This thesis represents the intricate journey between physiology and pharmacology. Our primary aim was to investigate the effects of different pharmacotherapies on antinociception and ventilatory control. Additionally, we delved into the inherent variabilities in patient phenotypes within the population to gain a deeper understanding of the individual effects of analgesics and the ventilatory effects of disease, particularly type 2 diabetes mellitus (T2DM). Summary of the main findings In chapter 1, we briefly introduce the reader to recent advancements in the use of ketamine in clinical practice (for pain management and depression), and the ventilatory depressant effect of opioids and alterations in ventilatory control in T2DM are discussed. Our goal was to highlight current challenges in pain management, emphasize the importance of considering risk factors and side effects, and propose strategies for investigating new or alternative therapies. In chapter 2, we examined the pharmacokinetics of oral-thin-film (OTF) administration of 50 mg and 100 mg S-ketamine and its major metabolites. These films were rapidly absorbed, with bioavailabilities of 26% and 29%, respectively, and exhibited relatively small variability in their pharmacokinetics. Therapeutic plasma concentrations for antinociception were achieved. The majority of S-ketamine was metabolized into S-norketamine, with about half further metabolized into S-hydroxynorketamine. These findings were attributed to the swallowing of the active substance, gastrointestinal absorption of the majority of S-ketamine, and a significant first-pass effect. In the complementary chapter 3, we investigated the pharmacodynamics of the aforementioned oral-thin-film. Both dosages exhibited antinociceptive effects with a rapid onset (approximately 30 minutes) and lasting effects of at least two hours. Psychotomimetic side effects, such as drug-high, followed a similar pattern. Our model did not detect contributions of S-norketamine and S-hydroxynorketamine to the antinociceptive or drug-high effects. We conclude that this administration form of S-ketamine may be suitable for the treatment of acute pain and breakthrough pain, a proposition that warrants further clinical studies. Moving on to chapter 4, where we examined the respiratory effects of a biased ligand at the µ-opioid receptor, oliceridine. We observed a lower potency of the respiratory depressant effect induced by oliceridine compared to morphine, a lower C50 for respiratory depression for both opioids in the elderly population, a shortened onset/offset of respiratory depression with oliceridine, and differences in oliceridine's pharmacokinetic profiles due to CYP2D6 polymorphisms 122
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