indication

For the treatment of cancer patients with severe pain that breaks through their regular narcotic therapy.

pharmacology

Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor but also binds to kappa and delta-type opioid receptors. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, Fentanyl exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Fentanyl may increase the patient's tolerance for pain and decrease the perception of suffering, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.

mechanism of action

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Fentanyl's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

toxicity

Fentanyl has an LD50 of 3.1 milligrams per kilogram in rats, and, 0.03 milligrams per kilogram in monkeys. The LD50 in humans is not known.

biotransformation

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system.

absorption

Bioavailability is 92% following transdermal administration and 50% following buccal administration.

half life

7 (range 3-12) hours

route of elimination

Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. Within 72 hours of IV fentanyl administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with less than 10% representing unchanged drug.

drug interactions

Amiodarone: Possible bradycardia, hypotension

Amprenavir: The protease inhibitor, amprenavir, may increase the effect and toxicity of fentanyl.

Bicalutamide: CYP3A4 Inhibitors like bicalutamide may increase the serum concentration of fentanyl. The risk of prolonged adverse effects, including potentially fatal respiratory depression is increased. Consider therapy modification.

Cimetidine: Cimetidine, a moderate CYP3A4 inhibitor, may decrease the metabolism of fentanyl. Closely monitor changes in the therapeutic and adverse effects of fentanyl if cimetidine is initiated, discontinued or dose changed.

Clotrimazole: CYP3A4 Inhibitors (Moderate) such as clotrimazole may increase the serum concentration of fentanyl. Concurrent use of fentanyl with any CYP3A4 inhibitor may result in increased fentanyl concentrations and could increase or prolong adverse effects, including potentially fatal respiratory depression. Patients receiving fentanyl and any CYP3A4 inhibitor should be closely monitored for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate.

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fentanyl. Concurrent use of fentanyl with any CYP3A4 inhibitor may result in increased fentanyl concentrations and could increase or prolong adverse effects, including potentially fatal respiratory depression. Patients receiving fentanyl and any CYP3A4 inhibitor should be closely monitored for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate.

Fluconazole: Fluconazole may increase levels/toxicity of fentanyl.

Fosamprenavir: The protease inhibitor, fosamprenavir, may increase the effect and toxicity of fentanyl.

Indinavir: The protease inhibitor, indinavir, may increase the effect and toxicity of fentanyl.

Itraconazole: Itraconazole may increase levels/toxicity of fentanyl.

Ketoconazole: Ketoconazole may increase levels/toxicity of fentanyl.

Nelfinavir: The protease inhibitor, nelfinavir, may increase the effect and toxicity of fentanyl.

Rifampin: Rifampin may decrease the serum level and therapeutic effect of fentanyl.

Ritonavir: Ritonavir increases the effect and toxicity of fentanyl/alfentanyl

Saquinavir: The protease inhibitor, saquinavir, may increase the effect and toxicity of fentanyl.

Telithromycin: Telithromycin may reduce clearance of Fentanyl. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Fentanyl if Telithromycin is initiated, discontinued or dose changed.

Tranylcypromine: Possible increased risk of serotonin syndrome.

Triprolidine: The CNS depressants, Triprolidine and Fentanyl, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of fentanyl by decreasing its metabolism. Adverse effects include life-threatening respiratory depression. Monitor for changes in the therapeutic and adverse effects of fentanyl if voriconazole is initiated, discontinued or dose changed.