brain and spinal cord.7 Finally, we need to be aware of the fact that we recently showed that ketamine benefit and harm (i.e. its schizotypical adverse effects) are intricately connected, and when none of these adverse effects occur the likelihood of a benefit (pain relief or anti-depressive effects) is reduced.8 The results of chapter 4, the effect of the biased ligand oliceridine on ventilatory control in elderly volunteers, agrees with evidence in animal models that shows the reduced duration and magnitude of respiratory depressant effect of oliceridine, compared to morphine.9 Also, clinical studies in postoperative patients point in that direction.10 Whether these underlying features can be attributed to biased agonism or low intrinsic efficacy remains disputed among molecular researchers.11 Considering the burden of perioperative respiratory effects, we need to realize that with proper monitoring the number of serious respiratory depression events following surgery is limited. For example, the PRODIGY trial, an observational study in more than 1,300 postoperative patients on opioids, showed that while 46% of patients had at least one respiratory event, there were just very rare incidences of the need for naloxone reversal, reintubation, or admittance to the intensive care unit because of opioid treatment.12 Still, less than 20% of patients exclusively treated with oliceridine in the postoperative period have a respiratory event, and most of such events are not related to the opioid treatment per se, but relate to ventilation/perfusion ( ˙VA/ ˙Q) mismatch and concomitant hypoxemia. 12 Further studies are needed to determine what the pharmacoeconomic advantage is of treatment with oliceridine in comparison to commonly used opioids and other analgesics such as morphine or hydromorphone. These generic opioids are cheap, effective, and albeit with a higher tendency to affect the ventilatory control system than oliceridine, are considered a safe drug when used appropriately in the perioperative setting. Furthermore, while outside the scope of this thesis, other actions are necessary beyond innovations in biomedical research, to reduce deaths and prevent further escalation of the opioid crisis around the globe. These include reforming regulatory systems, informed prescribing, and advancements in opioid stewardship. Additionally, efforts should be put towards preventing chronic pain and preventing substance use disorder by modification of risk factors at both individual and population levels. Finally, in chapter 5, the effect of insulin on ventilatory control is examined. The two main observations, carotid body insulin resistance in T2DM coupled with a carotid body that seems to be in a basal hyper-excitable state are important findings that have important health-related effects.13,14 The lack of increase in hypoxic response upon exposure to insulin in patients with T2DM, is relevant although an appreciable hypoxic response remained; the magnitude of the hypoxic response is quite variable among individuals. Still, the inability to enhance the response is a clear sign of insulin resistance. The carotid body 124
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