Opioid Toxicity

Terminology

Clinical Clarification

• Opioid toxicity is characterized by drowsiness and decreased respiration which may be severe, sometimes fatal. Most commonly occurs after intentional or accidental overdose ^[2]

• Primary toxic effect of opioid overdose is decreased rate and depth of respiration ^[2]

  • May result in death from hypoxia and respiratory arrest

  • May also lead to pulmonary edema

• Effects on other organs may include hypotension, bradycardia, and hypothermia ^[2]

• Some opioids can provoke histamine release that may progress to a severe hypersensitivity reaction ^[3]

  • Signs and symptoms may include pruritis, urticaria, anaphylaxis

• Serotonin syndrome may occur with some opioids (especially meperidine, methadone, tramadol) when combined with serotonin reuptake inhibitors or other serotonergic medications ^[3]

  • Signs and symptoms may include hyperthermia, tremor, diaphoresis, clonus, agitation

Classification

• Toxicity caused by short-acting opioids, such as: ^[4]

  • Codeine

  • Heroin (diacetylmorphine)

  • Fentanyl or fentanyl analogues

  • Hydrocodone

  • Hydromorphone

  • Morphine

  • Oxycodone

• Toxicity caused by longer-acting and delayed-release opioids, such as:

  • Extended-release morphine

  • Extended-release oxycodone

  • Extended-release oxymorphone

  • Methadone

• Toxicity caused by partial opioid receptor agonists or mixed agonist-antagonists, such as:

  • Buprenorphine

  • Butorphanol

  • Nalbuphine

  • Pentazocine

Diagnosis

Clinical Presentation

History

• History of illicit or nonprescribed opioid use ^[5]

  • 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 ^[5]

  • Pills or pill bottles found near patient

  • Records of recent opioid prescriptions in prescription drug monitoring program

• Presenting symptoms: ^[5]

  • Apnea

  • Depressed consciousness

    • Can range from drowsiness to coma

Physical examination

• Common signs ^[6]

  • Depressed respiratory rate is the most specific sign

    • 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

  • Reduced size and reactivity of pupils (miosis) ^[4][6]

    • Pupil constriction to less than 2-mm diameter

    • Not always present, particularly if opioids were ingested along with other substances

  • Hypotension, bradycardia, and hypothermia may be present ^[7]

  • Choking or gurgling sounds ^[4]

• Other examination findings ^[7]

  • Skin

    • Needle marks

      • Recent injection marks are small, red, inflamed, or surrounded by slight bruising

      • Repeated linear injection sites ("track marks") show pigmentation change, atrophied skin or scarring

      • Usually located on the antecubital fossae or lower arms, but may also be found on the legs, groin, neck

    • Some individuals may inject subcutaneously ("skin pop") in the arms or legs and this may lead to scarring or chronic open wounds

    • Pale, blue, or cold skin ^[4]

    • Evidence of fentanyl patches

  • Neurologic

    • Seizures may be seen with tramadol or meperidine, particularly if used concomitantly with other medicines that lower the seizure threshold ^[2]

    • Limp body ^[4]

  • Mucous membrane ^[7]

    • Mucous membrane cyanosis is a late sign of hypoxia

  • Pulmonary

    • Pulmonary edema in patients with apnea or severe bradypnea

      • Rales and frothy sputum are a late sign of severe opioid toxicity ^[2]

  • Cardiac

    • QTc prolongation may occur in some patients receiving methadone, increasing risk of ventricular arrhythmia, particularly torsades de pointes ^[8][9]

Causes and Risk Factors

Causes

• Opioid overdose ^[5]

  • Opioids exert their effects at three major opioid receptors (δ, κ, μ) ^[10]

  • Toxicity is dependent on opioid potency and dose, as well as individual tolerance at time of exposure

    • Susceptibility varies among individuals due to various factors, including differences in metabolism

    • Regular use of opioids leads to tolerance

      • Individuals with a history of opioid use disorder may lose tolerance after incarceration or residential drug treatment (without medications for opioid use disorder) and are at high risk for overdose

  • Overdose deaths may be due to prescription or illicitly-manufactured opioids ^[11]

    • Commonly prescribed opioids ^[12]

      • Codeine

      • Fentanyl

      • Hydrocodone

      • Hydromorphone

      • Methadone

      • Morphine

      • Oxycodone

      • Oxymorphone

    • Most common illicit opioids

      • Fentanyl

      • Heroin (diacetylmorphine)

• Partial agonists like buprenorphine usually do not cause lethal respiratory depression in adults unless combined with another respiratory depressant like alcohol, benzodiazepines, gabapentinoids, or antipsychotic medications ^[13]

  • Children are more susceptible to toxicity from buprenorphine and fatalities have been reported ^[14]

• Accidental overdose can occur when illicit drugs contain unexpectedly potent opioids such as fentanyl or its analogues (eg, carfentanyl, which has potency 100 times that of fentanyl and is used as a anesthetic for large animals)

Risk factors and/or associations

Age

• In the US in 2018, those aged 25 to 34 years had the highest rate of opioid overdose deaths ^[15]

• Advanced age is associated with reduced clearance of morphine, fentanyl, codeine, and oxymorphone, which increases risk of overdose (and requires more caution with prescribing) ^[16]

• Children are more likely than adults to experience respiratory depression and death after unintentional exposure to partial agonists such as buprenorphine ^[17][18]

• Children may be more sensitive to codeine dosing and can be accidentally overdosed owing to existence of rapid metabolizers of the prodrug codeine to the active drug morphine ^[19]

  • Avoid giving codeine to breastfeeding patients

Sex

• Opioid overdose rate is higher in men ^[15]

Ethnicity/race

• In the US in 2018, opioid overdose death rates were highest in non-Hispanic White populations, followed by American Indian/Alaska native populations and non-Hispanic Black populations ^[15]

Other risk factors/associations

• For those prescribed opioids, the risk of overdose is associated with higher prescribed doses and prescribing of long-acting opioids ^[20]

• Co-ingestion or co-prescribing of other drugs:

  • Alcohol ^[21]

  • Benzodiazepines ^[21]

  • Gabapentinoids

• Populations at greatest risk for opioid toxicity: ^[5]

  • People who have experienced a prior overdose

  • People with a history of substance use disorder or mental illness

  • People with long-term medical use of opioids

  • People with nonmedical use of prescription opioids (ie, use without a prescription or medical need)

• Hepatic impairment ^[16]

  • Especially important to consider when using oxycodone, morphine, or oxymorphone

• Renal impairment ^[16]

  • Particularly important when using morphine, hydromorphone, and other opioids with active metabolites

• Obesity

  • Increased risk of respiratory failure, but not mortality in one study ^[22]

Diagnostic Procedures

Primary diagnostic tools

• Primary diagnosis is based on: ^[23]

  • Classic symptoms of opioid overdose

    • Respiratory depression, often accompanied by central nervous system depression and miosis

  • Responsiveness to naloxone

    • Nonresponse to naloxone excludes opioid toxicity, but large doses of naloxone may be warranted before ruling this out

Laboratory

• Urine drug tests ^[14]

  • Performance characteristics of drug tests vary depending on the type of test and what is tested for

  • Do not rely on drug tests for initial diagnosis of suspected opioid overdose. Positive test for opioids does not confirm toxicity

  • Although positive results can indicate presence of opioids, negative results do not rule out their presence

    • Many routine drug panels test for opiates, and some opioids such as fentanyl or oxycodone may not be detected unless specifically tested for

Imaging

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

Functional testing

• ECG

  • QTc prolongation may occur in some patients receiving methadone, increasing the risk of ventricular arrhythmias, particularly torsades de pointes

    • Methadone prolongs QTc in a dose-dependent manner ^[9]

      • QTc intervals over 500 milliseconds are associated with methadone doses over 120 mg/day

      • Buprenorphine does not cause QT prolongation

  • QTc prolongation may also occur with loperamide toxicity ^[24]

Differential Diagnosis

Most common

• Most concerning alternative diagnoses

  • Other central nervous system depressant toxicity (eg, alcohol, barbiturate, benzodiazepine) ^[25]

    • Cannot differentiate easily by symptoms alone

    • Differentiate by ineffectiveness of naloxone

      • Measuring serum alcohol levels narrows diagnostic considerations

• Alpha-agonist toxicity (clonidine, xylazine, others)

  • Centrally acting α₁-agonists can cause signs and symptoms similar to opioid toxicity, including depressed mental status, respiratory depression, bradycardia, hypotension, and miosis

    • Clonidine is prescribed as an antihypertensive, but may be used non-medically to potentiate the effect of opioids or to treat opioid withdrawal; serious toxicity may result from co-ingestion with opioids or accidental ingestion by children

    • Xylazine is a veterinary anesthetic that is sometimes mixed with illicit fentanyl ^[26]

    • There are a number of over-the-counter topical sympathomimetics used as a nasal decongestants (oxymetazoline) or for red eyes (naphazoline, tetrahydrozoline); toxicity has been reported with accidental ingestion by children ^[26]

  • Partial response to naloxone has been reported, but may require high doses ^[23]

  • No easy or consistent way to differentiate from opioid toxicity

  • Urine tests for these drugs are not readily available

• Acute subdural hematoma ^[27]

  • Common presentation is depressed mental status

  • May be a complication of toxicity/overdose

  • CT scan results differentiate pure opioid toxicity from subdural hematoma

• Meningitis and encephalitis

  • Both present with confusion and depressed mental status

    • Additional symptoms include headache, vomiting, and fever

  • Neither respond to naloxone

  • Differentiate by CT scan for meningeal inflammation and lumbar puncture for evidence of infection

• Hypoglycemia

  • Presents with confusion and depressed mental status

  • Differentiate using a bedside blood glucose test and response to glucose administration

  • Methadone and tramadol have been associated with hypoglycemia ^[28]

Treatment

Goals

• Reverse opioid toxicity ^[6][29]

  • Treat with reversal agent

  • Secure airway

  • Restore respiratory status

Disposition

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 ^[30]

Respiratory depression

• May be needed with nonresponse to naloxone or resedation after naloxone wears off and continued observation in the emergency department is unavailable

Criteria for ICU admission ^[2][31]

• Patients whose toxicity is due to long-lasting and extended-release opioids

  • Long-lasting and extended-release opioids can cause resedation after naloxone wears off

  • Require prolonged observation for respiratory depression and airway compromise

  • Some may require a naloxone infusion

  • Patients who require endotracheal intubation

Recommendations for specialist referral

• Refer to addiction specialist to reduce the risk of recurrence and to treat opioid use disorder

Treatment Options

First priority is to restore respiration using a bag-valve mask until naloxone can be administered ^[2]

Advanced airway intervention is rarely required unless there are coingestants or other illnesses or injuries

Observe for and remove any fentanyl patches

Drug treatment is the same regardless of causative opioid

• Naloxone is the standard treatment of opioid toxicity ^[2]

  • Empiric administration to unresponsive patients with suspected opioid overdose is recommended to reverse respiratory depression

Drug therapy

• Naloxone ^[2][32]

  • IV administration is the preferred 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 endotracheal administration when IV is not an option

  • Not active orally because of 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 ^[1]

  • Toxic effects may reappear within 30 minutes of naloxone dosing, requiring further naloxone because of its short half-life

  • Toxicity from some opioids may require larger doses of naloxone

    • Synthetic opioids

      • Diphenoxylate

      • Fentanyl

      • Methadone

    • Partial agonists or mixed opioid agonist-antagonists

      • Buprenorphine

      • Butorphanol

      • Nalbuphine

      • Pentazocine

  • Intermittent IV, intramuscular, subcutaneous, or intraosseous dosage

    • Standard dose

      • Naloxone Hydrochloride Solution for injection; Neonates: 0.1 mg/kg/dose IV/IM; may require repeated doses.

      • 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.

      • 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/subcutaneously every 2 to 3 minutes as needed up to a total dose of 10 mg.

    • High dose

      • A higher-dose injectable naloxone was approved by the FDA because of reports of a need for higher doses to reverse synthetic opioid (fentanyl) overdose ^[33]

      • Naloxone Hydrochloride Solution for injection; Neonates: 5 mg IM/subcutaneously every 2 to 3 minutes as needed.

      • Naloxone Hydrochloride Solution for injection; Infants, Children, and Adolescents: 5 mg IM/subcutaneously every 2 to 3 minutes as needed.

      • Naloxone Hydrochloride Solution for injection; Adults: 5 mg IM/subcutaneously every 2 to 3 minutes as needed.

  • 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

    • Naloxone Hydrochloride Nasal spray, solution; Neonates: 4 or 8 mg (1 spray) intranasally every 2 to 3 minutes in alternating nostrils as needed.

    • Naloxone Hydrochloride Nasal spray, solution; Infants, Children, and Adolescents: 4 or 8 mg (1 spray) intranasally every 2 to 3 minutes in alternating nostrils as needed.

    • Naloxone Hydrochloride Nasal spray, solution; Adults: 4 or 8 mg (1 spray) intranasally 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 IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion and titrate dose as needed to patient response. 0.002 to 0.16 mg/kg/hour continuous IV/IO infusion has been suggested; however, most reports used 0.024 to 0.044 mg/kg/hour continuous IV infusion. When appropriate, wean dose by 25% increments.

    • 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 IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion and titrate dose as needed to patient response. 0.002 to 0.16 mg/kg/hour continuous IV/IO infusion has been suggested; however, most reports used 0.024 to 0.044 mg/kg/hour continuous IV infusion. When appropriate, wean dose by 25% increments.

    • Naloxone Hydrochloride Solution for injection; Adults: 2 to 4 mg IV bolus, followed by 4 mg/hour continuous IV infusion or 3.66 to 5 mcg/kg IV bolus, followed by 2.5 to 3.66 mcg/kg/hour continuous IV infusion. Alternatively, two-thirds of the initial IV bolus dose (mg) that resulted in reversal of symptoms per hour continuous IV infusion and titrate dose as needed to patient response.

Nondrug and supportive care

For apnea or severe respiratory depression ^[2]

• Provide ventilation with a bag-valve mask

• Perform chin-lift and jaw-thrust maneuvers to diminish hypercapnia

Procedures

Endotracheal intubation ^[2]

General explanation

• Insertion of a tube into the trachea to restore respiration

• Safely ensures oxygenation and ventilation while providing protection against aspiration

Indication

• To gain definitive control of the airway to restore respiration

Special populations

• Children

  • Overdose is characterized by: ^[2]

    • 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 ^[30]

  • Children who ingest opioids may require larger doses of naloxone because they often ingest a high dose per kilogram of body weight ^[2]

• Older adults (eg, those age 65 years or older)

  • Age-related changes in physiology and body composition may prolong intoxication ^[2]

• Pregnant patients ^[6]

  • Naloxone can and should be administered to pregnant patients in cases of overdose

Monitoring

• For patients with opioid toxicity, it is mandatory to monitor respiratory adequacy and cardiovascular stability

  • Use pulse oximetry or end-tidal CO₂ to monitor respiration

  • Use periodic blood pressure monitoring (every 15 minutes) to assess for hypotension

Complications and Prognosis

Complications

• Respiratory depression and apnea

  • Apneic patients who receive naloxone may develop noncardiogenic pulmonary edema ^[2]

• Central nervous system depression with airway compromise

  • Vomiting can result in aspiration of gastric contents into the lungs

• Prolonged immobilization may result in rhabdomyolysis or compartment syndrome

• Prolonged hypoxia may lead to irreversible brain damage

• Head trauma or brain injury due to falls related to loss of consciousness

• Multiorgan failure can occur secondary to prolonged hypotension, bradycardia, and hypothermia

• Death may occur in severe situations

• Treatment with naloxone can precipitate withdrawal symptoms, including: ^[1]

  • Anxiety, irritability, restlessness and agitation

  • Piloerection (goose flesh)

  • Hot and cold sweats

  • Muscle, bone, and joint aches

  • Tremor

  • Nausea, vomiting, and diarrhea

  • Increased pulse rate

Prognosis

• Recurrence is likely in patients with opioid use disorder ^[34]

• In one study, among individuals with an opioid overdose requiring medical treatment, 22% had another overdose within a year if they did not receive medications for opioid use disorder; for those who did (at any point during the year after), the rate was 10% ^[35]

Screening and Prevention

Prevention

• Limit prescribing of opioids and patient exposure to these drugs (primary prevention) ^[36][37]

  • Opioids have limited efficacy and significant risks

  • Short-term prescribing can lead to long-term use and use disorder ^[38]

• For individuals with opioid use disorder, initiate medications for opioid use disorder

  • Medications for opioid use disorder (ie, buprenorphine or methadone) reduce the risk of overdose and death , and are recommended by treatment guidelines ^[40][6][39]

  • Naltrexone is another medication used for treatment of opioid use disorder, but has not been shown to reduce the risk of overdose or mortality ^[40]

• Provide safe consumption sites for people with injection drug use ^[41]

  • Distribute naloxone with education about its use in communities where opioid use is common ^[36][37]

  • Provide naloxone to patients receiving chronic opioid therapy, particularly those requiring higher doses ^[36][37]