Discussion We studied oliceridine and morphine and measured isohypercapnic ventilation at an end-tidal PCO2 of 55 mmHg as a biomarker of drug effect in a sample of moderately overweight older men and women. Our main observations were as follows: (1) there was a 30% difference in respiratory potency between oliceridine and morphine with a 50% reduction of ˙VE55 (C50) observed at 29.9 ±3.5 ng/ml oliceridine and 21.1 ±4.6 ng/ml morphine; (2) oliceridine had a 5-times faster onset and offset of respiratory effect than morphine (blood-effect-site equilibration half-life, t1/2ke0, 44 ±6 min for oliceridine vs. 214 ±27 min for morphine); and (3) oliceridine metabolism was dependent on the CYP2D6 enzyme genotype. Simulations revealed that about 40% less oliceridine is needed to achieve the same level of respiratory depression in poor metabolizers compared with normal metabolizers over 24 h. The study was conducted in older subjects as opposed to the more typically young and healthy study population. Previously, we studied healthy young volunteers (18 to 30 yr) to determine the respiratory effects of a range of opioids, including morphine, morphine-6-glucuronide, oxycodone, fentanyl, and buprenorphine.20,21,23,26 Although these studies are of interest from a pharmacologic perspective, the current study sample is clinically more relevant, because patients aged 55 yr and older comprise the vast majority of patients in anesthetic practice. The differences in estimated model parameters indicate that, on bolus dose administration, oliceridine produces respiratory depression more rapidly than morphine, but the oliceridine effect wears off more quickly. In clinical practice, often higher opioid doses are administered than in our experimental study. This may be necessary, for example, to achieve rapid pain relief. Because we did not obtain pain data in our study (see next paragraph), we remain uninformed about how the ventilatory effects that we observed relate to the antinociceptive effects. This requires further study. Previously, Dahan et al.13 analyzed respiratory and antinociceptive oliceridine and morphine data in a younger cohort of healthy male volunteers (19 to 50 yr) to construct utility functions or therapeutic indices of the two opioids. They showed superiority for oliceridine compared with morphine in the utility U = P(A) – P(R), where P(A) is the probability for analgesia and P(R) is the probability of respiratory depression. In the current study, we had planned to construct similar utility functions and therefore measured antinociceptive responses (cold pressor and electrical pain tests, data not shown) in our subjects. However, we experienced early on that the older subjects had difficulty scoring the applied noxious stimuli. They consistently were insensitive to the intense cold-water stimuli (1.5°C) and we did not detect a dose- or time-dependent effect in the electrical pain assay. We, therefore, discarded the antinociceptive 88
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