Effect of Paroxetine or Escitalopram Co-administered with Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia: A Randomized Clinical Trial.

Abstract

Opioid-induced respiratory depression remains a critical public safety concern. Prior clinical findings demonstrated decreased hypercapnic ventilation after 5 days when paroxetine, a Selective Serotonin Reuptake Inhibitor (SSRI), was administered alone or with oxycodone. However, uncertainty remained whether chronic use of SSRIs could cause similar respiratory effects. This study investigated whether chronic use of paroxetine and another SSRI, escitalopram, lead to a similar decrease in ventilatory response to hypercapnia. In this randomized, double-blind, 3-period crossover trial, healthy participants were administered one of the following: paroxetine 40 mg from days 1 to 6 and 60 mg from days 7 to 21, escitalopram 20 mg from days 1 to 6 and 30 mg from days 7 to 21, and placebo from days 1 to 21. Oxycodone 10 mg was co-administered on days 6, 12, and 21. Hyperoxic-hypercapnic ventilation was measured using Duffin's rebreathing. Of the 27 participants, 22 (81%) completed the trial. Paroxetine and escitalopram both significantly decreased hyperoxic-hypercapnic ventilation when co-administered with oxycodone compared to oxycodone alone on day 21 (paroxetine mean difference, -6.5 L/min [1-sided 97.5% CI, -∞ to -3.1] P<0.001, escitalopram mean difference, -5.5 L/min [1-sided 97.5% CI, -∞ to -2.1] P=0.001) and when administered alone compared to placebo on day 20 (paroxetine mean difference, -6.5 L/min [1-sided 97.5% CI, -∞ to -2.1] P=0.003, escitalopram mean difference, -6.9 L/min [1-sided 97.5% CI, -∞ to -2.5] P=0.002). Both paroxetine and escitalopram, alone and co-administered with oxycodone, decrease hypercapnic ventilation after 21 days suggesting that selective serotonin reuptake inhibitors may have a class effect on hypercapnic ventilation that persists with chronic use.