Transcript Opiates and Respiratory Depression: Making the Case for

Opiates and Opiate
Pharmacology:
A Research Perspective
D John Doyle MD PhD FRCPC
Professor of Anesthesia
November 3, 2006
Download this talk at
opiateresearch.homestead.com
Outline
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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
Journal Reports
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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
Some Journal Types
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Peer-reviewed journals
Unreviewed paper archive collection
Open peer commentary journals
Open-access journals
Medical education journals
Newsletters
Internet discussion forums
Opiates
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 lifethreatening respiratory depression, which limits
both their utility and their safety.
From Anesthesiology: Volume 99(4) October 2003 pp 767-770
Papaver Somniferum
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 term
“A 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.”
Opium Products
Grow your own poppies!!
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
1 grain = 65 mg
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
Early victims of the War On Drugs.
A battle-scene from the First Chinese Opium War (1839-42)
http://opioids.com/images/opiumwar.html
DEA Schedule of Drugs
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.
"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“
Carfentanil synthesis:
[1] http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/carfentanil.html
[2] US Pat. 5,106,983
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 2003;41:700-5. ) 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.
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.
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 USA’s highest
medical research honor.
Opioid Receptors
There are three major subtypes of opioid receptors:
μ (mu), κ (kappa), and δ (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/wiki/Opioid_receptor)
Pasternak GW. Pharmacological mechanisms of opioid
analgesics. Clin Neuropharmacol. 1993 Feb;16(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.
• 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)
Tentative Classification of Opioid Receptor Subtypes and Their Actions
RECEPTOR
ANALGESIA

Peripheral

Supraspinal
2
Spinal
Supraspinal

Peripheral
1
Spinal
2
?
3
Supraspinal

Peripheral
1
Spinal
2
Supraspinal
Unknown
(receptor type not
indentified)
Supraspinal
RESPIRATORY
GASTRO
INTESTINAL
 Gastric secretion
 GI transit supraspinal and
peripheral
Antidiarrheal
Respiratory
depression
ENDOCRINE
OTHER
Skeletal muscle
rigidity
Pruritus
? Urinary retention
(and/or )
Biliary spasm (probably
>1 receptor type)
Prolactin release
Acetylcholine turnover
Catalepsy
 GI transit – spinal
and supraspinal
Most cardiovascular
effects
 ADH release
Sedation
(Pharmacology
unknown)
? Respiratory
depression
 GI transit – spinal
Antidiarrheal – spinal
and supraspinal
? Growth
hormone release
? Urinary retention (and
/ or )
Dopamine turnover
Pupillary constriction
Nausea and vomiting
Adapted from Pasternak GW: Pharmacological mechanisms of opioid analgesics. Clin Neuropharmacol 16:1, 1993.
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 17;98(2):235-40.
The involvement of different opiate receptor subtypes in opiateinduced 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.
Mu Opiate Receptor
Source: Goodman and Gillman 9th ed, p. 526
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.
Mu Receptor - Transmembrane View
The opioid receptors belong to the G protein-coupled receptor family. Opioid
agonists like morphine bind to opioid receptors, leading to activation of the Gprotein. 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.
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).
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
Kinds of Opiates
• Pure Opiate Agonists
(e.g., morphine)
• Mixed Agonist / Antagonists
(e.g., nalbuphine)
• Opiate Antagonists
(e.g., naloxone (Narcan®))
Opiate Agonists (partial list)
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Opium
Pantopon
Morphine
Meperidine
(Demerol ® )
• Hydrocodone
• Hydromorphone
(Dilaudid®)
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Heroin
Methadone
Oxycodone
Fentanyl
Alfentanil
Sufentanil
Remifentanil
Carfentanil
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 …..
Problems with Opiates
• Respiratory depression
• Addiction / dependence
• Less important issues:
– Constipation
– Itching
– Nausea / vomiting
– Mental clouding
Celebrity Heroin Overdoses
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Jonathan Melvoin — 34, keyboardist for the rock band Smashing Pumpkins
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Brad Nowell — 28, vocalist for the punk rock band Sublime
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Kristin Pfaff — 27, bass player with the grunge rock band Hole
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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
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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.”
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Darby Crash — 22, lead vocalist for the punk rock band Darby Crash & The
Germs
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Sid Vicious — 21, bass player for the punk rock band The Sex Pistols
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Janis Joplin — 30, legendary rock star found dead at Hollywood’s Landmark
Hotel
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.
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.
BEST EVIDENCE TOPIC REPORT
Emergency Medicine Journal 2006;23:221-223
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 it’s usage is however required to confirm this.
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
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 …
Opiates in Pain
Management
Landmine Injury
(www.trauma.org)
MEPERIDINE
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].
http://www.childcancerpain.org/IMAGES/steps_1.gif
Postop Pain Therapy
Examples
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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.
Patient Controlled Analgesia
CMAJ • March 6, 2001; 164 (5)
Patient-controlled 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 5–10
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.
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
Canadian Journal of Anesthesia 50:328-332 (2003)
Canadian Journal of Anesthesia 50:328-332 (2003)
Purpose: To identify the factors that threaten patient safety when using patientcontrolled analgesia (PCA) and to obtain an evidence-based estimate of the
probability of death from user programming errors associated with PCA.
Canadian Journal of Anesthesia 50:328-332 (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 mg•mL-1
solution of morphine was unavailable, so the nurse used a cassette that
contained a more concentrated solution (5 mg•mL-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 mg•mL-1
was entered instead of 5 mg•mL-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 65–667 deaths).
Canadian Journal of Anesthesia 50:328-332 (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.
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: 328–32.
D. John Doyle, MD PhD
Programming errors
from patient-controlled
analgesia
Canadian Journal of
Anesthesia 50:855-856
(2003)
Fentanyl
Lolipop
Fentanyl
Patch
Iontophoresis
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
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 V E 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.
Opiates and the search
for artificial bliss
"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 HUXLEY
1894 - 1963
"If it was possible to become free of
negative emotions by a riskless
implementation of an electrode - without
impairing intelligence and the critical mind
- I would be the first patient."
Dalai Lama (Society for Neuroscience
Congress, Nov. 2005)
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_notes/N
NVol11N4/Brain.html
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
Clinical Study for Alleviating Opiate Drug
Psychological Dependence by a Method of Ablating the
Nucleus Accumbens with Stereotactic Surgery
Stereotact Funct Neurosurg. 2003;81(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.
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 Aug;38(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.
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?
Readings
• http://www.nature.com/bjp/journal/v147/n1
s/pdf/0706435a.pdf [Review]
• http://www.nida.nih.gov/nida_notes/NNVol
11N4/Brain.html [The Brain's Drug Reward
Systems ]
• http://content.nejm.org/cgi/content/full/338/
17/1230 [Terminal Sedation]
The End