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Apr.27.2022

Opioid Toxicity

Synopsis

Key Points

  • Opioid toxicity results in severe—sometimes fatal—effects that most commonly occur after overdose, which can be intentional or accidental
  • Opioid toxicity causes respiratory depression, generally accompanied by depressed consciousness and miosis
    • Diagnosis is made based on these 3 primary symptoms, which may not always present together, paired with a positive response to naloxone
  • Opioid toxicity is often coupled with ingestion of other substances, such as acetaminophen or ethanol
  • Restore respiration using a bag-valve mask until naloxone can be administered
  • IV 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 coingestants
  • Naloxone, although necessary, can cause withdrawal symptoms, which can be stressful to patients and caregivers; cautious titration to desired effect (reversal of respiratory suppression) is recommended
  • Recurrence is likely in patients with opioid misuse history

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 screen or immunoassay results to confirm diagnosis
  • Admit to ICU if patient is intoxicated by long-lasting opioids, has recurrent respiratory depression, requires naloxone infusion, or requires intubation

Pitfalls

  • Naloxone can precipitate opioid withdrawal and is titrated for best effect
  • Do not attribute altered mental status to opioid toxicity solely based on positive drug screen results; the screen is qualitative, not quantitative
    • May present along with head trauma, which can hinder restoration of consciousness

Terminology

Clinical Clarification

  • Opioid toxicity results in severe—sometimes fatal—effects that most commonly occur after overdose, which can be intentional or accidental r1
  • Primary toxic effect of opioid overdose is decreased rate and depth of respiration leading to pulmonary edema r1
    • May result in death from hypoxia and respiratory arrest before pulmonary edema develops
  • Effects on other organs include hypotension, bradycardia, and decreased body temperature r1

Classification

  • Toxicity caused by short-acting opioids, such as: r2
    • Morphine sulfate
    • Fentanyl
      • Fentanyl analogues
        • Carfentanyl is the most potent analogue (ie, potency 100 times that of fentanyl) and is used as an anesthetic for large animals
        • Analogues with no licensed medical use include acetylfentanyl and butyrylfentanyl
    • Oxycodone
    • Hydrocodone
    • Codeine
    • Heroin
  • Toxicity caused by longer-acting and delayed-release opioids, including:
    • Extended-release morphine sulfate
    • Methadone
    • Oxymorphone
  • Toxicity caused by opioid receptor agonist-antagonist drugs, such as:
    • Agonist at one opioid receptor, antagonist at a different opioid receptor
      • Pentazocine
      • Butorphanol
      • Nalbuphine
      • Dezocine
    • Partial agonist at a single opioid receptor
      • Buprenorphine
      • Meptazinol

Diagnosis

Clinical Presentation

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 and Risk Factors

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
      • Commonly prescribed opioid receptor agonist/antagonist or partial-agonist drugs
      • 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

Age
  • Higher incidence of opioid poisoning deaths in those aged 25 to 64 years, with highest incidence among those aged 45 to 54 years r12c56c57
  • Advanced age is associated with reduced clearance of morphine, fentanyl, codeine, and oxymorphone, which increases risk of overdose (and requires more caution with prescribing) r11
  • Children are more likely than adults to experience respiratory depression and death after unintentional exposure to agonist/antagonists such as buprenorphine r10r13c58c59
  • 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 r14
    • Avoid giving codeine to breastfeeding patients
Sex
Ethnicity/race
  • Death rates in non-Hispanic White populations are 4 times higher than in Hispanic or Black populations r12c62c63c64
Other risk factors/associations
  • Opioid toxicity is most highly associated with people who are prescribed high doses of opioid analgesics (more than 100 mg of morphine or equivalent per day) r15c65
  • Also associated with people who seek care from multiple physicians or receive early refills r3c66c67
    • Risk of distribution to others
  • Prescription opioid death rates are highest in rural populations r3r12c68
  • Heroin death rates are highest in large central metropolitan areas r3c69
  • Populations at greatest risk for opioid toxicity: r3
    • People with mental illness c70
    • People who report long-term medical use of opioids c71
    • People who report nonmedical use of opioids in the past month (ie, use without a prescription or medical need) c72
  • Hepatic impairment r11c73
    • Especially important to consider when using oxycodone, morphine, or oxymorphone c74
    • Lower risk of toxicity with fentanyl and methadone c75
  • Renal impairment r11c76
    • Particularly important when using morphine, hydromorphone, and other opioids with active metabolites c77
    • Less risk with fentanyl and methadone c78

Diagnostic Procedures

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

Differential Diagnosis

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

Treatment

Goals

  • Reverse opioid toxicity r4r16
    • Treat with reversal agent
    • Secure airway
    • Restore respiratory status
    • Reverse central nervous system depression
  • Avoid precipitating withdrawal r20

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 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
Criteria for ICU admission r1r22
  • Patients whose toxicity is due to long-lasting and extended-release opioids
    • Long-lasting and extended-release opioids cause resedation after naloxone wears off
    • Require prolonged observation for respiratory depression and airway compromise
  • Patients who require a naloxone infusion
  • Patients who require orotracheal intubation

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

Treatment Options

First priority is to restore respiration using a bag-valve mask until naloxone can be administered r1

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 therapy is the standard treatment of opioid toxicity r1
    • Empiric administration to unresponsive patients with suspected opioid overdose is recommended to reverse respiratory depression; however, only small doses may be required. Larger doses may precipitate withdrawal unnecessarily
    • Small doses also may be used for diagnostic purposes for patients with decreased level of consciousness of unknown cause
  • Naloxone prescription or access to OTC naloxone is an important treatment option for people at high risk (eg, those with history of misuse)

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
Procedures
Orotracheal intubation r1c101
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: 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

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 c102c103c104c105c106c107c108c109c110c111c112c113c114
    • Apneic patients who receive naloxone frequently develop noncardiogenic pulmonary edema r1
  • Central nervous system depression with airway compromise
    • Vomiting can result in aspiration of gastric contents into the lungs c115
  • Head trauma or brain injury due to falls related to loss of consciousness c116c117
  • Multiple complications can occur secondary to prolonged hypotension, bradycardia, and hypothermia
  • Death may occur in severe situations c118
    • Accidental overdose can occur when nonpharmaceutical agents contain unexpected substances such as fentanyl or its analogues c119

Prognosis

  • Recurrence is likely in patients with opioid misuse history r3
  • In one study, about 1% of patients with nonfatal opioid overdoses went on to have fatal overdoses within 1 year r27
  • Mortality rate is 5.1 per 100,000 with opioid analgesics r28

Screening and Prevention

Screening c120

Prevention

  • Provider education and implementation of prescription drug monitoring programs assist in avoiding the following: r29r30c121
    • Inappropriate prescription of opioid analgesics c122
    • Chronic prescription of opioids for acute pain c123
    • Prescription of high-dose opioid analgesics c124
    • Inform patients that anyone who takes prescription opioids can become addicted to them r2
  • Use prescription and insurance data to screen and reduce opioid prescription for: r29r30c125
    • Patients seeking care from multiple physicians c126
    • Patients obtaining early refills c127
      • At risk for providing opioids to others
  • Increase availability of opioid-dependence treatment, especially office-based medication-assisted treatment with buprenorphine-naloxone r29r30c128
  • To decrease risk of opioid toxicity death, distribute naloxone and promote education about its use in communities where opioid toxicity is likely r29r30c129c130
  • Provide naloxone to patients receiving chronic opioid therapy, particularly those requiring higher doses, and train patient and family members how to administer intranasally when overdose is suspected r29r30c131c132
  • Refer opioid-misusing or opioid-dependent patients to Narcotics Anonymous or similar support programs r29r30c133
    • Inpatient and outpatient rehabilitation counseling is an important aspect of prevention c134
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