E-001 - EFFECT OF PAROXETINE OR QUETIAPINE COMBINED WITH OXYCODONE VS OXYCODONE ALONE ON VENTILATION DURING HYPERCAPNIA: A RANDOMIZED CLINICAL TRIAL.
Thursday, March 23, 2023
5:00 PM – 6:30 PM EDT
V. Gershuny1, J. Florian1, D. Strauss1, R. van der Schrier2, K. Burkhart1, M. Davis1, C. Wang1, X. Han1, K. Prentice3, A. Shah3, R. Racz1, V. Patel1, M. Matta1, O. Ismaiel1, J. Weaver1, R. Boughner4, K. Ford1, R. Rouse1, M. Stone1, C. Sanabria5, A. Dahan2; 1US Food and Drug Administration, Silver Spring, MD, United States, 2Leiden University Medical Center, Leiden, Netherlands, 3Booz Allen Hamilton Inc, McLean, VA, United States, 4KCAS Bioanalytical Services, Shawnee, Kansas, United States, 5Spaulding Clinical Research, West Bend, WI, United States.
Background: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with co-use, the US Food and Drug Administration evaluated whether other psychotropic drugs may cause similar effects. The goal was to determine whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.
Methods: In this randomized, double-blind, crossover clinical trial, 25 healthy participants were treated with oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo and ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) was assessed using rebreathing methodology.
Results: The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs oxycodone alone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], −4.9 L/min [1-sided 97.5% CI, −∞ to −0.6]; P= .01) and day 5 (25.1 vs 35.3 L/min; MD, −10.2 L/min [1-sided 97.5% CI, –∞ to –6.3]; P< .001) but was not significantly decreased with quetiapine plus oxycodone vs oxycodone alone on day 1 or day 5. No drug-related serious adverse events were reported.
Conclusion: Paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.
Florian, Jeffry, et al. Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial. JAMA 328.14, 1405-1414 (2022):
