Algera MH, Olofsen E, Moss L, et al. - A model‐based comparison with opioid‐naïve individuals was conducted to evaluate the tolerance to opioid‐induced respiratory depression in chronic high‐dose opioid users. Researchers conducted a pharmacokinetic‐pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid‐naïve subjects to evaluate tolerance to respiratory depression. Escalating doses of intravenous fentanyl were received by fourteen opioid‐naïve individuals and eight chronic opioid users (opioid‐naïve individuals: 75‐350 µg/70 kg; chronic users: 250‐700 µg/70 kg). They assessed isohypercapnic ventilation and nonlinear mixed‐effects modeling was applied to evaluate the fentanyl plasma concentration‐ventilation data. The data exhibited that 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, despite higher tolerance to fentanyl‐induced respiratory depression.