6 Summary, conclusions, and perspectives and phenotype variations. We could not relate the ventilatory effects to the antinociceptive effects, a critical aspect for evaluating the harm-benefit profile of this pharmacologic compound. We relate our inability to generate opioidinduced antinociception to the specific patient population that was examined by us (our population was insensitive to cold water stimuli). Elderly individuals have difficulty scoring nociception, particularly when exposed to opioids. This may be related to a series of age-related changes in physiology, such as reduced C-fiber density in the skin, alterations in central pain processing as well as cognitive changes. Additionally, obesity negatively affects the proper scoring of nociceptive stimuli. Finally, in chapter 5, we compared hypoxic sensitivity between patients with T2DM with healthy controls and studied the effects of hyperinsulinemia on hypoxic sensitivity. During fasting, we observed no differences between these two groups, however, intriguingly, during euglycemic-hyperinsulinemia significant changes emerged. Heightened hypoxic sensitivity was observed in healthy controls, but not in insulin-resistant individuals. Moreover, during hyperinsulinemia, hyperoxic inhibition increased in patients with T2DM, indicating increased carotid body discharge in this group. This suggests that T2DM negatively affects the carotid bodies with an indication of insulin resistance of that particular organ, albeit the carotid system seems to be in a hyper-excitable state. Clinical perspectives All topics discussed above merit further studies. Regarding chapter 2 and chapter 3, it is important to start clinical trials with the S-ketamine oralthin-film in patients, either in patients in acute pain (including breakthrough pain) as well as with therapy-resistant depression. The high levels of Shydroxynorketamine may hold promise for the management of the latter, as it has been identified as an active substance following (R,S)-ketamine administration.1,2 Besides a possible benefit of this particular administration form, we need to explore the ideal ketamine compositions (pure enantiomer or racemic ratio), efficacy and safety of different dosing regimens, which are expected to differ depending on the indication.3,4,5 Equally important is to determine the side effect profile for each indication. This may, for example, be done using utility function analysis, an approach that calculates the likelihood of benefit versus the likelihood of harm, as a function of effect-site concentration.6 We expect that due to the production of high concentrations of the hydroxynorketamine the utility function may be particularly positive when the S-ketamine OTF is used in the treatment of depression, while a lesser positive function, or even a negative function, may be expected in the treatment of acute pain, an effect that relies mostly on the ketamine concentrations in the 123
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