Opioid overdose

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Opioid overdose results from the toxic effects of exogenous opioids. Deaths related to opioid overdose have been steadily increasing in the United States over the past two decades because of a sharp increase in the prescription of opioids for chronic pain and increasing amounts of illegally manufactured fentanyl. Common clinical features of opioid overdose include respiratory depression, CNS depression, and miosis. Treatment of suspected opioid overdose requires airway management and prompt assessment of the need for naloxone to counter opioid-induced respiratory depression, which can be fatal. Inpatient admission is indicated for patients with ongoing respiratory depression, overdose from long-acting opioids, or medical complications from an opioid overdose. All patients with a noniatrogenic opioid overdose should undergo an assessment for substance use disorder (SUD) and be discharged with take-home intranasal naloxone.

• Opioid overdose is the most common cause of drug overdose death. ^[2]
  • From 2015 to 2022, annual opioid overdose deaths nearly tripled. ^[2]
  • Deaths typically involve high-potency synthetic opioids (e.g., fentanyl).

Epidemiological data refers to the US, unless otherwise specified.

Iatrogenic overdose occurs when a prescribed dose exceeds an individual's tolerance for opioids. Noniatrogenic overdose (i.e., in the setting of unhealthy drug use) may be intentional or unintentional (e.g., use of a higher dose than intended).

Risk factors for opioid overdose ^[3][4]

• Opioid-specific factors
  • High dose
  • High potency (e.g., fentanyl)
  • Long half-life (e.g., methadone)
• Patients with risk factors for opioid-related harm
  • Concurrent use of sedative-hypnotics
  • Mental health conditions (e.g., depression, SUD)
  • Prescriptions from multiple providers and/or pharmacies ^[4]
  • Release from incarceration in the last few weeks ^[5]
  • Recent cessation of medications for opioid use disorder (MOUD) ^[4]

Opioid-induced CNS depression is intensified when combined with other sedative-hypnotics (e.g., alcohol, benzodiazepines).

Opioid toxidrome ^[6]

The classic triad consists of:

• Altered mental status (e.g., CNS depression, euphoria)
• Bilateral miosis (pinpoint pupils) ^[7]
• Opioid-induced respiratory depression

The absence of miosis does not rule out opioid intoxication.

Opioid-induced respiratory depression (OIRD) ^[8][9]

• ↓ Respiratory rate and/or apnea
• ↓ Tidal volume
• Disordered control of breathing
• Signs of respiratory distress
• Signs of hypercapnic respiratory failure, e.g., ↑ EtCO₂
• Can progress to respiratory arrest

OIRD is the most common cause of death from opioid overdose and is treated with naloxone for opioid overdose.

Other clinical features ^[6]

• Respiratory: Noncardiogenic pulmonary edema
• Neurological
  • Myoclonic jerks; , seizures ^[10]
  • Diminished or absent gag reflex
• Gastrointestinal
  • Constipation and ↓ bowel sounds
  • Nausea, vomiting
• Cardiovascular
  • Bradycardia
  • Hypotension
• Other
  • Hypothermia
  • Pruritus, flushing

Clinical evaluation

• Opioid overdose is a clinical diagnosis based on suggestive clinical features (e.g., opioid toxidrome) and a compatible history of substance exposure.
• Begin empiric management of opioid overdose as soon as it is clinically suspected; do not wait for confirmatory diagnostic tests.
• Examine for signs of:
  • Skin and soft tissue infections
  • Compartment syndrome
  • Adherent fentanyl patches
  • Pulmonary edema
  • Cardiac murmur

Supportive investigations

Typically performed to evaluate for comorbid conditions, complications, and differential diagnoses.

• Laboratory studies
  • POC blood glucose to rule out severe hypoglycemia
  • Serum acetaminophen and salicylate levels
  • BMP to assess for AKI
  • CPK to assess for rhabdomyolysis
  • Urine drug testing if there is concern for multidrug toxicity
• ECG: Assess for life-threatening ECG findings, e.g., QTc ≥ 500 ms, cardiac arrhythmias and ectopy, and/or ischemic ECG changes. ^[11]

Do not delay treatment of suspected opioid overdose to await drug test results.

Acute management ^[6][7]

See “Approach to the poisoned patient” for a stepwise approach to patients with known or suspected poisoning.

• Follow an ABCDE approach (see “ABCDE approach in poisoning” for details).
• Start SpO₂ monitoring and establish IV access.
• Initiate oxygen therapy and airway management as needed.
• Administer naloxone for opioid overdose in patients with opioid-induced respiratory depression.
• Consider diagnostic tests to support the diagnosis, identify complications, and evaluate for comorbidities (see “Diagnostics”).
• Determine if the overdose was intentional, e.g., a suicide attempt.
• Assess for comorbid conditions.

If possible, perform basic airway maneuvers prior to administering naloxone to reduce the risk of pulmonary edema or acute lung injury after the reversal of apnea. ^[7]

Avoid naloxone in intoxicated patients without OIRD, i.e., with spontaneous respiratory rate > 12 breaths/minute. ^[12]

Naloxone for opioid overdose ^[7][12]

• Goal: restore respiratory drive while avoiding precipitated withdrawal
• Indication: opioid-induced respiratory depression (OIRD) ^[7][12]
  • There is no validated definition for the severity of opioid-induced respiratory depression.
  • Use clinical judgment in patients with stupor and a spontaneous respiratory rate ≤ 12 breaths/minute.
• Pharmacology
  • Mechanism of action: competitive μ-opioid receptor antagonist neutralizing opioid agonist effects
  • Onset (IV): < 2 minutes
  • Duration: 20–90 minutes (shorter than most opioids)
• Dosage: There is no consensus on the optimal regimen for in-hospital settings; follow local protocols when available. ^[6][7][13]
  • Choose the lowest possible starting dose to avoid precipitated withdrawal then titrate as needed to reverse OIRD.
  • Consider empiric dosage adjustment for:
    • The type and amount of opioids taken
    • Presence of opioid dependence
    • Patient weight
    • The risk of respiratory arrest
  • There is no direct correlation between OIRD severity and the naloxone dose required to reverse it. ^[7]

Naloxone has a dose-dependent duration of action that is shorter than most opioids. It does not shorten the duration of opioid toxicity. Repeat dosing and monitoring are often required. ^[7]

Starting dose ^[6][7][13]

The following dosages are suggested based on expert opinion and FDA guidance. ^[14]

• Preferred route: intravenous
  • Imminent respiratory arrest: Administer high-dose IV naloxone and begin emergency airway management. ^[6][15]
  • All other patients with OIRD: Begin with low-dose IV naloxone (off label). ^[6][7][13]
• No IV access
  • IM naloxone
  • Intranasal naloxone

Lower doses are typically sufficient for opioid-dependent patients. Higher doses are appropriate for opioid-naive patients and are typically required for any patients with synthetic opioid (e.g., fentanyl) overdose. ^[6][13][15]

In cardiac arrest, do not delay ACLS in order to administer naloxone. ^[14][15]

Subsequent dosage

Titrate further dosing of naloxone to clinical response: e.g., respiratory rate, tidal volume, EtCO₂, and other signs of respiratory distress or respiratory failure.

• No improvement
  • Repeat the dose every 2–3 minutes as needed.
  • Consider increasing the dose on each repeat administration if there is no response.
  • Repeat doses can range widely; follow local protocols and tailor to the individual clinical response. ^[7]
  • After ≥ 10 mg of naloxone, reconsider the diagnosis and evaluate for other causes of respiratory depression e.g., xylazine intoxication.
• Initial improvement with recurrent OIRD: Consider continuous naloxone infusion.
  • Start infusion at ⅔ the naloxone dose that initially reversed OIRD. ^[16]
  • Titrate the infusion based on clinical response.
• Precipitated opioid withdrawal: Do not administer additional naloxone.

Naloxone is typically unnecessary in intubated and mechanically ventilated patients. ^[12]

Mental health disorder management ^[4]

• Patients with a confirmed suicide attempt or multiple risk factors for suicidal behavior: Consult psychiatry and consider involuntary hospitalization.
• Stabilized patients with suspected or confirmed opioid use disorder
  • Consult addiction medicine and perform SUD assessment.
  • Offer medication-assisted treatment.

Disposition ^[6][7]

• Observation period: 4–6 hours after the last naloxone dose ^[17]
• Admit patients with:
  • Ongoing respiratory depression, e.g., mechanically ventilated patients requiring critical care admission.
  • Toxicity from long-acting or extended-release opioids (e.g., methadone, fentanyl patch)
  • Complications requiring inpatient management (e.g., rhabdomyolysis, suicidal ideation)
• Discharge criteria
  • All patients: alert with normal vital signs
  • Known or suspected intentional overdose: after safety assessment (e.g., by psychiatry)
  • Consider prescribing or providing home naloxone kits.

Monitor patients for 4–6 hours after administering naloxone for a resumption of opioid effects. ^[7]

Xylazine intoxication ^[18][19][20]

• Epidemiology
  • > 1200% increase in xylazine-associated overdose deaths in the U.S. from 2018 to 2021 ^[18]
  • High prevalence in Puerto Rico and New England ^[18]
• Etiology: consumption of recreational drugs (e.g., fentanyl) adulterated with xylazine ^[18]
• Mechanism of action: alpha-2 receptor agonist activity → inhibition of norepinephrine and dopamine release → peripheral vasoconstriction and CNS depression ^[21]
• Clinical features
  • Acute effects
    • Sedation, analgesia, euphoria
    • Bradycardia, hypotension, miosis, hypothermia
    • Respiratory depression
  • Effects of prolonged use
    • Drug tolerance
    • Necrotic skin ulcerations
  • Withdrawal syndrome
    • Severe if discontinuation is abrupt after prolonged use
    • Mimics OWS but not alleviated by opioid administration
• Diagnostics
  • Mass spectrometry: using serum or urine specimens
  • Blood glucose: possible hyperglycemia ^[20]
• Management
  • Supportive care
  • Airway management as needed
  • Patient education on harm reduction strategies

Sedation caused by xylazine intoxication does not improve with naloxone for opioid overdose and increases the risk of airway compromise. ^[18]

Toxicity from other substances ^[22]

• Clonidine
• Guanfacine
• Valproic acid
• Gamma-hydroxybutyrate
• Acute alcohol intoxication
• Sedative hypnotics
• Atypical antipsychotics
• See also “Approach to the poisoned patient.”

Cerebrovascular conditions ^[22]

• Pontine stroke
• Intracerebral hemorrhage

The differential diagnoses listed here are not exhaustive.

• Opioid withdrawal syndrome (OWS)
• Precipitated opioid withdrawal
• Concurrent toxidromes
• QRS widening, prolonged QTc interval
• Rhabdomyolysis, compartment syndrome, myoglobinuria
• Noncardiogenic pulmonary edema, acute lung injury
• Serotonin syndrome
• Biliary colic due to spasm of the sphincter of Oddi ^[10]
• Sensorineural hearing loss
• Infections (in individuals who inject drugs), e.g., cellulitis, abscess, endocarditis

We list the most important complications. The selection is not exhaustive.

• Harm reduction: Encourage safe-use strategies. ^[4]
  • Provide take-home naloxone for patients who are prescribed long-term opioids and/or using illicit opioids.
  • Advise patients about the availability of FDA-approved over-the-counter naloxone sprays.
  • Only using opioids in the company of others
  • Fentanyl test strips (if available) ^[23]
  • Safe opioid storage
• Prior to prescribing opioids for pain ^[24]
  • Check the prescription drug monitoring program.
  • Provide counseling on the use of prescription opioids.
  • Create a controlled-substances agreement.
  • Prescribe the lowest possible dosage of an immediate-release formulation.
  • Avoid prescribing concurrent opioids and benzodiazepines. ^[25]

Provide take-home naloxone kits to all patients with risk factors for opioid overdose. Train patients and close contacts on the use of naloxone for treating opioid overdose. ^[4]

• One-Minute Telegram 84-2023-2/3: Buprenorphine in the fentanyl era
• One-Minute Telegram 76-2023-1/3: Missed opportunities in the treatment of OUD

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