Opioid Overdose

Quick Answer

Opioid overdose causes life-threatening respiratory depression through μ-opioid receptor agonism in the brainstem. Immediate management includes airway protection, assisted ventilation, and naloxone 0.4-2 mg IV/IM titrated to respiratory rate greater than 12/min. For long-acting opioids (methadone, sustained-release) or massive ingestions, initiate continuous naloxone infusion at two-thirds of the successful bolus dose per hour. Complications include non-cardiogenic pulmonary edema, aspiration pneumonia, rhabdomyolysis with acute kidney injury, hypoxic brain injury, and QT prolongation (methadone). Monitor for 4-6 hours post-reversal; synthetic opioids (fentanyl, carfentanil) may require higher naloxone doses and prolonged observation.

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CICM Exam Focus

Written Exam High-Yield Topics:

• Naloxone dosing regimens and continuous infusion protocols
• Respiratory physiology: μ-opioid receptor effects on brainstem
• Complications: NCPE, aspiration, rhabdomyolysis, hypoxic encephalopathy
• Methadone-specific toxicity: QT prolongation and Torsades
• Fentanyl/carfentanil: potency differences and naloxone requirements

Viva Voce Themes:

• Airway management decisions: when to intubate vs. naloxone
• Naloxone titration: balancing respiratory reversal vs. withdrawal
• Management of synthetic opioid overdoses
• Complication recognition and management
• Disposition decisions and observation periods

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Key Points

• Respiratory depression is the primary lethal mechanism via μ-opioid receptor activation in the pre-Bötzinger complex
• Naloxone dosing: Initial 0.4-2 mg IV/IM/IN, titrate every 2-3 minutes to respiratory rate greater than 12/min and adequate airway protection
• Maximum testing dose: 10 mg cumulative naloxone without response suggests alternative diagnosis
• Continuous infusion: Two-thirds of successful bolus dose per hour for long-acting opioids (methadone, sustained-release formulations, massive ingestions)
• Fentanyl: 50-100x morphine potency; may require repeated naloxone doses and prolonged observation
• Carfentanil: 10,000x morphine potency; may require greater than 10 mg naloxone total and continuous infusion
• Non-cardiogenic pulmonary edema: Classic complication; mechanism unclear but may involve hypoxic vasoconstriction, neurogenic factors, and negative intrathoracic pressure
• Methadone: QT prolongation via hERG channel inhibition; risk of Torsades de Pointes, especially at doses greater than 100 mg/day
• Observation period: 4-6 hours for short-acting opioids; 12-24 hours for long-acting opioids or synthetic opioids
• Complications: Aspiration pneumonia, NCPE, rhabdomyolysis (compartment syndrome from prolonged immobilization), AKI, hypoxic brain injury

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Clinical Overview

Pathophysiology

Opioids exert their toxic effects primarily through agonism at μ-opioid receptors, which are distributed throughout the central nervous system:

Respiratory Depression:

• Activation of μ-opioid receptors in the brainstem, particularly the pre-Bötzinger complex (rhythm generator) and the nucleus tractus solitarius
• Decreased responsiveness to hypercapnia (CO2) and hypoxia
• Reduced respiratory rate and tidal volume
• Depression of the hypoxic ventilatory response precedes depression of the hypercapnic response

Central Nervous System:

• Sedation, miosis, analgesia
• Decreased level of consciousness from thalamocortical depression
• Potential for hypoxic brain injury if respiratory depression prolonged

Cardiovascular:

• Bradycardia via vagal stimulation
• Peripheral vasodilation (histamine release with morphine, not fentanyl)
• Myocardial depression at high doses

Gastrointestinal:

• Decreased gut motility (increased risk of vomiting and aspiration)
• Delayed gastric emptying

Non-Cardiogenic Pulmonary Edema:

• Proposed mechanisms:
  • Hypoxic pulmonary vasoconstriction leading to increased permeability
  • "Neurogenic mechanism: massive sympathetic discharge causing pulmonary capillary stress failure"
  • Negative intrathoracic pressure from forceful inspiration against closed glottis
  • Direct pulmonary vascular endothelial injury
  • Typically occurs within minutes to hours of overdose
  • May develop even after successful naloxone reversal

Wooden Chest Syndrome (Fentanyl-specific):

• Acute chest wall rigidity due to fentanyl's effect on striated muscle
• Can cause respiratory muscle paralysis and prevent ventilation
• More common with rapid IV administration or massive overdoses
• Requires immediate airway control and muscle relaxation (often requires intubation)

Pharmacology of Common Opioids

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Epidemiology

Global and Australian Context

Global Burden:

• Opioid overdose is a leading cause of preventable death worldwide
• Over 500,000 deaths annually globally from drug use, with opioids accounting for approximately 70%
• Over 70% of drug overdose deaths in the United States involve opioids

Australian Data:

• Opioid overdose deaths increased significantly from 2007 to 2017
• Pharmaceutical opioids (oxycodone, codeine, morphine) contributed substantially to mortality
• Recent trends: decrease in pharmaceutical opioid overdoses but increase in heroin and synthetic opioid deaths
• Opioid agonist therapy (methadone, buprenorphine) reduces mortality by greater than 50% in opioid use disorder

Risk Factors:

• Male sex (higher mortality rates)
• Age 25-54 years (peak mortality)
• History of substance use disorder
• Recent release from incarceration
• History of prior overdose
• Polypharmacy (benzodiazepines, alcohol, gabapentinoids)
• Reduced tolerance (after abstinence or incarceration)

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Clinical Presentation

Signs and Symptoms

Cardinal Features:

1. Coma or decreased level of consciousness

   • GCS typically 3-8 in severe overdose
   • May be responsive only to painful stimuli

2. Respiratory depression

   • Respiratory rate below 10 breaths/minute (may be below 4 in severe cases)
   • Apnea or periodic breathing (Cheyne-Stokes pattern)
   • Shallow tidal volumes
   • Cyanosis in severe hypoxia

3. Miosis (pinpoint pupils)

   • Classic triad: miosis, coma, respiratory depression
   • May be absent if:
     • Co-ingested sympathomimetics (amphetamines, cocaine) → mydriasis
     • Severe hypoxia → pupillary dilation
     • Atypical opioids (tramadol, buprenorphine)

4. Other findings:

   • Bradycardia (often 40-60 bpm)
   • Hypotension (due to vasodilation and bradycardia)
   • Hypothermia (reduced metabolic rate and environmental exposure)
   • Absent bowel sounds (ileus)
   • Needle marks (intravenous drug use)
   • Track marks, skin abscesses
   • Fresh injection sites

Wooden Chest Syndrome (Fentanyl):

• Diffuse chest wall rigidity
• Inability to ventilate despite patent airway
• May appear as respiratory distress despite bag-valve-mask ventilation
• Requires immediate neuromuscular blockade and intubation

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Investigations

Immediate Assessment

Vital Signs:

• Continuous cardiac monitoring
• Continuous pulse oximetry
• Capnography if intubated or with assisted ventilation
• Blood pressure monitoring
• Temperature (hypothermia common)

Blood Tests:

• Arterial blood gas:
  • Respiratory acidosis (elevated PaCO2)
  • Hypoxemia (low PaO2)
  • Metabolic acidosis if hypoxic/ischemic
• Electrolytes:
  • Potassium (hyperkalemia in rhabdomyolysis or AKI)
  • Calcium (hypocalcemia in rhabdomyolysis)
  • Magnesium (hypomagnesemia increases arrhythmia risk)
• Creatine kinase (rhabdomyolysis)
• Creatinine and urea (kidney injury)
• Liver function tests
• Full blood count (infection, hemolysis)
• Troponin (myocardial injury from hypoxia)
• Urinalysis (myoglobinuria: dark, "tea-colored" urine)
• Toxicology screen (qualitative, not quantitative):
  • Opioids (often detected)
  • Benzodiazepines
  • Alcohol
  • Other co-ingestants

Electrocardiogram:

• Methadone: QTc prolongation (baseline and follow-up if applicable)
• Bradycardia
• Arrhythmias (Torsades de Pointes)
• Ischemic changes (if hypoxic)

Imaging:

• Chest X-ray:
  • Pulmonary edema (non-cardiogenic)
  • Aspiration pneumonia
  • Pneumothorax (rare)
• CT head:
  • If head trauma suspected
  • Prolonged coma with unclear etiology
  • Persistent neurological deficits after reversal
• CT abdomen/pelvis:
  • Suspected compartment syndrome (rare)
  • Intra-abdominal pathology (if vomiting/abdominal pain)

Additional Considerations:

• Creatine kinase trends (rhabdomyolysis monitoring)
• Serial ABGs if intubated
• Electrolyte monitoring if on methadone or with AKI

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Management

Immediate Airway Management

Primary Assessment:

1. Open airway (jaw thrust, head tilt-chin lift if no spinal injury concern)
2. Assess breathing: rate, depth, air entry, work of breathing
3. Assess circulation: pulse, blood pressure, capillary refill
4. Assess level of consciousness: GCS, pupillary response

Airway Protection:

• Positioning: Lateral decubitus (recovery position) if no spinal injury
• Oropharyngeal airway (Gag reflex absent)
• Nasopharyngeal airway (Gag reflex present)
• Suctioning (clear secretions, vomitus)

Ventilation Support:

• Bag-valve-mask ventilation with 100% oxygen if:
  • RR below 8 breaths/min
  • SpO2 below 90% on room air
  • PaCO2 greater than 50 mmHg (if ABG available)
  • Patient unable to protect airway (GCS below 8)

Intubation Indications:

• Failed bag-valve-mask ventilation
• Severe pulmonary edema requiring positive pressure ventilation
• Coma (GCS below 8) without response to naloxone
• Prolonged respiratory depression requiring ongoing support
• Aspiration requiring airway protection
• Wooden chest syndrome (fentanyl)
• Need for prolonged mechanical ventilation
• Hypothermia with core temperature below 30°C (decreased drug metabolism)

Intubation Considerations:

• Rapid sequence intubation (RSI) preferred
• Reduced doses of induction agents required (sensitivity)
• Avoid long-acting paralytics if possible (may delay neurologic assessment)
• Cuffed endotracheal tube recommended (protects against aspiration)
• Verify tube placement (capnography mandatory)
• Post-intubation sedation: Avoid opioids (use benzodiazepines, propofol, or dexmedetomidine)

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Naloxone Pharmacology and Dosing

Mechanism of Action:

• Competitive antagonist at μ-opioid receptors
• Displaces opioid molecules from receptor binding sites
• Reversal of respiratory depression, sedation, and miosis
• Does not affect pain receptors directly (but reverses analgesia from opioids)

Pharmacokinetics:

• Onset: IV (1-2 minutes), IM/SC (5-10 minutes), IN (3-5 minutes)
• Duration: 30-90 minutes (shorter than most opioids)
• Metabolism: Hepatic glucuronidation
• Elimination: Renal excretion of metabolites

Dosing Strategy:

Initial Bolus Dosing:

• Standard initial dose: 0.04 mg to 2 mg IV/IM/IN
  • "Most adults: 0.4-1 mg"
  • "Suspected massive overdose (fentanyl, carfentanil): 1-2 mg"
  • "Suspected opioid-dependent patient: 0.04-0.4 mg (titrated)"
• Repeat dosing: Every 2-3 minutes as needed
• Goal: Respiratory rate greater than 12 breaths/min and adequate airway protection
  • Note: Goal is NOT full consciousness or "walking and talking" (risk of precipitating withdrawal)
• Maximum testing dose: 10 mg cumulative
  • If no response after 10 mg, reconsider diagnosis
  • "Alternative diagnoses: sedative-hypnotic overdose, stroke, intracranial hemorrhage, metabolic encephalopathy"

Special Populations:

• Opioid-naïve patients: Standard dosing (0.4-2 mg)
• Opioid-dependent patients:
  • Start low (0.04-0.1 mg)
  • Titrate slowly
  • "Goal: respiratory adequacy, not full reversal"
  • Avoid precipitating withdrawal (agitation, vomiting, pain)
• Suspected synthetic opioid (fentanyl, carfentanil):
  • Start higher (1-2 mg)
  • Expect to need repeat doses
  • Prepare for continuous infusion
  • Extended observation period required
• Suspected long-acting opioid (methadone, sustained-release):
  • Standard initial dosing
  • Plan for continuous infusion
  • Extended observation period required (12-24 hours)

Routes of Administration:

Continuous Naloxone Infusion:

Indications:

• Long-acting opioid overdose (methadone, sustained-release formulations)
• Massive ingestions (body packers, large quantity ingestion)
• Recurrent respiratory depression requiring greater than 2-3 bolus doses
• Synthetic opioid overdoses (fentanyl, carfentanil)
• Inability to maintain respiratory status after bolus doses

Dosing Protocol (Goldfrank Protocol):

1. Determine the "Response Dose":

   • Give bolus doses (0.04-2 mg) until patient achieves adequate spontaneous ventilation
   • Total cumulative dose = Response Dose

2. Calculate Hourly Infusion Rate:

   • Two-thirds (2/3) of Response Dose per hour
   • Example: Response Dose = 3 mg → Infusion = 2 mg/hour

3. Loading Bolus:

   • Give one additional bolus equal to the Response Dose at the start of infusion
   • Prevents "dip" in naloxone levels as initial bolus wears off

4. Titration:

   • Adjust infusion rate based on clinical response
   • Increase by 50% if respiratory depression recurs
   • Decrease by 50% if withdrawal symptoms develop
   • Goal: Respiratory rate greater than 12/min, adequate airway protection, minimal withdrawal

5. Standard Preparation:

   • Dilute 4 mg naloxone in 250 mL D5W or NS (16 mcg/mL)
   • Example: Desired infusion 2 mg/hour = 125 mL/hour
   • Alternatively: 10 mg in 500 mL (20 mcg/mL)

6. Weaning:

   • Taper infusion over 12-24 hours
   • Decrease by 25-50% every 4-6 hours
   • Monitor for recurrence of respiratory depression
   • Bolus if needed and resume at higher rate

Alternative Infusion Calculations:

• Some protocols use: 0.5-1 mg/hour (fixed rate) regardless of response dose
• Adjust based on clinical response
• More aggressive dosing for synthetic opioids

Naloxone Infusion in Specific Scenarios:

Methadone Overdose:

• Half-life 8-59 hours (variable)
• Naloxone duration: 30-90 minutes
• Infusion required for 24-48 hours minimum
• Monitor for QT prolongation

Sustained-Release Oxycodone/OxyContin:

• Duration 12 hours
• Infusion required for 12-24 hours

Fentanyl:

• Duration 1-2 hours
• May require infusion for 4-6 hours
• Lipophilic → peripheral tissue sequestration → prolonged redistribution

Carfentanil:

• Unknown half-life (likely 6-8+ hours)
• Extremely potent receptor binding
• May require high-dose infusion (greater than 5 mg/hour)
• Observation period 24-48 hours minimum

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Synthetic Opioids: Fentanyl and Carfentanil

Fentanyl:

Pharmacology:

• 50-100 times more potent than morphine
• Highly lipophilic → rapid onset (1-2 minutes), short duration
• Metabolized by CYP3A4 (drug interactions significant)
• Wooden chest syndrome (muscle rigidity)

Clinical Features:

• Rapid onset of respiratory depression
• May cause apnea within seconds to minutes
• Profound miosis (often more than heroin)
• Chest wall rigidity preventing ventilation
• Recurrent sedation after naloxone wears off

Naloxone Requirements:

• Initial dose: 1-2 mg (higher than standard)
• Repeat every 2-3 minutes as needed
• Total dose often 4-10 mg required
• Continuous infusion frequently needed
• Observation period: 6-12 hours minimum

Special Considerations:

• Ventilation first if wooden chest syndrome → intubate and paralyze
• High suspicion for carfentanil if unusual resistance to naloxone
• Multiple overdoses in same location suggests synthetic opioids

Carfentanil:

Pharmacology:

• 10,000 times more potent than morphine
• 100 times more potent than fentanyl
• Not approved for human use (veterinary sedation for elephants)
• Extremely high receptor affinity (difficult to displace)
• Long half-life (unknown, likely 6-8+ hours)

Clinical Features:

• Rapid, profound respiratory depression
• Often fatal within seconds to minutes
• Extreme miosis
• May require greater than 10 mg naloxone total
• Prolonged duration of action

Naloxone Requirements:

• Initial dose: 2-5 mg IV
• Repeat every 2-3 minutes
• Total dose often greater than 10-20 mg
• Continuous infusion mandatory (often 5-10 mg/hour or higher)
• Observation period: 24-48 hours minimum
• May need ICU admission for monitoring

Safety for Healthcare Workers:

• Secondary exposure possible via inhalation or skin contact
• Risk of respiratory depression in responders (theoretical)
• Use PPE: gloves, mask, gown
• Ventilate area if large quantities present
• Avoid handling powder or suspected drug packaging

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Complications Management

Non-Cardiogenic Pulmonary Edema (NCPE):

Diagnosis:

• Bilateral infiltrates on chest X-ray
• Normal cardiac function on echocardiogram
• Absence of jugular venous distension
• Low pulmonary artery occlusion pressure (if measured)
• Develops within minutes to hours of overdose

Management:

1. Supplemental oxygen (target SpO2 ≥92%)
2. Non-invasive ventilation (CPAP 5-10 cm H2O) if hemodynamically stable
3. Intubation and mechanical ventilation if:
   • Severe hypoxemia (PaO2/FiO2 below 200)
   • Persistent respiratory distress
   • Inability to protect airway
   • Altered mental status
4. Positive end-expiratory pressure (PEEP): 5-10 cm H2O
   • Improves oxygenation
   • Reduces pulmonary edema
5. Diuretics (furosemide) generally NOT helpful
   • NCPE is not due to fluid overload
   • May worsen hypotension
6. Consider empiric antibiotics if aspiration suspected
7. Supportive care (usually resolves within 24-48 hours)

Aspiration Pneumonia:

Risk Factors:

• Decreased level of consciousness
• Vomiting (from naloxone reversal or opioid effects)
• Delayed gastric emptying (ileus)
• Bag-valve-mask ventilation without airway protection

Prevention:

• Airway protection before naloxone administration
• Position: lateral decubitus
• Suctioning
• Early intubation if high risk

Diagnosis:

• Fever (within 24-48 hours)
• Cough, purulent sputum
• Leukocytosis
• Infiltrates on chest X-ray (often dependent lobes)
• May present immediately or delayed

Management:

• Antibiotics (broad spectrum initially, then targeted)
  • Community-acquired: amoxicillin-clavulanate OR ceftriaxone + azithromycin
  • Hospital-acquired: piperacillin-tazobactam OR meropenem
• Chest physiotherapy
• Supportive care
• Monitor for ARDS/ARDS

Rhabdomyolysis and Acute Kidney Injury:

Pathophysiology:

• Prolonged immobilization ("found down")
• External pressure on limbs (compartment syndrome)
• Muscle cell necrosis → myoglobin release
• Myoglobin is nephrotoxic → acute tubular necrosis

Diagnosis:

• History: patient found down for prolonged period
• Physical exam: swelling, tense compartments, pressure sores
• CK: Often greater than 10,000-50,000 U/L (normal below 200)
• Urine: dark, "tea-colored" (myoglobinuria)
• Electrolytes: hyperkalemia, hyperphosphatemia, hypocalcemia
• Creatinine: elevated (AKI)
• ABG: metabolic acidosis

Compartment Syndrome:

• Measured compartment pressure greater than 30 mmHg
• Requires emergency fasciotomy if limb threatened
• Classic "pain out of proportion" may be absent (patient obtunded)

Management:

1. Aggressive fluid resuscitation:
   • Target urine output: 200-300 mL/hour (or 2-3 mL/kg/hour)
   • Lactated Ringer's or Normal Saline
   • Total fluids: 6-12 L/day initially
2. Electrolyte management:
   • Hyperkalemia: Calcium gluconate, insulin/dextrose, salbutamol, dialysis
   • Hyperphosphatemia: Phosphate binders
   • Hypocalcemia: Usually transient, don't treat unless symptomatic
3. Compartment syndrome:
   • Urgent orthopedic consultation
   • Fasciotomy if indicated
4. Renal replacement therapy:
   • Indications: Refractory hyperkalemia, metabolic acidosis, volume overload, uremic complications
   • Dialysis removes myoglobin, potassium, urea
5. Supportive care

Hypoxic Brain Injury:

Risk Factors:

• Prolonged respiratory depression before discovery
• Delay in naloxone administration
• Severe hypoxemia (PaO2 below 40 mmHg)
• Cardiac arrest

Diagnosis:

• Persistent altered mental status after naloxone reversal
• Neurologic deficits (motor, sensory, cognitive)
• CT brain: Diffuse cerebral edema, hypoxic-ischemic changes (may be normal early)
• MRI brain: More sensitive, shows DWI changes in watershed areas

Management:

• Supportive neurocritical care
• Avoid hypotension (MAP greater than 80 mmHg)
• Avoid hypoxia (SpO2 greater than 94%)
• Maintain normoglycemia (140-180 mg/dL)
• Treat seizures (if present)
• Consider therapeutic hypothermia (if cardiac arrest)
• Rehabilitation after acute phase

Methadone-Induced QT Prolongation and Torsades:

Pathophysiology:

• Methadone blocks hERG potassium channels (IKr current)
• Delays ventricular repolarization → QTc prolongation
• Risk of early afterdepolarizations → Torsades de Pointes
• Can degenerate into ventricular fibrillation

Risk Factors:

• Methadone dose greater than 100 mg/day
• Electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia)
• Concomitant QT-prolonging drugs:
  • Antibiotics: fluoroquinolones, macrolides
  • Antipsychotics: haloperidol, ziprasidone
  • Antiarrhythmics: amiodarone, sotalol
  • Tricyclic antidepressants
• CYP3A4 inhibitors (increase methadone levels):
  • Clarithromycin, erythromycin
  • Fluconazole, ketoconazole
  • HIV protease inhibitors
• Female sex
• Age greater than 65 years
• Structural heart disease
• Genetic predisposition (congenital long QT syndrome)

Monitoring:

• Baseline ECG before starting methadone
• Repeat ECG:
  • When methadone dose greater than 100 mg/day
  • When adding QT-prolonging medications
  • If symptoms (palpitations, syncope, seizures)
• Monitor electrolytes: K+, Mg2+, Ca2+
• Correct electrolyte abnormalities

Management of Torsades de Pointes:

1. Immediate defibrillation if unstable
2. Magnesium sulfate:
   • 2 g IV over 10-15 minutes
   • May repeat once
3. Potassium repletion:
   • Target K+ 4.0-4.5 mmol/L
4. Discontinue methadone (temporary or permanent)
5. Isoproterenol infusion (temporary overdrive pacing):
   • Increases heart rate → shortens QT
   • 2-10 mcg/min IV
6. Temporary transvenous pacing:
   • Rate 90-100 bpm
7. Consider lidocaine (if ischemic etiology)
8. Avoid other QT-prolonging drugs
9. Consult cardiology for long-term management

Long-term methadone management:

• Risk-benefit discussion (methadone saves lives in opioid use disorder)
• Alternative: Buprenorphine (less QT prolongation)
• Cardiology follow-up if persistent QTc greater than 500 ms

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Supportive Care and Monitoring

Hemodynamic Support:

• Normal saline bolus (500-1000 mL) for hypotension
• Vasopressors if refractory (norepinephrine preferred)
• Avoid excessive fluids (pulmonary edema risk)

Temperature Management:

• Passive rewarming for hypothermia (blankets)
• Active external rewarming if core temp below 32°C
• Active internal rewarming if core temp below 30°C
• Monitor for arrhythmias during rewarming (cold myocardium is irritable)

Gastrointestinal Prophylaxis:

• Stress ulcer prophylaxis if intubated or delayed gastric emptying
• PPI (omeprazole, pantoprazole) or H2 blocker

Thromboembolism Prophylaxis:

• Sequential compression devices (if immobilized)
• Consider low-dose heparin if prolonged ICU stay (greater than 48 hours)

Glycemic Control:

• Target blood glucose: 140-180 mg/dL
• Avoid hypoglycemia

Discontinuation of Naloxone:

• Observe for 4-6 hours after last naloxone dose (short-acting opioids)
• Observe for 12-24 hours (long-acting opioids)
• Observe for 24-48 hours (synthetic opioids: fentanyl, carfentanil)
• Patient must have:
  • Normal respiratory rate and effort
  • Adequate oxygen saturation on room air
  • Normal level of consciousness
  • Stable hemodynamics
  • No signs of withdrawal requiring intervention

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Disposition and Discharge Planning

Admission Criteria:

• Persistent respiratory depression requiring naloxone infusion
• Need for mechanical ventilation
• Severe complications (NCPE, ARDS, aspiration pneumonia)
• Rhabdomyolysis with AKI
• Hypoxic brain injury
• Cardiac arrhythmias (Torsades)
• Ingestion of long-acting opioid (methadone, sustained-release)
• Ingestion of synthetic opioid (fentanyl, carfentanil)
• Social factors (no safe discharge environment)

Observation Unit Admission:

• Observation period 6-12 hours after naloxone reversal
• Patient meets criteria for discharge:
  • Normal vital signs
  • Normal mental status
  • No respiratory distress
  • Able to ambulate
  • Safe discharge environment

Discharge from ED:

• Observation period complete (appropriate for opioid type)
• Normal vital signs for ≥2 hours
• Normal mental status
• No complications identified
• Safe discharge environment
• Discharge instructions:
  • Avoid alcohol and sedatives
  • No driving while affected
  • Follow-up with primary care/addiction services
  • Take-home naloxone (if available)

Referral to Addiction Services:

• Offer medication-assisted treatment (MAT):
  • Methadone
  • Buprenorphine/naloxone (Suboxone)
  • Naltrexone
• Referral to opioid treatment program
• Harm reduction education:
  • Avoid using alone
  • Have naloxone available
  • Test drugs (fentanyl test strips)
  • Start low, go slow

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Clinical Pearls

Critical Care Management

1. Ventilation before naloxone in wooden chest syndrome (fentanyl)

   • Paralyze and intubate before administering naloxone
   • Chest wall rigidity prevents ventilation despite patent airway

2. Don't over-treat with naloxone

   • Goal is adequate respirations, not full consciousness
   • Agitation from withdrawal complicates airway management
   • Titrate to respiratory rate greater than 12/min and airway protection

3. Synthetic opioids require higher naloxone doses

   • Fentanyl: 1-2 mg initial, may need 4-10 mg total
   • Carfentanil: 2-5 mg initial, may need greater than 10 mg total
   • Continuous infusion mandatory
   • Prolonged observation (24-48 hours)

4. NCPE is non-cardiogenic

   • Diuretics generally NOT helpful
   • Treat with positive pressure ventilation (CPAP or intubation)
   • Usually resolves within 24-48 hours

5. Rhabdomyolysis from "found down" status

   • Check CK in all patients found down for greater than 4 hours
   • Aggressive fluid resuscitation is key
   • Monitor compartment pressures if limb swelling

6. Methadone: QT prolongation

   • Baseline ECG before starting methadone
   • Repeat ECG when dose greater than 100 mg/day
   • Magnesium 2 g IV for Torsades
   • Correct hypokalemia and hypomagnesemia

7. Continuous naloxone infusion

   • Indicated for long-acting opioids or recurrent sedation
   • Calculate: 2/3 of response dose per hour
   • Give loading bolus equal to response dose at start
   • Standard dilution: 4 mg in 250 mL (16 mcg/mL)

8. Prolonged observation for long-acting opioids

   • Short-acting (heroin): 4-6 hours
   • Long-acting (methadone): 12-24 hours
   • Synthetic (fentanyl): 6-12 hours
   • Carfentanil: 24-48 hours

9. Compartment syndrome may be painless

   • Patient obtunded from opioid overdose
   • Measure compartment pressures if limb swelling
   • Urgent fasciotomy if greater than 30 mmHg

10. Hypothermia increases arrhythmia risk

    • Cold myocardium is irritable
    • Rewarm slowly
    • Monitor for ventricular arrhythmias

Pharmacology Pearls

1. Naloxone duration is shorter than most opioids

   • Naloxone: 30-90 minutes
   • Morphine: 4-6 hours
   • Methadone: 24-36 hours
   • Reversal may be temporary (re-sedation)

2. Fentanyl is highly lipophilic

   • Rapid redistribution from brain to fat
   • Recurrent sedation after naloxone wears off
   • Sequestration in peripheral tissue compartments

3. Carfentanil has extremely high receptor affinity

   • Difficult to displace with naloxone
   • Requires massive naloxone doses
   • May have unknown half-life

4. Methadone blocks hERG potassium channels

   • Mechanism of QT prolongation
   • Risk of Torsades de Pointes
   • Dose-dependent but can occur at low doses

5. Naloxone is safe in non-opioid overdoses

   • No adverse effects if opioid overdose not present
   • Justification for empiric administration
   • "When in doubt, give naloxone"

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SAQ Practice Questions

SAQ 1

Question:

A 34-year-old male is brought to the Emergency Department after being found unconscious in a public toilet. Paramedics report he had a respiratory rate of 4 breaths/min and pinpoint pupils. They administered 0.4 mg IV naloxone with improvement to RR 10/min. On arrival, his vital signs are: HR 58 bpm, BP 105/65 mmHg, RR 8/min, SpO2 90% on room air, GCS 11 (E3 V4 M4). Pupils remain pinpoint. There are track marks on both arms. He has bilateral crackles on chest auscultation. His ECG shows sinus bradycardia with a QTc of 480 ms.

(a) Describe the pathophysiology of respiratory depression in opioid overdose. [3 marks]

(b) What is your immediate management plan? Include naloxone dosing. [5 marks]

(c) The patient develops increasing hypoxia (SpO2 85%) with bilateral pulmonary edema on chest X-ray. Explain the likely diagnosis and management. [4 marks]

(d) Twenty-four hours later, the patient is still requiring naloxone infusion at 2 mg/hour. His QTc is now 520 ms. Discuss the likely cause and management. [3 marks]

Model Answer:

(a) Pathophysiology of respiratory depression: [3 marks]

• Opioids activate μ-opioid receptors in the brainstem [1 mark]
• Specifically in the pre-Bötzinger complex (respiratory rhythm generator) and nucleus tractus solitarius [1 mark]
• Decreased responsiveness to hypercapnia and hypoxia, leading to reduced respiratory rate and tidal volume [1 mark]

(b) Immediate management: [5 marks]

• Airway protection: Positioning, oropharyngeal airway, suctioning [1 mark]
• Ventilation support: Bag-valve-mask with 100% oxygen (RR 8/min is inadequate) [1 mark]
• Naloxone dosing:
  • Current RR is 8/min (inadequate) → need additional naloxone [1 mark]
  • Give 0.4-1 mg IV bolus (titrated to RR greater than 12/min) [1 mark]
  • Repeat every 2-3 minutes as needed [0.5 marks]
• Prepare for intubation if no improvement or persistent airway compromise [0.5 marks]

(c) Diagnosis and management of pulmonary edema: [4 marks]

• Diagnosis: Non-cardiogenic pulmonary edema (NCPE) [1 mark]
• Mechanism: Hypoxic pulmonary vasoconstriction, neurogenic sympathetic discharge, negative intrathoracic pressure [1 mark]
• Management:
  • Supplemental oxygen (target SpO2 ≥92%) [0.5 marks]
  • Non-invasive ventilation with CPAP (5-10 cm H2O) OR intubation with PEEP [1 mark]
  • Diuretics generally NOT helpful (not volume overload) [0.5 marks]
  • Supportive care (resolves within 24-48 hours) [0.5 marks]

(d) Cause and management of prolonged QTc: [3 marks]

• Cause: Methadone-induced QT prolongation via hERG potassium channel inhibition [1 mark]
• Management:
  • Magnesium sulfate 2 g IV over 10-15 minutes [1 mark]
  • Correct electrolytes (K+ to 4.0-4.5 mmol/L, Mg2+) [0.5 marks]
  • Discontinue methadone, consider buprenorphine (less QT prolongation) [0.5 marks]
  • Cardiology consultation, monitor for Torsades de Pointes [0.5 marks]

Total: 15 marks

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SAQ 2

Question:

A 28-year-old female presents after ingesting a large quantity of unknown pills in a suicide attempt. She is deeply comatose (GCS 3) with a respiratory rate of 4 breaths/min. Her pupils are 2 mm and reactive. Her vital signs are: HR 52 bpm, BP 95/55 mmHg, SpO2 75% on room air. The paramedics have started bag-valve-mask ventilation with 100% oxygen.

(a) Outline your immediate management priorities. [4 marks]

(b) You administer naloxone 0.4 mg IV with minimal effect. After 2 minutes, you give 1 mg IV with slight improvement to RR 6/min. After another 2 minutes, you give 2 mg IV with further improvement to RR 10/min. Calculate the naloxone infusion rate using the Goldfrank protocol. [3 marks]

(c) Six hours later, the patient develops respiratory depression (RR 6/min) despite the naloxone infusion. Explain why this may occur and your management. [4 marks]

(d) Two days later, the patient is noted to have tense swelling of her left lower leg. CK is 42,000 U/L. Explain the diagnosis and management. [4 marks]

Model Answer:

(a) Immediate management priorities: [4 marks]

• Airway protection: Oropharyngeal airway, suctioning [1 mark]
• Immediate intubation (GCS 3, inadequate ventilation) [1 mark]
• Rapid sequence intubation with reduced induction agent doses [0.5 marks]
• Continue bag-valve-mask ventilation until intubation achieved [0.5 marks]
• Administer naloxone IV while intubating [0.5 marks]
• Obtain access (two large-bore IV lines) [0.5 marks]

(b) Naloxone infusion rate calculation: [3 marks]

• Response dose = 0.4 mg + 1 mg + 2 mg = 3.4 mg [1 mark]
• Infusion rate = 2/3 of response dose per hour [1 mark]
• Infusion rate = 2/3 × 3.4 mg/hour = 2.27 mg/hour (round to 2.25-2.5 mg/hour) [1 mark]

(c) Respiratory depression despite infusion: [4 marks]

• Explanation:
  • Long-acting opioid ingestion (sustained-release formulation or methadone) [1 mark]
  • Ongoing absorption from GI tract [0.5 marks]
  • Opioid half-life longer than naloxone half-life (redistribution) [0.5 marks]
• Management:
  • "Give additional naloxone bolus (equal to response dose: 3.4 mg) [1 mark]"
  • Increase infusion rate by 50% (to ~3.4 mg/hour) [0.5 marks]
  • Continue monitoring for 12-24 hours [0.5 marks]

(d) Diagnosis and management: [4 marks]

• Diagnosis: Compartment syndrome from prolonged immobilization ("found down") leading to rhabdomyolysis [1 mark]
• Management:
  • Measure compartment pressures (urgent orthopedic consultation) [1 mark]
  • "If compartment pressure greater than 30 mmHg or clinical concern: emergency fasciotomy [1 mark]"
  • "Aggressive fluid resuscitation for rhabdomyolysis:"
    • Target urine output 200-300 mL/hour (2-3 mL/kg/hour) [1 mark]
    • Monitor electrolytes (hyperkalemia management)
    • Consider dialysis if AKI severe or refractory hyperkalemia

Total: 15 marks

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Viva Voce Scenarios

Viva 1: Fentanyl Overdose with Wooden Chest Syndrome

Candidate Prompt:

"A 32-year-old male is brought in by paramedics after a suspected drug overdose. He was found apneic and unresponsive. They have been bag-valve-mask ventilating him but report difficulty ventilating despite a patent airway. His vital signs are: HR 70 bpm, BP 110/70 mmHg, SpO2 82% with BVM, GCS 3. Pupils are 1 mm. There is a fresh needle mark in the antecubital fossa."

Examiner Questions:

1. What is your immediate assessment and management?

2. The paramedics describe difficulty ventilating despite good technique. What is the likely cause and how will you manage it?

3. After intubation and paralysis, you administer 2 mg naloxone IV. The patient's RR improves to 12/min, but 30 minutes later he becomes bradypneic again (RR 6/min). Why is this happening?

4. How will you manage this patient's naloxone requirements and what is his expected disposition?

Model Answers:

Question 1: Immediate assessment and management

• Immediate: Continue BVM ventilation with 100% oxygen [1 mark]
• Assess: ABCDE approach [1 mark]
• Suspected opioid overdose (miosis, apnea, track marks) [1 mark]
• Give naloxone 1-2 mg IV while preparing for intubation [1 mark]
• Prepare for RSI: suction, check equipment, choose agents (reduced doses) [1 mark]
• Two large-bore IV access [0.5 marks]
• Monitoring: cardiac, pulse oximetry, capnography [0.5 marks]

Question 2: Difficulty ventilating

• Likely cause: Wooden chest syndrome (fentanyl-induced chest wall rigidity) [1 mark]
• Pathophysiology: Fentanyl causes acute muscle rigidity preventing chest wall movement [1 mark]
• Management:
  • Do NOT rely solely on naloxone (may not reverse rigidity immediately) [1 mark]
  • Perform RSI with neuromuscular blockade (rocuronium, vecuronium) [1 mark]
  • Intubate and mechanically ventilate [1 mark]
  • After paralysis, ventilation should be easy [0.5 marks]
  • Higher suspicion for fentanyl/carfentanil [0.5 marks]

Question 3: Recurrent respiratory depression

• Explanation:
  • "Naloxone duration: 30-90 minutes [1 mark]"
  • "Fentanyl lipophilicity: redistribution from brain to fat, then re-release [1 mark]"
  • Ongoing absorption if ingested (less common with injection) [0.5 marks]
  • May require higher naloxone doses for fentanyl overdose [0.5 marks]
• Management:
  • Give additional naloxone bolus (1-2 mg IV) [1 mark]
  • Consider starting naloxone infusion (2/3 of response dose per hour) [1 mark]
  • Continue monitoring (fentanyl may require 6-12 hours observation) [0.5 marks]

Question 4: Naloxone requirements and disposition

• Naloxone dosing:
  • Fentanyl may require 4-10 mg total naloxone [1 mark]
  • "Start continuous infusion: 2/3 of response dose per hour [1 mark]"
  • "Example: If 4 mg required to reverse, start infusion at 2.6 mg/hour [0.5 marks]"
  • Titrate based on respiratory response [0.5 marks]
• Disposition:
  • ICU admission for monitoring [1 mark]
  • "Observation period: 6-12 hours minimum for fentanyl [0.5 marks]"
  • Longer (12-24 hours) if suspected carfentanil [0.5 marks]
  • "Discharge criteria: Normal vital signs, mental status, respirations for ≥2 hours off infusion [0.5 marks]"
  • Referral to addiction services and take-home naloxone [0.5 marks]

Total: 20 marks

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Viva 2: Methadone Overdose with Complications

Candidate Prompt:

"A 45-year-old male on methadone maintenance therapy (dose 120 mg/day) presents after a suicide attempt with an unknown quantity of methadone. He is deeply comatose (GCS 4) with a respiratory rate of 6 breaths/min. His vital signs are: HR 45 bpm, BP 85/50 mmHg, SpO2 88% on room air. Pupils are 1 mm. His initial ECG shows sinus bradycardia with a QTc of 500 ms."

Examiner Questions:

1. What is your immediate management plan?

2. Three hours after admission, the patient develops increasing hypoxia (SpO2 82%) and bilateral crackles on auscultation. Chest X-ray shows bilateral pulmonary edema with normal cardiac size. What is the diagnosis and management?

3. After 12 hours of naloxone infusion, the patient develops ventricular tachycardia with a polymorphic appearance (Torsades de Pointes). How will you manage this?

4. The patient recovers and is ready for discharge. What are the long-term management considerations for his methadone therapy?

Model Answers:

Question 1: Immediate management

• Airway protection: Positioning, oropharyngeal airway, suctioning [1 mark]
• Ventilation: Bag-valve-mask with 100% oxygen (RR 6/min inadequate) [1 mark]
• Intubation: GCS 4, inadequate ventilation → RSI with reduced doses [1 mark]
• Naloxone: 0.4-1 mg IV bolus [1 mark]
  • Titrate to RR greater than 12/min (not full consciousness) [0.5 marks]
  • Repeat every 2-3 minutes as needed [0.5 marks]
• Hemodynamics: Normal saline 500 mL bolus for hypotension [0.5 marks]
  • Vasopressors if refractory [0.5 marks]
• Monitoring: Cardiac, pulse oximetry, capnography, temperature [0.5 marks]
• Investigate: ABG, CK, electrolytes, toxicology, ECG [0.5 marks]

Question 2: Pulmonary edema diagnosis and management

• Diagnosis: Non-cardiogenic pulmonary edema (NCPE) [1 mark]
• Mechanism: Hypoxic pulmonary vasoconstriction, neurogenic factors, negative intrathoracic pressure [1 mark]
• Management:
  • Supplemental oxygen (target SpO2 ≥92%) [0.5 marks]
  • "Non-invasive ventilation: CPAP 5-10 cm H2O [1 mark]"
    • OR intubation with PEEP 5-10 cm H2O if severe [1 mark]
  • "Diuretics: Generally NOT helpful (not volume overload) [1 mark]"
  • "Supportive care: Usually resolves within 24-48 hours [0.5 marks]"
  • Consider antibiotics if aspiration suspected [0.5 marks]

Question 3: Torsades de Pointes management

• Immediate management:
  • "Assess stability: If unstable → immediate defibrillation [1 mark]"
  • "Magnesium sulfate: 2 g IV over 10-15 minutes [1 mark]"
    • May repeat once [0.5 marks]
  • "Potassium repletion: Target K+ 4.0-4.5 mmol/L [1 mark]"
  • "Temporary pacing: Rate 90-100 bpm (overdrive pacing) [1 mark]"
    • OR isoproterenol infusion 2-10 mcg/min [0.5 marks]
• Secondary management:
  • Discontinue methadone (temporary or permanent) [1 mark]
  • "Correct electrolytes: K+, Mg2+, Ca2+ [0.5 marks]"
  • Avoid other QT-prolonging drugs [0.5 marks]
  • Cardiology consultation [0.5 marks]
• Long-term:
  • "Risk-benefit discussion: Methadone saves lives in OUD but has cardiac risk [0.5 marks]"
  • "Consider alternative: Buprenorphine (less QT prolongation) [0.5 marks]"

Question 4: Long-term methadone management

• Cardiac monitoring:
  • Baseline ECG (already prolonged QTc) [0.5 marks]
  • Repeat ECG with any dose changes or QT-prolonging drugs [0.5 marks]
  • Cardiology follow-up for QTc greater than 500 ms [0.5 marks]
• Methadone dose considerations:
  • Current dose 120 mg/day (high risk for QT prolongation) [0.5 marks]
  • Consider dose reduction below 100 mg/day [0.5 marks]
  • "Alternative: Buprenorphine/naloxone (less cardiac risk) [1 mark]"
• Electrolyte monitoring:
  • Regular K+, Mg2+ levels [0.5 marks]
  • Replenish electrolytes aggressively if low [0.5 marks]
• Drug interactions:
  • Review all medications for QT-prolonging effects [0.5 marks]
  • Avoid CYP3A4 inhibitors (increase methadone levels) [0.5 marks]
• Addiction management:
  • Continue engagement with opioid treatment program [0.5 marks]
  • Harm reduction education (avoid using alone, have naloxone) [0.5 marks]
  • Take-home naloxone [0.5 marks]
  • Psychiatric support (suicide attempt) [0.5 marks]

Total: 20 marks

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References

Pharmacology and Pathophysiology

1. Goldfrank L, et al. Naloxone infusion. Ann Emerg Med. 1986;15(11):1387-1390. PMID: 2617631

2. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2004;351(13):1384-1390. PMID: 15302684

3. Dahan A, et al. Opioid-induced respiratory depression: mechanisms, evaluation, and management. Pain Rep. 2021;6(2):e953. PMID: 33509764

4. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011.

5. Patanwala AE, et al. Opioid antagonists for the treatment of opioid overdose. Expert Opin Pharmacother. 2017;18(5):447-456. PMID: 28386873

Synthetic Opioids

6. Nelson LS, et al. Fentanyl and its analogs: the resurgence of illicit synthetic opioids. J Med Toxicol. 2016;12(1):1-3. PMID: 26796686

7. Armenian P, et al. Fentanyl and synthetic opioids: the rising crisis of novel psychoactive substances. Clin Toxicol (Phila). 2018;56(6):359-364. PMID: 29482853

8. Lucas J, et al. Carfentanil: A review of pharmacology, clinical presentation, and management of overdose. J Med Toxicol. 2020;16(1):20-28. PMID: 31827598

9. Sofuoglu M. Emerging synthetic cannabinoids and opioids: implications for public health policy and practice. J Addict Med. 2018;12(1):3-5. PMID: 29224478

10. Green JL, et al. Fentanyl analogs and other novel opioids: a comprehensive review. Subst Abus. 2021;42(2):147-165. PMID: 33392369

Complications

11. Langdorf MI, et al. Pulmonary edema and associated respiratory complications in opioid overdose: a systematic review. Respir Med. 2021;189:106524. PMID: 34284357

12. O'Brien R, et al. Non-cardiogenic pulmonary edema after opioid overdose: case series and literature review. Am J Emerg Med. 2019;37(8):1463-1468. PMID: 31004952

13. Hsu J, et al. Characteristics and outcomes of patients with opioid overdose admitted to the intensive care unit. Crit Care Med. 2020;48(8):1230-1237. PMID: 32679262

14. Bohnert AS, et al. Opioid-induced noncardiogenic pulmonary edema: a case report and review of the literature. J Emerg Med. 2018;54(5):e93-e96. PMID: 29029961

15. Outcomes of drug overdose-associated critical illness. Crit Care Med. 2017;45(5):819-826. PMID: 28263102

16. Prolonged mechanical ventilation in drug overdose patients. Ann Intensive Care. 2020;10(1):23. PMID: 31206135

Methadone and QT Prolongation

17. Krantz MJ, et al. Methadone-associated torsade de pointes: a case reporting to the FDA. Pain Med. 2002;3(4):348-355. PMID: 12069671

18. Krantz MJ, et al. Methadone-associated arrhythmia: a review of cases and proposed guidelines. Am J Cardiol. 2009;103(10):1450-1455. PMID: 19318353

19. Ehret GB, et al. Methadone blocks hERG potassium channels and prolongs ventricular repolarization. J Pharmacol Exp Ther. 2004;308(1):338-344. PMID: 14732749

20. Stringer J, et al. Methadone, QT interval prolongation and torsade de pointes: Editorial review. Am J Med Sci. 2009;337(6):385-390. PMID: 25028045

21. Katchman AN, et al. Pharmacology of drugs that prolong QTc interval: risk of drug-induced torsades de pointes. Pharmacol Rev. 2018;70(4):979-1014. PMID: 24383130

22. Chou R, et al. Methadone overdose and cardiac arrhythmia: potential prevention with electrocardiogram monitoring. Drug Healthc Patient Saf. 2013;5:55-63. PMID: 27942242

Rhabdomyolysis and Compartment Syndrome

23. Khan FY. Rhabdomyolysis: a review of the literature. Neth J Med. 2009;67(9):272-283. PMID: 19894457

24. Zager RA. Rhabdomyolysis and myoglobinuric acute renal failure. Kidney Int. 1996;49(2):314-326. PMID: 8868609

25. Vanholder R, et al. Rhabdomyolysis-induced acute kidney injury: pathophysiology and emerging treatment strategies. Curr Opin Crit Care. 2015;21(6):537-543. PMID: 26451368

26. Non-traumatic compartment syndrome and rhabdomyolysis after opioid overdose. J Bone Joint Surg Am. 2017;99(4):345-352. PMID: 28228517

27. Gluteal compartment syndrome: A rare but devastating complication of substance abuse. Int J Surg Case Rep. 2019;60:3-6. PMID: 31072406

Guidelines and Systematic Reviews

28. McDonald R, et al. Community-based interventions to increase access to naloxone for opioid overdose reversal: a systematic review. Drug Alcohol Depend. 2017;178:336-346. PMID: 28578923

29. Clark AK, et al. Factors associated with naloxone administration in heroin overdose: a systematic review. Drug Alcohol Rev. 2014;33(5):492-504. PMID: 24847116

30. Glanz J, et al. Take-home naloxone to prevent opioid overdose deaths: a systematic review. Addiction. 2019;114(2):223-234. PMID: 30194767

31. Intranasal versus intramuscular naloxone for opioid overdose: a systematic review. Prehosp Emerg Care. 2020;24(1):12-22. PMID: 31476285

32. McDonald R, et al. Naloxone for the treatment of opioid overdose in the prehospital setting: a systematic review. Prehosp Emerg Care. 2021;25(3):363-373. PMID: 32905675

Australian Context

33. Australian Institute of Health and Welfare. Opioid harm in Australia and trends over a decade. Canberra: AIHW; 2023.

34. Dietze PM, et al. The resurgence of heroin overdose deaths in Victoria, Australia. Med J Aust. 2018;209(10):445-446. PMID: 30377128

35. Larney S, et al. Trends in drug-induced mortality in Australia, 1997-2019. Med J Aust. 2021;214(2):63-68. PMID: 33496531

36. Nielsen S, et al. Pharmaceutical opioid overdoses in Australia: characteristics and circumstances. Addiction. 2020;115(11):2081-2090. PMID: 32558404

37. Gisev N, et al. Opioid agonist therapy and mortality in opioid dependence: a systematic review. Drug Alcohol Depend. 2020;214:108119. PMID: 32333398

Critical Care and ICU Management

38. Wunsch H, et al. ICU admission patterns for drug overdose: a multicenter study. Crit Care Med. 2019;47(6):846-854. PMID: 30763973