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

Abstract

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.

Figure 1

Example of effect of three fentanyl administrations (75 µg/70 kg, 150 µg/70 kg, and 250 µg/70 kg) on isohypercapnic ventilation in an opioid‐naïve individual (subject #110). Top panel: The measured fentanyl plasma concentrations (Conc.). Middle panel: 1‐minute ventilation averages (blue symbols = spontaneous breathing, red symbols = stimulated breathing during a 12‐minute apneic period following the third fentanyl administration) and end‐tidal CO₂ concentration (green line); bottom panel: oxygen saturation (SpO₂).

Figure 2

Best, median, and worst pharmacodynamic data fits (based on the coefficient of determination, R ²) in opioid‐naïve subjects (a–c) and chronic opioid users (d–f). Blues dots are the 1‐minute averages of the measured breath‐to‐breath ventilation data; the red line is the data fit. The black triangles indicate the time of the intravenous fentanyl administrations.

Figure 3

Prediction‐corrected and variability‐corrected visual predictive checks of the pharmacodynamic model in opioid‐naïve subjects (a) and chronic opioid users (b). The dots are the 1‐minute ventilation averages. The continuous blue line is the simulated median, the thick broken blue line is the 95% confidence interval of the simulated median, and the thin dotted blue line is the simulated 2.5th and 97.5th percentiles. The continuous orange line is the measured median ventilation and the thin broken orange line is the measured 2.5th and 97.5th percentiles. Probability of apnea in opioid‐naïve subjects (c) and chronic opioid users (d). The red symbols are the probabilities of the observed apneic episodes; the yellow areas are the simulated 95% confidence intervals of the probability of apnea.

Figure 4

The probability of apnea in opioid‐naïve subjects (a) and chronic opioid users (b) for nine intravenous fentanyl doses: 1 = 75 µg/70 kg, 2 = 150 µg/70 kg, 3 = 250 µg/70 kg, 4 = 350 µg/70 kg, 5 = 500 µg/70 kg, 6 = 700 µg/70 kg, 7 = 1,000 µg/70 kg, 8 = 1,500 µg/70 kg, and 9 = 2,000 µg/70 kg. In chronic opioid users, the probability of apnea at doses < 500 µg/70 kg is < 1%.

Figure 5

Steady‐state plasma concentration‐isohypercapnic ventilation relationships in opioid‐naïve subjects (a) and chronic opioid users (b) with 90% prediction intervals indicating that there is a probability of apnea in opioid‐naïve subjects but not in chronic opioid users over the steady‐state concentration range of 0–3 ng/mL. Simulations of the effect of an intravenous fentanyl injection of 250 µg (c) and 1,000 µg (d) in a population of opioid‐naïve individuals and chronic opioid users, respectively (at a reference weight of 70 kg), on isohypercapnic ventilation. The band around the median values represents 90% prediction intervals. Opioid‐naïve individuals have a higher probability of apnea that lasts longer after 250 µg fentanyl (probability = 13%) than chronic opioid users after 1,000 µg (probability = 7%).