The analgesic efficacy of fentanyl: relationship to tolerance and mu-opioid receptor regulation

Pharmacol Biochem Behav. 2008 Nov;91(1):115-20. doi: 10.1016/j.pbb.2008.06.019. Epub 2008 Jun 30.


This study determined if fentanyl analgesic efficacy predicts the magnitude of tolerance and mu-opioid receptor regulation. To estimate efficacy, mice were injected i.p. with saline or clocinnamox (CCAM), an irreversible mu-opioid receptor antagonist, (0.32-25.6 mg/kg) and 24 h later fentanyl cumulative dose-response studies were conducted. CCAM dose dependently shifted the fentanyl dose-response function to the right. The apparent efficacy (tau) of fentanyl, based on the operational model of agonism, was estimated as 58, indicating that fentanyl is a high analgesic efficacy agonist. Next, mice were infused with fentanyl (1, 2 or 4 mg/kg/day) for 7 days. Controls were implanted with placebo pellets. At the end of 7 days, morphine cumulative dose-response studies or mu-opioid receptor saturation binding studies were conducted. Fentanyl infusions dose dependently decreased morphine potency with the highest fentanyl dose reducing morphine potency by approximately 6 fold. Chronic infusion with fentanyl (4 mg/kg/day) significantly reduced mu-opioid receptor density by 28% without altering affinity, whereas lower infusion doses had no effect. Taken together, the present results strengthen the proposal that opioid analgesic efficacy predicts mu-opioid receptor regulation and the magnitude of tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Data Interpretation, Statistical
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Drug Tolerance
  • Fentanyl / pharmacology*
  • Male
  • Mice
  • Morphine / pharmacology
  • Pain Measurement / drug effects
  • Radioligand Assay
  • Receptors, Opioid, mu / drug effects*
  • Spinal Cord / metabolism


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Morphine
  • Fentanyl