Objective:Manifestation of intraoperative fever is impaired by volatile anesthetics and muscle relaxants. Opioids are common anesthetic adjuvants and remain the dominant treatment for postoperative surgical pain and sedation of critically ill patients. The effect of opioids on normal thermoregulatory control is well established. However, the extent to which these drugs might inhibit fever remains unknown. Accordingly, we tested the hypothesis that relatively low plasma concentrations of the μ-receptor agonist alfentanil reduce fever magnitude.Design:Prospective, randomized, crossover study.Setting:Outcomes Research Laboratory, at the Department of Anesthesia and Perioperative Care, University of California, San Francisco.Patients:Eight healthy male volunteers, aged 25-31 yrs, each studied on three separate days.Intervention:Each volunteer was given an intravenous injection of 30 IU/g interleukin (IL)-2, followed 2 hrs later by 70 IU/g. One hour after the second dose, the volunteers were randomly assigned to three doses of alfentanil: a) none (control); b) a target plasma concentration of 100 ng/mL; and c) a target concentration of 200 ng/mL. Opioid administration continued for 5 hrs.Methods and Main Results:Alfentanil significantly reduced the febrile response to pyrogen, decreasing integrated tympanic membrane temperatures from 7.5 ± 2.2°C·hr on the control day, to 4.9 ± 1.5°C·hr with 100 ng/mL alfentanil, and to 5.1 ± 1.7°C·hr with 200 ng/mL alfentanil (p= .011). Peak temperatures were also significantly reduced from 38.5 ± 0.4°C on the control day, to 38.0 ± 0.4°C on the 100 ng/mL-alfentanil day and 38.0 ± 0.6°C on the 200-ng/mL day (p= .019). Plasma cytokine concentrations increased after IL-2 administration, roughly in proportion to the elevation in core temperature. However, cytokine concentrations did not differ significantly among the treatment groups.Conclusion:Alfentanil significantly reduced the febrile response to IL-2 administration. However, the reduction was comparable at plasma concentrations near 100 and 200 ng/mL. These data indicate that concentrations of opioids commonly observed in critical care patients significantly inhibit the manifestation of fever.