active metabolite, and subsequently enhance respiratory depression.38 In our sample, all subjects had a glomerular filtration rate greater than 60 ml/min and a normal liver function. The morphine and oliceridine C50 values (Table 4.2) are lower than previously reported in several studies in younger volunteers.32 For example, we earlier observed a C50 for morphine respiratory effect of about 45 ng/ml in young volunteers in their twenties.39 Although we did not perform a direct comparison among different age cohorts, these observations point toward an increase in respiratory potency with increasing age for the two tested opioids. Our findings are consistent with earlier studies showing enhanced desired and undesired opioid effect with increasing age.37,40,41,42 For potent synthetic opioids, the age effect is well documented. For example, Scott et al.43 found that the fentanyl dose requirements to produce a similar electroencephalographic effect decreases by 50% at an increasing age (from 20 to 89 yr) in male patients. Similar observations were made for remifentanil.37 Cepeda et al.42 showed that the risk for postoperative respiratory depression rises with increasing age in 8,855 surgical patients receiving an opioid (fentanyl, meperidine, or morphine) for postoperative pain. Compared with younger patients (16 to 45 yr), those aged 61 to 70 yr, 71 to 80 yr, and 81 yr and older had, respectively, a 2.8, 5.4, and 8.7 times higher risk for the development of respiratory depression. The physiologic basis of the increased opioid respiratory sensitivity with age remains unknown but may be related to an age-dependent imbalance between excitatory and inhibitory neuronal pathways within the respiratory networks of the brainstem after opioid receptor activation.44 Possibly excitatory pathways are less active in the elderly, leading to increased sensitivity of the ventilatory control system to opioids. 90
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