Fentanyl is primarily metabolised by the cytochrome CYP3A4 enzymes in the liver to an inactive metabolite norfentanyl. Norfentanyl is excreted in the urine, less than seven per cent of fentanyl is excreted unchanged which makes it a suitable option for patients suffering from renal impairment,⁷ unlike morphine, diamorphine or the alternative opioids which are contra-indicated in renal impairment.

Drugs which induce and inhibit the action of cytochrome enzymes will affect the metabolism of fentanyl. Enzyme inducers will increase the enzymatic metabolism of fentanyl and accelerate its clearance, reducing plasma concentration and subsequent analgesic response. Carbamazepine, rifampicin, phenytoin and phenobarbital are all CYP3A4 inducers that will decrease the therapeutic effect of fentanyl.

Enzyme inhibitors will reduce the metabolism of fentanyl increasing the plasma concentration which could possibly increase or prolong the therapeutic effect and potentially lead to respiratory depression. Examples of enzyme inhibitors include macrolide antibiotics such as erythromycin or clarithromycin, azole antifungals including itraconazole and fluconazole, and the cardiovascular drugs verapamil, amiodarone, and diltiazem. Grapefruit juice can also inhibit cytochrome enzymes and patients should be cautioned about this potential interaction.

Drug bioavailability is increased by transdermal administration as this route avoids gastro-intestinal absorption and the consequent first pass metabolism within the liver.