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Fentanyl

Classification & Chemistry

• Lippincott Pharmacology, p. 718
• Roberts & Hedges' Clinical Procedures in Emergency Medicine

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Pharmacokinetics (ADME)

• Miller's Anesthesia 10e, p. 2803
• Goodman & Gilman's, ADME section

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Mechanism of Action

• Inhibits adenylyl cyclase (decreases cAMP)
• Opens inward-rectifying K+ channels (hyperpolarization)
• Closes voltage-gated Ca2+ channels
• Net effect: decreased neuronal excitability and reduced neurotransmitter release

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Pharmacodynamics & Clinical Effects

CNS

• Potent analgesia; C50 for analgesia = 1-2 ng/mL
• t½ke0 for analgesic effect = 10-20 minutes (longer than EEG effect, t½ke0 ~6.5 min)
• Sedation and dose-dependent respiratory depression
• Does NOT cause amnesia at standard doses

Cardiovascular

• Decreases heart rate via vagal activation
• Modest decrease in blood pressure
• Does NOT release histamine - minimal myocardial depression
• This makes it preferred for cardiac surgery and hemodynamically unstable patients

Respiratory

• Dose-dependent respiratory depression; apnea precedes loss of consciousness
• Rapid IV injection (especially >5 mcg/kg bolus) can cause wooden chest / chest wall rigidity - diaphragm, chest wall, and upper airway rigidity impairing ventilation (more common in pediatric patients and with high doses)
• Delayed respiratory depression possible via enterohepatic circulation

Other

• Nausea/vomiting: rare (advantage over morphine and meperidine)
• Nasal pruritus: a commonly observed reaction
• No histamine release
• Goodman & Gilman's, p. 256-258
• Roberts & Hedges', p. 728

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Routes of Administration

• Lippincott Pharmacology, p. 718-719
• Barash's Clinical Anesthesia 9e, p. 1555

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Clinical Uses

1. Anesthesia - intraoperative analgesia; dampens cardiovascular responses to laryngoscopy, intubation, skin incision; reduces inhalational agent and propofol requirements by ~50% at 1.5-3 mcg/kg IV. Should be given 5-10 min before anticipated noxious stimulus given the t½ke0.
2. Procedural sedation and analgesia (PSA) - preferred opioid in the ED; rapid onset, brief duration, hemodynamic stability, no histamine release. Often combined with midazolam or propofol. Fully reversible with naloxone.
3. Chronic pain - transdermal patch. Contraindicated in opioid-naive patients and for acute/postoperative pain.
4. Breakthrough cancer pain - transmucosal formulations (Actiq lozenge, Fentora buccal tab). Only for opioid-tolerant patients (defined as ≥60 mg oral morphine equivalent/day).
5. Cardiac surgery - high-dose fentanyl (5-75 mcg/kg) provides primary anesthesia with minimal cardiovascular depression.
6. Labor analgesia - IV or epidural in doses of 50-100 mcg/h; no significant neonatal effects on Apgar scores at these doses.

• Roberts & Hedges', Miller's Anesthesia 10e, Goodman & Gilman's

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Dosing (Selected)

• Procedural sedation: 1-2 mcg/kg IV (titrated)
• Anesthesia supplement: 1.5-3 mcg/kg IV; repeat dosing based on surgical duration
• High-dose cardiac anesthesia: 5-75 mcg/kg

• Neonates/young infants: 1-4 mcg/kg/dose IV Q2-4 h PRN (max 100 mcg/dose); continuous infusion 1-5 mcg/kg/hr
• Older infants/children: 1-2 mcg/kg/dose IV/IM Q30-60 min PRN (max 100 mcg/dose); infusion 1-3 mcg/kg/hr

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Drug Interactions

• CYP3A4 inhibitors (e.g., azole antifungals, macrolides, ritonavir): increase fentanyl plasma levels and risk of toxicity
• CYP3A4 inducers (e.g., rifampin, carbamazepine): reduce fentanyl efficacy
• CNS depressants (benzodiazepines, alcohol, neuroleptics): enhanced sedation and respiratory depression - significantly increased apnea/hypoxia risk
• MAOIs: potentially severe hypotension and CNS excitation
• Propofol: co-administration reduces requirements of both drugs synergistically

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Reversal & Overdose

• Fully reversible with naloxone (opioid antagonist)
• Chest wall rigidity: reverse with naloxone, positive pressure ventilation; if refractory, neuromuscular blocking agents (depolarizing or nondepolarizing) - ensure patient is not awake/aware when paralyzed
• Standard resuscitation: airway management, oxygen, IV naloxone 0.04-0.4 mg IV (titrate to avoid precipitating acute withdrawal in opioid-tolerant patients)

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Key Contraindications

• Transdermal patch: opioid-naive patients, acute/postoperative pain (dangerous due to delayed onset and inability to titrate)
• Transbuccal/transmucosal forms: only for patients consuming ≥60 mg oral morphine equivalent/day
• Children <2 years: transdermal patch safety not established

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Comparison to Related Opioids

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Remifentanil

Classification & Key Distinguishing Feature

• Miller's Anesthesia 10e, p. 2805

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Pharmacokinetics

Metabolism - The Defining Feature

• Miller's Anesthesia 10e; Morgan & Mikhail's Clinical Anesthesiology 7e, p. 354

Key Kinetic Parameters

• Barash's Clinical Anesthesia 9e, p. 2523; Goodman & Gilman's

Context-Insensitive Half-Life - The Clinical Advantage

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Pharmacodynamics

Potency

• 100-200 times more potent than morphine at the MOR
• CP50 for no clinical response to surgical stimulation: highly variable (1.5-79 ng/mL) - a 50-fold range across patients
• Gender difference noted: CP50 ~4.1 ng/mL (men) vs. ~7.5 ng/mL (women) in one abdominal surgery study (attributable to procedural differences)

CNS

• Rapid, intense analgesia
• Dose-dependent sedation and respiratory depression
• No intrinsic amnesia - requires a hypnotic co-drug (propofol, midazolam)
• Reduces MAC of volatile agents significantly: remifentanil at 1 ng/mL target reduces sevoflurane MAC from ~4% to ~0.36% in some studies
• Reduces propofol requirements by >60% at therapeutic concentrations

Cardiovascular

• Decreases heart rate (vagal activation) and blood pressure
• Rapid bolus injection: risk of hypotension and bradycardia
• Low histamine release (hemodynamically stable)

Respiratory

• Dose-dependent respiratory depression
• Peak respiratory depression after bolus: ~5 min
• Recovery of spontaneous ventilation: rapid after infusion discontinuation or rate reduction
• Infusion rates of 0.1 ± 0.05 mcg/kg/min can maintain analgesia while permitting spontaneous ventilation

Chest Wall Rigidity

• Can occur, especially with rapid bolus injection - related to peak concentration
• Reverse with opioid antagonist, positive pressure ventilation, or neuromuscular blockade if needed
• Barash's Clinical Anesthesia 9e; Miller's Anesthesia 10e

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Formulation - Critical Restriction

Remifentanil is CONTRAINDICATED for epidural or intrathecal (spinal) administration.

• Goodman & Gilman's; Miller's Anesthesia 10e, p. 2806

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Clinical Uses

1. Balanced General Anesthesia

• Continuous IV infusion: 0.1-1.0 mcg/kg/min for intraoperative analgesia
• Allows "most predictable and rapid trouble-free emergence" without postoperative respiratory depression
• Synergistic with propofol (TIVA) and volatile agents
• Dose adjusted between stimulation events (e.g., lower between intubation and incision)

2. Total Intravenous Anesthesia (TIVA) with Propofol

• Gold standard pairing; both drugs have short context-sensitive half-times allowing deep intraoperative analgesia without prolonged emergence
• Induction: remifentanil 2 mcg/kg with propofol; maintenance: 0.25-0.5 mcg/kg/min

3. Monitored Anesthesia Care (MAC) / Procedural Sedation

• Ideal for brief, painful procedures under regional or local anesthesia
• Clinical target: analgesia and patient comfort, not sedation
• Add midazolam (2 mg IV) or propofol for the hypnotic-amnesic component; midazolam reduces remifentanil requirements by up to 50%
• Practical infusion rates for MAC sedation: ~0.05-0.1 mcg/kg/min

4. ICU Sedation/Analgesia

• Short-term analgesia and sedation; rapidly titratable

5. Cardiac Surgery

• Induction: remifentanil 2 mcg/kg + propofol; maintenance: 0.25-0.5 mcg/kg/min for minimally invasive CABG

6. Neuroanesthesia

• Used where rapid neurological assessment post-procedure is needed

7. Spontaneously Breathing Patients

• Feasible at low infusion rates (<0.1-0.2 mcg/kg/min) with appropriate monitoring
• Miller's Anesthesia 10e; Barash's Clinical Anesthesia 9e

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Dosing Summary

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The Post-Remifentanil Analgesia Problem

• Administer a longer-acting opioid (morphine, fentanyl) 15-30 min before the end of surgery
• Add NSAIDs, acetaminophen, regional blocks as part of multimodal analgesia
• Failure to plan leads to immediate, intense post-emergence pain

"The need for alternative analgesic therapies should be anticipated and administered in a timely fashion" - Miller's Anesthesia 10e

Opioid-Induced Hyperalgesia (OIH)

• High-dose or prolonged remifentanil infusions can paradoxically lower the pain threshold after discontinuation - a phenomenon known as remifentanil-induced hyperalgesia
• Mechanism: central sensitization via NMDA receptors
• Management: ketamine (0.15 mg/kg bolus + 2 mcg/kg/min infusion) reduces intraoperative remifentanil requirements AND postoperative morphine consumption without adding side effects
• PubMed 2024 systematic review confirmed pharmacological interventions for remifentanil-induced hyperalgesia remain an active area of research [PMID: 39636808]
• Miller's Anesthesia 10e, p. 2837

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Drug Interactions

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Special Populations

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Summary Comparison: Remifentanil vs. Other Fentanyl Congeners

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