Fentanyl

Mechanism

💊 Common Business Names

Durogesic, Actiq, Abstral, PecFent, Fentanest, Instanyl.

🔬 Pharmacological Group

Selective agonist of the µ opioid receptor (MOP). Synthetic narcotic of the phenylpiperidine class.

Mechanism of Action

Fentanyl acts as a highly selective and potent agonist on opioid receptors:

• Pure µ opioid receptor (MOP) agonist: It has a very high affinity and intrinsic potency on these receptors at a central and peripheral level. It immediately inhibits the coupling of adenylate cyclase through the G_i protein, decreases intracellular concentrations of cAMP and blocks presynaptic voltage-gated calcium channels, interrupting the release of painful neurotransmitters. In parallel, it opens the postsynaptic potassium channels of the GIRK type, hyperpolarizing the afferent neuronal membrane.

Pharmacokinetics

Key Pharmacokinetics

The defining pharmacokinetic characteristic of fentanyl is its extreme lipophilicity, which determines its rapid transmembrane absorption and volume of distribution:

Indicators and dose

Dosage and Adjustment

• Adults:
  • Intense Chronic Pain (Opioid Tolerant Patients): Transdermal patch of 12 µg/h, 25 µg/h, 50 µg/h or 100 µg/h every 72 hours. The rotation of other opioids must be calculated strictly according to the equianalgesic equivalence tables.
  • Breakthrough Oncological Pain: Transmucosal absorption devices (Actiq or sublingual tablets) initiated at the lowest dose (100 - 200 µg) and titrated individually according to clinical response, regardless of the basal patch dose.
• Pediatrics: Not recommended for transdermal patches in children under 2 years of age. Only usable in specialized pediatric oncology and in children tolerant to previous doses equivalent to a minimum of 30 mg/day of oral morphine.
• Adjustment in Kidney Failure:
  • Cl_cr > 30 mL/min: No adjustment required for single doses, but monitor closely in continuous infusion or patches.
  • Cl_cr < 30 mL/min: Reduce the initial titration dose by 25-50% compared to the standard.
• Adjustment in Liver Impairment: In moderate hepatic impairment (Child-Pugh B), reduce the infusion rate or the initial transdermal dose by half, given the decrease in CYP3A4-mediated metabolism.

Security

Safety of Choice in Patients with Renal Failure

Unlike morphine, fentanyl is metabolized exclusively to non-toxic inactive metabolites by the CYP3A4 pathway and compounds with respiratory depressant properties do not accumulate in nephropathy. For this reason, fentanyl constitutes, along with methadone and buprenorphine, the major opioid analgesic of preferential choice in patients with advanced renal failure or patients undergoing hemodialysis programs.

Contraindications

• Absolute: Acute respiratory failure, severe obstructive bronchial asthma; head trauma with intracranial hypertension or suspected space-occupying tumor lesion; active paralytic ileus; management of mild acute pain, immediate postoperative period of minor or dental surgeries (in the case of transdermal patches, due to their pharmacokinetic delay in the onset of action).
• Relative: Bradycardia or pre-existing cardiac conduction disorders (fentanyl can enhance central vagal tone and induce severe bradyarrhythmias); severe cachexia or atrophy of the cutaneous stratum corneum (in the case of transdermal patches due to unpredictable alteration of the absorption pattern).

Adverse Effects (ADR)

• Frequent / Tolerable: Nausea, vomiting, postural dizziness, headache, deep drowsiness, local pruritus, constipation of lower initial intensity than with morphine, erythema at the patch site.
• Rare / Serious: Fatal respiratory depression. Muscular rigidity of the chest wall (wooden chest or chest rigidity of central origin, induced after rapid dose-dependent intravenous infusions that prevents assisted ventilation).
• "Wooden Chest" mechanism: After rapid intravenous administration of medium-high doses, fentanyl stimulates receptors in the spinal motor nuclei (interacting indirectly with central dopaminergic and noradrenergic systems). This induces a sustained tetanic contraction of the striated muscles of the thorax, diaphragm and larynx, blocking respiratory mechanics. It is reversible with Naloxone and non-depolarizing muscle relaxants.

Drug Interactions

• Potent CYP3A4 Inhibitors (Ritonavir, Ketoconazole, Itraconazole, Clarithromycin, Grapefruit Juice): They block the metabolic clearance of fentanyl, substantially raising its plasma levels and drastically increasing the risk of deep sedation and fatal respiratory depression.
• Potent CYP3A4 inducers (Rifampicin, Carbamazepine, Phenytoin, St. John's Wort): They accelerate the clearance of fentanyl, causing marked analgesic ineffectiveness and risk of triggering a withdrawal syndrome in dose-dependent patients.
• CNS depressants: Synergism of profound cardiorespiratory depression.

Pregnancy and Breastfeeding

Classified in FDA Category C. It easily crosses the placenta. Prolonged use causes fetal dependence and neonatal abstinence syndrome. Its peripartum administration can cause profound apnea in the newborn, requiring immediate availability of neonatal naloxone. Breastfeeding: Compatible with precautions; It is excreted in milk in low concentrations, but breastfeeding should be avoided in the first 4-6 hours after transmucosal or intravenous doses of fentanyl.