400 YEARS IN THE MAKING:

THE DISCOVERY OF CURARE AND ITS

ROLE IN TRANSFORMING ANESTHESIA

By: Adam Toth

3rd Year Medical Student
Des Moines University
 HISTORY
“Without history a man’s soul is purblind, seeing only the
things which almost touch his eyes”. -Thomas Fuller, Holy and
Profane State (1642)

“When we travel we must know our present position,

consult the map, and then plan the journey”. -John Thornton
 FAST FORWARD IN TIME

January 23, 1942: first successful trial of

curare in anesthesia, using cyclopropane
gas. Performed by Dr. Harold Griffith

“. . . Intocostrin, Squibb (Curare) 3.5cc given

intravenously in 1.5 minutes as operation started . . .
after 5 minutes, another 1.5cc of Intocostrin given.
Apparently complete relaxation of abdominal
muscles resulted and continued for 20 minutes,
during which time cyclopropane was lightened. At
the end of this period, muscle tone returned,
probably wearing off of curare effect. Cyclopropane
was then increased in concentration, and anesthesia
continued in the usual way. There was no
demonstrable change in pulse, blood pressure or
respiration” (1)
 ORIGINS OF CURARE
•Strychnos Toxifera

•Strychnos Toxifera •Chondodendron Tomentosum

Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2)
 must take great care, as if it got into an open wound this
also could prove fatal.

In this period the source of the poison was hotly

ORIGINS OF CURARE disputed. As we shall see later, this is not surprising as

several different genera of plants would prove to be
involved. Initially some authorities suggested that it came
from ‘venomous apples’ which resembled the ‘muscadel
pears’ of the Island of Sicily, Italy. These apples grew on
•Strychnos Toxifera
certain trees which were covered with many branches
and leaves. It is possible here that these writers were
describing Strychnos toxifera (see Schomburgk below and
Figure 1). The fruit of Strychnos does indeed look like an
apple although the plant is a rain jungle (forest) liana. The FIGURE 1 Strychnos toxifera. Bentham
British explorer John Hawkins also mentions ‘apples’
which are ‘fair and red’ as a possible source of the poison.5 Negro, the other continuing as the main stre
the Caribbean. The unusual link between the A
In order to understand the geographical origin of the the Orinoco is now called the Casiquiare Cana
arrow poison, we must now take a brief diversion into the its existence was denied for a considerable per
complex topography of the river basins of the Amazon; It was first reported by d’Acuna in 1641 and s
the Orinoco and the Essequibo (see Figure 2). The confirmed by de la Condamine (1742) a
Amazon is considered to have its origins 2,300 miles from Humboldt (1800).2, 3 The latter collected cura
the sea at the junction of two major rivers in Peru: the lianas) in this area (see Figure 2).
Marañon and the Ucayali. One thousand miles
downstream it is joined by another major river on its The Essequibo, 620 miles in length, runs thro
northern bank, the Rio Negro. Guiana (now Guiana) and also empties into the
In the upper reaches of this river lived the Ma
•Strychnos Toxifera •Chondodendron Tomentosum
The upper waters of the Orinoco river divide at a of Indians whose arrow poison came to be
watershed near its source; one part flows south to join the one of the most potent available. It was in th

HISTORY

Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2)
FIGURE 2 The river basins of the Amazon, Orinoco and Essequibo
 must take great care, as if it got into an open wound this
also could prove fatal.

In this period the source of the poison was hotly

ORIGINS OF CURARE disputed. As we shall see later, this is not surprising as

several different genera of plants would prove to be
involved. Initially some authorities suggested that it came
from ‘venomous apples’ which resembled the ‘muscadel
pears’ of the Island of Sicily, Italy. These apples grew on
•Strychnos Toxifera
certain trees which were covered with many branches
and leaves. It is possible here that these writers were
describing Strychnos toxifera (see Schomburgk below and
Figure 1). The fruit of Strychnos does indeed look like an
apple although the plant is a rain jungle (forest) liana. The FIGURE 1 Strychnos toxifera. Bentham
British explorer John Hawkins also mentions ‘apples’
which are ‘fair and red’ as a possible source of the poison.5 Negro, the other continuing as the main stre
the Caribbean. The unusual link between the A
In order to understand the geographical origin of the the Orinoco is now called the Casiquiare Cana
arrow poison, we must now take a brief diversion into the its existence was denied for a considerable per
complex topography of the river basins of the Amazon; It was first reported by d’Acuna in 1641 and s
the Orinoco and the Essequibo (see Figure 2). The confirmed by de la Condamine (1742) a
Amazon is considered to have its origins 2,300 miles from Humboldt (1800).2, 3 The latter collected cura
the sea at the junction of two major rivers in Peru: the lianas) in this area (see Figure 2).
Marañon and the Ucayali. One thousand miles
downstream it is joined by another major river on its The Essequibo, 620 miles in length, runs thro
northern bank, the Rio Negro. Guiana (now Guiana) and also empties into the
In the upper reaches of this river lived the Ma
•Strychnos Toxifera •Chondodendron Tomentosum
The upper waters of the Orinoco river divide at a of Indians whose arrow poison came to be
watershed near its source; one part flows south to join the one of the most potent available. It was in th

• These plants are known as ‘lianas’, or vines, which

grow attached to trees up to canopy level

• Location:
HISTORY

• 3 primary areas where curare was investigated by

explorers, between 1500-1700
• Upper Amazon, Orinoco and Essequibo river
basins Fig 1: map of river basins of the Amazon, Orinoco and Essequibo. (2)
FIGURE 2 The river basins of the Amazon, Orinoco and Essequibo
 ORIGINS OF CURARE
The word ‘curare’:
A generic term, indiscriminately describes many South American arrow poisons
Scientific definition: arrow poison capable of producing death by muscle paralysis
Origin of the term ‘curare’: derived from Indian word ‘uiraêry’ (3)
uira = bird, eor = to kill
variants of this word, including ‘curare’, come from attempts at Europeans to find
phonetic equivalents in their languages
 ORIGINS OF CURARE
The word ‘curare’:
A generic term, indiscriminately describes many South American arrow poisons
Scientific definition: arrow poison capable of producing death by muscle paralysis
Origin of the term ‘curare’: derived from Indian word ‘uiraêry’ (3)
uira = bird, eor = to kill
variants of this word, including ‘curare’, come from attempts at Europeans to find
phonetic equivalents in their languages

Uses of Curare by South American Indians

Prepared into a thick paste and coated onto arrow tips, which
were used in either blowguns or bows to hunt and kill prey quickly
Exerpt from Charles de la Condamine, French explorer:
“The Yameos propel by the breath small arrows of wood to a distance of 30 to 40 paces and
rarely miss their target . . . They cover the points of these little arrows . . . with a poison so active
that, when it is fresh, it will kill in less than a minute any animal whose blood it has entered . . .
We hardly ate anything killed in any other way than by these darts. There is no danger from this;
the poison only kills if it enters the blood; but it is no less mortal to man than to animals.” (4)
ORIGINS OF CURARE
 ORIGINS OF CURARE
Spanish Conquistadors of the 16th century told tales of South American Indians using
arrows tipped with a deadly poison
Peter Martyr d’Anghera
Italian ‘gossip columnist’, author of De Orbe Novo (1516)
Documents accounts of South American natives attacking and killing fellow
Spaniard explorers with poisoned arrows, that
“contained a kind of liquid which oozed out when the point broke” (5)
 ORIGINS OF CURARE
Spanish Conquistadors of the 16th century told tales of South American Indians using
arrows tipped with a deadly poison
Peter Martyr d’Anghera
Italian ‘gossip columnist’, author of De Orbe Novo (1516)
Documents accounts of South American natives attacking and killing fellow
Spaniard explorers with poisoned arrows, that
“contained a kind of liquid which oozed out when the point broke” (5)

Charles de la Condamine
French naturalist and mathematician, sent on expeditions by L’Academie
Royale de Sciences to measure the arcs of the earth’s surface
Spent 8 years making measurements, also led expeditions in Peru, where he
witnessed Ticunas Indians prepare and use arrow poison (7)
In 1743, credited as first to bring back samples of curare to Europe for study, at the
University of Leyden (8,9)
First scientists to study the samples:
Richard Brocklesby (1747), Monsieur Herissant (1748)
ORIGINS OF CURARE: PREPARATION
Peter Martyr’s “De Orbe Novo”:
“There are certain old women skilled in the art, who are shut in at
certain times and furnished with the necessary materials; during two
days these women watch and distil the ointment. As soon as it is
finished the house is opened, and if the women are well and not found
lying on the ground half dead from the fumes of the poison, they are
severely punished, and the ointment is thrown away as being valueless;
for the strength of the poison is such, that the mere odor of it, while
compounding almost kills its makers” (6)
Believed to be first written account of preparation of curare (3)
ORIGINS OF CURARE: PREPARATION
Peter Martyr’s “De Orbe Novo”:
“There are certain old women skilled in the art, who are shut in at
certain times and furnished with the necessary materials; during two
days these women watch and distil the ointment. As soon as it is
finished the house is opened, and if the women are well and not found
lying on the ground half dead from the fumes of the poison, they are
severely punished, and the ointment is thrown away as being valueless;
for the strength of the poison is such, that the mere odor of it, while
compounding almost kills its makers” (6)
Believed to be first written account of preparation of curare (3)

Edward Bancroft
In his Essay in 1769, documented table of ingredients “Take the Bark of the Root of
Woorara, six parts;
used by the Accawau Indians of Guiana to make curare: Of the Bark of Warracobba coura,
“The smallest quantity of this poison conveyed by a wound into the two parts;
Of the Bark of the Roots of Coura-
red blood vessels of an animal, causes it to expire in less than a
napi, Baketi, and Hatchybaly,
minute, without much apparent pain or uneasiness; though slight of each one part” (10)
convulsions are sometimes seen near the instant of expiration.” (10)
 ORIGINS OF CURARE

Alexander Von Humboldt

Spent years 1799-1803 in South America as a plant collector
First eyewitness account of the preparation of curare, by Indians of Esmeralda (11)
Identified source of curare poison as the bark and part of the sapwood of the Strychnos
family of lianas
“One judged by the degree of bitterness whether the concentration by the fire had proceeded far
enough . . . Curare is not dangerous unless it gains access to the blood; likewise, the vapor produced by
heating is not harmful” (11)
 ORIGINS OF CURARE

Alexander Von Humboldt

Spent years 1799-1803 in South America as a plant collector
First eyewitness account of the preparation of curare, by Indians of Esmeralda (11)
Identified source of curare poison as the bark and part of the sapwood of the Strychnos
family of lianas
“One judged by the degree of bitterness whether the concentration by the fire had proceeded far
enough . . . Curare is not dangerous unless it gains access to the blood; likewise, the vapor produced by
heating is not harmful” (11)

Sir Robert Schomburgk

1841, led expedition into British Guiana, persuaded Indian guides to show them where
curare plants grew and how to concoct the poison (12)
Confirmed Humboldt’s suspicion that the curare plant “belongs to the genus Strychnos”
“The mystery respecting the arrow-poison of the Indians, although not entirely cleared up, is in a
great measure removed. Neither snake’s teeth nor stinging ants form the active principle, but the
juice of a plant which we have described as Strychnos toxifera” (13)
EARLY LABORATORY EXPERIMENTATION

First to use samples of De la Condamine’s curare of the Ticunas Indians:

Richard Brocklesby - In 1747, administered poison to a cat and found that the heart
continued to beat for approximately 2 hours after its apparent death (9)
Monsieur Herissant - In 1748, introduced poison to a variety of animals, from birds
to horses. Confirmed curare only holds an effect if entered through bloodstream. Found
that neither sugar nor sea salt is the antidote. (8)
 EARLY LABORATORY EXPERIMENTATION

First to use samples of De la Condamine’s curare of the Ticunas Indians:

Richard Brocklesby - In 1747, administered poison to a cat and found that the heart
continued to beat for approximately 2 hours after its apparent death (9)
Monsieur Herissant - In 1748, introduced poison to a variety of animals, from birds
to horses. Confirmed curare only holds an effect if entered through bloodstream. Found
that neither sugar nor sea salt is the antidote. (8)
First glimpse into potential role in anesthesia
Sir Benjamin Brodie - physician and professor, who, in 1811-12, expanded upon the
work of Brocklesby
“Some woorara was inserted into a wound in a young cat ... In four minutes ... respiration entirely
ceased, and the animal appeared to be dead; but the heart was still felt acting ... Lungs were
artificially inflated about forty times in a minute ... At the end of another hour, [the cat] made
spontaneous efforts to breathe twenty-two times in a minute. The artificial respiration was
discontinued. She lay, as if in a state of profound sleep, for forty minutes, when she suddenly awoke,
and walked away.” (14)
Timeline of anesthesia: in the year of Brodie’s experimentation, Fanny Burney wrote “A Mastectomy: Letter to Esther Burney”
- a personal narrative describing her agonizing surgical procedure before the introduction of anesthesia
EARLY LABORATORY EXPERIMENTATION
What is the site of action of curare?
Claude Bernard, French physician turned physiologist
Student of physiologist Francois Magendia, who had been using
curare to keep animals still during experimentation (15)
In 1842, Bernard injected curare into ligated limb of a frog; found
that outside the ligature, muscle response to nerve stimuli were
prevented, yet muscles still responded to direct stimulation
Concluded that curare works by blocking conduction of nerve Fig. II: Apparatus for electrical stimulation of a nerve used
by Claude Bernard to establish site of action of curare.
impulse from the nerve to the muscle fiber (3,15) Cited from Anaesthesia and the Practice of Medicine:
Historical Perspectives

Timeline of anesthesia: in the year Claude Bernard identified curare’s mechanism of action, Crawford Long
performed the first documented surgical procedure using ether to remove a neck tumor
EARLY LABORATORY EXPERIMENTATION
What is the site of action of curare?
Claude Bernard, French physician turned physiologist
Student of physiologist Francois Magendia, who had been using
curare to keep animals still during experimentation (15)
In 1842, Bernard injected curare into ligated limb of a frog; found
that outside the ligature, muscle response to nerve stimuli were
prevented, yet muscles still responded to direct stimulation
Concluded that curare works by blocking conduction of nerve Fig. II: Apparatus for electrical stimulation of a nerve used
by Claude Bernard to establish site of action of curare.
impulse from the nerve to the muscle fiber (3,15) Cited from Anaesthesia and the Practice of Medicine:
Historical Perspectives

Timeline of anesthesia: in the year Claude Bernard identified curare’s mechanism of action, Crawford Long
performed the first documented surgical procedure using ether to remove a neck tumor

Sir Henry Dale

Nobel Prize winner for Physiology in 1936 for his work on the chemical
synapses of nervous impulse (16)
Localized curare’s effect to motor endplate acetylcholine receptor Fig. III: (d) action of curare as a competitive
antagonist of ACh receptors at the muscle
endplate. Cited from Sultan Qaboos University
“If the muscle was completely paralyzed . . . by curarine, stimulation of its motor nerve fibers Medical Library
caused the usual output of acetylcholine, though the muscle remained completely passive”
EARLY LABORATORY EXPERIMENTATION

Earliest therapeutic use of curare was for control of tetanus:

Prof. Sewell: recorded in 1835 as the first to treat
tetanus successfully in two horses, utilizing curare and
artificial respiration (17)
Sayre and Burrall - surgeons at Bellevue Hospital in
NY, first recorded administration of curare in 1858 to the
wound of a patient with tetanus. Died of severe spasm. (18)
EARLY LABORATORY EXPERIMENTATION

Earliest therapeutic use of curare was for control of tetanus:

Prof. Sewell: recorded in 1835 as the first to treat
tetanus successfully in two horses, utilizing curare and
artificial respiration (17)
Sayre and Burrall - surgeons at Bellevue Hospital in
NY, first recorded administration of curare in 1858 to the
wound of a patient with tetanus. Died of severe spasm. (18)

By 1859, there were 9 attempts and 7 failures of treating tetanus with curare (19)
“Its chemical nature is not uniform, even its source is variable, and its energies are unequal in various
specimens; the therapeutic action of curare is unreliable”
“Experiments upon large animals have shown that after the tetanic spasms have ceased, perhaps
controlled by . . . curare, death has followed apparently from paralysis of the organs of respiration. So that
the surgeon has the satisfaction of thinking that if he saves his patient from the disease, he may kill him
by the remedy”

Other early clinical uses of curare involved treating spasms in strychnine poisoning, rabies
and epilepsy - few were successful
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
Origin of the drug name tubocurarine:

In 1886, Boehm (25) believed that containers were fairly diagnostic of the
type of curare found in them: gourd-curare, pot-curare, and tube-curare.
- Note: this theory was later disproved by Richard Gill (21)

All 3 sources contained active quaternary alkaloids, which he named

“curarines”; thus from tube-curare came the name ‘tubocurarine’ (25)

In 1928, Spath, Leithe and Ladeck (26) obtained sample of Boehm’s

Fig VI: chemical structure of
d-tubocurarine
crystalline curine and traced it to the dried roots of Chondodendron
tomentosum
In 1935, Harold King (27) worked out the chemical structure of d-
tubocurarine from a tube-curare sample provided by the museum of the
Pharmaceutical Society
In 1943, Wintersteiner and Dutcher (28) isolated d-tubocurarine
from a crude sample of Chondodendron tomentosum.
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
Richard Gill - In the 1930s, took the historical
knowledge of curare and guided it into modern clinical use.
Background:
Worked for the American Rubber Company in 1927;
moved to Ecuador after 1929 stock market crash,
where he raised coffee, cacao and vegetables (20)
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
Richard Gill - In the 1930s, took the historical
knowledge of curare and guided it into modern clinical use.
Background:
Worked for the American Rubber Company in 1927;
moved to Ecuador after 1929 stock market crash,
where he raised coffee, cacao and vegetables (20)

Developed neurological symptoms in 1932; diagnosed

with multiple sclerosis by Dr. Walter Freeman, who
expressed interest in trying curare to treat his illness
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
312 ANESTHESIA
AND ANALGESIA .
. . Current Researches VOL.56, No. 2, MARCH-APRIL,
19

Richard Gill - In the 1930s, took the historical

knowledge of curare and guided it into modern clinical use.
Background:
Worked for the American Rubber Company in 1927;
moved to Ecuador after 1929 stock market crash,
where he raised coffee, cacao and vegetables (20)

Developed neurological symptoms in 1932; diagnosed

with multiple sclerosis by Dr. Walter Freeman, who FIG3. Richard Gill collecting curare in the jungle.
Fig IV: Richard Gill collecting curare (26)
expressed interest in trying curare to treat his illness
source of a form of curare. It was also the tified specimen of chondodendron toment
first authenticated variety of curare.24 sum.26 Harold King, working in Britain
National Institute for Medical Research
When Gill returned to the United States
In 1938, Gill organized anatcrates
expedition from
the end of 1938, he had with Ecuador into
him several
containing a total of 25 pounds of
1935, first isolated and determined t
chemical formula of the pure alkaloid, whi
he named d-tubocurarine chloride.27 Ho
prepared curare. To his dismay, he found ever, he was unable to identify the type
the jungle, spent 5 monthsthat collecting
the chemists at Merckvines
had dropped
their investigation of the curare plant and
identified as plant or species the alkaloid had come fro
although it pointed to the genus chond
were now studying an entirely different dendron as the probable source of the acti
Chondodendron Tomentosum plant(21)which had curarelike properties from
which they had isolated an alkaloid they
ingredient of the crude curare.
called erythroidine. Gill next offered his cu- Meanwhile, an orthopaedic surgeo
rare, in May 1939, to E. R. Squibb and Michael Burman, who in the 1930s was
Sons, who contracted to buy Gill’s product member of the Medical Staff of the Hosp
and subject it to laboratory investigation. tal for Joint Diseases, became interested
1934 in the use of curare for patients wi
Gill’s plants were identified as chondo- spastic paralysis.28 He came across the wo
dendron tomentosum by the Squibb chem- of Ranyard West29 in the course of his ow
ists, among who was Horace Holaday, father investigations. Between 1931 and 193
of Duncan Holaday, the anesthesiologist. West had investigated the action of cura
He devised the rabbit head-drop test, still on paralytic rigidity in man.2g Burman r
in use today to assay the strength of puri- ceived a supply of curare from the Mer
fied curare.25 No one as yet knew what the Institute of Therapeutic Research in Ra
active ingredient was. Holaday named the way, New Jersey, and began his study
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
312 ANESTHESIA
AND ANALGESIA .
. . Current Researches VOL.56, No. 2, MARCH-APRIL,
19

Richard Gill - In the 1930s, took the historical

knowledge of curare and guided it into modern clinical use.
Background:
Worked for the American Rubber Company in 1927;
moved to Ecuador after 1929 stock market crash,
where he raised coffee, cacao and vegetables (20)

Developed neurological symptoms in 1932; diagnosed

with multiple sclerosis by Dr. Walter Freeman, who FIG3. Richard Gill collecting curare in the jungle.
Fig IV: Richard Gill collecting curare (26)
expressed interest in trying curare to treat his illness
source of a form of curare. It was also the tified specimen of chondodendron toment
first authenticated variety of curare.24 sum.26 Harold King, working in Britain
National Institute for Medical Research
When Gill returned to the United States
In 1938, Gill organized anatcrates
expedition from
the end of 1938, he had with Ecuador into
him several
containing a total of 25 pounds of
1935, first isolated and determined t
chemical formula of the pure alkaloid, whi
he named d-tubocurarine chloride.27 Ho
prepared curare. To his dismay, he found ever, he was unable to identify the type
the jungle, spent 5 monthsthat collecting
the chemists at Merckvines
had dropped
their investigation of the curare plant and
identified as plant or species the alkaloid had come fro
although it pointed to the genus chond
were now studying an entirely different dendron as the probable source of the acti
Chondodendron Tomentosum plant(21)which had curarelike properties from
which they had isolated an alkaloid they
ingredient of the crude curare.
called erythroidine. Gill next offered his cu- Meanwhile, an orthopaedic surgeo
rare, in May 1939, to E. R. Squibb and Michael Burman, who in the 1930s was
Sons, who contracted to buy Gill’s product member of the Medical Staff of the Hosp
Offered his curare samples to pharmaceutical company
and subject it to laboratory investigation. tal for Joint Diseases, became interested
1934 in the use of curare for patients wi
Gill’s plants were identified as chondo- spastic paralysis.28 He came across the wo
E.R. Squibb in 1939, who ists,
agreed toHorace
buy hisfatherentire supply
dendron tomentosum by the Squibb chem-
among who was Holaday,
of Ranyard West29 in the course of his ow
investigations. Between 1931 and 193
of Duncan Holaday, the anesthesiologist. West had investigated the action of cura
He devised the rabbit head-drop test, still on paralytic rigidity in man.2g Burman r
in use today to assay the strength of puri- ceived a supply of curare from the Mer
fied curare.25 No one as yet knew what the Institute of Therapeutic Research in Ra
active ingredient was. Holaday named the way, New Jersey, and began his study
 MUCH NEEDED STEPS TOWARD
ISOLATING AND STANDARDIZING
Horace Holaday, E.R. Squibb chemist
He and others identified Gill’s plants as Chondodendron Tomentosum
Isolated d-tubocurarine and gave the trade name “Intocostrin” in 1939

Developed “Rabbit Head-Drop Test” to standardize strength of

purified curare (22)

Determines the relative potency of sample curare

preparations against a standard dose of Intocostrin
(d-tubocurarine chloride) (23)
Endpoint is relaxation of rabbit neck muscles to the
point that the animal’s head cannot be moved in
response to physical stimulus

Fig. V: rabbit head-drop assay. Endpoint visualized, where

rabbit is unable to raise its head. Original image from E.R.
Squibb institute. (22)
 INTRODUCTION OF INTOCOSTRIN
INTO PSYCHIATRY
Background:
Abram Elting Bennett, a neuropsychiatrist of Omaha, Nebraska,
had been using convulsive shock therapy to treat depression;
mid-1930s (24)
Convulsions produced by pentylenetetrazole (Metrazol) were
associated with 17% incidence of dislocation and 43-51% incidence
of compressive spinal fractures
Bennett used standardized preparations of Gill’s crude curare in
1939, provided first from A.R. McIntyre then from pharmaceutical
company E.R. Squibb
By 1940, Bennett had established standard doses of Intocostrin to
be used in tandem with Metrazol for shock therapy, and
performed 1,000 successful treatments
By 1941, over 30,000 treatments reported with only 2 deaths
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

Timeline of anesthesia: by 1847, John Snow begins to use ether anesthesia for major surgeries at St. George’s Hospital
in London

Lewis H. Wright
Anesthesiologist associated with E.R. Squibb, envisioned
potential of curare in anesthesia
Intrigued by Bennett’s presentation of curare use in shock
therapy at an AMA conference in 1940 (29)
“Between 1930-1935, many new anesthetic agents had been introduced which
did not produce good and adequate relaxation . . . I mentioned this use of
curare to many of my anesthesiologist friends. Most of them thought I was
crazy; that this Indian arrow poison to be used in the operating room was really
far from a modern scientific approach”

Felt strongly that anesthetic agents of the time - cyclopropane,

ethylene and IV barbiturates - could be augmented by the
addition of curare
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

E.M. Papper, Stuart Cullen and Harold Griffith were the first recipients of curare from
Wright
Failed uses by Papper and Cullen in 1940 (20)

E.M. Papper, anesthesiologist in NY, administered Intocostrin to a small number of

ether-anesthetized cats - all died from apparent asthma attack. Later gave to 2 patients
under ether anesthesia, spent the night resuscitating with a breathing bag; felt curare
was too dangerous from a respiratory standpoint

Stuart Cullen, NY anesthesiologist who,

similar to Papper, gave Intocostrin to several
dogs anesthetized with ether; witnessed
respiratory and asphyxial convulsions, and was
discouraged from applying to humans
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

Howard Griffith - country doctor in Montreal, worked as

general practitioner and part time anesthetist
What made him the ideal candidate for introducing curare into
anesthesia?
1) Little exposure to academic and laboratory medicine,
which was a roadblock for Papper and Cullen
2) Avid user of cyclopropane anesthesia - between 1933 and
1942 had published 14 articles mostly on cyclopropane use
(30)

3) Aware of risk of respiratory depression with

cyclopropane, and was avid user of endotracheal intubation
4) Able to effectively publish his experiences and
observations
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

January 23, 1942: first successful trial of

curare in anesthesia, using
cyclopropane gas. Performed by Dr.
Harold Griffith

“. . . Intocostrin, Squibb (Curare) 3.5cc given intravenously

in 1.5 minutes as operation started . . . after 5 minutes,
another 1.5cc of Intocostrin given. Apparently complete
relaxation of abdominal muscles resulted and continued for
20 minutes, during which time cyclopropane was lightened.
At the end of this period, muscle tone returned, probably
wearing off of curare effect. Cyclopropane was then
increased in concentration, and anesthesia continued in the
usual way. There was no demonstrable change in pulse,
blood pressure or respiration” (1)
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

Griffith releases preliminary report of 25 patients who received

Intocostrin with cyclopropane anesthesia (31)
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith

Griffith releases preliminary report of 25 patients who received

Intocostrin with cyclopropane anesthesia (31)

Follow-up from Stuart Cullen

After acknowledging Griffith’s success with Intocostrin in 1942,
Cullen followed suit and reported 131 cases of using curare for
abdominal wall relaxation during inhalation anesthesia (32)
Addressed his initial failure of curare in ether-anesthetized dogs:
Showed that ether, sodium thiopental and tribromethanol all
have ‘curariform’ actions, with ether having the greatest (33)
ALAS, D-TUBOCURARINE IN ANESTHESIA
4 Key players in introduction of d-tubocurarine to anesthesia: Lewis H.
Wright, E.M. Papper, Stuart C. Cullen, and Harold R. Griffith
318 ANESTHESIA AND ANALGESIA. . . Current Researches VQL.56, No. 2, MARCH-APRIL,
1977

FIG8. Presentation of the plaque a t the 10th Anniversary of the introduction of curare into clinical
Griffith accepting plaque at Queen Elizabeth Hospital,
anesthesia.

marking 10th anniversaryTranslation

of3. Martyr
first use
by FA of New
Mainutt. curare
York, GPin
Pd’A: De Orbe Novo (1516 Latin).
Put-
nam’s Sons, 1912, vol 1, p 75
anesthesia4. (20)
McIntyre AR: Curare: Its History, Nature,
and Clinical Use. Chicago, University of Chicago
Press, 1947
5. Thomas KB: Curare: Its History and Usage.
London, Pitman Medical Publishing Company Ltd,
Quoted by Lewis Wright: “this use of curare was the beginning of a chain of events
1964, p 24
6. Sykes WS: Essays on the First Hundred
resulting in benefit to more than 10,000,000
Years surgical
of Anaesthesia.patients
Ltd, 1960
Edinburgh, ES in a year throughout the
Livingstone

world” 7. (20)
Raleigh, Sir Walter: HAKLUYT’s Voyages,
vol 111, p 649. Discovery of the Large, Rich and
Beautiful Empire of Guiana (Imprinted in London
by Robert Robinson, 1596). Reprinted for the
HAKLUYT Society, London, 1868
 D-TUBOCURARINE IN ANESTHESIA

Personal accounts of the effects of d-tubocurarine:

 D-TUBOCURARINE IN ANESTHESIA

Personal accounts of the effects of d-tubocurarine:

Helen Barnes, London anesthetist, 1943

Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal
intubation, had 2 colleagues give her IV Intocostrin: (34)
“My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia
gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very
oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a
transient sensation of constriction in the throat”
 D-TUBOCURARINE IN ANESTHESIA

Personal accounts of the effects of d-tubocurarine:

Helen Barnes, London anesthetist, 1943

Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal
intubation, had 2 colleagues give her IV Intocostrin: (34)
“My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia
gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very
oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a
transient sensation of constriction in the throat”
Some physicians believed that if you increased the dose of Intocostrin for surgery, no
anesthetic would be necessary
 D-TUBOCURARINE IN ANESTHESIA

Personal accounts of the effects of d-tubocurarine:

Helen Barnes, London anesthetist, 1943

Wanting to test if curare would relax laryngeal muscles enough to facilitate tracheal
intubation, had 2 colleagues give her IV Intocostrin: (34)
“My sensations were dramatic. I feel that I experienced the sufferings of a patient with myasthenia
gravis. At once my vision became blurred and I almost ‘blacked out’ ... Ptosis was also very
oppressive, and was accompanied by extreme prostration, fatigue, a sense of impending death, and a
transient sensation of constriction in the throat”
Some physicians believed that if you increased the dose of Intocostrin for surgery, no
anesthetic would be necessary

Scott Smith, anesthetist of Salt Lake City, 1947

Offered himself as an experimental subject to evaluate whether curare has any central
depressing properties. His remarks were recorded: (35)
“[He] can distinguish heat from cold, sharp from dull and can feel pain pinprick . . . Ability to signal by
slight movement [of] left eyebrow almost gone. [He] indicates ... that he is perfectly conscious and that his
sensorium is unimpaired”
 IN CONCLUSION

The discovery of curare marks the beginning of the history of

neuromuscular blocking agents
Curare is a “drug with a long and romantic history” (36), taking over 400 years
to transform it from a mysterious Indian arrow poison into a clinically useful
drug
d-tubocurarine introduced into surgical anesthesia in the 1940s, where it
remained until slowly replaced by suxamethonium in the 1950s, then
atracurium, pancuronium and vecuronium in the 1980s.
 TIMELINE OF EVENTS

16th century: tales of Spanish conquistadors witnessing South American Indians hunt and attack with poison-tipped
arrows
1740s: Charles de la Condamine brings samples of curare to Europe to the University of Leyden. Two scientists, Brocklesby
and Herissant, conduct animal experiments with the samples, observe heart continues to beat after animal’s apparent
death
1800: Von Humboldt first eyewitness of curare preparation, identified plant source as Strychnos
1811: Benjamin Brodie administers curare to a cat and keeps alive with artificial respiration
1838: William Sewell, veterinarian, used curare to treat tetanus in two horses but failed
1842: Claude Bernard identified site of action of curare as the myoneural junction
1858: First clinical use of curare by Sayres and Burrall for treating tetanus
1930s: Richard Gill, sparked by thought that curare might help treat his multiple sclerosis, collected Chondodendron
Tomentosum vines and gave to company E.R. Squibb for analysis and standardization
1935: Harold King identifies chemical structure of d-tubocurarine from a crude sample of tube curare
1939: E.R. Squibb releases Intocostrin, purified d-tubocurarine from Gill’s Chondodendron samples. A.H. Holaday
develops rabbit-head-drop test to standardize the drug.
1940: Bennett reports first large scale tests of curare in humans, over 1000 successful Metrazol shock therapy treatments
using standard doses of Intocostrin. Lewis Wright envisions potential of d-tubocurarine for muscle relaxation in surgical
anesthesia. EM Papper and Stuart Cullen discouraged by their use of Intocostrin in ether-anesthetized animals.
1942: January 23rd, Harold Griffith first to use Intocostrin with surgical anesthesia, for an appendectomy
 BIBLIOGRAPHY

1. Griffith HR. The evolution of the use of curare in anesthesiology. Annals of the New York Academy of Science,
54:493-97, 1951.
2. Lee MR. Curare: The South American Arrow Poison. The Journal of the Royal College of Physicians of
Edinburgh 2005;35(i):83-92.
3. Mcintyre AR. Curare: Its History, Nature and Clinical Use. Chicago: University of Chicago Press, 1947.
4. De La Condamine CM. Relation Abregee d’un Voyage fait dans l’Interieur de l’Amerique Meridionale.
Memoires de l’Academie des Sciences; 62:391-492, 1745.
5. Martyr Pd’A. De orbe novo (1516 Latin). Translation by Francis Augustus MacNutt (New York: G. P. Putnam’s
Sons, 1912), 1:75.
6. ------. Ibid., 2: 385-86.
7. De La Condamine CM. Relation Abregee d’un Voyage fait dans l’Interieur de l’Amerique Meridionale.
Memoires de l’Academie des Sciences; 62:391-492, 1745.
8. Herissant M. Experiments made on a great number of living animals with the poison of Lamas and Ticunas.
Translation by Thomas S. Stack, M.D., Phil. Tr. Roy. Soc., London, 37:51-92, 1751.
9. Brocklesby RA. Letter to the President of the Royal Society concerning the Indian poison, sent over from M.
de la Condamine. Philosophical Transactions of the Royal Society of London 1747;44(ii):408.
10. Bancroft E. An essay on the natural history of Guiana and South America (London: T. Beckel & P.A. DeHont,
1769), p.286.
 BIBLIOGRAPHY

11. Humboldt AV, Bonpland A. Voyage aux régions équinoxiales du nouveau continent. Translation by A.R.
McIntyre, in Curare: Its History, Nature and Clinical Use. 5:ii, 1807.
12. Schomburgk R. On the urari, the arrow poison of the Indians of Guiana; with a description of the Plant from
which it is extracted. Ann. & Mag. Nat. Hist., 7:409, 1841.
13. Schomburgk R. Ralegh’s discovery of Guiana (London: Hakluyt Society, 1848), p.71n.
14. Brodie Sir BC. Further experiments and observations on the actions of poisons on the animal systems. Philos
Trans 102: 207-8, 1812.
15. Sykes K, Bunker J. Anesthesia and the Practice of Medicine: Historical Perspectives. London: Royal Society of
Medicine Press Ltd, 2007.
16. Dale H. Some Recent Extensions of the Chemical Transmission of the Effects of Nerve Impulses. The Nobel
Prize in Physiology or Medicine 1936. Nobel Lecture 1936.
17. Travers B. A further inquiry concerning constitutional irritation and the pathology of the nervous system.
London: Longman, Hurst, Rees, 1835; p.308-309.
18. Sayre LA, Burrall FA. Two cases of traumatic tetanus. New York Journal of Medicine, 4:250-253, 1858.
19. Editorial: Curare in tetanus. Lancet, 74:595-597, 1859.
20. Betcher AM. The civilizing of curare: a history of its development and introduction into anesthesiology.
Anesthesia and Analgesia, 56:305-319, 1977.
 BIBLIOGRAPHY

21. Gill RC. Curare: misconceptions regarding the discovery and development of the present form of the drug.
Anesthesiology, 7:14-24, 1946
22. McIntyre AR. Historical background, early use and development of muscle relaxants. Anesthesiology,
20:409-415, 1959.
23. Varney RF, Linegar CR and Holaday HA. The assay of curare by the rabbit “head-drop” method. JPET,
97:72-83, 1949.
24. Bennett AE. How ‘Indian arrow poison’ curare became a useful drug. Anesthesiology, 28:467-470, 1967.
25. Boehm R. Chemische Studien über das Curare. Translation by A.R. McIntyre, in Curare: Its History, Nature and
Clinical Use. (Leipzib, 1886), p.176.
26. Spath E, Leithe W, and Ladeck F. Curare alkaloids. I. Constitution of curine, Ber. d. deutsche Chem.,
61:1698-1709, 1928.
27. King H. Curare alkaloids. I. Tubocurarine, J. Chem. Soc., p.1381-89, 1935.
28. Wintersteiner O, Dutcher JD. Curare alkaloids from Chondodendron tomentosum. Science, 97:467-70, 1943.
29. Portion of an interview with Lewis H. Wright taped by David A. Davis, MD, Duke University, Durham, North
Carolina. Reproduced from Betcher AM, The civilizing of curare: a history of its development and
introduction into anesthesiology.
30. Griffith HR. Cyclopropane anesthesia: a clinical record of 350 administrations. Can Med Assoc J, 31:157-160,
1934.
 BIBLIOGRAPHY

31. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology, 3:418-420, 1942.
32. Cullen SC. The use of curare for the improvement of abdominal muscle relaxation during inhalation
anesthesia. Surgery, 14:261-266, 1943.
33. Gross EG, Cullen SC. The effects of anesthetic agents on muscular contraction. J Pharmacol Exp Ther,
7:358-365, 1943.
34. Barnes H. Use of curare for direct oral intubation. The Lancet, 241:478, 1943.
35. Smith SM, Brown HO, Toman JE, and Goodman LS. The lack of cerebral effects of d-tubocurarine.
Anesthesiology, 8:1-14, 1947.
36. Koelle GB. ‘Neuromuscular blocking agents’ in Louis Goodman and Alfred Gilman (editors), The
pharmacological basis of therapeutics, 5th ed., New York, Macmillan, 1975, p.575-588.