Opioid Toxicity

Quick Reference

Critical Alerts

:::danger[Immediate Life Threats]

• Airway is priority: Bag-valve-mask ventilation BEFORE and WHILE giving naloxone
• Apnea kills: Respiratory arrest leads to death within minutes
• Naloxone is the antidote: Administer immediately if opioid overdose suspected
• Fentanyl requires higher/repeated doses: May need 10+ mg naloxone total
• Renarcotization risk: Opioid may outlast naloxone effect (30-90 minutes)
• Never withhold naloxone for fear of withdrawal: Respiratory arrest is fatal, withdrawal is not :::

:::warning[High-Risk Scenarios]

• Polysubstance use: Benzos, alcohol, stimulants complicate presentation
• Long-acting opioids: Methadone, extended-release formulations need prolonged observation (12-24 hours)
• Tolerance loss: Post-detox, post-incarceration patients at highest risk
• Illicit fentanyl contamination: Unpredictable potency in street drugs :::

Classic Toxidrome - The Opioid Triad

Emergency Treatments

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Definition and Scope

Overview

Opioid toxicity (opioid overdose) is a life-threatening toxicological emergency caused by excessive opioid agonism at mu-opioid receptors in the central nervous system, resulting in respiratory depression, hypoxia, and death if untreated. The opioid epidemic has made this one of the most common toxicological emergencies, with illicit fentanyl now responsible for the majority of overdose deaths [1,2].

Recognition of the classic toxidrome and rapid administration of the competitive antagonist naloxone (Narcan®) can be immediately life-saving. Emergency physicians must balance effective reversal of respiratory depression against precipitating acute withdrawal in opioid-dependent patients.

Opioid Receptor Pharmacology

Opioids exert their effects through three main receptor subtypes:

The mu receptor is the primary mediator of both therapeutic analgesia and fatal respiratory depression. Full agonists (morphine, heroin, fentanyl) have no ceiling effect for respiratory depression, while partial agonists (buprenorphine) demonstrate a ceiling effect at higher doses [3].

Opioid Classification by Duration and Potency

By Duration of Action:

By Potency (Relative to Morphine):

Synthetic Opioids:

The rise of illicitly manufactured fentanyl (IMF) and fentanyl analogues has dramatically changed the overdose landscape. These synthetic opioids are:

• Extremely potent (micrograms rather than milligrams)
• Often pressed into counterfeit pills resembling prescription opioids
• Mixed with heroin, cocaine, methamphetamine without user knowledge
• Responsible for > 70% of opioid overdose deaths in the US [4]

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Epidemiology

Global Burden

Trends and Waves of the Opioid Epidemic

The opioid epidemic in Western countries has evolved through distinct waves [5]:

High-Risk Populations

Social Determinants

Overdose deaths disproportionately affect:

• Male sex (3:1 ratio over females)
• Rural communities (less access to naloxone, treatment)
• Economically disadvantaged populations
• Individuals with mental health comorbidities
• Previously incarcerated persons (129x risk in first 2 weeks post-release) [6]

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Pathophysiology

Mechanism of Opioid-Induced Respiratory Depression

The pathophysiology of fatal opioid overdose centers on depression of brainstem respiratory centers:

1. Pre-Bötzinger Complex Suppression

• The pre-Bötzinger complex in the ventrolateral medulla generates respiratory rhythm
• Mu-opioid receptor activation hyperpolarizes these neurons via GIRK channels
• Results in decreased respiratory rate and eventual apnea [7]

2. Chemoreceptor Blunting

• Central chemoreceptors normally respond to rising PaCO2
• Opioids blunt this hypercapnic ventilatory response
• Peripheral chemoreceptor response to hypoxia is also attenuated

3. Upper Airway Compromise

• Decreased pharyngeal muscle tone
• Increased risk of upper airway obstruction
• Contributes to obstructive hypoventilation

Progression to Death:

Opioid Binds Mu Receptors
         ↓
Respiratory Center Depression
         ↓
Hypoventilation (↓RR, ↓TV)
         ↓
Hypercapnia + Hypoxemia
         ↓
Loss of Consciousness
         ↓
Apnea
         ↓
Cardiac Arrest (Hypoxic)
         ↓
Death (Minutes)

Systems-Based Effects of Opioid Toxicity

Why Miosis Occurs

Opioids cause miosis through:

1. Stimulation of parasympathetic (Edinger-Westphal) nucleus
2. Pupillary constriction via cranial nerve III
3. Effect persists even in severe overdose

Exceptions to Miosis:

• Meperidine (anticholinergic metabolite normeperidine)
• Severe hypoxia (mydriasis from brain injury)
• Co-ingestion of anticholinergics/sympathomimetics
• Dextromethorphan (serotonergic, mydriasis)
• Propoxyphene

Non-Cardiogenic Pulmonary Edema (NCPE)

NCPE occurs in 0.5-2.5% of opioid overdoses, with several proposed mechanisms [8]:

Clinical features:

• Pink frothy sputum
• Bilateral crackles
• Usually develops within hours of overdose
• Generally resolves within 24-48 hours with supportive care
• May require positive pressure ventilation

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Clinical Presentation

Classic Toxidrome - Detailed Assessment

The Opioid Triad (Sensitivity ~90% when all three present):

Expanded Clinical Features:

Temporal Patterns by Route of Administration

History Taking

Essential Information (Often From EMS, Bystanders):

Atypical Presentations

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Red Flags and Complications

Immediate Life Threats

:::danger[Critical - Immediate Intervention Required]

Complications of Opioid Overdose

Aspiration Pneumonia:

• Occurs in 10-15% of overdose patients
• Loss of protective airway reflexes + decreased consciousness
• Bacterial pathogens: S. aureus, Streptococcus, anaerobes, gram-negatives
• Clinical: Fever, cough, infiltrate (typically RLL) within 24-72 hours
• Management: Antibiotics covering aspiration flora, supportive care [9]

Rhabdomyolysis:

• Found in 5-20% of patients with prolonged immobilization ("found down")
• Mechanism: Pressure-induced muscle necrosis from immobility
• Clinical: Limb swelling, tenderness, dark urine
• Laboratory: CK > 1000 IU/L (often > 10,000), myoglobinuria
• Complications: Acute kidney injury, hyperkalemia, compartment syndrome
• Management: Aggressive IV crystalloid resuscitation (goal UO 200-300 mL/hr) [10]

Compartment Syndrome:

• Complication of prolonged immobilization and rhabdomyolysis
• Classic 6 P's: Pain (out of proportion), Pressure, Paresthesias, Paralysis, Pulselessness, Pallor
• Compartment pressure > 30 mmHg or within 30 mmHg of diastolic
• Treatment: Emergent fasciotomy
• Most common in lower extremities (anterior compartment)

Hypoxic Brain Injury:

• Duration of hypoxia determines severity
• Clinical spectrum: Mild cognitive impairment → persistent vegetative state
• Poor prognostic signs: Bilateral absent pupillary responses, absent motor response, myoclonus
• May develop delayed post-hypoxic leukoencephalopathy (days to weeks later)

Acute Kidney Injury:

• Multifactorial: Rhabdomyolysis + hypotension + myoglobinuria
• May require renal replacement therapy
• Generally reversible with supportive care

QT Prolongation and Arrhythmias (Methadone):

• Methadone blocks HERG potassium channels
• QTc prolongation is dose-dependent
• Risk of torsades de pointes
• ECG monitoring essential for methadone overdose

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Differential Diagnosis

Conditions Mimicking Opioid Toxidrome

Polysubstance Considerations

Common Co-Ingestants:

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Diagnostic Approach

Clinical Diagnosis

Opioid overdose is a clinical diagnosis based on the triad + response to naloxone

Laboratory testing should NOT delay treatment. The combination of:

1. Decreased level of consciousness
2. Pinpoint pupils
3. Respiratory depression

...is highly specific for opioid toxicity. Response to naloxone is both diagnostic and therapeutic.

Bedside Assessment

Laboratory Studies

Urine Drug Screen Limitations

:::warning[Critical Point - UDS is Unreliable for Synthetic Opioids] Standard immunoassay-based urine drug screens have significant limitations:

Clinical Implication: A negative UDS does NOT rule out opioid overdose. Treat based on clinical presentation, not toxicology screen results. :::

Imaging

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Treatment

Principles of Management

1. Airway and breathing are the absolute priority
2. Ventilate before and during naloxone administration
3. Titrate naloxone to respiratory drive, not consciousness
4. Observe for renarcotization (opioid outlasts naloxone)
5. Address complications and coingestants
6. Initiate harm reduction before discharge

Airway Management

Immediate Actions:

Indications for Endotracheal Intubation:

• Persistent apnea despite naloxone
• Unable to protect airway (GCS ≤8)
• Severe aspiration
• Refractory hypoxemia
• Anticipated prolonged resuscitation

Intubation Considerations:

• RSI may be preferred over awake intubation
• Standard agents (etomidate, rocuronium) appropriate
• Be prepared for vomiting during laryngoscopy
• Video laryngoscopy reduces aspiration risk

Naloxone (Narcan) - Comprehensive Pharmacology

Mechanism: Pure competitive antagonist at opioid receptors (highest affinity for mu receptor). Displaces opioid from receptor, rapidly reversing effects [11].

Pharmacokinetics:

Routes and Dosing:

Titration Strategy:

:::tip[Optimal Dosing Approach]

1. Start low in opioid-dependent patients: 0.04-0.1 mg IV
2. Goal is respiratory drive, not full consciousness
3. Repeat every 2-3 minutes until adequate respirations
4. Most overdoses reverse with 0.4-2 mg total
5. Fentanyl may require 10+ mg (keep ventilating)
6. No response after 10 mg → reconsider diagnosis :::

Why Start Low in Opioid-Dependent Patients?

• Full reversal precipitates acute withdrawal
• Withdrawal causes: Agitation, vomiting, diaphoresis, piloerection
• Agitated patient may become combative, leave AMA
• Vomiting increases aspiration risk
• Goal: Restore safe breathing, not full arousal [12]

Fentanyl Overdose Considerations

Illicit fentanyl presents unique challenges:

Chest Wall Rigidity ("Wooden Chest"):

• Occurs with rapid IV fentanyl administration
• Diffuse rigidity impairs ventilation
• Treatment: Naloxone (may take minutes to resolve) + neuromuscular blockade if need to ventilate
• More common in anesthesia/procedural settings than street use

Naloxone Infusion Protocol

Indications:

• Recurrent respiratory depression despite boluses
• Long-acting opioid ingestion
• Large ingestion requiring multiple reversal doses

Preparation:

1. Determine effective reversal dose (dose that improved respirations)
2. Calculate hourly infusion rate = 2/3 of effective bolus dose
3. Mix in normal saline or D5W

Example:

• Patient reversed with 0.4 mg IV naloxone
• Infusion rate = 0.4 × 2/3 = 0.27 mg/hour (approximately 0.25 mg/hour)

Titration:

• Reassess every 15-30 minutes
• Increase infusion if sedation/respiratory depression recurs
• Decrease if withdrawal symptoms develop
• Continue until risk of renarcotization passes (based on opioid half-life)

Management of Opioid-Induced Withdrawal

When withdrawal is precipitated by naloxone:

Key Point: Withdrawal is uncomfortable but not life-threatening. It is always preferable to respiratory arrest.

Supportive Care Measures

Treatment Algorithm

OPIOID OVERDOSE SUSPECTED
         ↓
Assess Airway, Breathing, Circulation
         ↓
┌────────────────────────────────────────┐
│ Apneic or Severely Hypoventilating?    │
│         ↓ YES              ↓ NO        │
│ BVM Ventilation         Supplemental O2│
│         ↓                      ↓       │
└────────────────────────────────────────┘
         ↓
Administer Naloxone
• IV: 0.04-0.4 mg (start low if dependent)
• IN: 4 mg (2 mg per nostril)
• IM: 0.4-2 mg
         ↓
Assess Response (2-3 minutes)
         ↓
┌────────────────────────────────────────┐
│ Improved Respirations?                  │
│     ↓ YES              ↓ NO            │
│ Continue             Repeat Naloxone    │
│ Monitoring           (q2-3 min, up to 10 mg)│
│     ↓                      ↓           │
│                     Still no response?  │
│                     Consider:           │
│                     • Wrong diagnosis   │
│                     • CNS injury        │
│                     • Other coingestants│
└────────────────────────────────────────┘
         ↓
Observation Period
• Short-acting: 4-6 hours
• Long-acting: 12-24 hours
         ↓
Disposition Decision

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Disposition

Observation Period Guidelines

Discharge Criteria

:::tip[Safe for Discharge When ALL Met:]

• Observed minimum 4-6 hours (longer for long-acting opioids)
• No recurrent respiratory depression after naloxone effect wears off
• Stable mental status (GCS 15, alert and oriented)
• Stable vital signs (RR > 12, SpO2 > 94% on room air)
• No complications requiring treatment (aspiration, rhabdomyolysis, injury)
• Able to ambulate safely
• Able to tolerate oral intake
• Safe discharge environment (not alone, follow-up arranged)
• Naloxone kit provided with education
• Harm reduction counseling completed
• OUD treatment offered/referral made :::

Admission Criteria

ICU Admission Criteria

• Intubated/mechanically ventilated
• Hemodynamic instability requiring vasopressors
• Severe metabolic derangement
• Cardiac arrhythmias
• Severe rhabdomyolysis with AKI
• Multi-organ dysfunction

Leaving Against Medical Advice (AMA)

If patient wishes to leave AMA after receiving naloxone:

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Harm Reduction

ED-Based Interventions

The ED visit for opioid overdose is a critical touchpoint for initiating evidence-based harm reduction [13,14]:

Naloxone Prescribing and Distribution

Who Should Receive Naloxone:

• Every patient treated for opioid overdose
• Every patient with opioid use disorder
• Patients on high-dose opioids for chronic pain
• Family members/contacts of people who use opioids
• Anyone who requests it

Available Formulations:

Overdose Prevention Education

Teach patients and families:

Recognizing Overdose:

• Unresponsive, unable to wake up
• Slow, shallow, or stopped breathing
• Choking, gurgling sounds (agonal respirations)
• Blue/gray lips or fingertips
• Limp body

Responding to Overdose (SAVE ME):

1. Stimulate: Shout name, sternal rub
2. Airway: Head-tilt chin-lift
3. Ventilate: Rescue breaths if trained
4. Emergency: Call 911
5. Medicate: Give naloxone
6. Evaluate: Stay until help arrives

Reducing Overdose Risk

Counsel patients on:

• Never use alone (or use with someone who has naloxone)
• Start with smaller dose after any period of abstinence
• Avoid mixing opioids with benzodiazepines, alcohol, gabapentinoids
• Test drugs with fentanyl test strips if available
• Carry naloxone at all times
• Keep naloxone accessible (not locked away)
• Inform friends/family about naloxone location

ED-Initiated Buprenorphine

Starting buprenorphine in the ED increases treatment engagement:

Eligibility:

• Moderate-severe opioid use disorder
• Opioid withdrawal (COWS score ≥8-12)
• Motivated for treatment
• No contraindications

Protocol:

1. Confirm withdrawal (COWS ≥8-12)
2. Administer buprenorphine 4-8 mg SL
3. Reassess at 60-90 minutes
4. Additional 4 mg if needed (max 16 mg day 1)
5. Arrange next-day follow-up with addiction medicine/waivered provider
6. Bridge prescription if immediate follow-up not available

Contraindications:

• Current sedative intoxication
• Need for full agonist analgesia
• Severe hepatic impairment
• Known allergy

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Special Populations

Opioid-Dependent Patients

Key Considerations:

• Lower initial naloxone doses (0.04-0.1 mg IV)
• Titrate slowly to avoid precipitating withdrawal
• Goal: Respiratory drive, not full arousal
• Expect some withdrawal symptoms even with careful titration
• Do not discharge until observed and stable

Managing Precipitated Withdrawal:

• Supportive care is primary treatment
• Benzodiazepines for severe agitation
• IV fluids for dehydration
• Antiemetics for nausea/vomiting
• Allow natural resolution over 1-2 hours

Pregnancy

Principles:

• Naloxone is safe and should be given when indicated
• Pregnancy does NOT change threshold for administration
• Fetal risks of maternal hypoxia far outweigh risks of naloxone
• May precipitate fetal withdrawal (monitor after reversal)
• Consult OB for ongoing management
• Consider OUD treatment initiation

Neonatal Abstinence Syndrome:

• Neonates born to opioid-dependent mothers may develop withdrawal
• Onset typically 24-72 hours after birth
• Features: Tremor, irritability, high-pitched cry, feeding difficulties
• Not a reason to withhold naloxone from mother

Pediatric Considerations

Accidental Ingestion:

• Most common in ages 1-5 years
• Often prescription medications (grandparent's medications)
• May be asymptomatic initially; delayed onset with ER formulations

Naloxone Dosing (Pediatric):

• 0.1 mg/kg IV/IM/IN (max 2 mg per dose)
• Repeat every 2-3 minutes as needed
• Same titration principles as adults

Special Considerations:

• Lower threshold for admission (all symptomatic children)
• Child protective services may need involvement
• Prevention counseling for caregivers

Elderly Patients

• Increased sensitivity to opioids (pharmacokinetic and pharmacodynamic changes)
• More likely to have polypharmacy
• Higher risk of adverse events from overdose
• May have accidental overdose from medication confusion
• Consider reduced naloxone dosing
• Higher risk of complications (aspiration, falls, cardiac events)

Cardiac Arrest Secondary to Opioid Overdose

AHA/ACLS Guidelines (2020):

• Standard high-quality CPR
• Naloxone 2 mg IV/IO (or IM/IN if no access)
• Aggressive airway management
• Standard ACLS interventions
• Rhythm most commonly PEA or asystole (hypoxic)
• Treat underlying cause (hypoxia) with ventilation [15]

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Quality Metrics and Documentation

Performance Indicators

Documentation Requirements

Essential Elements:

• Time of presentation and estimated time of ingestion/use
• Substances involved (reported and suspected)
• Initial vital signs and mental status
• Presence of classic toxidrome findings
• Prehospital naloxone (dose, response)
• ED naloxone (each dose, timing, response)
• Observation period and reassessments
• Complications identified and treated
• Discharge planning and harm reduction interventions
• Follow-up arrangements

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Key Clinical Pearls

Diagnostic Pearls

1. The triad is highly specific: CNS depression + miosis + respiratory depression = opioid toxicity until proven otherwise
2. Miosis may be absent: Meperidine, mixed ingestions, hypoxic injury, very early/late presentation
3. UDS misses fentanyl: Treat the patient, not the toxicology screen
4. Polysubstance use is the norm: Assume co-ingestants until proven otherwise
5. Response to naloxone is diagnostic: Improvement with naloxone confirms opioid involvement

Treatment Pearls

6. Ventilate before you medicate: BVM before and during naloxone administration
7. Start low in dependent patients: 0.04-0.1 mg IV to avoid precipitating severe withdrawal
8. Titrate to breathing, not consciousness: Goal is RR > 12, not full arousal
9. Fentanyl requires persistence: Keep giving naloxone, keep ventilating
10. Renarcotization is real: Observe 4-6 hours minimum (longer for long-acting opioids)
11. Never withhold naloxone: Respiratory arrest kills; withdrawal does not

Disposition Pearls

12. Time observation to opioid half-life: Short-acting 4-6 hours, long-acting 12-24 hours
13. Prescribe naloxone to everyone: Every overdose patient should leave with naloxone
14. Offer treatment: ED-initiated buprenorphine dramatically improves outcomes
15. Harm reduction saves lives: Brief intervention is evidence-based

Exam Pearls

16. Know naloxone pharmacology: Routes, doses, duration, titration principles
17. Recognize atypical presentations: Meperidine (seizures, mydriasis), methadone (QT prolongation)
18. Understand opioid receptor subtypes: Mu is primary target for toxicity and reversal
19. Know complications: Aspiration, rhabdomyolysis, compartment syndrome, NCPE
20. Emergency management priorities: Airway first, naloxone second

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Viva Scenarios

Scenario 1: Classic Presentation

Stem: A 28-year-old man is brought to ED by ambulance after being found unresponsive in a park. GCS 5 (E1V2M2), pupils 1mm bilaterally, RR 4, SpO2 78% on arrival.

Expected Discussion Points:

• Immediate recognition of opioid toxidrome
• Airway management with BVM ventilation first
• Naloxone dosing and route selection
• Monitoring for response and renarcotization
• Observation period determination
• Harm reduction interventions before discharge

Scenario 2: Fentanyl Requiring High-Dose Naloxone

Stem: A 35-year-old woman with known IV heroin use presents with apnea. She receives 2 mg naloxone IV with no improvement. Pupils 2mm, no respiratory effort.

Expected Discussion Points:

• Recognition that fentanyl may require higher doses
• Continuation of ventilatory support while escalating naloxone
• Total dose limits and when to reconsider diagnosis
• Naloxone infusion indications
• Lipophilic nature of fentanyl and redistribution

Scenario 3: Methadone Overdose with QT Prolongation

Stem: A 45-year-old man on methadone maintenance is found unresponsive at home. ECG shows QTc 580ms. He responds partially to naloxone but remains sedated.

Expected Discussion Points:

• Long observation period required for methadone
• QT prolongation management
• Torsades de pointes risk and prevention
• Naloxone infusion considerations
• Role of electrolyte replacement (magnesium)

Scenario 4: Opioid-Dependent Patient with Precipitated Withdrawal

Stem: After receiving 2 mg naloxone IV for respiratory depression, a patient becomes severely agitated, vomiting, with profuse diaphoresis, HR 120, BP 180/100.

Expected Discussion Points:

• Recognition of precipitated withdrawal syndrome
• Why this occurs (rapid receptor displacement)
• Supportive management strategies
• Prevention through careful titration
• Duration of withdrawal symptoms

Scenario 5: Rhabdomyolysis Complicating Overdose

Stem: A 30-year-old is found down for unknown duration. After naloxone reversal, his right leg is tense and painful. CK returns at 45,000 IU/L, creatinine 2.8 mg/dL.

Expected Discussion Points:

• Mechanism of pressure-induced rhabdomyolysis
• Fluid resuscitation targets
• Compartment syndrome assessment (6 P's)
• When to measure compartment pressures
• Indications for fasciotomy
• Renal protection strategies

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MCQ Practice Questions

Question 1

A 32-year-old woman with chronic pain presents with RR 6, pinpoint pupils, and GCS 7. She is opioid-naïve and took "extra" oxycodone. What is the most appropriate initial naloxone dose?

A. 0.04 mg IV B. 0.4 mg IV C. 2 mg IV D. 4 mg IN E. 10 mg IV

Answer: B

Explanation: In opioid-naïve patients, standard doses (0.4 mg IV) are appropriate as there is no concern for precipitating withdrawal. Lower doses (0.04 mg) are reserved for opioid-dependent patients. The goal is rapid but controlled reversal of respiratory depression.

Question 2

A 45-year-old man on methadone maintenance is brought in after overdose. He responds to naloxone and becomes alert. What is the minimum observation period?

A. 2 hours B. 4 hours C. 6 hours D. 12 hours E. 24 hours

Answer: D or E (12-24 hours)

Explanation: Methadone has a very long half-life (24-60 hours), far exceeding naloxone's duration (30-90 minutes). Patients are at high risk of renarcotization and require extended observation of at least 12-24 hours.

Question 3

Which opioid is MOST likely to cause seizures?

A. Morphine B. Fentanyl C. Methadone D. Tramadol E. Hydromorphone

Answer: D

Explanation: Tramadol has multiple mechanisms including inhibition of norepinephrine and serotonin reuptake. It lowers the seizure threshold and can cause seizures, especially in overdose or in patients with seizure risk factors.

Question 4

A patient found unresponsive has pinpoint pupils but does not respond to 10 mg total naloxone. Which diagnosis should be considered?

A. Fentanyl overdose requiring more naloxone B. Clonidine overdose C. Heroin overdose D. Oxycodone overdose E. Buprenorphine overdose

Answer: B

Explanation: Clonidine overdose causes miosis, sedation, and hypotension similar to opioids but does not respond to naloxone. After 10 mg of naloxone with no response, alternative diagnoses including clonidine, pontine hemorrhage, or organophosphate poisoning should be considered.

Question 5

A patient has CK of 35,000 IU/L after prolonged immobilization during overdose. What is the target urine output for rhabdomyolysis treatment?

A. 0.5 mL/kg/hr B. 1 mL/kg/hr C. 3 mL/kg/hr (200-300 mL/hr) D. 50 mL/hr E. No specific target

Answer: C

Explanation: Aggressive IV fluid resuscitation targeting urine output of 200-300 mL/hr (approximately 3 mL/kg/hr) is the cornerstone of rhabdomyolysis management to prevent myoglobin-induced acute kidney injury.

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Revision Summary