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

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.