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    Opioid Toxicity

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    Mar.28.2023

    Opioid Toxicity

    Synopsis

    Key Points

    • Opioid toxicity is characterized by respiratory depression, generally accompanied by depressed consciousness and miosis and may be fatal
      • Diagnosis is made based on the 3 primary symptoms (which may not all be present) plus a positive response to naloxone
    • Opioid toxicity may be coupled with ingestion of other substances
    • The priority is to restore respiration using a bag-valve mask until naloxone can be administered
    • Naloxone, a competitive opioid antagonist, is the gold standard reversal agent
      • Continuously observe patients receiving naloxone because it has a short half-life
      • 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 co-ingestants or overdose on long-acting opioids r1
    • Recurrence is likely in patients with opioid use disorder

    Urgent Action

    • First priority is to restore respiration
    • If symptoms are present, begin treating with naloxone to reverse opioid toxicity; do not wait for drug test results to confirm diagnosis
    • Admit to ICU if patient is intoxicated by long-acting opioids, has recurrent respiratory depression, requires naloxone infusion, or requires intubation

    Pitfalls

    • Naloxone can precipitate opioid withdrawal
    • A negative drug test result does not rule opioid toxicity
    • Do not attribute altered mental status to opioid toxicity solely based on positive drug test results; co-ingestion with alcohol and other drugs is common
      • May present with concurrent head trauma, which can hinder restoration of consciousness

    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 r2
    • Primary toxic effect of opioid overdose is decreased rate and depth of respiration r2
      • 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 r2
    • Some opioids can provoke histamine release that may progress to a severe hypersensitivity reaction r3
      • 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 r3
      • Signs and symptoms may include hyperthermia, tremor, diaphoresis, clonus, agitation

    Classification

    • Toxicity caused by short-acting opioids, such as: r4
      • 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 r5c1
      • 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 r5c2
      • Pills or pill bottles found near patient
      • Records of recent opioid prescriptions in prescription drug monitoring program
    • Presenting symptoms: r5
      • Apnea c3
      • Depressed consciousness c4
        • Can range from drowsiness to coma c5c6

    Physical examination

    • Common signs r6
      • 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 (miosis) r4r6c11c12
        • 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 may be present r7c14c15c16
      • Choking or gurgling sounds r4c17
    • Other examination findings r7
      • Skin
        • Needle marks c18
          • Recent injection marks are small, red, inflamed, or surrounded by slight bruising c19c20
          • Repeated linear injection sites ("track marks") show pigmentation change, atrophied skin or scarring c21c22
          • 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 r4c23c24
        • 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 r2c25
        • Limp body r4
      • Mucous membrane r7c26
        • Mucous membrane cyanosis is a late sign of hypoxia
      • Pulmonary
        • Pulmonary edema in patients with apnea or severe bradypnea c27
          • Rales and frothy sputum are a late sign of severe opioid toxicity r2c28c29
      • Cardiac
        • QTc prolongation may occur in some patients receiving methadone, increasing risk of ventricular arrhythmia, particularly torsades de pointes r8r9c30c31

    Causes and Risk Factors

    Causes

    • Opioid overdose r5c32
      • Opioids exert their effects at three major opioid receptors (δ, κ, μ) r10c33
      • 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 r11
        • Commonly prescribed opioids r12
        • Most common illicit opioids
          • Fentanyl c42
          • Heroin (diacetylmorphine) c43
    • 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 r13
      • Children are more susceptible to toxicity from buprenorphine and fatalities have been reported r14
    • 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 r15c44c45
    • Advanced age is associated with reduced clearance of morphine, fentanyl, codeine, and oxymorphone, which increases risk of overdose (and requires more caution with prescribing) r16
    • Children are more likely than adults to experience respiratory depression and death after unintentional exposure to partial agonists such as buprenorphine r17r18c46c47
    • 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 r19
      • Avoid giving codeine to breastfeeding patients
    Sex
    • Opioid overdose rate is higher in men r15c48c49
    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 r15c50c51c52
    Other risk factors/associations
    • For those prescribed opioids, the risk of overdose is associated with higher prescribed doses and prescribing of long-acting opioids r20c53
    • Co-ingestion or co-prescribing of other drugs: c54c55
      • Alcohol r21
      • Benzodiazepines r21
      • Gabapentinoids
    • Populations at greatest risk for opioid toxicity: r5
      • 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 r16c56
      • Especially important to consider when using oxycodone, morphine, or oxymorphone c57
    • Renal impairment r16c58
      • Particularly important when using morphine, hydromorphone, and other opioids with active metabolites c59
    • Obesity
      • Increased risk of respiratory failure, but not mortality in one study r22

    Diagnostic Procedures

    Primary diagnostic tools

    • Primary diagnosis is based on: r23
      • Classic symptoms of opioid overdose c60
        • Respiratory depression, often accompanied by central nervous system depression and miosis
      • Responsiveness to naloxone c61
        • Nonresponse to naloxone excludes opioid toxicity, but large doses of naloxone may be warranted before ruling this out

    Laboratory

    • Urine drug tests r14c62
      • 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) c63

    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 r9
          • 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 r24

    Differential Diagnosis

    Most common

    • Most concerning alternative diagnoses
      • Other central nervous system depressant toxicity (eg, alcohol, barbiturate, benzodiazepine) r25c64c65c66c67
        • Cannot differentiate easily by symptoms alone
        • Differentiate by ineffectiveness of naloxone
          • Measuring serum alcohol levels narrows diagnostic considerations
    • Alpha-agonist toxicity (clonidine, xylazine, others) c68
      • 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 r26
        • 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 r26
      • Partial response to naloxone has been reported, but may require high doses r23
      • No easy or consistent way to differentiate from opioid toxicity
      • Urine tests for these drugs are not readily available
    • Acute subdural hematoma r27
      • 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 c69c70d1
      • Both present with confusion and depressed mental status d2
        • 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 c71
      • 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 r28

    Treatment

    Goals

    • Reverse opioid toxicity r6r29
      • 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 r30

    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 r2r31
    • 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 r2

    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 r2
      • Empiric administration to unresponsive patients with suspected opioid overdose is recommended to reverse respiratory depression

    Drug therapy

    • Naloxone r2r32c72
      • 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 r1
      • 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 r33
          • 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 r2

    • Provide ventilation with a bag-valve mask c73
    • Perform chin-lift and jaw-thrust maneuvers to diminish hypercapnia c74c75
    Procedures
    Endotracheal intubation r2c76
    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: r2
        • 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 r30
      • Children who ingest opioids may require larger doses of naloxone because they often ingest a high dose per kilogram of body weight r2
    • Older adults (eg, those age 65 years or older)
      • Age-related changes in physiology and body composition may prolong intoxication r2
    • Pregnant patients r6
      • 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 c77c78c79c80c81c82c83c84c85c86c87c88c89
      • Apneic patients who receive naloxone may develop noncardiogenic pulmonary edema r2
    • Central nervous system depression with airway compromise
      • Vomiting can result in aspiration of gastric contents into the lungs c90
    • 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 c91c92
    • Multiorgan failure can occur secondary to prolonged hypotension, bradycardia, and hypothermia
    • Death may occur in severe situations c93
    • Treatment with naloxone can precipitate withdrawal symptoms, including: r1
      • 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 r34
    • 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% r35

    Screening and Prevention

    Screening c94

    Prevention

    • Limit prescribing of opioids and patient exposure to these drugs (primary prevention) r36r37c95
      • Opioids have limited efficacy and significant risks c96
      • Short-term prescribing can lead to long-term use and use disorder r38
    • For individuals with opioid use disorder, initiate medications for opioid use disorder c97
      • Medications for opioid use disorder (ie, buprenorphine or methadone) reduce the risk of overdose and deathr40, and are recommended by treatment guidelines r6r39c98
      • Naltrexone is another medication used for treatment of opioid use disorder, but has not been shown to reduce the risk of overdose or mortality r40
    • Provide safe consumption sites for people with injection drug use r41c99
      • Distribute naloxone with education about its use in communities where opioid use is common r36r37
      • Provide naloxone to patients receiving chronic opioid therapy, particularly those requiring higher doses r36r37
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