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-naive subjects to quantify tolerance to respiratory depression. Fourteen opioid-naive individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naive 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-naive subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n=3) and 475 µg (n=6), and in seven chronic opioid users after a cumulative dose of 600 (n=2), 1100 (n=2) and 1800 µg (n=3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory EMAX model. Differences in tolerance between populations were successfully modeled. C50 , the effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naive 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-naive and opioid-tolerant.