title: Pharmacokinetics of non-intravenous formulations of fentanyl.
abstract: Fentanyl was structurally designed by Paul Janssen in the early 1960s as a potent opioid analgesic (100-fold more potent than morphine). It is a full agonist at μ-opioid receptors and possesses physicochemical properties, in particular a high lipophilicity (octanol:water partition coefficient >700), which allow it to cross quickly between plasma and central nervous target sites (transfer half-life of 4.7-6.6 min). It undergoes first-pass metabolism via cytochrome P450 3A (bioavailability ~30 % after rapid swallowing), which can be circumvented by non-intravenous formulations (bioavailability 50-90 % for oral transmucosal or intranasal formulations). Non-intravenous preparations deliver fentanyl orally-transmucosally, intranasally or transdermally. Passive transdermal patches release fentanyl at a constant zero-order rate for 2-3 days, making them suitable for chronic pain management, as are iontophoretic transdermal systems. Oral transmucosal and intranasal routes provide fast delivery (time to reach maximum fentanyl plasma concentrations 20 min [range 20-180 min] and 12 min [range 12-21 min], respectively) suitable for rapid onset of analgesia in acute pain conditions with time to onset of analgesia of 5 or 2 min, respectively. Intranasal formulations partly bypass the blood-brain barrier and deliver a fraction of the dose directly to relevant brain target sites, providing ultra-fast analgesia for breakthrough pain. Thanks to the development of non-intravenous pharmaceutical formulations, fentanyl has become one of the most successful opioid analgesics, and can be regarded as an example of a successful reformulation strategy of an existing drug based on pharmacokinetic research and pharmaceutical technology. This development broadened the indications for fentanyl beyond the initial restriction to intra- or perioperative clinical uses. The clinical utility of fentanyl could be expanded further by more comprehensive mathematical characterizations of its parametric pharmacokinetic input functions as a basis for the rational selection of fentanyl formulations for individualized pain therapy.
authors.affiliation: Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, J. W. Goethe-University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. j.loetsch@em.uni-frankfurt.de
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.forename: Carmen
authors.initials: C
authors.lastname: Walter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Oertel
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000042:Absorption; D000279:Administration, Cutaneous; D000281:Administration, Intranasal; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004333:Drug Administration Routes; D005283:Fentanyl / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism; D008657:Metabolic Clearance Rate; D009297:Nasal Mucosa / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D051544:Cytochrome P-450 CYP3A; D005283:Fentanyl