Chronic
opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired
opioid effect. Intake of high-dose or potent
opioids may cause life-threatening
respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of
fentanyl in chronic
opioid users and
opioid-naïve subjects to quantify tolerance to
respiratory depression. Fourteen
opioid-naïve individuals and eight chronic
opioid users received escalating doses of intravenous
fentanyl (
opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the
fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in
opioid-naïve subjects after a cumulative
fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic
opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of
fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (Emax ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50%
ventilatory depression, was 0.42 ± 0.07 ng/mL in
opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic
opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to
fentanyl-induced
respiratory depression,
apnea still occurred in the
opioid-tolerant population indicative of the potential danger of high-dose
opioids in causing life-threatening
respiratory depression in all individuals,
opioid-naïve and
opioid-tolerant.