Transcript Opioid poisoning - Case presentation (May to Sept)

Opioid poisoning
Dr Ian Cheung
AED PWH
General information on opioids
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opiates
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indicates natural derivatives of the poppy plant,
such as morphine and codeine
opioids
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denote natural opiates, semi-synthetic (e.g.
hydrocodone) and synthetic compounds (e.g.
fentanyl), as well as endogenous opioids
The History of Opioids
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A 6000-year-old Sumerian tablet
The Egyptians
The Greeks
1000AD Arab traders introduce to China
China and opium trade
The Opium War of 1839
1902 Structure of morphine determined
1952 Australians were the largest heroin consumer
in the world.
1973 Kosterlitz & Snyder discovered opioid
receptors and endogenous opioids.
General information on opioids
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Papaver somniferum or opium poppy
 grows in various parts of the world
 sedative, anaesthetic and fixing qualities
 contains several active alkaloids
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morphine (10%-15%) , codeine (1%-3%)
and tebaine (1%-2%)
semi-synthetic drugs are produced
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heroin and hydromorphon
General information on opioids
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Papaver somniferum or opium poppy
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Morphine was first isolated from opium in
1805 by a German pharmacist, Wilhelm
Sertürner (1783-1841)
He named it morphium - after Morpheus,
the Greek god of dreams
The Opium Poppy :
Papaver Somniferum
鴉片罌粟
The Opium Poppy: Papaver Somniferum
Common names:
White Poppy, Opium Poppy, Mawseed, Herb of
Joy, Mohn, Klapper-Rosen, Mago, Magesamen,
Weismagen, wilder Magen, Magensaph,
Rosule, Adormidero, Hashas, Kheshkhash Abu
Al Noum, O Fang, O Fu Jung, O P'Ien,
Tengkoh, Ya P'Ien, Yu Mi. "
Papaver (罌粟科罌粟屬，發音為pa‘pah-ver)。拉丁語 pappa 是食物或牛奶
之意，引申形容果實所流出的白色乳汁。
somniferum (種名，發音為som-'neefei-rum)，somnifer ，導致睡眠的。按古
希臘常用罌粟果實來裝飾睡神 Hypnos，
而羅馬睡神則稱為Somnus。罌粟屬約50
種，本種可供製作鴉片，可稱為鴉片罌粟
(英文是 opium poppy)。
Pharmacokinetics
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absorption
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readily absorbed from GI tract, nasal mucosa, lung
subcutaneous, intramuscular, and intravenous route
bound free morphine accumulates in kidney, lung, liver, and
spleen
CNS is primary site of action (analgesia/sedation)
Pharmacokinetics
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metabolism/excretion
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metabolic transformation in liver
conjugation with glucuronic acid to water-soluble
metabolites (morphine-3-glucuronide & morphine-6glucuronide)
excreted by kidney
half life is 2.5 to 3 hours (does not persist in body tissue)
morphine 3 glucuronide in main excretion product
lose 90% in first day
duration of 10 mg dose is 3 to 5 hours
General information on opioids
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Tebaine
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extracted of Papaver bracteatum
can be processed into codeine and semi-synthetic
compounds (hydrocodon, oxycodon, oxymorphon)
General information on opioids
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Codeine
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metabolizes into morphine in the organism
however, hepatic microsomic ferment, which
enables this transformation (cytochrome P450
IID6) is absent in 10% of people.
General information on opioids
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Semi-Synthetic opioids
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Heroin
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It takes approximately ten kilograms of Opium to
make one kilogram of Heroin.
metabolised to morphine
hydrocodone
oxycodon
oxymorphon
General information on opioids
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Synthetic opioids
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pethidine,
methadone,
pentazocine,
fentanyl,
dextropropoxyphen,
propoxyphene…
Clinical and molecular effects of
exogenous and endogenous opioids
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A lot of new information appeared during the last 20
years
The endogenous peptides with opiate-like activity.
The three major classes currently recognized are the
ENKEPHALINS, the DYNORPHINS, and the
ENDORPHINS.
Each of these families derives from different
precursors, proenkephalin, prodynorphin, and proopiomelanocortin, respectively.
There are also at least three classes of opioid
receptors, but the peptide families do not map to the
receptors in a simple way.
Clinical and molecular effects of
exogenous and endogenous opioids
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opiate receptors
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present in both the central and the peripheral nervous systems
Mu (μ)-receptors: 2 subtypes – Mu1 and Mu2
 Mu1-receptors responsible for most of the supraspinal and
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peripheral analgesic effects and euphoria
Mu2-receptors responsible for respiratory depression,
delayed gastrointestinal motility, miosis, pruritus and physical
dependence
has high affinity for enkephalins and beta-endorphin but low
affinity for dynorphins
activate by morphine, codeine, and methadone
Schwartz M. Opiates and narcotics. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical
Management of Poisoning and Drug Overdose. 3d ed. Philadelphia: WB Saunders; 1998:505-22.
Clinical and molecular effects of
exogenous and endogenous opioids
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opiate receptors
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Kappa (κ)-receptors: 3 subtypes – Kappa 1, 2 & 3
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activated by other endogenous opioids (for example,
dinomorphine)
produce spinal (κ1) and supraspinal (κ3) analgesia
separately from  receptor function
play a part in miosis (κ1), respiratory depression,
nausea and dysphoria (κ2)
endogenous ligands are the dynorphins
Clinical and molecular effects of
exogenous and endogenous opioids
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opiate receptors
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Delta(δ) receptors :
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mediate spinal analgesia but are also found in cortical
regions
Modulation of  receptors function and dopaminergic
neurons
endogenous ligands for the δ receptor are the
enkephalins
Some research suggests that they may also be related
to seizures
Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE,
Molinoff PB, Ruddon RW, Gilman A, eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 9th ed. New York: McGraw-Hill; 1996:521-55.
Clinical and molecular effects of
exogenous and endogenous opioids
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orphan opioid receptor
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has not been found to be activated by traditional
opioids - hence an "orphan" receptor
role of the orphan opioid receptor has not been
definitively characterised
Henderson G, McKnight AT (1997). The orphan opioid receptor and its endogenous ligand nociceptin/orphanin FQ. Trends Pharmacol Sci 18, 293-300.
Clinical and molecular effects of
exogenous and endogenous opioids
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opiate receptors
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Sigma (σ) receptors : 2 subtypes – Sigma 1 & 2
 once thought to be a type of opioid receptor
 However, pharmacological testing indicated that the sigma
receptors were activated by drugs completely unrelated to
the opioids, and their function was unrelated to the function
of the opioid receptors.
 designated as a separate class of receptors
 associate with dysphoria (opposite of euphoria);
hallucination (both visual & auditory); respiratory and
vasomotor stimulation; mydriasis
 Agonist: dextromethorphan; antagonist: haloperidol
Fries, DS (2002). Opioid Analgesics. In Williams DA, Lemke TL. Foye's Principles of Medicinal
Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins.
Clinical and molecular effects of
exogenous and endogenous opioids
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opiate receptors
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Several possible effects at the various receptors,
but typically grouped as follows:
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Agonist (1, 2, )
Agonist-antagonist ( agonist,  antagonist):
produces withdrawal symptoms in opioid ()
dependent patients.
Antagonist (1, 2,  antagonist)
Partial agonist (1, 2 partial agonist, 
antagonist)
Common Opioid
Agonists and Antagonists
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Codeine: naturally occurring agonist; often combined with acetaminophen; antitussive;
needs metabolism to morphine for analgesic effect (not everyone capable of this
metabolism)
Dextromethorphan (Robitussin DM, Coricidin): semisynthetic agonist; antitussive,
nonanalgesic; abused for psychotomimetic effects
Diphenoxylate (Lomotil): synthetic agonist; combined with atropine as antidiarrheal
agent
Fentanyl (Sublimaze): synthetic agonist; very high potency and short acting
Heroin: semisynthetic agonist; derived from morphine (diacetylmorphine)
Loperamide (Imodium): synthetic agonist; antidiarrheal agent
Meperidine (Demerol): synthetic agonist; also called pethidine; metabolite is a
convulsant; serotonin syndrome (see clinical effects)
Methadone (Dolophine): synthetic agonist; very long acting; opioid substitution therapy
Morphine: naturally occurring; the gold standard
Naloxone (Narcan): semisynthetic antagonist; short acting
Naltrexone (Trexan): semisynthetic antagonist; very long acting
Pentazocine (Talwin): semisynthetic agonist-antagonist; psychotomimetic
Propoxyphene (Darvon): synthetic agonist; seizures, cardiac dysrhythmias in overdose
Tramadol (Ultram): synthetic agonist; seizures may occur at therapeutic doses
Roles of the main types of opioid receptors
µ
Analgesia
Supraspinal
Spinal
Peripheral
Respiratory depression
Pupil constriction
Reduced GI motility
Euphoria
Dysphoria
Sedation
Physical dependence
+++
++
++
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++
++
+++
–
++
+++
d

–
++
–
++
–
++
–
–
–
–
–
+
++
–
+
+
–
+++
++
+
See Rang, Dale and Ritter, p. 575
Clinical and molecular effects of
exogenous and endogenous opioids
• Miosis
• is
mediated by a mu receptor-related excitatory action
at the parasympathetic nerve that innervates the pupil
Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE,
Molinoff PB, Ruddon RW, Gilman A, eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 9th ed. New York: McGraw-Hill; 1996:521-55.
CLINICAL PRESENTATION
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Pinpoint pupils
Respiratory depression
Bradycardia
Hypotension
Hypothermia
Pulmonary edema
Seizures
Diagnosis
Altered Mental states (GCS<12)
plus one of the following:
1. RR <12 breaths/min
2. miotic pupils
3. circumferential evidence or history of opioid use
The opioid toxidrome was first described in the 1970s as a
triad of depressed level of consciousness, miotic pupils, and
decreased respiration
Khantzian EJ, McKenna GJ. Acute toxic and withdrawal reactions associated with
drug use and abuse. Ann Intern Med. 1979;90:361-72.
Naloxone
as a diagnostic tool ??
Diagnosis
Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with
altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52.
• examined the usefulness of clinical criteria to
predict a final diagnosis of opiate overdose (N=730)
• clinical criteria alone:
sensitivity of 92% and specificity of 76%
• a complete naloxone response + clinical criteria
sensitivity of 86% and specificity of 97%
Diagnosis
Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with
altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52.
Major conclusion:
1. most patients with undifferentiated abnormal mental status
and no clinical signs of opiate intoxication would not benefit
from naloxone
2. no occult opiate intoxications would be missed if this drug
was not given.
Diagnosis
Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with
altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246-52.
Implications:
1. The utility of naloxone as a diagnostic aid is questionable;
2. the drug should be used only to treat life-threatening
respiratory depression.
3. addition of naloxone only worsened the sensitivity for
making this diagnosis
4. not every patient who responds to naloxone has an opiate
overdose
Assessment of suspected
sole opioid poisoning
Adequate ventilation?
Yes
• Observation alone until
normal level of consciousness
• If no improvement after 4 hours,
consider alternative diagnosis
No
1. BVM ventilation with 100% O2
2. Naloxone 0.2-0.4mg IV/SC/IM
3. Repeated dosing up to 10mg
if no improvement in 2-3mins
Consider intubation if
1. inability to ventilate adequately with BVM
2. poor oxygenation despite adequate ventilation
3. persistent hypoventilation after 2nd dose of naloxone
Complete naxolone response:
• Observation for 2-3 hours for complication or resedation
• Repeated naloxone ONLY for clinical significant hypoventilation
• Consider naloxone drip for long-acting opioid, like methadone,
body packer (2/3 of the effective reversal dose per hour)
• CXR for patients with respiratory symptoms
• Appropriate substances abuse referral
Incomplete diagnosis:
• higher doses of naloxone
for opioid like proproxyphene,
fentanyl.
• consider alternative diagnosis
Naloxone
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Naloxone is a potent antagonist at the mu, kappa,
and delta receptors that is devoid of agonist activity
It is readily absorbed intravenously intramuscularly,
and via endotracheal tube.
In its oral form, naloxone undergoes extensive
hepatic metabolism and is inactive.
Because of its high lipid solubility, it rapidly enters
the central nervous system and has a rapid onset of
action.
Naloxone
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Peak brain levels of naloxone occur within 15
minutes and decline by 50% within the first hour.
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After intravenous injection, the effects of naloxone
occur in 1 to 2 minutes and last 45 to 90 minutes.
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Naloxone is hepatically metabolized to naloxone-3glucuronide, an inactive compound that is renally
excreted.
Naloxone
• Naloxone 0.2-0.4mg IV/SC/IM
• Repeated dosing up to 10mg if no improvement in
2-3mins
• Lower starting doses can be used for obvious
heroin abuser as long as ventilatory support is
adequate
• Higher naloxone doses may be necessary to
reverse the effects of synthetic oral opiates e.g.
propoxyphene, fentanyl, body packer.
Moore RA et al. Naloxone: underdosage after narcotic poisoning. Am J Dis Child
1980:134(2): 156-8
Naloxone(Children)
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The initial dose in children is 10 to 30 microgram per
kg, followed by a dose of 100 microgram per kg if
there is no response.
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Infusion should be at a rate of 30 microgram per kg
per hour.
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Infusion may be recommended in the case of
opioids with a long half-life (e.g. methadone,
dextropropoxyphene, body packer).
Naltrexone
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same effect of naloxone except it is used orally so
can't use it if for person with acute toxicity
long duration of activity
single dose block action of heroin effects for 24
hours
used for emergency treatment, once stabilized, give
patient naltrexone
patient get no euphoric effect from heroin so person
gets off heroin (negative reinforcement)
approved for use by the FDA
also used for treatment of alcoholism
Laboratory and bedside testing
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based on the medical history and physical
examination
H’sitx, SaO2, ABG, ECG, Temp
APAP and ASA level
CXR for respiratory symptoms or hypoxia
Laboratory and bedside testing
Urine drug screens:
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Immunoassay assess for morphine as a screen for
heroin
common false –ve: synthetic opioids that are
structurally unlike morphine but have significant
opioids toxicity, examples are methadone,
propoxyphene, fentanyl, pethidine, dextromethophan
methadone will show up on its own assay
Laboratory and bedside testing
Urine drug screens:
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Unexpected false positives occassionally, such as
fluoroquinolones, quinolone antibiotics, rifampicin
Dextromethorphan may cause false positive PCP
screen
+ve test implies recent exposure to opioid
Jennifer L Zacher. False-positive urine opiate screening assoicated with
fluoroquinolone use. Ann Pharmacother 2004; 38:1525-8
Laboratory and bedside testing
Comment from YC: (quoted without prior permission)
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In summary, opioids immunoassay has limited (if any)
role in the acute management of suspected opioids
poisoned patients simply because of the false +ve
and –ve. We still have to back to our clinical
toxidrome and the responsiveness to naloxone in
deciding our management.
The Road to H
by Isadore Chein and colleagues(1964)
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‘H’ is for heaven
‘H’ is for hell
‘H’ is for heroin
Heroin
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Heroin is named after the German word for
hero, heroisch.
In 1993, heroin was implicated in more than
3805 deaths nationwide
Relatively easily synthesize from morphine
and acetic anhydride
Heroin Abuse in the United States. Rockville, MD: U.S. Department of Health
and Human Services; 1997
Heroin
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also known as diacetylmorphine
first synthesized by the Bayer Company in
1889 as a "less addicting morphine
substitute"
It takes approximately ten kilograms of Opium
to make one kilogram of Heroin
de Ridder M. Heroin: new facts about an old myth. J Psychoactive Drugs.
1994;26:65-8
Heroin
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an agonist on the mu, kappa, and delta
receptors in the central nervous system
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Heroin is more lipid soluble than morphine
and other opiates; thus, it crosses the bloodbrain barrier within 15 to 20 seconds and
achieves relatively high brain levels
Way EL, Kemp JW, Young JM, Grassetti DR. The pharmacologic effects of
heroin in relationship to its rate of biotransformation. J Pharmacol Exp Ther.
1960;129:144-54
5-10 mins
20-30 mins
68%
via ivi
<5%
via ivi
Oldendorf WH, Hyman S, Braun L, Oldendorf SZ. Blood-brain barrier: penetration of morphine, codeine, heroin, and
methadone after carotid injection. Science. 1972;178:984-6.
Heroin
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accounts for both the "rush" experienced by
users and the toxicity.
Peripheral tissues (blood, kidney, and liver)
can also hydrolyze heroin to 6monoacetylmorphine and then to morphine
Way EL, Kemp JW, Young JM, Grassetti DR. The pharmacologic effects of
heroin in relationship to its rate of biotransformation. J Pharmacol Exp Ther.
1960;129:144-54
Intra-venous Heroin Dosages
w/ no tolerance
w/ heavy tolerance
Common 5 - 10 mg
20 - 40 mg
8 - 15 mg
40 - 60 mg
Strong
Onset
Duration
: 10 - 20 seconds
: 4 - 5 hours
REMARKS: The charts above shows intraveinous (IV) dosages in milligrams (mg) for individuals with
different levels of tolerance. Because people quickly develop tolerance to the effects of heroin, and because
batches of heroin vary from extremely low (2-3%) to extremely high (98%) purity, dosages will vary
dramatically depending on whether an individual has been using regularly, and for how long. The numbers
on this page are approximations only and should not be used to determine actual dosages.
Smoked Heroin Dosages
Common
15 - 25 mg
Strong
20 - 30 mg
Onset
Peak Onset
Peak Duration
Duration
: 5 - 10 seconds
: 10 minutes
: 5 - 6 minutes
: 3 - 5 hours
Heroin
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The route of heroin administration also strongly affects
the drug's potential to cause death or overdose.
Most fatal and nonfatal heroin overdoses occur when
the drug is administered intravenously.
intramuscular and subcutaneous routes accounted for
only 0.3% and 0.5% of nonfatal heroin overdoses,
respectively. (Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment
of opioid overdoses in an urban setting. Acad Emerg Med. 1996;3:660-7)
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These routes allow extensive peripheral hydrolysis and
therefore limit toxicity
Only one death from oral heroin administration has
been reported (Rop PP, Fornaris M, Salmon T, Burle J, Bresson M.
Concentrations of heroin, 06-monoacetylmorphine, and morphine in a lethal case
following an oral heroin overdose. J Anal Toxicol. 1997;21:232-5)
Heroin Combinations
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Pure heroin is a white powder. (No.4)
Heroin is usually “cut” (diluted) with lactose.
When heroin first enters the U.S., it may be 95%
pure, by the time it is sold, it is 3 to 5% pure.
Heroin has a bitter taste and is often cut with
quinine.
Heroin combined with cocaine is called
“speedballing.”
Complications
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hospitalization rate among patients with
treated heroin overdoses: 3% to 7%
admission diagnosis:
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non-cardiogenic pulmonary edema (1% to 2.4%)
pneumonia (0.5%)
possible endocarditis (0.25%)
persistent altered mental status or respiratory
depression (0.7% to 4%)
Smith DA, Leake L, Loflin JR, Yealy DM. Is admission after intravenous heroin
overdose necessary? Ann Emerg Med. 1992;21:1326-30.
Complications
Noncardiogenic pulmonary edema
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exact mechanism is unknown
associated with both heroin and naloxone
usually clinically apparent immediately or within 2
hours of administration of the drug
Most patients require mechanical ventilation
because of severe hypoxia
respond in 24 to 36 hours with supportive care
Benowitz NL, Rosenberg J, Becker CE. Cardiopulmonary catastrophes in drugoverdosed patients. Med Clin North Am. 1979;63:267-96
Complications
Noncardiogenic pulmonary edema
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61/ 64 patients with noncardiogenic pulmonary
edema reported in the literature had significant
symptoms at arrival in the emergency department
or within 2 hours of arrival
Only 3 patients have had delayed symptom onset
while under medical observation
Complications
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Pneumonia (aspiration),
Rhabdomyolysis,
Compartment syndrome,
Endocarditis, and
Wound botulism
co-ingestion
trauma
Safe discharge of some patients who have taken
an overdose of opioids may be possible after one
hour
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Three part question
In [patients given naloxone for the treatment of
opioid overdose] is [a lack of recurrence of
symptoms after one hour] a sensitive predictor for
[the patient being able to be safely discharged from
the department]?
Clinical scenario
A 30 year old opioid addict is brought to the
emergency department having overdosed on heroin.
He is successfully treated with a titrated bolus of
naloxone. You wonder when it will be safe to
discharge the patient.
Safe discharge of some patients who have taken
an overdose of opioids may be possible after one
hour


Search strategy
Medline 1966-02/02 using the OVID interface.
[{exp narcotics OR opioid.mp OR opiate.mp OR morphine.mp OR
buprenorphine.mp OR codeine.mp OR dextromoramide.mp OR
diphenoxylate.mp OR dipipanone.mp OR dextropropoxyphene.mp OR
diamorphine.mp OR heroin.mp OR alfentanil.mp OR fentanyl.mp OR
remifentanil.mp OR meptazinol.mp OR methadone.mp OR
nalbuphine.mp OR oxycodone.mp OR pentazocine.mp OR
pethidine.mp OR phenazocine.mp OR tramadol.mp} AND {exp
overdose OR overdos$.mp OR exp poisons OR poison$.mp OR "acute
intoxic$".mp OR "acute toxic$".mp} AND {exp patient admission OR
admission.mp OR exp patient discharge OR discharge.mp OR
observ$.mp OR monitor$.mp OR predict$.mp}] LIMIT to human AND
English.
Search outcome
194 papers were found of which only 5 were relevant to the setting.
Safe discharge of some patients who have taken
an overdose of opioids may be possible after one
hour

Relevant paper(s)
Author, date
and country
Patient group
Smith DA et al,
1992,
USA
124 patients
presenting to an ED
with a heroin
overdose
Osterwalder JJ,
1995,
Switzerland
192 patients
attending an ED
with clinical
suspicion of opioid
od
Study type
(level of
evidence)
Observational
Observational
Outcomes
Key results
Study weaknesses
Time to decision
20 mins
Treatments given were neither standardised
nor randomised so analysis of outcome
could not be performed in relation to mode
of treatment
Further treatment after
discharge
None
Time to decision
15 mins
No attempt was made to compare the
outcomes of different treatment modes
Reattendance if
discharged
1 patient died
The period of observation in the ED was not
recorded
Follow-up was poor so it is possible that
patients who sought further treatment or who
died elsewhere would have been missed

Relevant paper(s) (con’t)
Author, date
and country
Patient group
Watson WA et
al,
1998,
USA
84 patients
attending an ED
who had been
given naloxone for
a presumed opioid
od
Vilke GM et al,
1999,
USA
317 patients with a
clinical suspicion
of opioid od who
refused to be
transported to the
ED after being
given naloxone by
the paramedics
Christenson J et
al,
2000,
Canada
573 patients
attending an ED
with clinical
evidence of opioid
intoxication who
had been given
naloxone either in
the prehospital
setting or ED
Study type
(level of
evidence)
Observational
Observational
Observational
Outcomes
Key results
Subsequent
recurrence of
opioid toxicity
Patients who have
taken a longacting
opioid are more likely
to experience a
recurrence of toxicity
Death
No patients treated
with naloxone died
Reattendence
of the
ambulance
within 12 hours
Nil
Clinical
prediction rule
to predict safe
discharge
Patients can be safely
discharged one hour
after administration of
naloxone if they have
normal mobility,
SpO2 >92%,
respiratory rate 1020/min, heart rate 50100/min, temperature
35-37.5 C, GCS 15/15
Study weaknesses
No follow-up of patients was attempted after
admission to hospital/discharge from the ED to
assess the incidence of late complications
The period of observation in the ED was not
recorded
Variable doses and routes of administration of
naloxone were used
No follow-up of patients was attempted to ascertain
if they received subsequent treatment or died in
another area or attended the ED by other means of
transport
The rule has not been validated yet
The pattern of drug abuse in Vancouver is different
from other cities, so there are concerns about
whether these results can be applied to different
populations (eg those that misuse a higher
proportion of longer acting agents)
Safe discharge of some patients who have taken
an overdose of opioids may be possible after one
hour

Comment(s)
The evidence consists of observational studies, three of which are
retrospective reviews of medical records and thus there are concerns
regarding the reliability of the data collected. In addition, only
Christenson's study attempts to apply a "rule-out" strategy by
attempting to identify the clinical variables that predict a low risk of
delayed complications from the opioid overdose. Futher work is
required to validate the rule in different populations by further
prospective studies. Also, comparative trials need to be undertaken to
assess the validity of the rule for different opiod overdoses.

Clinical bottom line
The evidence suggests that if a patient remains well one hour after
administration of naloxone, then it is safe to discharge them.
Safe discharge of some patients who have taken
an overdose of opioids may be possible after one
hour

Level of evidence
Level 3 – Small numbers of small studies or great heterogeneity or very
different population.
References
1.
Smith DA, Leake L, Loflin JR et al. Is admission after intravenous heroin overdose
necessary? Ann Emerg Med 1992;21(11);1326-30.
2.
Osterwalder JJ. Patients intoxicated with heroin or heroin mixtures: how long should they
be monitored? Eur J Emerg Med 1995;2(2);97-101.
3.
Watson WA, Steele MT, Muelleman RL, et al. Opioid toxicity recurrence after an initial
response to naloxone. J Toxicol Clin Toxicol 1998;36(1-2);11-17.
4.
Vilke GM, Buchanan J, Dunford JV et al. Are heroin overdose deaths related to patient
release after prehospital treatment with naloxone? Prehospital Emerg Care 1999;3(3);1836.
5.
Christenson J, Etherington J, Grafstein E, et al. Early discharge of patients with presumed
opioid overdose: development of a clinical prediction rule. Acad Emerg Med
2000;7(10);1110-18.
Optimal observation period



Aim: guarantee that most or all cases of
delayed complications (e.g.noncardiogenic
pulmonary edema) would occur during
medical observation
If rate of noncardiogenic pulmonary edema is
2x the rate reported in recent series (5%)
and extrapolate from published reports: 95%
of cases would occur within the first 2 hours
of observation
Optimal observation period
A patient with a heroin overdose:
 4.75% chance of developing noncardiogenic
pulmonary edema during a 2-hour
observation period and
 0.25% chance of developing late-appearing
symptoms
 acceptable risk?
Methadone






pharmacological activity similar to morphine, same
potency as morphine
long duration of activity
absorbed well orally
16 to 20 hour duration of action
powerful pain reliever
used in maintenance program for narcotic treatment
HO
CH3
O
CH3CH2 C
N CH3
HO
C
O
Morphine
Methadone
CH2 CH
CH3
N
CH3
Dextromethorphan

Common ingredient of cough preparations and other
OTC preparations; pure forms available over the internet

Referred to by proper name, also called DM, Robo,
Robo shots, Robitussin DM; abuse is widespread in
some parts of the US; middle and high-school and
college students

A semisynthetic opioid agent, but it operates primarily at
the  receptor; chemical structure similar to
phencyclidine and urine tests may be falsely positive for
phencyclidine.
INGREDIENTS: per teaspoon (5ml) : Guaifenesin, USP 200mg and
Dextromethorphan Hydrobromide, USP 10 mg.
DM (Dexromethorphan HBr)
非麻醉性鎮咳劑，作用於延腦的咳嗽中樞，能有效抑制嚴重咳嗽，減少咳嗽次
數。特別適用於乾咳。療效與codeine（可待因）相當，但無抑制呼吸、睡眠或
誘發成癮之副作用。 .
Dextromethorphan
Well absorbed from GIT
 Onset is rapid: 15-30 mins after ingestion
 Half-life approx. 2-4 hours in normal
people
 metabolized in liver extensively to
dextrorphan (active metabolite)
 excreted via kidney.

Dextromethorphan




Produces central nervous system depression with less
respiratory effect than other opioids unless massive
doses are ingested.
Has some serotonergic effects and is implicated as
causative of the serotonin syndrome in patients using
monoamine oxidase inhibitors.
Choreoathetosis and other bizarre movements may be
noted, particularly in children.
Care is supportive including sedation for dysphoria.
Sandra M. Schneider. Dextromethorphan poisoning reversed by Naloxone. Am
J Emerg Med. 1991;9:237-8
Propoxyphene

is extensively metabolized in liver, where it
is oxidized to nor-propoxyphene (1/4 to ½
as active an analgesic as propoxyphene)

Half-life for propoxyphene in young
averages 13 hrs; for its metabolites approx.
22.2 hrs

Mainly excrete by kidney
Propoxyphene



Produces fast sodium-channel blockade
causing wide-complex cardiac dysrhythmias
Cardiac toxicity is responsive to sodium
bicarbonate and lidocaine, but not naloxone
Higher doses of naloxone is needed for
opioid toxicity
Moore RA et al. Naloxone: underdosage after narcotic poisoning. Am J Dis Child
1980:134(2): 156-8
Fentanyl (Sublimaze)

First synthesized in Belgium in the late 1950s, fentanyl, with an
analgesic potency of about 80 times that of morphine, was
introduced into medical practice in the 1960s as an intravenous
anesthetic under the trade name of Sublimaze®.

Thereafter; two other fentanyl analogues were introduced;
 alfentanil (Alfenta®), an ultra-short (5-10 minutes) acting
analgesic, and
 sufentanil (Sufenta®), an exceptionally potent analgesic (5 to
10 times more potent than fentanyl) for use in heart surgery.

Today, fentanyls are extensively used for anesthesia and
analgesia.
HO
Fentanyl (Sublimaze)
O
N CH3
HO
Morphine
H

synthetic drug
different structure than morphine
80 to 100 times more potent than morphine
very short acting opioid (30-45 min)
used as preoperative medication
onset of action is 5 minutes
O






N CH2CH2
CH3CH2C N
Fentanyl
highly abused ,known as “China White” in Pittsburgh;
“Tango & Cash” in New York City as street name
Fentanyl (Sublimaze)




Duragesic®, for example, is a fentanyl transdermal
patch used in chronic pain management, and
Actiq® is a solid formulation of fentanyl citrate on a
stick that dissolves slowly in the mouth for
transmucosal absorption.
Actiq® is intended for opiate-tolerant individuals and is
effective in treating breakthrough pain in cancer
patients.
Carfentanil (Wildnil®) is an analogue of fentanyl with
an analgesic potency 10,000 times that of morphine
and is used in veterinary practice to immobilize certain
large animals.
Actiq®
"Perc-O-Pop's" or "Lollipop's"
are street terms for Actiq®, (raspberry-flavored lozenge attached to a handle)
a form of fentanyl.
Fentanyl (Sublimaze)


Illicit use of pharmaceutical fentanyls
first appeared in the mid-1970s in the
medical community and continues to be
a problem in the United States.
The biological effects of the fentanyls are
indistinguishable from those of heroin,
with the exception that the fentanyls
may be hundreds of times more potent.
Source: DEA
Fentanyl (Sublimaze)

Fentanyls are most commonly used by
intravenous administration, but like heroin, they
may also be smoked or snorted.

associated with muscle rigidity

respond to naloxone, but may require higher
than normal doses
Source: DEA
Tramadol (Tramal™)




a novel synthetic analgesic agent
dual mechanism of action: both opioid and
monoaminergic
only weakly bind to mu receptors (agonist)
appear to inhibit reuptake of biogenic amines:
serotonin (5-HT) and norepinephrine (NE);
and stimulating 5-HT release
Bamigbade TA, et al. Actions of tramadol, its enantiomers and principal metabolite,
0-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal
raphe nucleus. Br J Anaes 1997;79:352-6
Tramadol (Tramal™)

Respiratory depression is less pronounced,
and occurs less often but can occur, in
particular with overdose (as described in
children) or with impaired renal function,
possibly due to retention of the active
metabolite M1.
Barnung SK, Treschow M, Borgbjerg FM. Respiratory depression following oral
tramadol in a patient with impaired renal function. Pain 1997;71:111-2.
Tramadol (Tramal™)



In overdose, it can also cause seizures and coma
while cardiovascular toxicity seems to be limited to
mild tachycardia and hypertension.
When seizures do occur, they are commonly of short
duration and are easily treatable.
In one reported case of a seizure, the convulsions
were induced by naloxone administration. Hence,
although respiratory depression in overdose can be
treated with the naloxone, low doses should be used
to avoid rebound effects including pain, hypertension,
tachycardia and seizures.
Spiller H, Gorman S, Villalobos D, Benson B, Ruskosky D, Stancavage M, et al.
Prospective multicenter evaluation of tramadol exposure. Clinical Toxicology
1997;35:361-364
Tramadol (Tramal™)

Caution in epileptics & those on tricyclics, SSRIs,
high dose opioids (seizure threshold-lowering
medication)

Contraindicated in patients on MAOIs, because of
the risk of developing serotonin syndrome.
Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. J R
Soc Med 1999;92:474-5.
Abdominal radiography in 'Body
Packers'.


Three part question
In [patients suspected of internal drug carriage
('Body-Packers', 'Body-Stuffers')] is [plain abdominal
radiography] of [diagnostic utility]?
Clinical scenario
A 26 year old male in custody is brought to the
emergency department with abdominal pain. He
claims to have ingested a large amount of 'drugfilled packages'. He is tachycardic. Examination is
otherwise normal. You wonder if plain abdominal xray is indicated.
Abdominal radiography in 'Body
Packers'.


Search strategy
Medline 1966-03/04 using the Ovid interface.
[(Exp Radiography, Abdominal OR abdominal
radiography.mp OR abdominal x-ray.mp OR plain
abdominal x-ray.mp OR plain film abdomen.mp)
AND (body packers.mp OR body stuffers.mp OR
body pack$.mp OR body stuff$.mp)] LIMIT to
Human AND English.
Search outcome
Altogether 12 papers were found of which 2 were
relevant to the topic of interest.
Abdominal radiography in 'Body
Packers'.

Relevant paper(s)
Author, date and
country
Patient group
Study type (level of
evidence)
Outcomes
Karhunen PJ et al,
1992,
Finland
82 patients suspected of
internal drug carriage
Prospective
observational series
Detection of internal
drug packages using
abdominal radiography
Heirholzer J et al,
1995,
Germany
12 patients suspected of
internal drug carriage
Prospective
observational series
Detection of internal
drug packages using
abdominal radiography
and ultrasound
Key results
Study weaknesses
Sensitivity 90%
Small numbers
Specificity 97%
No blinding
7 out of 12 cases
detected
Small study
Questionable gold
standard applied
Comment(s)
The possibility of internal carriage of drugs is an increasingly frequent
presentation to urban emergency departments. A diagnostic dilemma is usual
owing to credibility of the presentation. It is important, therefore, that clinicians
understand the utility of any investigations used. In particular the failure to
appreciate the possibility of a false negative result might prove fatal.
Abdominal radiography in 'Body
Packers'.

Clinical bottom line
A single abdominal radiograph is insufficiently
sensitive to rule-out abdominal drug carriage.
However, specificity is high and a positive
finding is diagnostic. (R/in but NOT R/out)
References
 Karhunen PJ, Suoranta H, Penttila A, et al. Pitfalls in the diagnosis of
drug smuggler's abdomen. J Forensic Sci 1991;36(2):397-402.
 Hierholzer J, Cordes M, Tantow H, et al. Drug smuggling by ingested
cocaine-filled packages: conventional x-ray and ultrasound. Abdom
Imaging 1995;20(4):333-8.
Suggested algorithm for the management of “body packers.”
CT indicates computed tomography; IV, intravenous; NG, nasogastric; and PO, by mouth.
From: Traub: Arch Pediatr Adolesc Med, Volume 157(2).February 2003.174–177
Delayed activated charcoal in opioid
poisoning


Three part question
In [patients with opioid poisoning] does [delayed
administration of activated charcoal] [reduce
absorption of the poison?]
Clinical scenario
A twenty year-old lady presents to the Emergency
Department claiming to have taken 100 co-codamol
tablets two hours ago. The guidelines suggest that
activated charcoal is of no benefit at this stage.
However, you are aware that opioids encourage
gastric stasis and wonder if there is any evidence
that activated charcoal is still of benefit to this
patient.
Delayed activated charcoal in opioid
poisoning


Search strategy
Medline using OVID interface 1966 - June
2003
[exp Narcotics OR opioid.mp OR opiate.mp
OR co-proxamol.mp OR co-codamol.mp]
AND [exp charcoal OR activated charcoal.mp]
limit to (human and english language)
Search outcome
34 papers were identified, of which only one
was relevant to the question.
Delayed activated charcoal in opioid
poisoning

Relevant paper(s)
Author, date and
country
Patient group
Laine K, Kivisto KT et
al
1997
Finland
32 healthy volunteers,
each receiving 100mg
pholcodeine,
randomised into four
groups to receive no
activated charcoal, 25g
immediately, 25g at 2
hours or 25g at 5 hours.
The 5-hours group also
received a further 10g
activated charcoal
every 12 hours for 84
hours
Study type (level of
evidence)
Outcomes
Key results
Absorption of
pholcodeine
Significant reduction
when given at 0 and 2
hours
Maximum serum
pholcodeine level
Significantly lower
when given
immediately; lower but
not significant in 2hour group
PRCT
Study weaknesses
Small numbers (32
patients in total)
Delayed activated charcoal in opioid
poisoning

Comment(s)
There is a paucity of evidence with regard to this topic and no
clinical trials have looked at codeine, dextropropoxyphene, cocodamol or co-proxamol overdose and delayed activated
charcoal administration. The only clinical trial to be done in this
area used pholcodine, a weak opioid. This trial demonstrated a
reduction in absorption when charcoal was administered after 2
hours.
Reduction of absorption of the poison may be particularly
desirable in cases involving preparations containing opioid and
paracetamol, as such overdoses are more likely to lead to
significant harm. Dextropropoxyphene (as in co-proxamol), taken
in relatively small doses may lead to cardiotoxicity, convulsions
and death. Any reduction in the absorption of this poison by
delayed activated charcoal would be particularly desirable.
Delayed activated charcoal in opioid
poisoning

Clinical bottom line
Delayed activated charcoal should be considered in the case of
pholcodine overdose.
Although there is no direct evidence for the efficacy of delayed
activated charcoal with other opioids, the available evidence
does suggest that it should also be considered in oral overdose.
References
Laine K, Kivisto KT, Ojala-Karlsson P, Neuvonen PJ. Effect of Activated Charcoal
on the Pharmacokinetics of Pholcodine, with Special Reference to Delayed
Charcoal Ingestion. Therapeutic Drug Monitoring 1997;19(1):46-50.
.
Oral Heroin Dosages
Common
50 - 70 mg
Although oral use of heroin is uncommon among
party and weekend users, it is sometimes used
this way as a pain medication, by field workers,
and by addicts trying to ween themselves off.