Opioids can cause respiratory/ventilatory depression, and this can be exacerbated when opioids are co-administered with benzodiazepines. Research suggests this is caused by a reduced respiratory/ventilatory response to counteract increasing levels of systemic carbon dioxide (CO2). It is unknown whether certain other sedative psychotropic drugs can exacerbate opioid-induced respiratory/ventilatory depression. Studies were conducted to evaluate the effects of selected drugs in a non-clinical model. This clinical study will evaluate two drugs (quetiapine and paroxetine) that caused an effect when combined with oxycodone in the non-clinical model.~Study designs were evaluated that would allow a safe and controlled assessment of the effects of drug combinations on respiratory/ventilatory depression and a methodology was selected called the Read breathing procedure which introduces increased levels of CO2 to cause study participants to increase ventilation by having study participants rebreathe through a circuit with 93% oxygen (O2) and 7% CO2. Previous studies have shown this hypercapnic ventilatory response can be decreased by opioids and benzodiazepines and potentially other drugs. Using this procedure, low doses of opioids or benzodiazepines can be administered that have minimal-to-no effects on respiration/ventilation when study participants are going about normal activities breathing room air, however ventilation is decreased relative to the expected increase in ventilation as CO2 levels are increased during rebreathing. Thus, there is minimal risk of true respiratory depression (i.e. inadequate gas exchange) and, if needed, the investigators can immediately halt the experiment and have the study participant breathe room air or 100% O2.~Using the Read rebreathing methodology, the current clinical study was designed to generate data characterizing changes in the ventilatory response to hypercapnia when administering quetiapine and paroxetine alone or in combination with oxycodone. Information obtained from this study will inform on the potential for the specific studied drugs to affect ventilation when combined with an opioid and may also demonstrate the utility of this study design and methodology as an approach for evaluating the effect of an investigational drug and drug combinations on ventilatory depression. Thus, this study includes a lead-in reproducibility phase to quantify the intra- and inter-subject variability within a day and between days. In addition, this study includes a positive control phase with relatively low doses of opioid (oxycodone) alone, benzodiazepine (midazolam) alone and their combination to help assess assay sensitivity. While opioids and benzodiazepines have been studied alone and in combination with the rebreathing method previously, many of these studies are older and it is important to define the reproducibility and effects of the drugs at relatively low doses. Together, these components of the study will further define the reproducibility and sensitivity of the methodology that could be applied to a broader range of investigational drugs in the future to assess their safety when combined with opioids.~In addition, pupillary measurements have been used to study the pharmacodynamic effects of opioids and opioid antagonists (Skulberg et al, 2018; Rollins et al, 2014) and there has been interest in expanding its use in clinical studies. However, there are limited data directly comparing pupillary changes to ventilatory changes and some drugs may influence the pupillary response to opioids (Kummer et al, 2011). As an exploratory endpoint, this study will obtain quantitative pupillometry measurements before and after each rebreathing assessment to allow for comparisons of pupillary changes to ventilatory changes when subjects receive different drugs and drug combinations.~This study includes three parts: A Lead-In Reproducibility Phase and two main parts (Part 1 and Part 2). The lead-in reproducibility phase will quantify the intra- and inter-subject variability of the Read Rebreathing methodology within a day and between days. Part 1 is a positive control phase with doses of an opioid (oxycodone) alone, benzodiazepine (midazolam) alone, their combination, and placebo to help assess ability of the procedure to detect changes in ventilation. Part 2 will assess whether two sedative psychotropic drugs (quetiapine and paroxetine), selected due to their effects in a nonclinical model, decrease the ventilatory response to hypercapnia compared to an opioid (oxycodone) alone. The doses of oxycodone and midazolam were selected to be less than those previously administered in healthy volunteers undergoing the Read Rebreathing or similar respiratory circuit procedures that increase the inspired level of CO2. The doses of quetiapine and paroxetine were selected to reach clinical steady-state levels.~The Lead-In Reproducibility Phase will have up to 10 healthy volunteer participants enrolled in two cohorts of approximately five. Participants will perform the Read Rebreathing procedure five times on day 1 and five times on day 2.~Part 1 will be a 4-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive four different treatments (oxycodone, midazolam, oxycodone + midazolam, and placebo) in a random order across each of the 1-day study periods. There will be two days of washout between each period. During each period, participants will perform the Read Rebreathing procedure seven times, for a total of 28 rebreathing assessments in Part 1. For Part 1, blood samples will also be collected for determination of study drug concentration.~Part 2 will be a 3-period randomized crossover study with approximately 20 healthy volunteer participants. Participants will receive three different treatments (oxycodone, oxycodone + quetiapine, and oxycodone + paroxetine) in a random order across each of the 5-day periods. Oxycodone will only be administered on day 1 and day 5 of each treatment period. The other drugs will be administered every day of the treatment period such that there will be lower concentrations on day 1 and higher concentrations on day 5, which are the days when oxycodone is co-administered. Read Rebreathing assessments will be performed on day 1 and day 5 to investigate the effect of paroxetine and quetiapine when combined with oxycodone compared to oxycodone alone. In addition, Read Rebreathing assessments will be performed on day 4 to determine the effect of paroxetine alone and quetiapine alone compared to placebo. There will be seven days of washout between each period. During each period, participants will perform the Read Rebreathing procedure 17 times, for a total of 51 rebreathing assessments in Part 2. For Part 2, blood samples will also be collected for determination of study drug concentration.
Opioids can decrease breathing and co-administration of benzodiazepines with opioids can further decrease breathing. It is unknown whether certain other drugs also decrease breathing when co-administered with opioids. The objective of this study is to determine whether certain drugs combined with an opioid decrease breathing compared to breathing with an opioid alone.~In order to assess this, this study will utilize the Read Rebreathing method, where study participants breathe increased levels of oxygen and carbon dioxide. The increased levels of carbon dioxide cause the study participants to increase breathing. This increased breathing response can be decreased by opioids and benzodiazepines, and potentially other drugs. Using this procedure, low doses of opioids or benzodiazepines can be administered that have minimal-to-no effects on breathing when study participants are going about normal activities breathing room air, however breathing increases less than expected as carbon dioxide levels are increased. This study will also obtain quantitative pupillometry measurements before and after each rebreathing assessment to allow for comparisons of pupillary changes to ventilatory changes when subjects receive different drugs and drug combinations.~This study includes three parts: A Lead-In Reproducibility Phase and two main parts (Part 1 and Part 2). The Lead-In Reproducibility Phase will measure the variability between study participants and between repeated uses of the method in the same study participant within a day and between days. Part 1 will study an opioid alone, benzodiazepine alone, and their combination to show the methodology will detect changes in breathing at low doses of the drugs that are known to affect breathing. Part 2 will assess whether two drugs, selected due to their effects on breathing in a nonclinical model, decrease the breathing response when combined with an opioid compared to when an opioid is administered alone.