CLINICAL

TOXICOLOGY

Cebrian, Lizbeth Aura DP.

OPIOIDS
I. 11 BACKGROUND
Pain is arguably the most
common
reason why patients seek treatment, especially in the ED. The modern
physician wields many tools to relieve pain, the most potent of which are
opioids. The term narcotic specifically refers to any substance that
induces sleep, insensibility, or stupor, and it is used to refer to opioids or
opioid derivatives. It is derived from the Greek "narke" that means
"numbness or torpor." It is common, however inaccurate, that the public
uses the term narcotics for any illicit psychoactive substance
In cultivation since approximately 1500 BC, pure opium is a mixture
of alkaloids extracted from the sap of unripened seedpods of Papaver
somniferum (poppy). Opiates, such as heroin, codeine, or morphine, are
natural derivatives of these alkaloids. The term opiate is often used
(albeit slightly incorrectly) to refer to synthetic opiate derivatives, such as
oxycodone, as well as true opiates
Pharmacology
Opioids are a group of analgesic agents commonly used in clinical
practice. There are three classical opioid receptors (DOP, KOP and MOP),
while the novel NOP receptor is considered to be a non-opioid branch of
the opioid receptor family. Opioids can act at these receptors as agonists,
antagonists or partial agonists. Opioid agonists bind to G-protein coupled
receptors to cause cellular hyperpolarisation. Most clinically relevant
opioid analgesics bind to MOP receptors in the central and peripheral
nervous system in an agonist manner to elicit analgesia. Opioids may
also be classified according to their mode of synthesis into alkaloids,
semi-synthetic and synthetic compounds.
Epidemiology
Opioids are prescribed widely, often in concert with other
analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs) or
muscle relaxants. Given all toxicologic presentations, pure opioid
ingestions are generally a small proportion of ED overdose cases. The
etiology of overdoses presenting to an ED often reflects local prescribing
tendencies. Polypharmacy overdoses that include opioids can be a
challenge for even the most experienced clinician. Fortunately,
pharmacologic reversal of the opioid component can assist in the
diagnosis of these potentially complex cases.
Data from the Drug Abuse Warning Network (DAWN) from 19901996 indicated that the abuse of opioid analgesics (as recorded from the
number of hospital ED visits) is low; compared with the abuse of other
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drugs, the abuse of opioid analgesics accounts for 3.8-5.1% of ED

presentations.
In 1998, a total of 36,848 opiate exposures (pure and mixed
preparations) were reported to US poison control centers, of which 1227
(3.3%) resulted in major toxicity and 161 (0.4%) resulted in death.
The CDC reports that methadone contributed to 31.4% of opioidrelated deaths in the United States from 1999-2010. Methadone also
accounted for 39.8% of all single-drug opioid-related deaths. The
overdose death rate associated with methadone was significantly higher
than that associated with other opioid-related deaths among multidrug
and single-drug deaths.
Mortality / Morbidity
The predominant cause of morbidity and mortality from pure opioid
overdoses is respiratory compromise. Less commonly, acute lung injury,
status epilepticus, and cardiotoxicity occur in the overdose setting. Case
reports of increased incidence of mortality have been documented in
patients with coexistent stenosing lesions of the upper airway.
Morbidities due to co-ingestants must be considered in
polypharmacy overdoses, and they vary depending on the co-ingestant.
Intent of the overdose also plays a role; the addition of suicidal intent is
linked to increased emergency department usage, and such intent could
suggest higher dosages of narcotics or co-ingestants.
II.

CHEMISTRY
Opioid analgesics are categorized into six groups according to
chemical structure.
Morphinans

Phenanthrenes

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Benzomorphans

Cyclohexanols

Phenylheptylamines

Phenylpiperidines

pKa: 6.5 8.7

Solubiltiy: Most opioids are lipid soluble
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Partition coefficient:

III.

MECHANISM OF TOXICITY
In general, opioids share the ability to stimulate a number of
specific opiate receptors in the CNS, causing sedation and respiratory
depression. Death results from respiratory failure, usually as a result of
apnea or pulmonary aspiration of gastric contents. In addition, acute
noncardiogenic pulmonary edema may occur by unknown mechanisms.

IV.

TOXICOKINETICS
ABSORPTION:
Opioids are well absorbed by most tissues; numerous routes of
administration are effective, Opioids are ingested orally, and the effective
oral dose depends on the drugs bioavailability and the effect of first-pass
metabolism. Parenteral administration of opioids by intramuscular,
intravenous or subcutaneous injection is common. Less common routes
of administration include transdermal absorption and epidural and
intrathecal injections.
DISTRIBUTION:
The distribution of opioids depends on chemical and physiological
factors in addition to specific properties of the drug. Some opioids
including oxycodone, codeine, and buprenorphine demonstrate a volume
of distribution consistent with the plasma compartment (3L/70kg),
whereas other more lipophilic opioids such as heroin have a much higher
volume of distribution (25L/70kg). Plasma protein biding greatly affects
opioid distribution and varies largely among opioids, ranging from 20% to
95%. Opioids concentrate in the tissues of highly perfused organs such as
the lungs, brain, kidney, liver, and spleen. Opioids further accumulate in
lipid and skeletal muscle reservoirs and cross placental barriers to
varying degrees.

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METABOLISM:

EXCRETION:
Most opioids and their metabolites are excreted in the urine, with
only a small amount of glucuronide conjugates eliminated in the feces or
bile via enterohepatic circulation.
V.

CLINICAL TOXICOLOGY
Signs & Symptoms
1. Acute Toxicity
Profound coma
Depressed respiration (2-4 min)
Cyanosis
Low blood pressure
Pinpoint pupils
Decreased urine formation
Low body temperature
Flaccid muscles
2. Chronic Toxicity
Nausea
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Respiratory depression
Miosis
Constipation
FIRST AID of Poisoning
Chest Compressions: CPR involves chest compressions at least 5
cm deep and at a rate of at least 100 per minute in an effort to
create artificial circulation by manually pumping blood through the
heart.
Rescue Breathing: In addition, the rescuer may provide breaths by
either exhaling into the subject's mouth or nose or utilizing a
device that pushes air into the subject's lungs. This will only be
effective if the airway is clear.
Current recommendations place emphasis on high-quality
chest compressions over artificial respiration; a simplified CPR
method involving chest compressions only is recommended for
untrained rescuers.
Chest compressions alone can at least circulate existing
oxygen in the blood. A full first aid response to an opioid overdose
includes chest compressions and rescue breathing.
Algorithm of treatment:
A. Emergency and supportive measures
1. Maintain an open airway and assist ventilation if necessary
Administer supplemental oxygen.
2. Treat coma, seizures, hypotension, and noncardiogenic pulmonary
edema if they occur.
B. Decontamination
Administer avctivatied charcoal orally if conditions are appropriate.
Gastric lavage is not necessary after small to moderate ingestions
if activated charcoal can be given promptly. Consider whole-bowel
irrigation after ingestion of sustained-released products.
C. Enhanced elimination
Because of the very large volumes of distribution of the opioids and
the availability of an effective antidotal treatment, there is no role
for enhanced elimination procedures.
Available Antidotes and mechanism of action of antidotes
1. Nalaxone a specific opioid antagonist with no agonist properties of
its own; large doses may be given safely
2. Nalmefene an opioid antagonist with a longer duration of effect (3-5
hours)
3. Sodium bicarbonate systemic alkalizer increases the plasma
carbonate, buffers excess hydrogen ion concentration and raises blood
pH, thereby reversing the clinical manifestations of acidosis; effective
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for QRS interval prolongation

propoxyphene poisoning
VI.

or

hypotension

associated

with

BIBLIOGRAPHY
1. Backmund, M., Edlin, B., Meyer, K., Reimer, J., & Schuetz, C. (2009). The
risk of emergency room treatment due to overdose in injection drug
users. Journal of Addictive Diseases, 28(1), 68-73.
2. Byard, R.W., & Gilbert, J.D. (2005). Narcotic administration and stenosing
lesions of the upper airwaya potentially lethal combination. Journal of
Clinical Forensic Medicine, 12(1), 29-31.
3. Eguchi, M. Recent advances in selective opioid receptor agonists and
antagonists. Med Res Rev 2004; 24:182-212.
4. Olson K. (2012). Poisoning & Drug Overdose. America: The McGraw Hill
Companies.
5. Pathan, H., & Williams, J. (2012). Basic opioid pharmacology: an update.
British Journal of Pain, 6(1), 11-16.
6. Shaw, L.M. (2001). The Clinical Toxicology Laboratory Contemporary
Practice of Poisonic Evaluation (T.C. Kwong, Ed.) New York.
7. Smith, H.S. (2009). Opioid Metabolism. Mayo Clinic Proceedings, 84(7),
613-624.
8. Vital signs: risk for overdose from methadone used pain relief United
States, 1999-2010. (2010). MWWR. Morbidity and mortality weekly
report, 61(26), 493-500.

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QUESTIONNAIRE
I. True or False
1. Opioids are a group of anesthetic agents.
2. Opioids agonists bind to Gq-protein coupled receptors to cause cellular
hyperpolarization.
3. Opioids analgesics can be classified to seven groups according to chemical
structure.
4. Most opioids and their metabolites are not excreted in the urine.
5. Nalaxone is an opioid antagonist and can be given as an antidote to opioid
toxicity.
II. Multiple-choice
6. The predominant cause of morbidity and mortality from pure opioid
overdoses is ____.
a. respiratory compromise
b. seizure
c. hypertension
d. heart attack
7. Nalmefene:
a. acts via MOP agonism only
b. has shorter duration effect
c. has longer duration effect
d. is a phenylpiperidine derivative
8. Morphine octanol/water partition coefficient;
a. 1.5
b. 1.3
c. 1.4
d. 1.2
9. Side-effects commonly encountered with opioids include:
a. increased respiratory rate
b. nausea and vomiting
c. diarrhea
d. dilated pupils
10. Opioid receptors:
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a. are G-protein coupled

b. are exclusively found in the central nervous system
c. the nociceptin receptor is considered a non-opioid branch of the opioid
receptor family
d. stimulation may produce analgesia
III. Matching type
A. Morphinans
B. Phenanthrenes
C. Benzomorphans
D. Cyclohexanols
E. Phenylheptylamines
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.

Morphine
Levorphanol
Codeine
Nalbuphine
Butorphanol
Hydrocodone
Fentanyl
Meperidine
Pentazocine
Tramadol

ANSWER KEY:
1. False
2. False
3. False
4. False
5. True
6. A
7. C
8. C
9. B
10. A
11. B
12. A
13. B
14. B
15. A
16. B
17. E
18. E
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19. C
20. D

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