FENTANYL CITRATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
Fentanyl is a potent synthetic opioid agonist that primarily acts on mu-opioid receptors in the central nervous system, leading to analgesia, sedation, and euphoria. It also interacts with kappa and delta opioid receptors to a lesser extent. By binding to these receptors, fentanyl inhibits adenylate cyclase, reduces cAMP production, closes voltage-gated calcium channels, and opens inwardly rectifying potassium channels, resulting in hyperpolarization and reduced neurotransmitter release.
| Metabolism | Fentanyl is primarily metabolized in the liver via CYP3A4-mediated N-dealkylation to norfentanyl, which is inactive. Other minor metabolites include despropionylfentanyl and hydroxyfentanyl. Approximately 75% of the dose is excreted in urine as metabolites, with <10% excreted as unchanged drug. The remainder is excreted in feces. |
| Excretion | Primarily hepatic metabolism (N-dealkylation to norfentanyl and other metabolites); less than 10% excreted unchanged in urine; approximately 9% excreted in feces via biliary elimination. |
| Half-life | Terminal elimination half-life: 3-12 hours (mean 4-6 hours in adults). Context: Prolonged with hepatic impairment, elderly, or continuous infusion (context-sensitive half-life increases with infusion duration). |
| Protein binding | Approximately 80-85% bound to plasma proteins (mainly alpha-1 acid glycoprotein, and to a lesser extent albumin). |
| Volume of Distribution | Steady-state volume of distribution (Vdss): 3-5 L/kg in adults; extensive tissue distribution, contributing to prolonged effects with cumulative dosing. |
| Bioavailability | Intravenous: 100%; Intramuscular: 100%; Oral transmucosal: approximately 50% (33% buccal, remainder swallowed and subject to first-pass metabolism); Transdermal: approximately 75-92% (after 24-hour application, fraction of dose absorbed depends on site and skin condition); Sublingual: ~50%; Intranasal: approximately 70%. Oral (GI) absorption: low (first-pass metabolism ~30% bioavailable). |
| Onset of Action | Intravenous: 30 seconds to 1 minute; Intramuscular: 7-15 minutes; Transdermal: 12-24 hours (steady state achieved after 2-3 applications); Intranasal: 5-15 minutes; Oral transmucosal: 5-15 minutes. |
| Duration of Action | Intravenous: 30-60 minutes (analgesic effect); Transdermal: 72 hours (with residual depression up to 24 h after removal); Intranasal/Oral transmucosal: 30-60 minutes (analgesic effect). Note: Respiratory depression may outlast analgesic effect. |
Initial adult dose 50-100 mcg IV/IM every 1-2 hours as needed for pain; for anesthesia induction 2-20 mcg/kg IV.
| Dosage form | TROCHE/LOZENGE |
| Renal impairment | No specific dose adjustment in renal impairment; use with caution and monitor for respiratory depression in severe renal impairment (eGFR <30 mL/min). |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50%; Class C: reduce dose by 75% or avoid. |
| Pediatric use | Initial dose 1-2 mcg/kg IV/IM every 1-2 hours as needed; maximum single dose 100 mcg. |
| Geriatric use | Initial dose 25-50 mcg IV/IM; consider 50% dose reduction and titration cautiously due to increased sensitivity and risk of respiratory depression. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| FDA category | Positive |
| Breastfeeding | Fentanyl is excreted in breast milk in low concentrations; M/P ratio approximately 0.2-0.4. Minimal risk with single doses, but caution with repeated use due to potential for infant sedation and respiratory depression. Avoid breastfeeding for 24 hours after high-dose or prolonged administration. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; and RISK OF MEDICATION ERRORS.
| Common Effects | Constipation |
| Serious Effects |
["Hypersensitivity to fentanyl or any component of the formulation","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Known or suspected gastrointestinal obstruction, including paralytic ileus","Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of such use","Acute pain management (for transmucosal immediate-release fentanyl formulations) in opioid-non-tolerant patients","Not for use in opioid-non-tolerant patients (for transdermal system)"]
| Precautions | ["Respiratory depression: dose-related and potentially fatal; monitor respiratory status, especially during initiation and dose escalation.","Addiction, abuse, and misuse: potential for opioid use disorder; assess risk before prescribing.","Life-threatening respiratory depression in patients with chronic pulmonary disease or decreased respiratory reserve.","Accidental exposure: even small doses can cause fatal respiratory depression in children and non-opioid-tolerant adults.","Neonatal opioid withdrawal syndrome: prolonged use during pregnancy can result in withdrawal in the newborn.","Interactions with CNS depressants (e.g., benzodiazepines, alcohol) increase risk of profound sedation, respiratory depression, coma, and death.","Adrenal insufficiency: rare but may occur with prolonged use.","Severe hypotension: may occur in patients with compromised ability to maintain blood pressure or volume depletion.","Gastrointestinal effects: may cause constipation; avoid use in patients with known or suspected paralytic ileus.","Seizures: may exacerbate pre-existing seizure disorders.","Serotonin syndrome: risk when used concomitantly with serotonergic drugs.","Biliary tract spasm: may cause constriction of sphincter of Oddi.","Risk of medication errors: confusion with other fentanyl formulations or strengths; ensure proper product selection and dosing.","Use in elderly, cachectic, or debilitated patients: start with reduced doses and titrate slowly.","Hepatic or renal impairment: may require dose adjustment, especially severe impairment."] |
Loading safety data…
| First trimester: Data limited; potential for neural tube defects at supratherapeutic doses in animal studies. Second trimester: No specific structural malformations reported; use only if clearly needed. Third trimester: Prolonged use may lead to neonatal respiratory depression, withdrawal syndrome, and neonatal opioid withdrawal syndrome (NOWS). Avoid chronic use near term. |
| Fetal Monitoring | Monitor maternal respiratory rate, oxygen saturation, sedation level, and pain intensity. Fetal: Continuous fetal heart rate monitoring during labor if used for analgesia; assess for signs of fetal bradycardia or non-reassuring status. Neonatal: Observe for respiratory depression, bradycardia, and withdrawal if used near delivery. |
| Fertility Effects | No direct human data on fertility impairment. Animal studies show no adverse effects on fertility at clinical doses. Chronic opioid use can disrupt menstrual cycle and reduce fertility in women; men may experience erectile dysfunction and reduced libido. |