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Lecture Outcomes

1) Describe key steps and processes involved in opium production
2) List significant historical and scientific events throughout the discovery,
development, and human use of opium
3) Describe the action of morphine on the human body and the main receptor
involved
4) Describe the harmful effects accompanying morphine abuse, the modern opioid
epidemic and its impact on society and individuals
5) Discuss the challenges involved in finding a balanced approach to opioid use

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Aim of Lecture

To explore the historical and
scientific factors surrounding
the discovery and human usage
of the powerful pain-relieving
drug morphine.

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History of Morphine – the Oldest Drug?

Derived from resin of opium poppy (papaver somniferum)
Distinct from common poppies
Long history of human usage
2100 BC
Sumerian clay tablet, one of the oldest lists of prescription
medicines
Hul Gil, the ‘joy plant.’
1500 BC
Greek statue with poppy seeds in hair and closed eyes
suggesting sedation
300 BC to 100 AC
Recommended for use before surgery by Greco-Roman
physicians such as Theophrastus, Celsus, Galen

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History of Morphine – Modern

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Harvesting Opium – A Specialist Task

 Wait 2 weeks after petals fall
 When pod turns dark & crown sticks up it is
lanced with a special knife (3-4 blades – cut
1-1.5 mm)
 Timing on the day is crucial & resin or sap
is allowed to seep overnight
 Pharmacological activity takes a few hours
to emerge
 Wait for sap to turn brown & sticky
 Scraped using a blunt knife (up to 5-6 times)

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History of Morphine – Heroin

1874
 Heroin - diacetylated morphine
 Invented in a UK pharmacy (Wright)
 Distasteful to his dogs!
1897
 Felix Hofmann prepared heroin at
Bayer (German company)
 Heinrich Dreser fanatically promoted
heroin as safe alternative to
morphine
 Widely sold OTC in USA, Europe, etc
 (e.g., cough mixture, “soothing syrups” for
children)

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History of Morphine – The Opium Wars

17th Century - British took control of Indian
opium-producing areas
1750 - Opium became main commodity of
British trade with China (1767:2000 chests/yr)
1839-1842 (First Opium War)
Begins after Lin Zexu, a Chinese commissioner,
confiscates illegal foreign opium imports
(Britain sent warships in response)
1856-1860 (Second Opium War)
Britain & France vs. China

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Early 20th C
Heroin Products
(USA)

soothing syrup

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History of Morphine – Military

1843
Dr Alexander Wood (Scottish) invents
hypodermic syringe
Pioneers i.v. morphine use (his wife fatally
overdosed!)
1859-1865 (US Civil War)
 ≈ 400,000 troops opium addicted
“The returning veteran … had a leather thong around
his neck and a leather bag (with) Morphine Sulfate
tablets, along with a syringe and a needle issued to
the soldier on his discharge…This was called the
“Soldier’s Disease.” (Gerald Starkey)

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History– The Opium Craze

17 and 18th Century Britain, etc
 Opium mainly prized for its analgesic effects
(presurgical and pre-antibiotic era - many people
lived with chronic painful ailments)
 High prevalence of tuberculosis (painful lung condition
– opium helped control pain)
 Also, toothache (widespread before modern dentistry)
Its euphoric effects also made opium popular
for recreational purposes
 Especially among elites - literati, intellectuals
 1821, Confessions of an English Opium Eater, Thomas
de Quincey

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Types of Opioid Receptors photo

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The Scale of 18th C Indian Opium Production [Dormandy (2012)]

it was fucking high

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19th C British Parliamentarian – William Wilberforce

Pioneering antislavery politician, social
activist, philanthropist (1759-1833)
1807 passage of his antislavery Bill “one of
the turning events in the history of the
world”
Took opium for 45 years (addicted)
Struggled with its hallucinatory powers
and its depressions
 Took opium before addressing British
House of Lords
”To that I owe my success as a
public speaker.”

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Types of Opioid Receptors

Inhibitory G-protein coupled receptors – contain around 400 amino acids and
7 transmembrane domains
3 major classes (90% of amino acids are identical in each)

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Heroin History – The US Experience

Early 20th century – major US epidemic
 1914, Harrison Narcotic Act (federal
regulation and taxation of opioids)
New York, 1915 -1920s, heroin black
market began (compact drug)
Emergence of i.v. heroin abuse
Addicts began collecting & selling scrap
metal (“junkies”)
 1922: NY, heroin linked to 260 murders
 1924, Congress banned heroin production

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The Science of Morphine: Pain Relief

 Morphine is the prototypical opiate and
our best analgesic (pain-relieving drug)
 Binds to opioid receptors in brain & spinal
cord (strong agonist)
 Inhibits transmission of pain signals
from periphery
 ↓ brain’s perception/awareness of pain
 Also causes euphoria (contentment &
wellbeing - major reason for abuse)
 This is different to analgesic NSAIDS (e.g.,
aspirin, ibuprofen) that suppress the
production of pain signalling molecules in
inflamed tissues (e.g. prostaglandins)

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Opioid Receptors are Mainly Located in the CNS, GI-Tract and
Nerve Endings in Peripheral Tissues

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Opioid Addiction

Definition: Compulsive use of drugs for
nonmedical reasons; it is
characterized by a craving for mood
altering drug effects, not pain relief.
 Morphine and related drugs have very high
addiction potential:
 Physical dependence and tolerance occur readily (i.e.
user needs higher doses to achieve euphoric
response)
 Also a high capacity for psychological dependence
 Withdrawal symptoms can be incapacitating
(but rarely fatal)
 Opioid addiction is damaging to individuals,
families, communities, etc
 Societal attitudes swing between libertarianism and
prohibition

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Morphine Mimics the Effects of Naturally-Occurring Endorphins

Endorphins (from endogenous & morphine) =
small neuropeptides
Made in CNS by controlled digestion of protein
precursor (pre-POMC)
Released during pain, pleasure & stress
An important family member is β–endorphin
Agonist at µ- & δ-opioid receptors
Suppress pain transmission but also cause
euphoria (e.g., exercise, etc)
 Short duration of effect
Quickly broken down by metabolism
Morphine has longer a duration of action

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morphine side effects

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Chemists have Created many Morphine-like Narcotic Analgesics photo

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Swinging Societal Attitudes towards Opioids photo

Narcotic Drugs Vary in the Timing of their Properties & Duration of Effect photo

Medical Uses of Morphine & Opioid Analgesics

Goals in Opioid Therapy:
 Pain relief
 Improved quality of life
 Improved functional capacity
Main Uses:
 Strong & moderate acute pain
 Palliative care (esp. cancer)
 Treatment of diarrhea
 Relief from coughing
 Use for chronic pain questionable (e.g., back pain)

The Modern Opioid Epidemic

In the USA:
 2.5 million people diagnosed with
opioid use disorder
 100K+ deaths annually from
opioid-related OD
 Opioids account for ≈75% of fatal
drug overdoses
 Fentanyl is major culprit currently
 Contribution of heroin declining

NAS: A Sad Consequence of the Opioid Epidemic

NAS: Neonatal Abstinence Syndrome
A drug-withdrawal syndrome in newborns due
to maternal use of opioids during pregnancy
 Symptoms (soon after birth):
 Irritability
 Poor sucking reflex
 Poor weight gain
 Seizures
 High muscle tone (hypertonia)
 Autonomic nervous system dysfunction
Major implications for neonatal intensive care
units (NICUs)
↑ hospitalisaRon of newborns
↑ cost of caring for newborns
Lifelong consequences for affected individuals
(ill health)

Lecture Conclusions

Human knowledge of opium poppy resin (papaver
somniferum) is >4000 years old
Early 19th C – extraction of morphine
Morphine a strong μ-receptor agonist that exerts analgesic
actions on pain-signalling neurons in the spinal cord and CNS
Many semisynthetic and synthetic narcotic analogues
available
Differ in receptor affinity, PK, adverse effect profiles, etc
 Significant side-effects include high abuse potential &
respiratory depression
 The modern opioid epidemic is the latest phase of humanity’s
long struggle in using these powerful drugs safely and effectively

Further Reading

1) Dormandy, T (2012) Opium: Reality’s Dark Dream, Yale.
2) Hirai, AH et al (2021) Neonatal Abstinence Syndrome and Maternal
Opioid-Related Diagnoses in the US, 2010-2017 JAMA. 325: 146-155.
3) Le Couteur, P and Burreson, J (2003) Napoleon’s Buttons: How 17
Molecules Changed History, p. 249-256.
4) Li, JJ (2006) Laughing Gas, Viagra & Lipitor, p. 162-163, OUP.
5) Somogyi, AA et al (2022) New pharmacological perspectives and
therapeutic options for opioids: Differences matter. Anaesth Intensive
Care 50: 127-140.
6) Tolia, VN et al (2015) Increasing incidence of the neonatal abstinence
syndrome in U.S. neonatal ICUs. NEJM 372: 2118-26.

Lecture Outcomes

1) recognise the dangerous and traumatic nature of surgical operations before the
discovery of general anaesthetics
2) describe 19th century scientists and clinicians and their roles in the discovery
of classic general anaesthetics N2O, CO2, ether, and chloroform
3) summarise benefits and problems that accompanied the introduction and
use of early general anaesthetics in the 19th century
4) describe the four classic stages of anaesthesia, the two broad groups of modern
general anaesthetics used in Australia and the general mechanism of action of many
modern general anaesthetics
5) describe six stages of modern anaesthesia during a modern surgical procedure
and the choice and purpose of drug co-administration
6) identify ongoing challenges confronting the use of general anaesthetics in modern
medicne

Aim of Lecture

To explore the historical,
scientific and clinical factors
surrounding the discovery and
development of general
anaesthetic (GA) agents

Surgical Horrors before Anaesthetics - I: The Ancient World

“The surgeons take great care to make the
patients bear the cutting quietly. They cut
as tenderly as possible, even giving in a
little, and giving time for the patient to
take a breath.” [While the subjects]
“wail
against those who are cutting them” …
[the surgeons] “ignore these things and
consider only the health of the patients.”
John Chrysostom
4th C Constantinople
Homilies

Surgical Horrors Before Anaesthetics – II: Early Modern Era (18th C)

Last resort (surgeons did operations rarely)
Brutal tools → severed =ssue fast!
Many “assistants” → pa=ent restraint
Hot cauterising tools (to stop blood loss)
Patient reflexes → risk of injuries
High mortality - blood loss & infections
Patients had to assume certain postures

Surgical Horrors before Anaesthetics - III: Personal Account

“A Terror which Passes all Description”
“Yet—when the dreadful steel was plunged into the
breast—cutting through veins—arteries—flesh—
nerves—I needed no injunctions not to restrain my
cries. I began a scream that lasted unintermittingly
during the whole time of the incision —& I almost
marvel that it rings not in my Ears still! So
excruciating was the agony.”
Fanny Burney
Endured a mastectomy, Sep 30, 1811, wrote her account 6
months later

A Ghastly Ordeal for Surgeon’s Too!

“When all was done, & they lifted
me up that I might be put to
bed… I then saw my good friend
Dr Larrey, pale nearly as myself,
his face streaked with blood, &
his expression depicting grief,
apprehension, & almost horror.”
Fanny Burney

Key Events in the 19th C Emergence of Modern Anaesthesia - I

“Laughing Gas” (Nitrous Oxide) Paves the Way
* A gaseous oxide of nitrogen (N2O)
* The only early agent still in wide use
* Isolated by Joseph Priestly in 1770s – “dephlogisticated
nitrous air”
* First animal studies by Humphrey Davy
* Pneumatic Institute, Bristol, UK
* Mice, fish, snails, earthworms, lizards - “seemingly dead”
* Fully recovered in shallow water
* But intense activity before insensibility
* Once satisfied of safety, Davy self- inhaled with very
pleasurable effects
* April 1799, inhaled 4 quarts from silk bag: “extraordinary
powers of action”

Key Events in the 19th C Emergence of Modern Anaesthesia - II

Carbon Dioxide and an Italian Dog’s Tale
* Odourless & colourless gas found in 1750s by Joseph Black
* Associated with “bad air” in mine shafts
* Grotto del Cane, Naples
* Tourist attraction at base of volcano
* CO2 released from fissures produced reversible collapse of
unfortunate dogs
* Henry Hill Hickman, young Shropshire surgeon, 1824
* Began studies of “torpid state” in CO2-exposed dogs, mice,
rabbits
* Surgically removed limbs, dressed wounds, etc before animals
recovered
* Noted absence of pain response to knife
* Met enormous clinical resistance

Key Events in the 19th C Emergence of Modern Anaesthesia - III

A Public Demonstration & An Observant Dentist
* 1844, Gardner Quincy Colton began public
demonstrations of Laughing Gas in USA (attracted 1000’s)
* 10 Dec, Hartford, CT, dentist named Horace Wells in
attendance at show
* Noted pain insensibility of N2O-treated man
* Injured shin while running amuck
* Colton helped Wells make N2O gas
* Then anaesthetic effects noted during a tooth extraction
* Premature public demonstration at Massachusetts
General Hospital went badly (Wells blamed his
nerves!)
* “no-one was inclined to assist me in further
experiments”
* Committed suicide 33 y.o.

Key Events in the 19th C Emergence of Modern Anaesthesia - IV

Friday October 16, 1846
Ether and a Dentist’s Success
* New dental technology (“false teeth”) created need for
safer extractions Dentists wanted patients to return!
* Diethyl ether (CH3CH2OCH2CH3) 16th C
* Sold as a stimulant “Sweet Vitriol”
* 1842, Dr Crawford Long began using ether for surgery
(rural GA, US)
* 1846, William Thomas Green Morton used ether for
public demo of cranio-facial surgery at Massachusetts GH
* Excised tumour from Edward Abbott’s jaw
* Had tested ether privately for 2 y
* A better showman than Wells!
* Involved in protracted patent battles

Key Events in the 19th C Emergence of Modern Anaesthesia - V

Stodgy London GP Pioneers Scientific Study of Ether
* Ether was unpredictable clinically:
* Caused initial excitement in many patients
* Patients perceived as noxious & pungent
* Didn’t always achieve pain-free state
* Some patients woke too soon
* No standardised delivery tools (volatile)
* “No-one has yet determined even the proper dose of ether to be
given” (Boullay)
* John Snow studied the physical-chemical properties of ether
* E.g., effect of temperature on vaporisation
* Developed temp-controlled metal inhaler
* 1847 - On the Inhalation of Ether in Surgical Operations
identified 4 stages of anaesthesia

Key Events in the 19th C Emergence of Modern Anaesthesia - VI

Breakthrough Discovery of Chloroform by Scottish Obstetrician
James Young Simpson
* Edinburgh, Scotland
* Frustrated by ether limitations
* Search for other anaesthetics
* David Waldie, chemist, suggested
chloroform (CHCl3)
* 4 Nov, 1847, Simpson and 2
assistants discovered chloroform
anaesthesia during “after-dinner”
testing
* Soon became popular with UK
surgeons including John Snow
* Made modern surgical era
possible

Medical Impact of Early General Anaesthetics

Allowed reversible unconsciousness with:
Amnesia (no memory of procedure),
Akinesia (no involuntary movements)
Analgesia (no pain sensation)
Surgery much safer for patients & doctors
Big impact on civilian & military medicine
Surgeons developed new tools and skills (more like cutting
a motionless cadaver!)
By reducing traumatic experiences for all parties, allowed
incremental attention to other problems (e.g., sterility,
pain, etc)
Emergence of anaesthesiology as a clinical speciality (more
focus on better gas delivery & patient monitoring during
surgery)

Modern General Anaesthetics Used in Australia

Issues that Emerged with Early General Anaesthetics

Ether & chloroform provided an unpleasant clinical
experience for many patients:
Slow onset of action
Slow recovery of consciousness
Unpleasant taste
Explosions in theatres (esp. ether)
Liver and heart toxicity (chloroform)
Post-operative side effects
Potential for drug abuse & dependence
Potential for criminal abuse:
“Chloroform muggings” – e.g. 1850 assault on elderly
clergyman provoked public outrage [Kendal, UK]
Sexual assaults on female patients by doctors and dentists

The Hunt for a Perfect Inhalational (“Gas”) Anaesthetic

Chemically stable
Non-flammable/non-explosive
Potent, allowing mixing with O
2
Low blood solubility
Hastens induction & recovery (less hangover)
Non-toxic/non-irritant to airways
Minimal impact on heart function
Easily reversible
Analgesic
Minimal interactions with other drugs
Inexpensive

How Do General Anaesthetics (GA) Work? photo

How Do General Anaesthetics (GA) Work?

Complex effects on nerve cells underlie GA-induced
loss of consciousness
“Membrane effect” theory unpopular
No “common receptor” for all anaesthetic agents
Multiple mechanisms likely
BUT, at clinically-used concentrations, many GA’s
↑ the
sensitivity of inhibitory GABA
A receptors on brain cells to
inhibitory neurotransmitter γ–amino-butyric acid (GABA)
Opens GABA receptor channel, increasing chloride ion
(Cl
-) flow into cell, making it “hyperpolarised”
Harder for brain cell to transmit electrical impulses
(depolarise)
This inhibitory effect results in depression of nerve cell
activity
Note: Ketamine & N
2O don’t affect activity of GABA
A-receptors!

stages of Anaesthesia

Three Key Goals in Modern Surgical Anaesthesia photo

Typical Stages in Modern Anaesthesia

Anaesthetics Machines - 100 Years of Technical Development

Ongoing Challenges in Modern Anaesthesia

Avoiding malignant hyperthermia (very rare)
Extreme rise in body temperature due to “meltdown” in
skeletal muscles (excessive metabolism due to CaII influx)
Associated mainly with volatile anaesthetics
Heritable with a strong genetic basis
Minimising organ damage
Rare but can involve harm to heart, liver, kidneys, etc
Understanding & minimising long term effects
E.g. Neurocognitive impact in elderly
Limit environmental impact of spent gases
Well-trained workforce & well-equipped hospitals
Modernisation of facilities & replacing aged equipment

Lecture Conclusions

Few discoveries in pharmaceutical innovation
history have more profoundly improved
human wellbeing
Radical improvements in surgery and postoperative outcomes for patients
Balanced and judicious mixing of gaseous and
injectable anaesthetics as appropriate for
particular surgical scenarios
 E.g., short- versus long-term procedures
Ongoing challenges mainly include
improvement in drugs & procedures to
minimise post-operative harm

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Drugs of Pain Relief Flashcards

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