On days when oxycodone was administered, paroxetine significantly reduced the ventilatory response to hypercapnia in a study of 25 healthy participants. Quetiapine did not have this effect when combined with oxycodone, a finding relevant to opioid-induced respiratory depression. “Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings,” the authors conclude.
The preliminary trial used a randomized, double-blind, crossover design to test the effects of oxycodone 10 mg on days 1 and 5 of a 5-day course of paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo. Based on a primary outcome measure of ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation), the study showed that “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).
These results are is concerning because “the ventilatory response to hypercapnia … is the primary feedback mechanism for the body to rescue itself from opioid-induced respiratory depression,” the authors write. “The secondary outcomes supported that paroxetine decreased the ventilatory response to hypercapnia through a direct pharmacodynamic effect rather than by a pharmacokinetic interaction because paroxetine had a similar effect on its own compared with placebo on day 4. Furthermore, exploratory concentration-response modeling supported that the increase in oxycodone concentration with paroxetine did not explain the observed effect of paroxetine on the primary outcome.…”