Opioid overdose

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. ^[1]
  • From 2015 to 2022, annual opioid overdose deaths nearly tripled. ^[1]
  • 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 ^[2][3]

• Opioid-specific factors
  • High dose
  • High potency (e.g., fentanyl)
  • Long half-life (e.g., methadone)
• Any opioid use in patients with the following:
  • Concurrent use of sedative-hypnotics
  • Mental health conditions (e.g., depression, SUD)
  • Prescriptions from multiple providers and/or pharmacies ^[3]
  • Release from incarceration in the last few weeks ^[4]
  • Recent cessation of medications for opioid use disorder (MOUD) ^[3]

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

• Respiratory
  • Opioid-induced respiratory depression: ↓ respiratory rate and ↓ tidal volume
  • Noncardiogenic pulmonary edema
• Neurological
  • Altered mental status (e.g., CNS depression, euphoria)
  • Bilateral miosis (pinpoint pupils) ^[6]
  • Myoclonic jerks; , seizures ^[7]
  • Diminished or absent gag reflex
• Gastrointestinal
  • Constipation and ↓ bowel sounds
  • Nausea, vomiting
• Cardiovascular
  • Bradycardia
  • Hypotension
• Other
  • Hypothermia
  • Pruritus, flushing

Altered mental status, respiratory depression, and miosis are the classic triad of opioid intoxication. However, the absence of miosis does not rule out opioid intoxication.

Respiratory depression is the most common cause of death in opioid overdose.

Acute management ^[5][6]

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 initiate oxygen therapy and airway management as needed.
• Obtain IV access.
• Administer naloxone if indicated (e.g., in patients with opioid-induced respiratory depression).
• Assess for comorbid conditions.
• If opioid use disorder is suspected: ^[3]
  • Consult addiction medicine and perform SUD assessment.
  • Offer medication-assisted treatment.

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. ^[6]

Naloxone administration ^[6][8]

There is no consensus on the optimal naloxone dosage for in-hospital settings; follow local protocols when available.

• Goal: restore respiratory drive while avoiding precipitated withdrawal
• Indication: moderate to severe opioid-induced respiratory depression ^[6][8]
  • 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.
• Initial dose: Choose the lowest possible initial dose. ^[9]
  • IV naloxone (preferred) or IM naloxone ^[6]
  • Intranasal naloxone
• Subsequent dosage
  • No improvement
    • Repeat naloxone administration every 2–3 minutes as needed.
    • After ≥ 10 mg of naloxone, reconsider diagnosis and evaluate for other causes of respiratory depression.
  • Initial improvement with recurrent respiratory depression: Consider continuous naloxone infusion.
  • Precipitated opioid withdrawal: Do not administer additional naloxone.
• Characteristics
  • Mechanism of action: competitive μ-opioid receptor antagonist neutralizing opioid agonist effects
  • Onset (IV): < 2 minutes
  • Duration: 20–90 minutes (shorter than most opioids)

Do not administer naloxone to patients with opioid intoxication who do not have respiratory depression (e.g., patients with a spontaneous respiratory rate ≥ 12 breaths/minute) or those who are already intubated and on a ventilator. ^[8]

Naloxone has a dose-dependent duration of action that is shorter than most opioids and does not shorten the duration of opioid toxicity. Monitor patients for 4–6 hours after administering naloxone for a resumption of opioid effects. ^[6]

There is no direct correlation between the dose of naloxone required to reverse opioid-induced respiratory depression and the severity of opioid intoxication. Start low to avoid precipitated withdrawal and increase the dose as needed. ^[6]

Diagnostics ^[5][6]

Consider the following to identify comorbid conditions.

• Safety assessment: in patients with risk factors for suicidal behavior
• Physical examination to assess for:
  • Skin and soft tissue infections
  • Compartment syndrome
  • Fentanyl patches
  • Pulmonary edema, murmur
• 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. ^[10]

Disposition ^[5][6]

• Observation period: 4–6 hours after the last naloxone dose ^[11]
• Admit patients with:
  • Ongoing respiratory depression
  • 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)

• Opioid withdrawal syndrome (OWS)
• Precipitated opioid withdrawal: the acute onset of opioid withdrawal syndrome triggered by opioid antagonists (e.g., naloxone) or partial agonists (e.g., buprenorphine)
• 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 ^[7]
• Sensorineural hearing loss
• Infections (in individuals who inject drugs)

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

• Harm reduction: Encourage safe-use strategies. ^[3]
  • Provide take-home naloxone for all patients with risk factors for opioid overdose. ^[5]
  • Only using opioids in the company of others
  • Fentanyl testing strips
  • Safe opioid storage
• Prior to prescribing opioids for pain ^[12]
  • 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. ^[13]

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. ^[3]