PII-107 - CLINICAL STUDY TO INVESTIGATE THE EFFECT OF ADMINISTRATION OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND AN OPIOID ON VENTILATION.

D. Keshishi¹, J. Florian², P. Salcedo¹, K. Burkhart¹, R. Rouse¹, A. Shah³, R. DePalma³, G. Vegesna³, V. Patel¹, V. Gershuny², C. Hsiao¹, M. Stone¹, D. Strauss¹, A. Dahan⁴, R. van der Schrier⁴; ¹FDA, Silver Spring, MD, United States, ²U.S. Food and Drug Administration, Silver Spring, MD, United States, ³FDA, Silver Spring,MD, United States, ⁴Leiden University, Leiden, Netherlands.

Background: Opioid-induced respiratory depression is a critical public safety concern given the rise of opioid-related deaths in the US. In response to the addition of boxed warnings to benzodiazepines and opioids about the increased risk of respiratory depression with concomitant use, the US Food and Drug Administration conducted a study that found paroxetine decreased hypercapnic ventilation after 5 days. This study investigates whether chronic use of another Selective Serotonin Reuptake Inhibitor (SSRI) could cause similar respiratory effects.

Methods: This randomized, double-blind, 3-way crossover trial was conducted in 25 healthy participants to evaluate the effects of paroxetine or escitalopram alone and in combination with oxycodone on hypercapnic ventilatory response over 21 days. Interventions consisted of oxycodone 10mg on days 6, 12 and 21 (administered at 3 hours) combined in a randomized order with: paroxetine 40mg on days 1-6 increased to 60mg days 7-21, escitalopram 20mg on days 1-6 increased to 30mg on days 7-21, and placebo for days 1-21 (all treatment doses administered at 0 hours). Duffin’s modified rebreathing method was used to obtain the minute ventilation at end-tidal PCO2 of 55 mmHg (VE55) on days 20 and 21 as the co-primary outcomes.

Results: Compared to placebo-oxycodone (mean VE55=26.7 L/min (95% CI, 22.3 to 31.2)), both paroxetine-oxycodone (VE55= 20.2 L/min (95% CI, 15.8 to 24.6); mean difference, -6.5 L/min [1-sided 97.5% CI, -∞ to -3.1] P< 0.001)) and escitalopram-oxycodone (VE55=21.2 L/min (95% CI, 16.8 to 25.6); mean difference, -5.5 L/min [1-sided 97.5% CI, -∞ to -2.1] P=0.001) significantly decreased ventilation on day 21 at 5 hours.
Compared to placebo (mean VE55=37.4 L/min (95% CI, 32.4 to 42.3)), both paroxetine (VE55= 30.8 L/min (95% CI, 25.9 to 35.7); mean difference, -6.5 L/min [1-sided 97.5% CI, -∞ to -2.1] P=0.003)) and escitalopram (VE55=30.4 L/min (95% CI, 25.5 to 35.3); mean difference, -6.9 L/min [1-sided 97.5% CI, -∞ to -2.5] P=0.002) significantly decreased ventilation on day 20 at 5 hours.

Conclusion: Both paroxetine and escitalopram, alone and when combined with oxycodone, decrease hypercapnic ventilation after 21 days. These results build upon previous study findings with paroxetine and suggest that SSRIs as a class may have effects on hypercapnic ventilation that persist with chronic use.