4 Oliceridine respiratory effects data obtained in the study. We demonstrated earlier that volunteers (mean age 37 yr, body mass index under 30 kg/m2) were not able to reliably score thermal or electrical stimuli after opioid administration.27 This may be even worse in the elderly because the nociceptive fibers in the skin are affected by the normal aging process and there is also evidence for functional alterations in pain-processing regions in the brain of elderly individuals.28,29 Additionally, we showed that a sample of predominantly women with morbid obesity (mean age 43 yr, body mass index range 43 kg/m2) were hypoalgesic to noxious stimuli and had difficulty grading thermal and electrical stimuli.30 All of these factors could have impacted the pain measurement in our current study. It was not possible to compare the respiratory safety of oliceridine and morphine in the older subjects of the present study because of our inability to construct utility functions. This is particularly so because respiratory depression is related to drug dose and plasma concentration, speed of drug infusion, timing of measurement and underlying pain, which are considered in the utility function. Similarly, a comparison with our previous study in younger volunteers should be made with caution given the many differences in protocol, such as the inclusion of only male subjects, venous sampling, and a different respiratory test in the earlier study.13 Despite these differences, a comparison of respiratory potency ratios (C50 oliceridine)/(C50 morphine) remains meaningful. The ratio equaled 1.4 in the current study and was 1.6 in the cohort of younger men.13 This shows that the potency ratio is maintained over the age ranges studied (19 to 50 yr and 56 to 87 yr). Further, the estimated blood-effect site equilibration half-lives are in the same range as observed in earlier morphine and oliceridine respiratory studies.13,21,31,32 Additional studies in preferably acute pain patients, comparing multiple age cohorts, on pain relief and respiration, are needed for definite conclusions. The pharmacokinetic profile of oliceridine was altered in three poor metabolizers related to the CYP2D6 genotype. All three had a significantly lower clearance (CL1) with higher plasma oliceridine concentrations than the other CYP2D6 genotypes. Similar observations were reported earlier.33 In reviewing the pharmacokinetic data, we also need to consider the effects of age and body mass index. Among other physiologic changes, at an increasing age, glomerular filtration rate is reduced and there is a shift in the distribution of fat and muscle mass.34,35 The latter may account for the decreased morphine compartmental volumes compared with volumes reported in younger volunteers with mean age 26 yr.36 Similar observations were made for remifentanil showing reduced compartments volumes with increasing age.37 Our oliceridine pharmacokinetic parameter estimates agree with the pooled analysis of seven oliceridine data sets in acute pain patients of which more than half had an age range of 40 to 65 yr.7 For morphine, a possible age-related reduction in renal function may cause accumulation of morphine-6-glucuronide, morphine’s 89
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