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

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.

Figure 1.. Flow of Participants in Study, Interventions and Overall Study Design

^aTen participants had a Mallampati score greater than 2, (predicts difficult tracheal intubation); 5, deemed unlikely to comply with protocol; 5, tested positive for alcohol or illicit drugs; 7, abnormal medical history, laboratory results, or physical examination findings. ^bParticipant was not needed as a replacement. ^cFive participants replaced the 6 who did not complete all treatment periods. The study design planned for 5 replacements. ^dOne participant was included in the primary analysis for only day 1, after which the participant discontinued. ^eSee the Methods section for timing of study drug administration. Participants received 4 mg of ondansetron 30 minutes before each dose of oxycodone on days 1 and 5 only to prevent nausea and vomiting. ^fVentilation increases at an approximately linear rate after carbon dioxide (Pco₂) is higher than the ventilatory recruitment threshold (VRT). The opioid causes small decreases in ventilation below the VRT, shifts the VRT to the right, and decreases the rate of rise in ventilation as Pco₂ increases further.^,,,

Figure 2.. Minute Ventilation at End-Tidal Carbon Dioxide of 55 mm Hg

A, Bars indicate medians; box borders, IQRs; and circles, outside the range. Whiskers extending from box borders to the last observation within 1.5 × the IQR. B, For dosing administration, see the Figure 1. Data points indicate model-estimated means and whiskers 2-sided 95% CIs. C, The primary outcome comparisons at 5 hours are on days 1 and 5; secondary outcomes, day 4, the secondary outcome comparison. Data points indicate the model-estimated mean difference; whiskers, the upper 1-sided 97.5% CIs.

Figure 3.. Oxycodone Concentration-Response Model and Observed Data for Drug Combinations

The oxycodone concentration–response model is based on a linear mixed-effect model with all data from oxycodone alone. The downward sloping black line indicates the prediction; the shaded region, 95% CI (mean slope, −0.29 L/min per ng/mL [95% CI, −0.47 to −0.11); mean intercept, 39.8 L/min [95% CI, 34.0 to 45.7]; see eMethods 3 and eTable 3 in Supplement 2). Data points represent the observed data from the 5-hour time point on day 5 (primary end point) for mean ventilation at 55 mm Hg carbon dioxide (values in Table 2) and geometric mean oxycodone plasma concentration with placebo plus oxycodone was 14.7 ng/mL (coefficient of variation [CV], 31%); oxycodone concentration with paroxetine, 18.2 ng/mL (CV, 21%); and oxycodone concentration with quetiapine, 19.6 ng/mL (CV, 21%).