significant. No formal sample size analysis was performed. A previous study from our laboratory enrolled 15 subjects and was able to detect a significant difference between two opioids (oxycodone and tapentadol) on ˙VE55 in a young healthy population (mean difference 5 l/min, 95% CI –7 to –3 l/min).23 In the current study, we planned to enroll 18 subjects to consider some variability in the data obtained from an older sample and possible withdrawal of up to 3 subjects. The time to peak effect after a bolus dose is determined by both the bloodeffect-site equilibration half-life and the pharmacokinetics.24 This composite measure may be useful for the design of target-controlled infusion systems where the available models from the literature are evaluated. From the estimated parameters for both oliceridine and morphine, we calculated the time to peak effect using the method described in Minto et al.24 implemented in R (the root of the derivative of the effect-site concentration function of time after a unit bolus dose). Simulations We simulated the effect of multiple doses to reach a level of respiration depression of maximal 65% of isohypercapnic baseline ventilation in a typical 70-kg patient. The simulations were performed in R using implementation of the final models and estimated typical population parameters with simulated data obtained at 1-min intervals. After a bolus dose, a subsequent sequence of doses, three to four per hour, mimicking patient-controlled analgesia, was simulated while advancing simulated time considering a lockout time of 6 min. Three runs were done: one for morphine and two for oliceridine with normal and low elimination clearance. The bolus dose was 10 times and 3 times higher than the subsequent repetitive dose (10:1 and 1.5:0.5), for morphine and oliceridine, respectively, as applied clinically.14,15 72
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