The analgesic efficacy of fentanyl: Relationship to tolerance and μ-opioid receptor regulation

Abstract

This study determined if fentanyl analgesic efficacy predicts the magnitude of tolerance and μ-opioid receptor regulation. To estimate efficacy, mice were injected i.p. with saline or clocinnamox (CCAM), an irreversible μ-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 ( τ) 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 μ-opioid receptor saturation binding studies were conducted. Fentanyl infusions dose dependently decreased morphine potency with the highest fentanyl dose reducing morphine potency by ≈ 6 fold. Chronic infusion with fentanyl (4 mg/kg/day) significantly reduced μ-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 μ-opioid receptor regulation and the magnitude of tolerance.