Effect of Paroxetine or Escitalopram Coadministered with Oxycodone versus Oxycodone Alone on Ventilation during...

Opioid-induced respiratory depression remains a critical public safety concern. Previous 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, led to a similar decrease in ventilatory response to hypercapnia.

In this randomized, double-blind, three-period crossover trial, healthy participants were administered one of the following: 40 mg paroxetine from days 1 to 6 and 60 mg from days 7 to 21, 20 mg escitalopram from days 1 to 6 and 30 mg from days 7 to 21, and placebo from days 1 to 21. A dose of 10 mg oxycodone was coadministered 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 coadministered with oxycodone compared to oxycodone alone on day 21 (paroxetine mean difference, -6.5 l/min; one-sided 97.5% CI, -∞ to -3.1; P < 0.001; escitalopram mean difference, -5.5 l/min; one-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; one-sided 97.5% CI, -∞ to -2.1; P = 0.003; escitalopram mean difference, -6.9 l/min; one-sided 97.5% CI, -∞ to -2.5; P = 0.002).

Both paroxetine and escitalopram, alone and coadministered with oxycodone, decrease hypercapnic ventilation after 21 days, suggesting that SSRIs may have a class effect on hypercapnic ventilation that persists with chronic use.