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: Jörn Lötsch, Carmen Walter, Michael J Parnham, Bruno G Oertel, Gerd Geisslinger
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 52 Issue 1 Pg. 23-36 (Jan 2013) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 23100195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Analgesics, Opioid
• Receptors, Opioid
• Cytochrome P-450 CYP3A
• Fentanyl

Topics

• Absorption
• Administration, Cutaneous
• Administration, Intranasal
• Administration, Oral
• Analgesics, Opioid (chemistry, pharmacokinetics, pharmacology)
• Blood-Brain Barrier (metabolism)
• Cytochrome P-450 CYP3A (metabolism)
• Drug Administration Routes
• Fentanyl (chemistry, pharmacokinetics, pharmacology)
• Half-Life
• Humans
• Liver (metabolism)
• Metabolic Clearance Rate
• Nasal Mucosa (metabolism)
• Receptors, Opioid (metabolism)
• Skin (metabolism)
• Time Factors