Fentanyl Citrate

Approved Indications:

• Severe acute pain requiring opioid analgesia and not responsive to non-opioids or weaker opioids.
• Chronic pain in opioid-tolerant patients, especially in cancer pain or palliative care settings.
• Breakthrough cancer pain in opioid-tolerant patients, particularly using transmucosal or intranasal formulations.
• Anesthesia adjunct:
• Premedication before surgery
• Induction and maintenance of general anesthesia
• As an analgesic in combination with sedatives or anesthetic agents
• Procedural sedation/analgesia, including during cardiac catheterization, endoscopy, and short invasive procedures.

Important Off-label Uses:

• Severe neuropathic pain unresponsive to conventional therapies
• Refractory dyspnea in advanced diseases like COPD or cancer
• Pain management in ICU (e.g., mechanical ventilation patients)
• Labor analgesia (via epidural, often in combination)

Adults:

• IV (analgesia): 25–100 mcg slow IV bolus every 1–2 hours as needed; adjust per response.
• IV (anesthesia adjunct): 2–20 mcg/kg depending on procedure length and need.
• Transdermal patch (chronic pain): Initial dose typically 12 mcg/hour to 25 mcg/hour every 72 hours in opioid-tolerant patients; titrate upward every 3 days.
• Buccal tablet/lozenge (breakthrough pain): Initial 100 mcg; titrate upward as needed. Not interchangeable between products.
• Intranasal spray: Initial 100 mcg/nostril; titrate to effect; limit frequency based on formulation.

Pediatrics:

• IV (anesthesia/ICU): 1–5 mcg/kg/dose or infusion (0.5–5 mcg/kg/hour); varies with age and condition.
• Not approved for chronic or breakthrough pain via transmucosal forms in most pediatric populations.

Elderly:

• Start at lower end of dosing range due to increased sensitivity. Monitor for respiratory depression.

Renal/Hepatic Impairment:

• Use with caution; reduced clearance may lead to accumulation. Initiate at lower doses and titrate cautiously.

Administration Routes:

• IV, IM, transdermal patch, transmucosal lozenge/tablet, buccal tablet, sublingual spray, intranasal spray, epidural, intrathecal.

Duration & Frequency:

• Varies per route: IV bolus (short-acting), transdermal (72-hour), transmucosal (episodic pain).

Fentanyl Citrate is a synthetic opioid agonist that binds selectively to the μ-opioid receptors in the central nervous system, especially in the brain and spinal cord. This binding activates inhibitory G-proteins, reducing intracellular cAMP, and suppresses ascending pain pathways by inhibiting pain signal transmission. It also increases pain threshold and alters the emotional response to pain. Fentanyl produces profound analgesia, sedation, and respiratory depression. It has a rapid onset and high potency due to its high lipid solubility.

• Absorption:
• Rapid absorption via IV, transmucosal, and intranasal routes.
• Transdermal: slow systemic absorption over 72 hours.
• Bioavailability:
• IV: 100%
• Buccal: ~50%
• Transdermal: ~92%
• Distribution:
• Highly lipophilic; widely distributed into body tissues.
• Volume of distribution: 3–8 L/kg.
• 80–85% plasma protein binding.
• Metabolism:
• Primarily hepatic via CYP3A4 to inactive norfentanyl.
• Elimination:
• Half-life (IV): 2–4 hours; transdermal: ~17 hours.
• Excreted mostly in urine (inactive metabolites) and some in feces.

• Pregnancy:
• Not assigned under new FDA labeling; previously Category C.
• May cause neonatal respiratory depression or withdrawal if used close to delivery.
• Use only if potential benefits justify risks.
• Lactation:
• Fentanyl is excreted into breast milk in low amounts.
• Considered compatible with breastfeeding in small doses (e.g., post-operative), but long-term use or high doses warrant caution.
• Monitor infants for sedation or poor feeding.

• Primary Class: Opioid Analgesic
• Subclass: Synthetic Phenylpiperidine Opioid
• Anesthesia Adjunct (High-potency narcotic agonist)

• Known hypersensitivity to fentanyl or components
• Acute or severe bronchial asthma without resuscitative equipment
• Significant respiratory depression
• Non-opioid-tolerant patients (for certain forms like transdermal or transmucosal)
• Paralytic ileus or gastrointestinal obstruction (especially for long-acting forms)
• Concurrent MAOI use or within 14 days (risk of serotonin syndrome)

• Black Box Warnings:
• Risk of fatal respiratory depression
• Serious risk of misuse, abuse, and addiction
• Accidental exposure (especially in children)
• CYP3A4 interaction may cause increased levels
• Neonatal opioid withdrawal syndrome with prolonged use during pregnancy
• Precautions:
• Use cautiously in elderly, debilitated, or opioid-naïve individuals
• Titrate slowly in renal or hepatic impairment
• Avoid in head injuries due to risk of increased intracranial pressure
• Careful monitoring required with CNS depressants, alcohol, benzodiazepines
• Monitor for serotonin syndrome with serotonergic drugs

Common Side Effects (by body system):

• CNS: Drowsiness, dizziness, sedation, euphoria, headache
• GI: Nausea, vomiting, constipation
• Dermatologic: Pruritus, sweating, rash (esp. transdermal)
• Respiratory: Dyspnea, respiratory depression (dose-dependent)

Serious/Rare Effects:

• Profound respiratory depression
• Hypotension, bradycardia
• Serotonin syndrome (especially with SSRIs/SNRIs)
• Chest wall rigidity (with rapid IV administration)
• Dependency and withdrawal symptoms

• Major Drug-Drug:
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): ↑ fentanyl levels, ↑ toxicity
• CYP3A4 inducers (e.g., carbamazepine, phenytoin): ↓ efficacy
• CNS depressants (benzodiazepines, alcohol, antipsychotics): additive sedation and respiratory depression
• MAOIs, SSRIs, SNRIs, TCAs: ↑ risk of serotonin syndrome
• Drug-Food Interaction:
• High-fat meals may increase absorption of buccal/transmucosal forms.
• Alcohol potentiates CNS depression and respiratory risk.
• Enzyme System:
• Metabolized by hepatic CYP3A4 enzyme system.

• FDA Safety Alerts reinforce strict limits on transdermal and transmucosal forms to opioid-tolerant patients only.
• New Labeling Requirements for risk of misuse and accidental exposure.
• Updated recommendations for safer co-prescription with benzodiazepines and serotonergic agents.
• Emphasis on prescriber education under REMS (Risk Evaluation and Mitigation Strategy) for long-acting opioids.

• IV/Injection: Store at 20°C to 25°C; protect from light.
• Transdermal patches: Store below 30°C; avoid exposure to heat (e.g., heating pads, saunas).
• Buccal/intranasal/sublingual: Store at 20°C to 25°C in original packaging; avoid moisture.
• General Handling:
• Keep out of reach of children due to fatal overdose risk.
• Dispose of used patches properly (fold adhesive sides together).
• Do not freeze injectables; protect all formulations from light and heat.