Opiates and Opiate Pharmacology: A Research Perspective

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Opiates and Opiate Pharmacology A Research
Perspective

• D John Doyle MD PhD FRCPC
• Professor of Anesthesia
• November 3, 2006

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Download this talk at opiateresearch.homestead
.com
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Outline

• History
• Kinds of opiates
• Opiates vs. Narcotics (and Psychotic vs. Insane)
• Opiates and pain management
• Opiate receptors
• Opiates and the brain
• Opiates and respiratory depression
• Opiates and addiction
• Opiates and social policy
• Opiates and the search for artificial bliss

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Journal Reports

• Laboratory Investigations
• Clinical Trials (many types)
• Classical Reviews
• Systematic Reviews
• Best Evidence Reports
• Case Reports
• How I Do It Reports
• Safety Reports
• Pro / Con Debates
• Editorials
• Advocacy Pieces
• Statement of Hypotheses
• Letters to the Editor

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Some Journal Types

• Peer-reviewed journals
• Unreviewed paper archive collection
• Open peer commentary journals
• Open-access journals
• Medical education journals
• Newsletters
• Internet discussion forums

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Opiates
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• The sedative, analgesic, and euphoric effects of
  opioids have been known since antiquity. First
  described by the Sumerians some 6,000 yr ago, the
  euphoric and analgesic properties of the seed-pod
  exudate of papaver somniferum are described in
  Homer's Iliad and were well known to physicians
  by the time of Hippocrates (460-377 B.C.E.).
  However, since the time of Pliny the Elder (23-79
  C.E.), it has also been known that opioids may
  produce life-threatening respiratory depression,
  which limits both their utility and their safety.
  
• From Anesthesiology Volume 99(4) October 2003
  pp 767-770

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Papaver Somniferum
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Opiates vs. Narcotics (and Psychotic vs. Insane)

• Opiate binds to opiate receptors
• Narcotic legal term U.S. Controlled Substances
  Act
• Example Cocaine is a narcotic but not an
  opiate
• Psychotic clinical term
• Insane legal termA person is insane, and is
  not responsible for criminal conduct if, at the
  time of such conduct, as a result of a severe
  mental disease or defect, he was unable to
  appreciate the nature and quality or the
  wrongfulness of his acts. This is because
  willfull intent is an essential part of most
  offenses and a person who is insane is not
  capable of forming such intent. Mental disease or
  defect does not otherwise constitute a defense
  the person has the burden of proving the defense
  of insanity by clear and convincing evidence.

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Opium Products
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Grow your own poppies!!
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Laudanum is an opium tincture, sometimes
sweetened with sugar and also called wine of
opium. It contains the equivalent of 10
milligrams of morphine per milliliter. Laudanum's
weaker cousin, paregoric, also known as
camphorated tincture of opium, is 1/25th the
strength of laudanum, containing only 0.4
milligrams of morphine per milliliter.
1 grain 65 mg
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1 grain 65 mg
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Opium Wars

• The Opium Wars were two wars fought in the
  mid-1800s that were the climax of a long dispute
  between Britain and China concerning around the
  opium trade. The Chinese Emperor had banned opium
  in China due to its harmful effects on Chinese
  citizens and on Chinese culture the British
  Empire, however, saw opium as a profitable good
  for commercial trade, as its import would help
  balance Britain's huge trade deficit with China.
  The Opium Wars and the unequal treaties signed
  afterwards led in part to the downfall of the
  Chinese Empire, as many countries followed
  Britain and forced more treaties to increase
  trade within China.
• Modified from http//en.wikipedia.org/wiki/Opium_
  wars

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Early victims of the War On Drugs. A
battle-scene from the First Chinese Opium War
(1839-42)
http//opioids.com/images/opiumwar.html
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DEA Schedule of Drugs
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Morphine Morphine was first isolated in 1804 by
the German pharmacist Friedrich Wilhelm Adam
Sertürner, who named it "morphium" after
Morpheus, the Greek god of dreams. But it was not
until the development of the hypodermic needle
(1853) that its use spread.
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"For instance, carfentanil is approximately 4000
times as potent as heroin and has an extremely
favorable therapeutic index .... Hence, an easy
week's work for two chemists could provide 1
(one) kilogram of carfentanil which would be
equivalent to four metric tons of pure
heroin Donald A. Cooper (DEA) in "Future
Synthetic Drugs of Abuse
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Carfentanil synthesis 1 http//designer-drug
s.com/pte/12.162.180.114/dcd/chemistry/carfentanil
.html 2 US Pat. 5,106,983
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It is thought that in the 2002 Moscow theater
hostage crisis, the Russian military made use of
an aerosol form of carfentanil to subdue Chechen
hostage takers. Its short action, easy
reversability and excellent therapeutic index
(10600 vs. 300 for fentanyl) would make it a
near-perfect agent for this purpose. Wax et al.
(Ann Emerg Med 200341700-5. ) surmise that the
Moscow emergency services had not been informed
of the use of the agent, and therefore did not
have adequate supplies of naloxone or naltrexone
(opioid antagonists) to prevent complications in
many of the victims.
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Opiate Receptors

• Discovered by Solomon Snyder and others in the
  1970s
• Discovery inspired by the teleological question
  why do drugs like morphine have the effect they
  do? (Endogenous opiate hypothesis)
• The endogenous opioid classes are dynorphins,
  enkephalins and endorphins.

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Solomon Snyder Many advances in molecular
neuroscience have stemmed from Dr. Snyder's
identification of receptors for neurotransmitters
and drugs and elucidation of the actions of
psychotropic agents.   He pioneered the labeling
of receptors by reversible ligand binding in the
identification of opiate receptors and extended
this technique to all the major neurotransmitter
receptors in the brain.   Discovering that
human brains contain receptors to opiates such as
heroin or morphine was another significant find.
It led him and others to "natural" opiates, the
enkephalins and endorphins that form the basis of
the "runner's high." In 1978, the opiate work won
Snyder a shared Lasker Award, the USAs highest
medical research honor.
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Opioid Receptors

• There are three major subtypes of opioid
  receptors µ (mu), ? (kappa), and d (delta). The
  receptors were named using the first letter of
  the first ligand that was found to bind to them.
  Morphine was the first chemical shown to bind to
  mu receptors. The first letter of the drug
  morphine is m'. But in biochemistry there is a
  tendency to use Greek letters so they converted
  the 'm' to µ. Similarly a drug known as
  ketocyclazocine was first shown to attach itself
  to kappa receptors. (http//en.wikipedia.org/wik
  i/Opioid_receptor)

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• Pasternak GW. Pharmacological mechanisms of
  opioid analgesics. Clin Neuropharmacol. 1993
  Feb16(1)1-18. The description of multiple
  classes of opioid receptors has had a major
  impact on our understanding of the mechanisms of
  analgesia. Three major classes of opioid
  receptors have been defined mu, kappa, and
  delta. The mu receptors have been further
  subclassified into two distinct subtypes (mu 1
  and mu 2), as have the delta receptors (delta 1
  and delta 2). Kappa receptors have been
  subdivided into kappa 1, kappa 2, or kappa 3
  subtypes. All of these subtypes modulate pain
  perception, with the exception of the kappa 2
  receptor, which has not been adequately examined.
  Supraspinal systems have been described for mu 1,
  kappa 3, and delta 2 receptors while mu 2, kappa
  1, and delta 1 receptors modulate pain at the
  spinal level. In addition to their ability to act
  independently, the various systems also interact
  synergistically with each other. Thus, the relief
  of pain involves the complex interaction of at
  least six receptor systems. This review discusses
  the implications of opiate receptor multiplicity
  on the control of pain.

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• Activation of the mu receptor by an agonist such
  as morphine causes analgesia, sedation, reduced
  blood pressure, itching, nausea, euphoria,
  decreased respiration, miosis (constricted
  pupils) and decreased bowel motility often
  leading to constipation.
• Some of these effects, such as sedation, euphoria
  and decreased respiration, tend to disappear with
  continued use as tolerance develops.
  (http//en.wikipedia.org/wiki/Opioid_receptor)

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Tentative Classification of Opioid Receptor Subtypes and Their Actions Tentative Classification of Opioid Receptor Subtypes and Their Actions Tentative Classification of Opioid Receptor Subtypes and Their Actions Tentative Classification of Opioid Receptor Subtypes and Their Actions Tentative Classification of Opioid Receptor Subtypes and Their Actions Tentative Classification of Opioid Receptor Subtypes and Their Actions
RECEPTOR ANALGESIA RESPIRA- TORY GASTRO INTESTINAL ENDOCRINE OTHER
? Peripheral ? Gastric secretion ? GI transit - supraspinal and peripheral Antidiarrheal Skeletal muscle rigidity Pruritus ? Urinary retention (and/or ?) Biliary spasm (probably gt1 receptor type)
? Supraspinal Prolactin release Acetylcholine turnover Catalepsy
?2 Spinal Supraspinal Respiratory depression ? GI transit spinal and supraspinal Most cardiovascular effects
? Peripheral ? ADH release Sedation
?1 Spinal
?2 ? (Pharmacology unknown)
?3 Supraspinal
? Peripheral ? Respiratory depression ? GI transit spinal Antidiarrheal spinal and supraspinal ? Growth hormone release ? Urinary retention (and / or ?)
?1 Spinal Dopamine turnover
?2 Supraspinal
Unknown (receptor type not indentified) Supraspinal Pupillary constriction Nausea and vomiting
Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993. Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993. Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993. Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993. Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993. Adapted from Pasternak GW Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 161, 1993.
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Morin-Surun MP, Boudinot E, Gacel G, Champagnat
J, Roques BP, Denavit-Saubie M. Different effects
of mu and delta opiate agonists on respiration.
Eur J Pharmacol. 1984 Feb 1798(2)235-40. The
involvement of different opiate receptor subtypes
in opiate-induced respiratory depression was
studied in the unanaesthetized rat. Synthetic
opioid agonists, specific for mu or delta
receptors, were administered intraperitoneally in
freely moving rats while respiratory parameters
were recorded by means of the whole body
plethysmographic method. TRIMU-4
(Tyr-D-Ala-Gly-NH-CH(CH3)-CH2-CH(CH3)2), a
specific agonist of the mu receptor, reduced the
tidal volume and did not change the respiratory
frequency. DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr), a
relatively specific agonist of the delta receptor
subtype, reduced respiratory frequency and was
significantly less effective on tidal volume than
was TRIMU-4. It is concluded that the respiratory
depression occurring after the administration of
opiates in clinical practice is a dual
complementary effect involving mu and delta
receptors.
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Mu Opiate Receptor
Source Goodman and Gillman 9th ed, p. 526
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A map of the brain showing the concentration of
mu receptors. The red, orange and yellow areas
have the highest concentrations of mu receptors,
and therefore the most activity of opioid
chemicals.
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Mu Receptor - Transmembrane View
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The opioid receptors belong to the G
protein-coupled receptor family. Opioid agonists
like morphine bind to opioid receptors, leading
to activation of the G-protein. Activity of
adenylate cyclase and the voltage-dependent Ca2
channels is suppressed, while inward rectifier K
channels and the mitogen-activated protein kinase
(MAPK) cascade are activated. Chronic exposure of
the opioid receptors to agonists induces cellular
adaptation mechanisms, which may be involved in
opioid tolerance, dependence, and withdrawal
symptoms.
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G protein-coupled receptors
Schoneberg, T., et al., Structural basis of G
protein-coupled receptor function. Mol. Cell.
Endocrinol., 151, 181-193 (1999). LeVine, H.,
3rd., Structural features of heterotrimeric G
protein-coupled receptors and their modulatory
proteins. Mol. Neurobiol., 19, 111-149
(1999). Morris, A.J., et al., Physiological
regulation of G protein-linked signaling.
Physiol. Rev., 79, 1373-1430 (1999).
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Other Kinds of Receptors

• The cannabinoid receptors are a class of
  receptors under the G-protein coupled receptor
  superfamily. Their ligands are known as
  cannabinoids.
• There are currently two known subtypes, CB1 which
  is expressed mainly in the brain, but also in the
  lungs, liver and kidneys and CB2 which is mainly
  expressed in the immune system and in
  hematopoietic cells.
• Mounting evidence suggests that there are novel
  cannabinoid receptors, that is, non-CB1 and
  non-CB2, which are expressed in endothelial and
  CNS. However, these have not been cloned yet.
• From http//en.wikipedia.org/wiki/Cannabinoid_
  receptor

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Kinds of Opiates

• Pure Opiate Agonists(e.g., morphine)
• Mixed Agonist / Antagonists (e.g., nalbuphine)
• Opiate Antagonists (e.g., naloxone (Narcan))

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Opiate Agonists (partial list)

• Opium
• Pantopon
• Morphine
• Meperidine (Demerol )
• Hydrocodone
• Hydromorphone (Dilaudid)

• Heroin
• Methadone
• Oxycodone
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil
• Carfentanil

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Why Opiates?

• Particularly effective in treating severe pain
  (kidney stones, orthopedic surgery)
• Dirt cheap (morphine 10 mg IV costs under 25
  cents)
• Effective in lower doses when used in conjunction
  with less effective analgesics (e.g.,
  acetaminophen, NSAIDs)
• Remarkably nontoxic to liver, kidneys
• BUT ..

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Problems with Opiates

• Respiratory depression
• Addiction / dependence
• Less important issues
• Constipation
• Itching
• Nausea / vomiting
• Mental clouding

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Celebrity Heroin Overdoses

• Jonathan Melvoin 34, keyboardist for the rock
  band Smashing Pumpkins
• Brad Nowell 28, vocalist for the punk rock band
  Sublime
• Kristin Pfaff 27, bass player with the grunge
  rock band Hole
• River Phoenix 23, film star of such movies as
  My Private Idaho, of a drug overdose. Autopsy
  blood test verified the presence of lethal levels
  of heroin, cocaine, alcohol and valium in his
  blood at the time of death.
• Stefanie Sargeant 25, guitarist with the grunge
  rock band 7 Year Bitch
• John Belushi 33, star of Animal House and
  Saturday Night Live, of a drug overdose after
  injecting a heroin-cocaine mixture commonly
  called a speedball.
• Darby Crash 22, lead vocalist for the punk rock
  band Darby Crash The Germs
• Sid Vicious 21, bass player for the punk rock
  band The Sex Pistols
• Janis Joplin 30, legendary rock star found dead
  at Hollywoods Landmark Hotel

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Heroin Users Warned About Deadly Additive

• By Peter Slevin and Kari Lydersen
• Washington Post June 4, 2006
• CHICAGO -- The largest clue that something had
  changed in Chicago's vibrant heroin market came
  in February, when police found a dozen users
  sprawled unconscious in one place. One day in
  April, there were dozens more.
• Toxicologists at the Cook County morgue
  discovered fentanyl, a powerful painkiller many
  times stronger than morphine, in the bodies of
  addicts who died. A small amount of fentanyl in a
  dose of heroin adds a pop that many users have
  come to crave.

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CMAJ September 19, 2000 Battling opiate
overdoses D. John Doyle I thoroughly
enjoyed your recent articles on substance abuse
in the June 13 issue of CMAJ, especially Kyle
Stevens' essay. I cannot help but think that if
the narcotic antagonist naloxone was made readily
available to heroin addicts and others as a harm
reduction measure (perhaps as an expansion of a
needle exchange program) there would be fewer
deaths from opiate overdose. After all, most
addicts would have little trouble subcutaneously
or intravenously injecting naloxone into an
unresponsive friend while awaiting a 911
response, and the drug would certainly not be
used for recreational purposes. Indeed, this idea
is being seriously explored in the addiction
literature.
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• BEST EVIDENCE TOPIC REPORT
• Emergency Medicine Journal 200623221-223
• Intranasal naloxone in suspected opioid overdose
  
• ABSTRACT
• A short cut review was carried out to establish
  whether intransasal naloxone is effective in
  suspected opiate overdose. 596 papers were
  screened, of which eight presented the best
  evidence to answer the clinical question. The
  author, date and country of publication, patient
  group studied, study type, relevant outcomes,
  results and study weaknesses of these best papers
  are tabulated. The clinical bottom line is that
  it is likely that intranasal Naloxone is a safe
  and effective first line prehospital intervention
  in reversing the effects of an Opioid overdose
  and helping to reduce the risk of needle stick
  injury. A large, well conducted trial into its
  usage is however required to confirm this.

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Rapid Opiate Detoxification And Naltrexone
Induction

• Rapid Opiate Detoxification is a method of
  rapidly detoxifying the body of opiates without
  the patient experiencing significant
  withdrawal. This is done under general anesthesia
  and takes 4 to 8 hours.
• Being unconscious, the patient does not
  experience the agonizing withdrawal symptoms of
  quitting "cold turkey reducing the potential of
  an individual returning to using as a result of
  the withdrawal symptoms.

AAROD Anesthesia Assisted Rapid Opiate
Detoxification
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Rapid Opiate Detoxification Too Good to Be
True?

• Induce general anesthesia, including IV access,
  tracheal intubation, positive pressure
  ventilation, full monitoring
• Titrate in large dose of IV naltrexone or
  naloxone to displace all opiates from the
  receptors
• Manage the resulting metabolic / hemodynamic
  storm with vasodilators, beta blockers and other
  drugs (akin to a pheochromcytoma storm)
• 8 hours later, wake up the now detoxified patient
• BUT

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Opiates in Pain Management
Landmine Injury (www.trauma.org)
MEPERIDINE
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Classes of Analgesics The WHO Pain Management
Ladder
WHO has developed a four-step "ladder" for pain
relief. If pain occurs, there should be prompt
oral administration of drugs in the following
order 1 nonopioids (aspirin and
acetaminophen) then, as necessary, 2 mild
opioids (codeine) then 3 strong opioids such
as morphine, until the patient is free of pain.
To calm fears and anxiety, additional drugs
adjuvants should be used.  To maintain
freedom from pain, drugs should be given by the
clock, that is every 3-6 hours, rather than on
demand. Surgical intervention on appropriate
nerves may provide further pain relief if drugs
are not wholly effective Step 4.
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http//www.childcancerpain.org/IMAGES/steps_1.gif
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Postop Pain TherapyExamples

• Tylenol 3 1 to 2 tabs PO q4h prn
• Morphine 5-10 mg IM or SQ q4h prn
• Morphine 2-4 mg IV q1h prn
• Meperidine 100 mg IM q3h prn
• Morphine 5 mg via epidural catheter q12h
• Morphine IV PCA 1.5 mg IV with lockout 6 minutes
  and max hourly dose of 10 mg.

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Patient Controlled Analgesia
61
CMAJ March 6, 2001 164 (5) Patient-controll
ed analgesia. D. John Doyle and Kim J. Vicente
Patient-controlled analgesia (PCA) is a
computer-based medical technology now used
extensively in Canada to treat postoperative
pain. A typical PCA machine contains an embedded
microcomputer programmed to give, for instance, 1
mg of morphine intravenously every time the
patient pushes a button on the end of a cable. To
prevent excessive drug administration, the
onboard computer ignores further patient demands
until a lockout period (usually set for 510
minutes) has passed. Recently, the Institute
for Safe Medication Practices reported that a
patient had received a lethal morphine overdose
while connected to the Abbott Lifecare 4100 PCA
Plus II machine. This machine is easily
misprogrammed by caregivers, who must manually
enter the PCA parameters, and it needs a more
sensible and forgiving user interface. A number
of patients have received opiate overdoses as a
result of PCA errors insertion of a 5 mg/mL
morphine cartridge when the machine is expecting
a 1 mg/mL concentration, or acceptance of the
default (initial) drug concentration when the
correct action is to scroll up to the correct
value, among other errors. In 1997, ECRI
documented 3 deaths that occurred while patients
were connected to the Lifecare 4100.5 In at least
2 of the cases, the alleged reasons for the
deaths were the same. In the mode of operation in
use, when nurses program the drug concentration
the Lifecare 4100 display shows a particular
concentration (e.g., 0.1 mg/mL). Nurses can
either accept this initially displayed value or
modify it using the arrow controls. The critical
flaw in the design is that in this situation the
Lifecare 4100 offers the minimal drug
concentration as the initial choice. If nurses
mistakenly accept the initially displayed minimal
value (e.g., 0.1 mg/mL) instead of changing it to
the correct (and higher) value (e.g., 2.0 mg/mL),
the machine will "think" that the drug is less
concentrated than it really is. As a result, it
will pump more liquid, and thus more narcotic,
into the patient than is desired. The purpose
of this letter is to warn clinicians of
continuing fatal drug overdoses from the Abbott
Lifecare 4100 PCA Plus II machine. If you use
this machine, please contact your risk management
officer and your biomedical engineering
department for advice. Fortunately, Abbott is not
the only supplier of PCA machines. We have
informed American and Canadian regulatory
authorities they are, of course, now studying
the problem.
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What is Action Research?

• Action research is often aimed at achieving a
  particular social goal, such as eliminating
  disparities in access to health care or improving
  patient safety

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Canadian Journal of Anesthesia 50328-332 (2003)
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Canadian Journal of Anesthesia 50328-332 (2003)
Purpose To identify the factors that threaten
patient safety when using patient-controlled
analgesia (PCA) and to obtain an evidence-based
estimate of the probability of death from user
programming errors associated with PCA.
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Canadian Journal of Anesthesia 50328-332 (2003)
Clinical features A 19-yr-old woman underwent
Cesarean section and delivered a healthy infant.
Postoperatively, morphine sulfate (2 mg bolus,
lockout interval of six minutes, four-hour limit
of 30 mg) was ordered, to be delivered by an
Abbott Lifecare 4100 Plus II Infusion Pump. A
drug cassette containing 1 mgmL-1 solution of
morphine was unavailable, so the nurse used a
cassette that contained a more concentrated
solution (5 mgmL-1). 7.5 hr after the PCA was
started, the patient was pronounced dead. Blood
samples were obtained and autopsy showed a toxic
concentration of morphine. The available evidence
is consistent with a concentration programming
error where morphine 1 mgmL-1 was entered
instead of 5 mgmL-1. Based on a search of such
incidents in the Food and Drug Administration MDR
database and other sources and on a denominator
of 22,000,000 provided by the device
manufacturer, mortality from user programming
errors with this device was estimated to be a low
likelihood event (ranging from 1 in 33,000 to 1
in 338,800), but relatively numerous in absolute
terms (ranging from 65667 deaths).
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Canadian Journal of Anesthesia 50328-332 (2003)
Conclusion Anesthesiologists, nurses, human
factors engineers, and device manufacturers can
work together to enhance the safety of PCA pumps
by redesigning user interfaces, drug cassettes,
and hospital operating procedures to minimize
programming errors and to enhance their detection
before patients are harmed.
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• Correspondence
• Programming errors from patient-controlled
  analgesia
• Jonathan D. Lamb, MD FRCPC
• To the Editor
• I read with interest this case report of the
  tragic death of a young woman while receiving
  patient-controlled analgesia (PCA) post-Cesarean
  delivery. The authors conclude their report with
  several recommendations. These are all very
  sensible. The most important recommendation, not
  mentioned however, concerns the initial nursing
  assessment of a loudly snoring and unarousable
  patient while receiving PCA on the ward. This
  obviously can be an urgent and life-threatening
  situation which must be dealt with expeditiously.
  Typically a nursing protocol exists which
  provides for an immediate and effective response.
  Did this not exist, or, if so, was it not
  followed? A different and more favourable outcome
  might have resulted.
• An astute and appropriately trained nurse is the
  last line of defense for a wide range of untoward
  and potentially critical situations, such as
  could arise from a PCA programming error. This,
  in my opinion, is the paramount message in this
  tragic case, and not the programming error
  itself.
• Reference
• Vicente KJ, Kada-Bekhaled K, Hillel G, Cassano
  A, Orser BA. Programming errors contribute to
  death from patient-controlled analgesia case
  report and estimate of probability. Can J Anesth
  2003 50 32832.

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D. John Doyle, MD PhD Programming errors from
patient-controlled analgesia Canadian Journal of
Anesthesia 50855-856 (2003)
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Fentanyl Lolipop
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Fentanyl Patch
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Iontophoresis
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CO2 Response Curve

• Normal PCO2 maintained at 40 mmHg
• If PCO2 incrementally increases (e.g., from
  increased CO2 production due to increased
  metabolic rate), alveolar ventilation will
  increase to blunt the rise in PCO2
• If PCO2 incrementally decreases (e.g., from
  decreased CO2 production due to decreased
  metabolic rate), alveolar ventilation will
  decrease to blunt the drop in PCO2

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Anesthesiology Volume 99(4) October 2003 pp
767-770 Curve A represents the normal carbon
dioxide response of an awake individual the
hockey stick appearance at low values of Paco2
corresponds to the observation that following
hyperventilation, awake individuals do not become
apneic but rather show a modest decrease in VE
until Paco2 returns to its resting value. Curve B
represents the carbon dioxide response curve
following administration of a sedative or
anesthetic medication, which decreases its slope
by 50. Note that the curve no longer has a
hockey stick shape but rather falls linearly to a
VE of 0 (the apneic threshold). Once apnea
develops, the Pco2 must increase to approximately
the resting value before ventilation restarts,
accounting for the hysteresis loop (line B).
Curve C represents the carbon dioxide excretion
hyperbola, which depends on the principle of
conservation of mass Assuming constant carbon
dioxide production, increasing VE will decrease
Paco2, whereas decreasing VE tends to increase
Paco2. In the awake state, point X (the
intersection of carbon dioxide response curve A
with carbon dioxide excretion hyperbola C)
defines the resting Paco2 and VE, whereas point Y
represents the values of Paco2 and VE during
sedation or anesthesia.
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Opiates and the search for artificial bliss
76

• "If we could sniff or swallow something that
  would, for five or six hours each day, abolish
  our solitude as individuals, atone us with our
  fellows in a glowing exaltation of affection and
  make life in all its aspects seem not only worth
  living, but divinely beautiful and significant,
  and if this heavenly, world-transfiguring drug
  were of such a kind that we could wake up next
  morning with a clear head and an undamaged
  constitution - then, it seems to me, all our
  problems (and not merely the one small problem of
  discovering a novel pleasure) would be wholly
  solved and earth would become paradise."
• ALDOUS HUXLEY1894 - 1963

77

• "If it was possible to become free of negative
  emotions by a risklessimplementation of an
  electrode - without impairing intelligence and
  the critical mind - I would be the first
  patient."
• Dalai Lama (Society for Neuroscience Congress,
  Nov. 2005)

78
Scientists investigating which brain structures
may be involved in the human drug reward system
have learned a great deal from studies with rats.
Because the chemistry of the human brain and the
rat brain is similar, they believe that the
process of drug addiction may be the same for
both. The illustrations shown here use
information gathered from animal studies to show
what areas may be involved in reward systems in
the human brain. http//www.nida.nih.gov/nida_n
otes/NNVol11N4/Brain.html
79
Nucleus Accumbens

• "At a purely chemical level, every experience
  humans find enjoyable - whether listening to
  music, embracing a lover, or savoring chocolate -
  amounts to little more than an explosion of
  dopamine in the nucleus accumbens as exhilarating
  and ephemeral as a firecracker."
• J Madelaine Nash

80
Clinical Study for Alleviating Opiate Drug
Psychological Dependence by a Method of Ablating
the Nucleus Accumbens with Stereotactic Surgery

• Stereotact Funct Neurosurg. 200381(1-4)96-104
  ABSTRACT
• The aim of this study was to explore a new way
  of treating drug addiction by ablating the
  nucleus accumbens (NA(C)), which has a close
  relationship with drug-induced psychological
  dependence, using stereotactic surgery, blocking
  the mesocorticolimbic dopamine circuit,
  alleviating craving for drugs and lowering the
  relapse rate after detoxification. On the basis
  of animal experiments, stereotactic surgery was
  performed in 28 patients by making a lesion in
  the NA(C) bilaterally to treat opiate drug
  dependence. Indications, the criterion of
  therapeutic effect, treatment process and the
  therapeutic and safety evaluation index of the
  surgery were formulated particularly. The mean
  follow-up period was 15 months. Relapse has not
  occurred in 11 cases up till now. Drug-free time
  in these patients has been more than half a year
  in 4 cases (more than a year in 3 cases), and
  less than half a year in 7 cases. Relapse
  occurred in 15 cases after surgery. Drug-free
  time in these patients was more than half a year
  in 3 cases, between 1 month and half a year in 10
  cases and less than 1 month in 2 cases. The
  therapeutic effect was excellent in 7 cases
  (26.9), good in 10 cases (38.5) and poor in 2
  cases (7.7). Another 7 cases were still under
  investigation at the time of writing. Relapse
  rates after surgery were 7.7, 38.5 and 57.5
  within 1 month, between 1 month and half a year
  and after more than half a year, respectively.
  There were no common complications of surgery
  such as intracranial hematoma or infection in
  these patients after operation. Character type
  was changed slightly in 2 cases, and 4 cases
  suffered temporary memory loss, which did not
  affect their daily lives and learning function.
  They all recovered within 1 month. There were
  different degrees of effectiveness of treating
  drug addicts' psychological dependence by making
  lesions in the NA(C) bilaterally with
  stereotactic surgery. No particular complications
  occurred. The operation is safe and feasible. The
  mean follow-up time in this study was 15 months.
  The effectiveness was satisfactory. The relapse
  rate of drug addicts after detoxification was
  clearly reduced.

81
Case Study Boy with Congenital Absence of Pain

• Accornero N, Berardelli A, Medolago L.
  Congenital absence of pain.Manfredi M, Bini G,
  Cruccu G, Arch Neurol. 1981 Aug38(8)507-11.
• A 16-year-old boy had congenital absence of
  pain sensitivity and no impairment of other
  sensory modalities. Routine electrophysiologic
  investigation showed no abnormalities. The
  threshold and latency of electrically elicited
  corneal reflex and cortical potentials evoked by
  tooth pulp stimulation were normal, but
  suprathreshold electric stimulation of corneal
  mucosa and dental pulp, as well as electric
  stimulation of dorsal roots, did not elicit pain.
  The total CSF opioid activity was raised.
  However, naloxone hydrochloride administration
  failed to reverse the analgesia. The axon reflex
  to intradermal injection of histamine
  dihydrochloride was absent. Cutaneous nerve
  branches showed unspecific changes affecting part
  of unmyelinated axons. Most of the unmyelinated
  as well as the myelinated axons were normal. We
  consider the case an example of congenital
  indifference to pain.

82
Case Study Boy with Congenital Absence of Pain

• Question What was the underlying genetic
  mutation?
• Question What protein was not correctly produced
  as a result?
• Question How is this protein involved in the
  transduction of pain?

83
Readings

• http//www.nature.com/bjp/journal/v147/n1s/pdf/070
  6435a.pdf Review
• http//www.nida.nih.gov/nida_notes/NNVol11N4/Brain
  .html The Brain's Drug Reward Systems
• http//content.nejm.org/cgi/content/full/338/17/12
  30 Terminal Sedation

84
The End