Preliminary Communication 

October 11, 2022

Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial

Jeffry Florian, Rutger van der Schrier, Victoria Gershuny, et al

JAMA. 2022;328(14):1405-1414. doi:10.1001/jama.2022.17735

Key Points

Question  Do specific psychotropic drug–opioid combinations further decrease the ventilatory response to hypercapnia beyond the respiratory depression caused by opioids alone?

Findings  In this randomized crossover clinical trial that included 25 healthy participants, paroxetine plus oxycodone significantly decreased mean hypercapnic ventilation compared with placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min, respectively) and day 5 (25.1 vs 35.3 L/min, respectively), whereas quetiapine plus oxycodone did not significantly decrease mean hypercapnic ventilation compared with placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min, respectively) or day 5 (34.7 vs 35.3 L/min, respectively).

Meaning  Further research is needed to determine the clinical relevance of the finding of decreased ventilation during hypercapnia when paroxetine is combined with oxycodone under experimental conditions.

Abstract

Importance  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 simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects.

Objective  To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.

Design, Setting, and Participants  Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021.

Interventions  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.

Main Outcomes and Measures  Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary).

Results  Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone 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 placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, −1.2 L/min [1-sided 97.5% CI, −∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, −0.6 L/min [1-sided 97.5% CI, −∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, −9.3 L/min [1-sided 97.5% CI, −∞ to −3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, −∞ to 6.4]; P = .67). No drug-related serious adverse events were reported.

Conclusions and Relevance  In this preliminary study involving healthy participants, 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.

Trial Registration  ClinicalTrials.gov Identifier: NCT04310579