FROM JUNGLE ROOTS TO TODAY'S OPERATING ROOM
Anesthesiologist changed surgeries with curare
The history of surgery is often divided into an era described as “before Griffith” and one as “after Griffith” based on Dr. Harold Griffith's introduction of curare in 1942 as a muscle relaxant in surgery. This solved a problem that had plagued surgeons since the discovery of anesthesia 100 years earlier.
The dose of ether, cyclopropane or chloroform that rendered a patient unconscious had little effect on the autonomic nervous system, which meant that when an incision was made, muscles would twitch and even go into spasm, creating difficulties for the surgeon. Use of a higher dose of anesthetic was a workaround, but that had problems of its own. Sometimes the patient wouldn't wake up.
Working as an anesthesiologist at Montreal's Homeopathic Hospital, Griffith was aware of curare's recent introduction as a treatment for the seizures that were a side-effect of the drug Metrazol used to treat depression.
Curare controlled seizures by impairing muscular activity but notably had no effect on the heart. Lewis Wright, a physician at the Squibb pharmaceutical company in charge of marketing curare as Intocostrin for seizures, suggested to Griffith that the drug could be useful as a muscle relaxant in surgery.
Griffith administered curare without first doing any animal experiments or seeking permission from an ethics committee. It is a different world today and a surgeon could not introduce a drug on a whim. However, it should be mentioned that Griffith was aware that an antidote for curare overdose was available and he had it on hand should it be needed.
Physostigmine, isolated from the Calabar bean, had been found by Austrian physiologist Jacob Pal to counter the effects of curare, though its mechanism of action was not known. That was only discovered after English pharmacologist Sir Henry Dale determined that curare produces paralysis by blocking the receptor on nerve cells for acetylcholine, the neurotransmitter needed for muscular activity. It is this activity that physostigmine counters by inactivating acetylcholinesterase, the enzyme that normally breaks down acetylcholine. As a result, the concentration of acetylcholine is increased and it displaces curare from the receptor.
Once the molecular structure of curare's active ingredient, tubocurarine, was determined in 1948, chemists were able to produce a number of analogs that performed better and eventually replaced tubocurarine.
Griffith was a Mcgill University graduate in medicine and had spent a year at the Hahnemann Homeopathic College in Philadelphia. Whether he ever practised homoeopathy isn't clear, but certainly his position as an anesthesiologist did not involve the use of non-existent molecules, the hallmark of homoeopathy. The name Homeopathic Hospital was also a curiosity since it actually functioned as a regular hospital. Perhaps some homeopathic remedies were used, but certainly not in surgical cases.
The path of curare from the jungles of South America to the operating room is a fascinating one.
As early as 1516, Europeans learned about the use of poisoned arrows by South American natives from the writings of Peter Martyr d'anghiera, an Italian who chronicled stories he had heard from travellers to the New World. He described how the Spanish Conquistadores had been attacked with poison arrows and gave a fanciful, but fabricated account of the preparation of the poison from plants by women and the determination of its potency by how many of the women were found “half dead” from the toxic vapours.
In 1745, French explorer Charles Marie de La Condamine brought the first sample of curare back to Europe after seeing natives hunt small animals using a blowpipe and poisoned darts. He gave some of the poison to physicians at Leiden University in the Netherlands who injected it into a cat and found that it produced paralysis. British naturalist Charles Waterton had also encountered curare on his South American travels, and in 1825, together with surgeon Benjamin Brodie, performed a classic experiment that actually laid the foundation for the use of curare in surgery.
Brodie and Waterton injected a female donkey with curare whereupon it quickly stopped breathing and collapsed as its respiratory muscles became paralyzed. The animal's heart, however, kept beating. At this point, Brodie made an incision in the windpipe and used bellows to pump air into the animal's lungs. He kept this up for two hours, when much to his surprise the donkey raised its head and proceeded to get up, apparently none the worse for wear.
The experiment had demonstrated that at a sublethal dose, curare was capable of producing paralysis that lasted until the effect of the drug wore off. Clearly, curare had therapeutic potential, but further experiments were hampered by the scarcity of the drug.
That problem wasn't solved until American Richard Gill found a job as a salesman for a rubber company that led to his settling in Ecuador where he learned about curare from the native tribesmen he befriended. Unfortunately, a fall from a horse left him partially paralyzed, suffering from painful bouts of muscle spasms. When he returned to the U.S., his physician, Walter Freeman, mentioned that muscle spasms were amenable to treatment with curare. This was the same Freeman who would become infamous for introducing the “ice pick lobotomy” to treat mental illness, a procedure he performed on President John F. Kennedy's sister Rosemary with frightful consequences.
Motivated to gather a sufficient quantity of curare, Gill returned to Ecuador and put together an expedition to seek out the plants from which curare could be extracted. After five months in the jungle and watching natives prepare the arrow poison, he returned with 12 kilograms of crude curare.
Curiously, there is no historical record of Gill using curare to treat himself, but Nebraskan psychiatrist Abram Bennett heard about Gill's exploits from Freeman and contacted him for a sample. He had in mind to mitigate the side-effects of Metrazol that he had been prescribing. When this was successful, the Squibb pharmaceutical company bought all of Gill's curare, and Horace Holaday, one of its chemists, found a way to produce a standardized version that was then marketed as Intocostrin, the drug that Griffith used. He reported that “within one minute it made the abdomen as soft as dough.”
The rest, as they say, is history. joe.schwarcz@mcgill.ca
Joe Schwarcz ( joe.schwarcz@mcgill.ca) is director of Mcgill University's Office for Science & Society (mcgill.ca/oss). He hosts The Dr. Joe Show on CJAD Radio 800 AM every Sunday from 3 to 4 p.m.