Pharmacokinetics of non-intravenous formulations of fentanyl

Clin Pharmacokinet. 2013 Jan;52(1):23-36. doi: 10.1007/s40262-012-0016-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

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


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