Effect of Selective Serotonin Reuptake Inhibitors (SSRIs) and an Opioid on Ventilation
Condition: Hypercapnia; Ventilatory Depression
MeSH terms: Respiratory Insufficiency; Hypercapnia
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Placebo and Oxycodone; Paroxetine and Oxycodone; Escitalopram and Oxycodone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Oxycodone; Paroxetine; Escitalopram
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: This is a 3-period, double-blind, randomized crossover study. The duration of each treatment period will be 21 days in addition to a three-week washout between periods. The duration of study participation will be 106 days (excluding the screening period).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other