Tolerance to Opioid‐Induced Respiratory Depression in Chronic High‐Dose Opioid Users: A Model‐Based Comparison With Opioid‐Naïve Individuals

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 (E_max ) 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.