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Opioid intoxication
May 3, 2021 by Josh Farkas

CONTENTS
Rapid Reference
Diagnosis
Presentation
Differential diagnosis
Evaluation
Naloxone basics
Treatment overview

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Opioid naive pathway

Doing OK pathway
Too Sleepy pathway
Dying pathway
Intubated pathway
Additional treatment may be needed for certain agents:
Methadone
Loperamide
Podcast
Questions & discussion
Pitfalls

rapid reference
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presentation
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opioid toxidrome – key features

Somnolence
Reduced respiratory rate
This is the most important clinical finding.
Respiratory rate <12/minute was highly predictive of a response to naloxone in one series of patients presenting with
altered mental status.(1996818)
A normal respiratory rate or tachypnea suggests the absence of a clinically significant opioid toxidrome.
Don't trust the recorded vitals, which are often incorrect. Count the patient's breaths manually.
Pupil size?
Classically, opioid intoxication causes small (“pinpoint”) pupils. However, severe opioid intoxication causes
hypercapnia, triggering a sympathetic response which may normalize the pupil size.(25068603) Also, some opioids
have serotonergic effects that dilate the pupils (e.g., meperidine and tramadol). Finally, coingestion with

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sympathomimetics may block this effect. Thus, small pupils suggest opioid intoxication, but normal pupil size doesn't
exclude it.

“opioid-plus” syndromes
Serotonin syndrome and seizures can be caused by meperidine, tramadol, or dextromethorphan.
Methadone commonly causes QT prolongation and torsade de pointes.
Loperamide in massive quantities may cause QT prolongation and torsade de pointes, but it may also cause QRS
prolongation and monomorphic ventricular tachycardia (more on this below).

physical examination
In addition to the usual toxicology examination, carefully examine the skin for any fentanyl patches.

differential diagnosis
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intoxication with a different agent

Alpha-agonist intoxication (e.g., clonidine) may cause bradycardia and somnolence, but without bradypnea.
Benzodiazepine or alcohol ingestion may present similarly, with suppression of respiration and mental status.
Gamma hydroxybutyrate (GHB) intoxication.

polysubstance intoxication
Opioids are often coingested with acetaminophen when patients overdose on combination pills (e.g., Percocet or Vicodin).
Opioids may be coingested with a sympathomimetic such as cocaine or amphetamine (a combination known as a
“speedball”). In this case, administration of naloxone will unmask the effects of the sympathomimetic intoxication, often
leading to marked agitation.
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chronic opioid + acute pathology

Many patients are on chronic opioids (either therapeutically or recreationally). The superposition of an acute illness (e.g.,
stroke) may create a confusing picture:
Patients will often have evidence of opioid ingestion.
Patients generally have a partial response to naloxone (e.g., with pupil dilation and agitation), but often without
complete normalization of mental status. Increased arousal following naloxone is due to elicitation of opioid withdrawal,
rather than reversal of opioid intoxication.
The key to the diagnosis may be features which don't otherwise fit with an opioid toxidrome (e.g., fever, focal neurological
findings, failure to improve over time, incomplete response to naloxone).

More on the differential diagnosis of delirium, or stupor/coma.

evaluation
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The evaluation should be tailored to the individual patient's presentation. Commonly involved:

Acetaminophen & salicylate levels.

Creatine kinase, if there is a concern regarding compartment syndrome from prolonged immobilization.
Serum ethanol level.
EKG.

naloxone pharmacology
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naloxone basics
Naloxone is an opioid antagonist.
Administration of naloxone to someone not on opioids will have minimal effect (even in massive doses).
For an acute opioid intoxication in a patient not chronically on opioids, large doses of naloxone are safe to use. The goal
here is to fully block any opioid effect. If an excessive dose of naloxone is used, it won't matter. Consequently, for an acute
opioid intoxication that is severe (e.g., procedural sedation gone awry with subsequent apnea), rapid administration of high
doses of naloxone is logical.
For patients who are on chronic opioids, administering high doses of naloxone may induce an immediate state of opioid
withdrawal (including severe pain, agitation, and emesis). Consequently, for an acute-on-chronic opioid intoxication, the goal
is to use just enough naloxone to prevent aspiration or apnea, but not so much as to induce withdrawal.

naloxone pharmacology
Naloxone can be given via several routes (e.g., nebulized, intramuscular, or intravenous).
Intravenous administration is preferred, if access is available.
For emergent application in the emergency department, intramuscular access may be used.
Following IV administration, the onset of action is prompt (within 1-2 minutes). This allows for rapid dose up-titration in
situations where the patient isn't crashing.
Naloxone's duration of action is about 20-90 minutes. Most opioids have a longer half-life than the naloxone, so the
naloxone will wear off before the opioid intoxication resolves. Consequently, patients will often become re-sedated as the
naloxone wears off.

naloxone up-titration

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For a patient who isn't in acute danger from apnea, naloxone can be gradually up-titrated (unless, as discussed above, the
context is known to be an acute intoxication, where one can be much more aggressive in terms of up-titrating the dose).
The starting dose is somewhat controversial, but beginning with ~0.05 – 0.1 mg is generally reasonable. Some advocate for
using even smaller doses, which is entirely fine if there is sufficient time to dilute out the naloxone.
The goal of naloxone administration is to achieve adequate ventilation and airway protection (not necessarily a full state of
arousal). Shooting for airway protection may avoid eliciting opioid withdrawal, pain, and agitation.
If naloxone isn't working, successively larger doses may be given every 3-5 minutes (e.g., 0.1 mg, 0.2 mg, 0.4 mg, 1 mg,
etc.)
The maximal naloxone dose which could be given is unclear. Many textbooks and articles refer to a maximal cumulative
dose of 10 mg total. Patients who have large intoxications with synthetic fentanyl derivatives (e.g., carfentanill) might require
higher doses of naloxone than have traditionally been used for heroin intoxication.

naloxone infusion
Most opioids have a longer duration of action than naloxone, so repeated doses or an infusion of naloxone are often needed
to prevent re-sedation.
The usual starting dose for an infusion is ~2/3rds of the initial cumulative dose which was required to revive the patient (e.g.,
if the patient responds well to 1 mg, then start the infusion at 0.6 mg/hour). One or two PRN doses of naloxone may be
needed while waiting to receive the naloxone infusion from pharmacy.
For patients on chronic opioids, as their acute intoxication wears off the naloxone will start to induce a state of withdrawal.
Patients will start complaining of pain, at which point the naloxone may be down-titrated or held (while observing the patient
for possible re-sedation).

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