Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Limited, Capital House, 85 King William Street, London EC4N 7BL, UK
Pharmacotherapeutic group: Opioid analgesic
ATC code: N01AH01
Fentanyl is a well established chemical entity. It is an opioid analgesic with a high affinity for the μ-opioid receptor.
Fentanyl can be used as an analgesic supplement to general anaesthesia or as the sole anaesthetic. Fentanyl preserves cardiac stability, and obtunds stress-related hormonal changes at higher doses. A dose of 100 micrograms (2.0 ml) is approximately equivalent in analgesic activity to 10 mg of morphine. The onset of action is rapid. However, the maximum analgesic and respiratory depressant effect may not be noted for several minutes. The usual duration of action of the analgesic effect is approximately 30 minutes after a single IV dose of up to 100 micrograms. Depth of analgesia is dose-related and can be adjusted to the pain level of the surgical procedure. Fentanyl has a broad safety margin. In rats, the ratio LD50/ED50 for the lowest level of analgesia is 277, as compared with 69.5 and 4.6 for morphine and pethidine respectively.
Like other opioid analgesics, fentanyl, depending upon the dose and speed of administration, can cause muscle rigidity, as well as euphoria, miosis and bradycardia.
Histamine assays and skin-wheal testing in man, as well as in vivo testing in dogs, have indicated that clinically significant histamine release is rare with fentanyl.
All actions of fentanyl are immediately and completely reversed by a specific opioid antagonist, such as naloxone.
Fentanyl is a lipid-soluble drug and its pharmacokinetics can be described in terms of a three-compartment model. Following intravenous injection, there is a short distribution phase during which high concentrations of fentanyl are achieved quickly in well-perfused tissues such as the lungs, kidneys and brain.
The drug is redistributed to other tissues; it accumulates more slowly in skeletal muscle and yet more slowly in fat, from which it is gradually released into the blood. Up to 80% of fentanyl is bound to plasma proteins.
Fentanyl is primarily metabolised in the liver, probably by N-dealkylation, and it is excreted mainly in the urine with less than 10% representing the unchanged drug. The terminal half-life of fentanyl is 3.7 hours.
In vitro fentanyl showed, like other opioid analgesics, mutagenic effects in a mammalian cell culture assay, only at cytotoxic concentrations and along with metabolic activation. Fentanyl showed no evidence of mutagenicity when tested in in vivo rodent studies and bacterial assays. There are no long-term animal studies to investigate the tumor-forming potential of fentanyl.
Some tests on female rats showed reduced fertility as well as embryo mortality. These findings were related to maternal toxicity and not a direct effect of the drug on the developing embryo. There was no evidence of teratogenic effects.
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