History

• History of nonprescribed opioid use or misuse ^r3c1
  • Medical records may indicate previous use
  • Family or friends may confirm opioid use
  • Needles or other paraphernalia found near patient
• History of prescribed opioid use ^r3c2
  • Pills, pill bottles, or drug paraphernalia found near patient
• Common symptoms even without any available history ^r3
  • Apnea ^c3
  • Depressed consciousness ^c4
    • Can range from drowsiness to coma ^c5c6

Physical examination

• Common signs ^r4
  • Depressed respiratory rate is the most specific sign ^c7
    • Respiratory rate of 12 breaths or fewer per minute, with stupor, is highly suggestive of acute opioid toxicity, especially when accompanied by miosis and/or depressed consciousness ^c8c9c10
  • Reduced size and reactivity of pupils ^r2r4c11c12
    • Pupil constriction to less than 2-mm diameter ^c13
    • Not always present, particularly if opioids were ingested along with other substances
  • Hypotension, bradycardia, and hypothermia are usually present ^r5c14c15c16
  • Choking or gurgling sounds ^r2c17
• Other examination findings ^r5
  • Skin
    • Evidence of fentanyl patches ^r1c18
    • Needle track marks ^c19
      • Recent injection marks are small, red, inflamed, or surrounded by slight bruising ^c20c21
      • Old injection sites show pigmentation change and atrophied skin ^c22c23
    • Pale, blue, or cold skin ^r2c24c25
  • Neurologic
    • Seizures often are associated with overdose of tramadol, propoxyphene, and meperidine, particularly if used concomitantly with medicines that lower seizure thresholds ^r1c26
    • Limp body ^r2
  • Mucous membrane ^r5c27
    • Mucous membrane cyanosis is a late sign of hypoxia and hypotension
  • Pulmonary
    • Pulmonary edema in patients with apnea or severe bradypnea ^c28
      • Rales and frothy sputum are a late sign of severe opioid toxicity ^r1c29c30
  • Cardiac
    • QTc prolongation may occur in some patients receiving methadone, increasing chance of developing a ventricular arrhythmia, particularly torsades de pointes ^r6c31c32

Causes

• Overdose of opioid drugs ^r3c33
  • Opioid drugs are substances that bind to 1 or more of the 4 opioid receptors (δ, κ, μ, and nociceptin receptors) ^c34
  • Toxicity is not necessarily dependent on dose of opioid used but instead depends on individual tolerance at time of exposure
    • Tolerance may be dramatically different in patient subpopulations
  • More overdose deaths are due to prescription opioids than nonprescription forms ^r7
    • Commonly prescribed opioids ^r8
      • Hydrocodone ^c35
      • Oxycodone ^c36
      • Morphine ^c37
      • Codeine ^c38
      • Hydromorphone ^c39
      • Oxymorphone ^c40
      • Methadone ^c41
      • Fentanyl patch ^c42
      • Tapentadol ^c43
      • Diphenoxylate ^c44
      • Fentanyl ^c45
    • Commonly prescribed opioid receptor agonist/antagonist or partial-agonist drugs
      • Pentazocine ^c46
      • Butorphanol ^c47
      • Nalbuphine ^c48
      • Dezocine ^c49
      • Buprenorphine ^c50
      • Meptazinol ^c51
    • Most common nonprescription opioids
      • Heroin ^c52
      • Fentanyl (diverted or illicitly produced; typically added to heroin) ^c53
      • Carfentanyl (diverted from veterinary sources; typically added to heroin) ^c54
      • Loperamide (in supratherapeutic doses) ^c55
• Overdose of buprenorphine usually does not cause lethal respiratory depression in adults unless administered intravenously or combined with another respiratory depressant, but lethal respiratory depression can occur in elderly or weak patients ^r9
  • Death from buprenorphine in children results from respiratory depression, usually following unintentional exposure secondary to medication being stored in sight, accessed from a bag or purse, or not being stored in its original packaging ^r10
• Effects of toxic metabolites ^r11
  • Normeperidine from meperidine: lowers seizure threshold and accumulates with repeated dosing
  • Morphine-3-glucuronide from morphine: lowers seizure threshold and may be responsible for myoclonus and allodynia

Risk factors and/or associations

Primary diagnostic tools

• Primary diagnosis is based on: ^r4r16
  • Classic symptoms of opioid overdose ^c79
    • Respiratory depression, often accompanied by central nervous system depression and miosis
  • Responsiveness to naloxone ^c80

Laboratory

• Urine toxicology tests ^r17c81
  • Screen for acetaminophen levels
  • Do not rely on toxicology screens for the initial diagnosis or management of suspected opioid overdose
  • Positive screen for opioids does not confirm toxicity
  • Although positive toxicology results can indicate presence of opioids, negative results do not necessarily mean absence of opioids
    • Some opioids, such as fentanyl, may not be detectable using typical toxicology screening methods

Imaging

• Obtain chest radiographs in patients with opioid toxicity who have rales or hypoxia (to evaluate for pulmonary edema or aspiration pneumonia) ^c82

Functional testing

• Can use ECG to monitor bradycardia ^r17c83
• QTc prolongation may occur in some patients receiving methadone, increasing the chance of developing a ventricular arrhythmia, particularly torsades de pointes ^r6
  • Doses above 100 mg daily produce a dose-dependent QTc prolongation
    • Regular monitoring of the QTc is recommended for patients receiving therapy who have baseline prolonged QT intervals greater than 501 milliseconds
  • QTc prolongation may also occur with loperamide toxicity ^r18

Most common

• Clonidine and oxymetazoline toxicity (particularly in pediatric patients) ^c84c85c86c87
  • Both drugs are centrally acting α₁-blockers that cause depressed mental status, bradycardia, hypotension, and miosis
  • Partial response to naloxone is common
    • No easy or consistent way to differentiate from opioid toxicity
    • Urine test for these drugs is typically available only at reference laboratories
      • Results will not change patient management
  • Most children with clonidine or oxymetazoline toxicity will be treated as if they had opioid toxicity, and vice versa
  • Nonresponse to naloxone is the best way to determine that the diagnosis is likely something other than opioid toxicity, but eliciting a response in patients with opioid toxicity may require large doses of naloxone
• Acute subdural hematoma ^r17c88
  • Common presentation is depressed mental status
  • CT scan results differentiate pure opioid toxicity from subdural hematoma
• Other central nervous system depressant toxicity (eg, alcohol, barbiturate, benzodiazepine, cannabinoid) ^{r19c89c90c91c92c93}
  • Cannot differentiate easily by symptoms alone
  • Differentiate by ineffectiveness of naloxone
    • Combined with quantitative alcohol serum levels, narrows diagnostic considerations
• Meningitis and encephalitis ^c94c95d1
  • Both present with confusion and depressed mental status ^d2
    • Additional symptoms include headache, vomiting, and fever
  • Neither respond to naloxone
  • Differentiate by using CT scan to reveal meningeal inflammation and using lumbar puncture to show evidence of infection
• Hypoglycemia ^c96
  • Presents with confusion and depressed mental status
  • Differentiate using a bedside blood glucose test and response to glucose administration

Admission criteria

Admit children age 3 years or younger who were exposed to opioids other than immediate-release formulations for 24-hour observation if ingestion of agents is suspected from history but cannot be confirmed ^r21

Respiratory depression

• Occurs after nonresponse to naloxone or during resedation after naloxone wears off and continued observation in the emergency department is unavailable

Recommendations for specialist referral

• Refer to medical toxicologist for specialty management of opioid toxicity
• Refer to pain or addiction specialist to prevent recurrence and treat opioid use disorder

Drug therapy

• Naloxone ^r1r23c97
  • Dose is empiric and depends on the amount of opioid that the patient received or has taken
  • IV administration is the most common and preferable method of delivery
    • IV naloxone continuous infusion is difficult and has several drawbacks
      • Difficult to titrate adequate dose to maintain adequate respiration while avoiding precipitating withdrawal
        • Recommended infusion strategy of hourly dose to match dose required to reverse apnea has not been validated
      • Relying on an IV infusion of drug to maintain ventilation
        • IV catheters can become kinked, be pulled out, or become otherwise dysfunctional
      • Patients still require ICU admission for monitoring
  • Use intramuscular, intranasal, or pulmonary administration when IV is not an option
  • Do not administer orally because it has high first-pass metabolism rate
  • Observation must last longer than the expected elimination time for naloxone. Minimum observation time for naloxone is 1 to 2 hours, but observe patient 4 to 6 hours in case there are coingestants ^r24
  • Toxic effects often reappear within 30 minutes of naloxone dosing, requiring further naloxone because it has a short half-life
  • Gradual titration of naloxone dose is preferred over isolated larger doses to avoid precipitating withdrawal
  • Opioids that require larger doses of naloxone ^r23
    • Natural opium derivatives
      • Codeine
      • Methadone
    • Synthetic opiates
      • Diphenoxylate
      • Propoxyphene
    • Mixed opioid agonist-antagonists
      • Pentazocine
      • Butorphanol
      • Nalbuphine
    • Partial agonist
      • Buprenorphine
  • Intermittent IV, intramuscular, subcutaneous, or intraosseous dosage (standard syringe)
    • Naloxone Hydrochloride Solution for injection; Neonates: 0.1 mg/kg/dose IV/IM; may require repeated doses. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes as needed.
    • Naloxone Hydrochloride Solution for injection; Infants and Children younger than 5 years or weighing 20 kg or less: 0.1 mg/kg/dose IV/IO; may require repeated doses. FDA-approved labeling recommends 0.01 mg/kg/dose IV, IM, or subcutaneously every 2 to 3 minutes as needed.
    • Naloxone Hydrochloride Solution for injection; Children and Adolescents 5 to 17 years or weighing more than 20 kg: 2 mg IV/IO; may require repeated doses.
    • Naloxone Hydrochloride Solution for injection; Adults: 0.4 to 2 mg IV, IM, or subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg.
      • High doses (eg, 5-10 mg) of naloxone have been required to reverse buprenorphine-induced respiratory depression; it may take up to 3 hours before maximum reversal is observed. ^r25
        • Prompt consultation with a medical toxicologist is prudent.
      • Giving bolus doses of naloxone, followed by an IV infusion (eg, 4 mg/hour), has been described to treat buprenorphine overdose. ^r25
  • Endotracheal dosage
    • Naloxone Hydrochloride Solution for injection; Infants and Children younger than 5 years or weighing 20 kg or less: 0.2 to 0.3 mg/kg/dose ET.
    • Naloxone Hydrochloride Solution for injection; Children and Adolescents 5 to 17 years or weighing more than 20 kg: 4 to 6 mg/dose ET.
    • Naloxone Hydrochloride Solution for injection; Adults: 0.8 to 5 mg ET.
  • Intranasal dosage (Narcan nasal spray)
    • Naloxone Hydrochloride Nasal spray, solution; Neonates: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
    • Naloxone Hydrochloride Nasal spray, solution; Infants, Children, and Adolescents: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
    • Naloxone Hydrochloride Nasal spray, solution; Adults: 1 spray (2 mg or 4 mg of naloxone) intranasally; repeat dose every 2 to 3 minutes in alternating nostrils as needed.
  • Continuous IV or intraosseous infusion dosage
    • Naloxone Hydrochloride Solution for injection; Neonates: Limited data available. If repeated intermittent doses are required, calculate initial infusion rate based on effective intermittent dose; use two-thirds up to the full intermittent dose as initial hourly infusion rate and titrate as needed. A continuous infusion rate of 0.002 to 0.16 mg/kg/hour IV/IO has been suggested; however, most reports have utilized 0.024 to 0.044 mg/kg/hour IV. When appropriate, wean in 25% increments while closely monitoring patient.
    • Naloxone Hydrochloride Solution for injection; Infants, Children, and Adolescents: Limited data available. If repeated intermittent doses are required, calculate initial infusion rate based on effective intermittent dose; use two-thirds up to the full intermittent dose as initial hourly infusion rate and titrate as needed. A continuous infusion rate of 0.002 to 0.16 mg/kg/hour IV/IO has been suggested; however, most reports have utilized 0.024 to 0.044 mg/kg/hour IV. When appropriate, wean in 25% increments while closely monitoring patient.
    • Naloxone Hydrochloride Solution for injection; Adults: Optimal dosing not established; not FDA approved. One common dosing nomogram recommends an initial IV infusion rate in mg/hour that is 2/3 of the initial IV naloxone dose (in mg) that resulted in reversal of symptoms (e.g., if 0.8 mg IV effectively reversed symptoms, then use 0.5 mg/hour IV infusion initially). Titrate to patient response.
• Naloxone can precipitate withdrawal symptoms, including: ^r26
  • Anxiety, irritability, and restlessness
  • Patients can become violent and uncooperative
  • Goose flesh
  • Hot and cold sweats
  • Muscle, bone, and joint aches
  • Tremor
  • Nausea, vomiting, and diarrhea
  • Increased resting pulse rate

Nondrug and supportive care

For apnea of fewer than 12 breaths per minute ^r1

• Provide ventilation with a bag-valve mask ^c98
• Perform chin-lift and jaw-thrust maneuvers to diminish hypercapnia ^c99c100

Special populations

• Children
  • Overdose is characterized by: ^r1
    • Unexpectedly severe poisoning based on dose received
    • Prolonged toxic effects
  • Admit children age 3 years or younger who were exposed to opioids other than immediate-release formulations for 24-hour observation if ingestion of agents is suspected from history but cannot be confirmed ^r21
  • Children who ingest opioids may require larger doses of naloxone because they often ingest a higher dose than adults per kilogram of body weight ^r1
• Older adults (eg, those age 65 years or older)
  • Age-related changes in physiology and body composition may cause persistent intoxication ^r1
• Pregnant patients ^r4
  • Naloxone can and should be administered to pregnant patients in cases of overdose to save the mother's life