of the Inca or Tawantinsuyo Empire in 1532. Pedro Pizarro (1515–1571), Francisco Pizarro’s cousin who played a leading role in the capture of the last king of the Incas, described coca consumption by the nobles and high officials of the Inca Empire.⁸ After the fall of the Inca Empire in the early 1500s, coca consumption spread to the population at large, creating a drastic change in the entire social system.

When the Spaniards conquered South America, they initially ignored the aboriginal claims that the leaf gave them vigor and liveliness. They self-righteously declared the practice of chewing the leaf the “work of the Devil.”⁵ But once they found that the claims of the natives were true, they not only legalized the leaf, but they taxed it—taking 10% of the value of each crop! The taxes were then used to support the Roman Catholic Church—the main source of revenue for the church to thrive. In 1609, Padre Blas Valera wrote: “Coca protects the body from many ailments, and our doctors use it in powdered form to reduce the swelling of wounds, to strengthen broken bones, to expel cold from the body or prevent it from entering, and to cure rotten wounds or sores that are full of maggots. And if it does so much for outward ailments, will not its singular virtue have even great effect in the entrails of those who eat it?”⁹ If the padre was blessed with the ability to foresee the future, perhaps his enthusiasm would have been redirected toward limiting the use of the leaf, and the field of anesthesia might have taken a different turn.

Another member of the clergy, Bernabé Cobo, who spent his life bringing Christianity to the Incas, is the first to describe the anesthetic effects of coca. In a 1653 manuscript, he mentioned that toothaches could be alleviated by chewing the coca leaves. In 1859, an Italian physician by the name of Paolo Mantegazza had witnessed the use of coca by the natives in Peru. He wrote a paper describing the medicinal use in the treatment of “a furred tongue in the morning, flatulence and whitening of the teeth.”¹⁰

Needles & Syringes

If local anesthetic drugs are the bullets used when fighting pain, the gun needed to fire it is made up of a syringe and a needle. Without the bullets, the gun is useless and, just as certainly, without the gun, the bullets will have little effect. The development of the hypodermic syringe and needle was therefore an important prerequisite for the use of cocaine for anything but topical application. A thorough sifting of the available historical evidence and independent reexamination of the sources support the following outline of the facts. In 1845, Francis Rynd described the idea of introducing a solution of morphine hypodermically in the neighborhood of a peripheral nerve to alleviate neuralgic pain.¹¹ He introduced the solution by means of gravity, passively through a cannula once the trocar had been removed.

Several centuries past before the development of a syringe to deliver medicine was described by Alexander Wood (Figure 1-5). Wood, a contemporary of James Young Simpson, was, in 1855, the first to combine needle and syringe for hypodermic medication. He used the equipment manu-factured by a gentleman by the name of Ferguson who had developed the graduated glass syringe and hollow needle for the purpose of treating aneurysms by injecting ferric perchloride into the aneurysm to form a coagulated mass. Wood, a physician interested in the treatment of neuralgia, reasoned that morphine might be more effective if it were injected close to the nerve supplying the affected area. Although morphine may have some peripheral actions, and the effect of Wood’s morphine was almost certainly central, he was nevertheless the first to think of the possibility of producing nerve blockade by direct drug injection. Thus he has been called the “father-in-law” of local anesthesia—all he lacked was an agent that worked locally. Wood’s contribution was therefore his procedure of subcutaneous injection. This technique was subsequently adopted by C. Hunter and renamed hypodermic injection presumably because Hunter’s purpose was to provide systemic absorption of medications injected.^12,13

Figure 1-5. Early syringe.

The Introduction of Cocaine

The growth in Western science and technology exploded during the nineteenth century. Six years after Charles Darwin’s controversial book, On the Origin of Species by Means of Natural Selection, Joseph Lister was an important figure in changing the face of surgery. He applied Pasteur’ principles of bacterial growth in eliminating sepsis in the operating theatre. Other prominent figures contributed to the understanding of human physiology, eg, Sydney Ringer’s discovery of the need for calcium and potassium to maintain cardiac excitability, significantly advancing medical care. And then there was cocaine.

Although the stimulant and hunger-suppressant effects of coca had been known for years, the isolation of the cocaine alkaloid was not achieved until 1855. Scientists attempted to isolate cocaine, but none were successful for two reasons: coca did not grow in the colder environment of Europe, and the chemistry involved was unknown at that time. Finally in 1855, the German chemist Friedrich Gaedcke was able to isolate the cocaine alkaloid and publish the description in the journal Archieves de Pharmacie. In 1856, Friedrich Wöhler asked a colleague to bring him a large amount of coca leaves from South America. Wöhler then gave the leaves to Albert Niemann, a PhD student at the University of Göttingen in Germany, who then developed an improved purification process. His dissertation, On a New Organic Base in the Coca Leaves, published in 1860, earned him his doctoral degree. Of interest, he described cocaine as having “a bitter taste, promotes the flow of saliva, and leaves a peculiar numbness, followed by a sense of cold when applied to the tongue.”^14,15 Following Niemann, the first experimental study on cocaine was conducted by a former naval surgeon from Peru, Thomas Moreno y Maiz. He discovered that the injection of cocaine solutions caused insensitivity in rats, guinea pigs, and frogs. But it wasn’t until 1880 when Basil Von Anrep experimented on himself, that the application of cocaine for surgery was appreciated. Von Anrep injected a small amount of cocaine under the skin on his arm and noted that the area became insensitive to pinpricks. He did the same to his tongue with the same effect. He published his findings with the caveat “the animal experiments have no practical application; nevertheless I would recommend trying cocaine as a local anesthetic in persons of melancholy disposition.”¹⁶

Figure 1-6. Cari Koller.

The groundwork was in place, but the final step toward the clinical use of cocaine had yet to be taken. Viennese ophthalmologist Karl Koller (1857–1944) rose to the challenge (Figure 1-6). Koller was an intern working in the Viennese General Hospital, where he was befriended by Sigmund Freud¹⁷ (Figure 1-7). Freud wanted to know more about the stimulating action of cocaine, which he hoped might prove useful in curing one of his close friends of morphine addiction. This friend was a pathologist and had developed an agonizingly painful thenar neuroma secondarily to cutting himself during the performance of an autopsy. Freud was able to obtain a supply of cocaine from the pharmaceutical firm, Merck. He shared it with Koller, who helped him investigate its effects on the nervous system during the spring of 1884.¹⁸

Koller had dreams of achieving an appointment to assistant, and knew his chances would be greatly enhanced by the creation of a respectable piece of research. The research he produced proved worthy enough, but interpersonal animosity intervened, and he was not awarded the position. Deeply disappointed, he moved first to the Netherlands, then to the United States.¹⁹ In July 1884, Freud published a review of cocaine and his experiments with the drug, again noting, but without lending any particular attention to, the alkaloid’s anesthetic effect on mucous membranes.²⁰ It was Koller who grasped the importance of this observation. His discovery was no accident, for he was keenly aware of the limitations of general anesthesia in ophthalmic surgery. Koller understood what others had failed to recognize because of his past experience in the field of ophthalmology. Many eye surgeries at that time were still being performed without anesthesia. Almost four decades after the discovery of ether, general anesthesia by mask had a number of limitations for ophthalmic surgery, eg, the anesthetized patient could not cooperate with his surgeon, the anesthesiologist’s apparatus interfered with surgical access. At that time, many surgical incisions in the eye were not closed, as fine sutures were not yet available. Vomiting from chloroform or ether threatened to cause extrusion of the internal contents of the globe, markedly increasing the risk of permanent blindness. As a medical student, Koller had worked in a laboratory searching for a topical ophthalmic anesthetic to overcome the restrictions posed by general anesthesia. The medications available at that time had proved to be ineffective.

Figure 1-7. Sigmund Freud.

One day, Freud gave Koller a small sample of cocaine in an envelope, which he slipped into his pocket (an everyday occurrence in many American and European cities to this day). When the envelope leaked, a few grains of cocaine stuck to Koller’s finger, which he casually licked with his tongue. His tongue became numb—if he had been able to mouth the word Eureka with a numb tongue, he may well have done so at this precise instant. At that moment, Koller realized that he had found what he had been searching for. He immediately created a suspension of cocaine crystals in his laboratory.² Koller realized that this had been noted by all who had worked with cocaine and that “in the moment it flashed upon me that I was carrying in my pocket the local anesthetic for which I had searched some years earlier”.¹ In Freud’s absence, he and another colleague, Joseph Gartner, dissolved a trace of the white powder in distilled water and instilled the solution into the conjunctival sac of a frog. After a minute or so, “the frog allowed his cornea to be touched and he also bore injury to the cornea without a trace of reflex action or defense.” Koller wrote: “One more step had yet to be taken. We trickled the solution under each other’s lifted eyelids. Then we placed a mirror before us, took pins, and with the head tried to touch the cornea. Almost simultaneously we were able to state ‘I can’t feel anything’”.²¹’²² Then, he experimented with dog and guinea pig corneas with 2 to 5% cocaine solutions.²³

Koller soon achieved the extraordinary notoriety he had longed for when in September of 1884 he performed the first ophthalmologic surgical procedure on a patient with glaucoma using local anesthesia. The German Ophthalmologist Society Congress was to meet in Heidelberg in September of 1884 where Koller was going to present his findings. Unfortunately, he was unable to attend. He asked Dr. Joseph Brettauer, an ophthalmologist from Trieste, to present his paper at the Congress. The effect of his work was immediate. Koller was able to present his findings in October of that year to the Viennese Medical Society. He published his findings in late 1884.²¹

Physicians in the United States soon heard about Koller’s amazing work. Dr. Henry Noyes of New York, an attendee of the Heidelberg Congress, published a summary of Koller’s work in the New York Medical Record.²⁴ Another American physician, Dr. Bloom, translated Koller’s article into English and published it in The Lancet in December of that same year. Koller’s work was the trigger for the development of regional/local anesthesia. In the subsequent year, more than 60 publications on local anesthesia with cocaine appeared in the United States and Canada.

One of the most significant publications was that of N. J. Hepburn, an ophthalmologist from New York.¹⁵ Self-experimentation was the standard for drug trials in those days. To determine whether a drug was safe or effective, the researcher or physician commonly tried the drug on himself. It takes courage to try a new drug on a patient, but it takes a particular and much greater form of courage to try that drug on yourself. Hepburn was no different from his colleagues. He gave himself a succession of subcutaneous injections of 0.4 mL (8 mg) of cocaine at 5-min intervals. By the eighth injection, the stimulating effects of the drug were strong enough that he decided it was best to stop. Unfortunately, Hepburn didn’t stop with those initial injections. He repeated the “experiment” 2 days later and 4 days after that, each time increasing the total amount of cocaine injected. Most likely by this time he was hopelessly addicted.

By November of 1884, the ophthalmologist C. S. Bull reported that he had been able to use cocaine to produce anesthesia of the cornea and conjunctiva in more than 150 cases.²⁵ He was enthusiastic about the advantages of the drug in that he saved time required for complete anesthesia with ether; patients were less nauseated, the engorgement of the ocular blood vessels (caused by ether) was eliminated, and he was less hampered by the anesthesia equipment required for inhalation anesthesia. Cocaine revolutionized eye, nose, and mouth surgery. Operations that had been exceedingly difficult or painful became routine when topical or injectable cocaine was used. Koller didn’t forget the contribution of his friend, Freud. He gave him the credit as his muse. Despite his disillusionment at not being foremost with the discovery, Freud is considered by many to be the founder of psychopharmacology because of his initial use of cocaine. He is considered the predecessor in the discovery and experimentation with mescaline, LSD, and amphetamines to modify behavior and to attempt to cure mental illness.²⁰

Dangers of Cocaine

The “wonder drug” cocaine was soon sold everywhere and in almost everything. Following its isolation from the coca leaf, cocaine emerged as an ingredient in wine both in the United States and in Europe in amounts up to 7 mg/oz. In the original recipe for Coca-Cola (1866), coca leaves were included in the ingredients. It wasn’t until 1906 when the Pure Food and Drug Act was passed that the Coca-Cola company began using decocainized leaves.¹⁴ Until 1916, cocaine could be purchased over the counter at Harrods in London. It was found in tonics, toothache cures, and medicines (Figure 1-8). Coca cigarettes were sold with the promise of lifting depression. Those who purchased cocaine were promised in ads by the pharmaceutical firm Parke-Davis, that it could “make the coward brave, the silent eloquent, and render the sufferer insensitive to pain.” In the operatic world, it became commonplace to use cocaine to ease the pain of sore throats and to shrink nasal mucous membranes to enable the singers to improve the resonation of their voices.

Had cocaine’s use been restricted to enhancing opera singing and local anesthesia, it would have become the achievement of nineteenth-century medicine. As had happened earlier with brandy, tobacco, morphine, and other drugs, cocaine was administered in too high concentrations and with too few precautions. In 1886 William Hammond, a former US Army Surgeon General, assured an audience of physicians that cocaine addiction did not exist. Based on self-experimentation, he concluded that regular use of cocaine was as easy to stop as quitting coffee. It did not have the addictive qualities of drugs like opium. But when Hammond finished his lecture, an addiction specialist named Jansen Mattison offered a rebuttal. He related incidences of fierce addictions in patients under his care. He described cocaine’s damaging effect on nerves and its ability to produce hallucinations, delusions, and emaciation. Many other practitioners began to encounter serious side effects.^26,27

Figure 1-8. Cocaine toothache drops.

Mattison knew what he was talking about. Over the next several years, medical journals published hundreds of case reports of “cocainism.” Unfortunately, many of the addicts were medical practitioners who had experimented on themselves, most notably Freud and William Stewart Halsted.^28,29 The opiate addicts, promised a cure for their addiction, switched to cocaine, but continued to use both drugs, further compromising their health.

Several researchers deserve the credit for making the infiltration of cocaine safer. Maximillian Oberst, Ludwig Pernice, and Carl Ludwig Schleich, all from Germany, described the use of low concentrations of cocaine as effective means of local anesthetic.³⁰ The Parisian surgeon Paul Reclus described the use of very low concentrations of cocaine as effective anesthesia without harmful side effects for tooth extractions and pulpotomies.³¹

About the same time, Halsted was experimenting with low concentrations of cocaine applied by compression devices. Unfortunately, he too became addicted to both cocaine and morphine and could not publish his results.^12,17,29 Over time, the maximum “safe” cocaine dosage for infiltration anesthesia was established at 50 mg.

AFTER COCAINE

As the undesirable effects of cocaine, most notably addiction and toxicity, gradually became known, new anesthetic drugs were sought to replace it. Local methods to provide anesthesia had to await the development of less toxic drugs. As part of the purification process of cocaine, Niemann had hydrolyzed benzoic acid from cocaine. Once the clinical usefulness of cocaine became evident, efforts were made by various researchers to identify the active portion of the cocaine molecule and to create new substances that possessed local anesthetic activity without the adverse side effects. Most of the chemical work involving the creation of local anesthetics took place in Germany from 1900 to 1930.³²

Niemann, in his pioneer work, had hydrolyzed benzoic acid from cocaine. In the search for other benzoic acid esters with local anesthetic properties, amylocaine (stovaine) was introduced in 1903. It became popular for spinal anesthesia until it was shown to be an irritant. But it was the development of procaine in 1904 by the German chemist Alfred Einhorn that revolutionized local anesthetics.³³ On November 27 1904, Einhorn (1856–1917) patented 18 para-aminobenzoic acid derivatives that had been developed in the Meister Lucius and Brüning plants at Höchst, in Hesse, Germany. His compound Number Two was to bring about a radical change in local anesthetic practice. He named the new anesthetic, Novocain.¹¹ Procaine (Novocain) was introduced into clinical practice by Professor Heinrich Braun in 1905. Braun published a study comparing this new anesthetic to stovaine and alypine, two other promising local anesthestics.³⁴ Procaine was found to be safe and quickly became the standard local anesthetic drug. Within a short time, procaine completely replaced cocaine as the most commonly used local anesthetic. But because of the short duration of action and prominent allergic potential limiting its clinical effectiveness, the search for longer lasting compounds continued.^11,18,26,35

In the years that followed, several local anesthetics were synthesized and used in clinical practice until side effects or other unfavorable characteristics were noted. In 1925 Karl Meischer synthesized dibucaine and in 1928 Otto Eisleb synthesized tetracaine. Both were effective local anesthetics and had the desirable qualities of longer duration and potency, but systemic toxic effects limited their usefulness for regional techniques other than for spinal anesthesia. Most of the compounds developed during this time were amino ester derivatives, similar to cocaine, with similar allergic potential.

A major breakthrough came in the mid 1940s when the Swedish chemists, Nils Löfgren and Bengt Lundquist, developed a new local anesthetic they called lidocaine. Lidocaine was an amino amide derivative, a stable compound not influenced by exposure to high temperatures, and, most importantly, one that did not have the allergic potential of the ester-type local anesthetics. With the development of this amide-type anesthetic drug, a whole new class of new local anesthetics were synthesized. In 1957 Af Ekenstam developed mepivacaine and bupivacaine, and in 1969 Lofgren and Claes Tegnér developed prilocaine. Prilocaine’s synthesis began because of a desire to produce a local anesthetic with a potency similar to that of lidocaine but without lidocaine’s systemic toxic effects. Unfortunately, it was soon discovered that large doses of prilocaine produced a metabolite that caused methemoglobinemia. Although probably not clinically significant, this discovery severely limited its use in clinical practice.³⁶ In 1972 etidocaine was introduced to the clinical scene, but was soon discovered to lack a differential sensory-motor blockade. Its clinical usefulness was therefore limited.

The only new ester local anesthetic developed in more recent times was chloroprocaine. Its rapid hydrolysis reduced the possibility of systemic toxicity, but its usefulness was restricted to procedures of short duration that did not produce a high degree of postoperative pain. In modern regional practices it has been used both in spinal anesthesia and in nerve blocks for short, relatively painless procedures.

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