Drugs of Pain Relief

Question 1

Lecture Outcomes

Answer 1

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

Question 2

Aim of Lecture

Answer 2

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

Question 3

History of Morphine – the Oldest Drug?

Answer 3

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

Question 4

History of Morphine – Modern

Question 4

Harvesting Opium – A Specialist Task

Answer 4

 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)

Question 5

History of Morphine – Heroin

Answer 5

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)

Question 5

History of Morphine – The Opium Wars

Answer 5

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

Question 6

Early 20th C
Heroin Products
(USA)

Answer 6

soothing syrup

Question 6

History of Morphine – Military

Answer 6

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)

Question 7

History– The Opium Craze

Answer 7

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

Question 7

Types of Opioid Receptors photo

Answer 7

Question 7

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

Answer 7

it was fucking high

Question 8

19th C British Parliamentarian – William Wilberforce

Answer 8

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.”

Question 9

Types of Opioid Receptors

Answer 9

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)

Question 9

Heroin History – The US Experience

Answer 9

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

Question 10

The Science of Morphine: Pain Relief

Answer 10

 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)

Answer 11

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

Question 12

Opioid Addiction

Answer 12

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

Question 12

Morphine Mimics the Effects of Naturally-Occurring Endorphins

Answer 12

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

Question 13

morphine side effects

Answer 13

Question 13

Chemists have Created many Morphine-like Narcotic Analgesics photo

Answer 13

Question 14

Swinging Societal Attitudes towards Opioids photo

Answer 14

Question 14

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

Answer 14

Question 15

Medical Uses of Morphine & Opioid Analgesics

Answer 15

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)

Question 16

The Modern Opioid Epidemic

Answer 16

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

Question 17

NAS: A Sad Consequence of the Opioid Epidemic

Answer 17

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)

Question 17

Lecture Conclusions

Answer 17

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

Question 18

Further Reading

Answer 18

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.

Question 19

Lecture Outcomes

Answer 19

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

Question 20

Aim of Lecture

Answer 20

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

Question 20

Surgical Horrors before Anaesthetics - I: The Ancient World

Answer 20

“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

Question 21

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

Answer 21

* 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

Question 22

Surgical Horrors before Anaesthetics - III: Personal Account

Answer 22

“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

Question 23

A Ghastly Ordeal for Surgeon’s Too!

Answer 23

“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

Question 24

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

Answer 24

“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”

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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.

Question 26

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

Answer 26

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

Question 26

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

Answer 26

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

Question 26

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

Answer 26

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

Question 27

Medical Impact of Early General Anaesthetics

Answer 27

* 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)

Question 28

Modern General Anaesthetics Used in Australia

Answer 28

Question 28

Issues that Emerged with Early General Anaesthetics

Answer 28

* 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

Question 29

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

Answer 29

* 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

Question 30

How Do General Anaesthetics (GA) Work? photo

Answer 30

Question 30

How Do General Anaesthetics (GA) Work?

Answer 30

* 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!

Question 31

stages of Anaesthesia

Answer 31

Question 32

Three Key Goals in Modern Surgical Anaesthesia photo

Answer 32

Question 33

Typical Stages in Modern Anaesthesia

Answer 33

Question 34

Anaesthetics Machines - 100 Years of Technical Development

Answer 34

Question 35

Ongoing Challenges in Modern Anaesthesia

Answer 35

* 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

Question 36

Lecture Conclusions

Answer 36

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

Question 37

Further Reading

Answer 37

1) Aptowicz, CO (2014) Dr. Mutter's Marvels: A True Tale of Intrigue and Innovation at the Dawn of Modern Medicine, Avery. 2) Li, JJ (2006) Laughing Gas, Viagra & Lipitor, Chapter 7, OUP. 3) Sneader, W (2005) Drug Discovery – A History, p. 78-86, Wiley. 4) Snow, SJ (2008) Blessed Days of Anaesthesia: How Anaesthetics Changed the World, OUP. 5) Waller, DG et al (2021) Medical Pharmacology & Therapeutics, 6th ed., Chapter 17, Elsevier. 6) Whalen, K et al (2019) Pharmacology, Lippincott Illustrated Reviews, 7th ed., Wolters Kluwer.