Fentanyl

Drug Name

• Generic Name: Fentanyl Citrate
• Pronunciation: fen-ta-nyl
• Common Brand Names (US): Sublimaze®

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Drug Class

• Pharmacologic Class: Opioid Agonist (Phenylpiperidine derivative)
• Therapeutic Class: Opioid Analgesic, General Anesthetic Adjunct
• Schedule: Schedule II Controlled Substance

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Mechanism of Action (MOA)

Fentanyl is a potent, synthetic µ-opioid receptor agonist. It binds to µ-opioid receptors in the central nervous system (CNS) and peripheral tissues. This binding:

• Inhibits the presynaptic release of excitatory neurotransmitters (e.g., substance P, glutamate).
• Hyperpolarizes postsynaptic neurons by increasing potassium efflux.
• Ultimately leads to a blockade of pain signal transmission from the periphery to the brain.

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Pharmacokinetics

• Onset: Very rapid (30-60 seconds) due to high lipophilicity, allowing quick crossing of the blood-brain barrier.
• Distribution: Initially distributes to highly perfused tissues (brain, lungs), then redistributes to muscle and fat. This redistribution is the primary reason for its relatively short duration of action after a single bolus.
• Metabolism: Almost exclusively metabolized in the liver by the cytochrome P450 enzyme CYP3A4 to the inactive metabolite norfentanyl.
• Excretion: Metabolites are excreted primarily in the urine. Less than 10% is excreted unchanged.
• Context-Sensitive Half-Life: Remains relatively short for infusions up to 2-3 hours but increases significantly with prolonged infusions due to saturation of peripheral tissue sites.

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Pharmacodynamics

Pharmacodynamics describes the drug's effects on the body. The effects of fentanyl are dose-dependent and characteristic of potent µ-opioid agonism:

• Analgesia: Provides profound analgesia, particularly effective for visceral and somatic pain.
• Sedation & Hypnosis: Dose-dependent sedation, progressing to loss of consciousness at high doses.
• Respiratory Depression: The most significant adverse effect. It blunts the brainstem's response to hypercapnia (elevated CO2) and hypoxia, leading to decreased respiratory rate, tidal volume, and apnea.
• Cardiovascular Effects: Generally hemodynamically stable due to minimal histamine release. It can cause bradycardia via central vagal stimulation.
• Muscle Rigidity: Can cause intense rigidity of the chest wall, abdominal wall, and glottic muscles, especially with high doses or rapid IV administration, making ventilation difficult or impossible.
• Miosis: Causes pinpoint pupils through µ-receptor action on the Edinger-Westphal nucleus.
• Nausea & Vomiting: Stimulates the chemoreceptor trigger zone (CTZ) in the medulla.
• Cough Suppression: A direct effect on the medullary cough center.

 

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Dosing & Administration

• Route: Intravenous (IV), Intramuscular (IM), Transdermal (patch), Intrathecal, Epidural, Transmucosal (lozenge).
• IV Dosing (Intraoperative):
  • Bolus (Adjunct to Induction): 50-250 mcg (1-5 mcg/kg).
  • Bolus (Intraoperative Analgesia): 25-100 mcg, titrated to effect.
  • Infusion (Maintenance): 0.5-5 mcg/kg/hr, titrated to hemodynamic and autonomic response.
• Administration Note: Must be administered slowly. Rapid bolus injection can cause severe chest wall rigidity, coughing, and laryngospasm.

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Clinical Uses / Indications

• General Anesthesia: As a primary component of a balanced anesthetic for induction and maintenance.
• Analgesia: For moderate to severe pain, both intraoperatively and postoperatively (via PCA).
• Procedural Sedation: For painful procedures in the emergency department or endoscopy suite.
• Regional Anesthesia Adjunct: Added to spinal or epidural anesthetics to prolong analgesia.
• Chronic Pain Management: Via transdermal patches for opioid-tolerant patients with chronic pain.

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Contraindications

• Absolute:

  • Known hypersensitivity to fentanyl or other morphinomimetics.
  • Acute or severe bronchial asthma (in an unmonitored setting or without resuscitative equipment).

• Relative:

  • Significant respiratory depression.
  • Paralytic ileus.
  • Use with or within 14 days of Monoamine Oxidase Inhibitors (MAOIs) (due to risk of unpredictable CNS and respiratory depression).

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Adverse Effects / Side Effects

• Respiratory: Apnea, respiratory depression, chest wall rigidity.
• Cardiovascular: Bradycardia, hypotension (usually secondary to bradycardia or histamine release in susceptible individuals).
• Gastrointestinal: Nausea, vomiting, constipation.
• CNS: Sedation, dizziness, headache, muscle rigidity.
• Other: Urinary retention, pruritus, miosis.

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Drug Interactions

• CNS Depressants: (e.g., benzodiazepines, barbiturates, propofol, alcohol, other opioids) have additive sedative and respiratory depressant effects.
• CYP3A4 Inhibitors: (e.g., erythromycin, ketoconazole, ritonavir) can increase fentanyl plasma levels, increasing the risk of toxicity.
• CYP3A4 Inducers: (e.g., carbamazepine, phenytoin, rifampin) can decrease fentanyl levels, potentially reducing its efficacy.

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Monitoring Parameters

• Standard Anesthesia Monitoring: ECG, NIBP, SpO2, EtCO2, Temperature.
• Respiratory Status: Continuous monitoring of end-tidal CO2 is essential to detect respiratory depression before desaturation occurs. Post-operative monitoring of respiratory rate and oxygen saturation is critical.
• Level of Consciousness: Assess depth of anesthesia/sedation.
• Muscle Rigidity: Be prepared to treat rigidity with a rapid-acting neuromuscular blocker (e.g., succinylcholine) or naloxone.

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Key Considerations for the Anesthesia Provider

• Potency: Remember its high potency; dosing errors are common and can be fatal. Double-check all doses.
• Chest Wall Rigidity: Be prepared for this, especially with doses > 5 mcg/kg or rapid boluses. It is treated with immediate paralysis and controlled ventilation.
• Context-Sensitive Half-Life: For long cases (>3-4 hours), fentanyl infusions can lead to significant accumulation and prolonged post-operative respiratory depression. Consider switching to a shorter-acting opioid like remifentanil or using a non-opioid technique.
• Post-Operative Monitoring: Patients receiving intraoperative fentanyl require diligent post-operative monitoring, as the effects can outlast the surgical procedure.

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Summary / "Bottom Line"

Fentanyl is a highly potent, rapid-onset synthetic opioid that is a cornerstone of modern anesthesia. Its primary advantage is hemodynamic stability, but its main risk is profound and rapid-onset respiratory depression and chest wall rigidity. Careful titration, awareness of its context-sensitive half-life, and vigilant post-operative monitoring are essential for safe use.

 
Next: Remifentanil & Sufentanil →
 

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Related Opioids - Remifentanil and Sufentanil

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Remifentanil and Sufentanil are ultra-short-acting and ultra-potent fentanyl analogs, respectively. They share the same core MOA but have distinct pharmacokinetic profiles that define their clinical niche.

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Remifentanil

• Key Differentiator: Its metabolism is unique among opioids. It is an ester-based molecule metabolized by non-specific plasma and tissue cholinesterases. This makes its metabolism independent of liver or kidney function.
• Pharmacokinetics:
  • Onset: Extremely rapid (30-60 seconds).
  • Offset: Extremely rapid. The context-sensitive half-life is consistently 3-5 minutes, regardless of the duration of the infusion. This is its defining characteristic.
• Clinical Pearls / Use Cases:
  • Total Intravenous Anesthesia (TIVA): The ideal opioid for TIVA due to its rapid titratability and predictable offset.
  • Neurosurgery: Allows for a rapid emergence for a quick neurological assessment.
  • Airway Surgery: Useful for procedures requiring the patient to be deeply anesthetized but then wake up quickly (e.g., direct laryngoscopy, bronchoscopy).
  • ICU Sedation: Allows for rapid neurological exams in critically ill patients.
• Important Consideration: Due to its rapid offset, analgesia disappears within minutes of stopping the infusion. It is mandatory to establish a longer-acting analgesic plan (e.g., morphine, hydromorphone, regional block) before discontinuing the remifentanil infusion. Bradycardia is also very common and often requires treatment.

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Sufentanil

• Key Differentiator: It is the most potent opioid available for clinical use, approximately 5-10 times more potent than fentanyl.
• Pharmacokinetics:
  • Onset: Very rapid, similar to fentanyl.
  • Duration: Intermediate duration. Its context-sensitive half-life is shorter than fentanyl's for prolonged infusions but significantly longer than remifentanil's.
• Clinical Pearls / Use Cases:
  • Cardiac Anesthesia: Its extreme potency makes it excellent for blunting the intense sympathetic response to sternotomy and cannulation. It provides profound analgesia with hemodynamic stability.
  • Major Vascular & Neurosurgery: Used in high-stress, painful procedures where deep analgesia is required.
  • Induction of Anesthesia: Can be used as the primary analgesic component for induction.
• Important Consideration: Because of its extreme potency, dosing errors are exceptionally dangerous. Chest wall rigidity is very common and can be severe even with small doses. Meticulous dosing and slow administration are critical.

 
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