This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram with an opioid on ventilation. Ventilation will be assessed using a rebreathing methodology. This study will evaluate chronic and acute dosing of paroxetine and escitalopram combined with an opioid as well as chronic and acute dosing of the two drugs without coadministration of an opioid. This study is a 3-period, randomized, placebo-controlled crossover study conducted with 25 healthy participants. Each participant will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, escitalopram/oxycodone) in a randomized order.
This study is designed to evaluate the effects of the coadministration of paroxetine or escitalopram, two selective serotonin reuptake inhibitors (SSRI), with an opioid on hypercapnic ventilation. Hypercapnic ventilation will be assessed under both hyperoxic and hypoxic conditions using the Duffin rebreathing method. This method allows for critical physiological measurements and thresholds to be captured that can then be used to model the effects of drugs when there are dynamic changes in oxygen partial pressure (PO2) and carbon dioxide partial pressure (PCO2), such as during a real-world opioid overdose. SSRIs take approximately 3 weeks to reach maximal therapeutic effect, which correlates with the time required for pre-synaptic inhibitory serotonergic receptors to desensitize. Therefore, drug-effects on ventilation should be evaluated under steady state conditions. This study is randomized, placebo-controlled crossover study which includes three 21-day periods conducted with 25 healthy participants. Participants will receive each of the 3 treatments (placebo/oxycodone, paroxetine/oxycodone, or escitalopram/oxycodone) in a randomized order. Paroxetine dosing will range from 40-60 mg once daily (QD) and escitalopram dosing will range from 20-30 mg QD. Subjects will receive 10 mg oxycodone on three different days each period. Subjects will undergo 6 days of rebreathing and time-matched pupillary assessments along with 3 separate days of ECG assessments each period. Additionally, blood samples will be collected for determination of plasma concentrations for each study drug on days with rebreathing and ECG assessments.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
Enrollment
27
Participants will receive placebo on days 1-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.
Participants will receive 40 mg paroxetine (2 x 20 mg tablets) on days 1-6 and 60 mg paroxetine (3 x 20 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.
Participants will receive 20 mg escitalopram (2 x 10 mg tablets) on days 1-6 and 30 mg escitalopram (3 x 10 mg tablets) on days 7-21 for this treatment period. Oxycodone 10 mg (2 x 5 mg tablets) will be administered on days 6, 12, and 21 of this treatment period.
Spaulding Clinical Research
West Bend, Wisconsin, United States
Minute Ventilation at 55mm Hg End Tidal CO2 (VE55) Under Hyperoxic Conditions on Day 21
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 21.
Time frame: 5 hours on day 21
VE55 Under Hyperoxic Conditions on Day 20
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 20.
Time frame: 5 hours on day 20
VE55 Under Hyperoxic Conditions on Day 6
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 6.
Time frame: 5 hours on day 6
VE55 Under Hyperoxic Conditions on Day 12
Comparison of escitalopram or paroxetine with oxycodone to oxycodone alone. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 12.
Time frame: 5 hours on day 12
VE55 Under Hyperoxic Conditions on Day 5
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 5.
Time frame: 5 hours on day 5
VE55 Under Hyperoxic Conditions on Day 11
Comparison of escitalopram or paroxetine to placebo. Rebreathing data will be analyzed by regression of the minute ventilation versus partial pressure of end tidal CO2 (PETCO2) data to estimate VE55. Resulting VE55 data will be compared using a linear mixed effects model. Comparison will be at 5 hours on day 11.
Time frame: 5 hours on day 11
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