PII-026 - COMPARISON OF CHANGES IN PUPIL DIAMETER AND HYPERCAPNIC VENTILATION FOR OXYCODONE AND PSYCHOTROPIC DRUGS ADMINISTERED ALONE OR IN COMBINATION

V. Gershuny¹, D. Strauss¹, J. Florian¹, R. Rouse¹, A. Shah^1,2, K. Prentice^1,2, K. Ford¹, R. Racz¹, K. Burkhart¹, P. Salcedo¹, M. Matta¹, O. Ismaiel¹, V. Patel¹, M. Davis¹, R. van der Schrier³, A. Dahan⁴, C. Wang¹, C. Sanabria⁵, R. Boughner⁶; ¹U.S. Food and Drug Administration, ²Booz Allen Hamilton, ³Leiden University Medical Center, ⁴Leiden University, ⁵Spaulding Clinical Research, ⁶KCAS Bioanalytical Services.

Background: Measuring pupil diameter is an easy, non-invasive method of identifying opioid overdose in patients. However, there are limited investigations into the relationship between changes in pupil diameter and ventilation for opioids alone or in combination with other drugs.

Methods: In a two-part, double-blind, crossover trial, 20 participants received oxycodone 10 mg, midazolam 0.0375 mg/kg or 0.075 mg/kg, both midazolam and oxycodone or placebo (Part 1), and an additional 25 participants received oxycodone 10 mg on days 1 and 5 of each 5-day treatment period and either paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo (Part 2). The outcomes were pupil diameter and minute ventilation at end-tidal pCO2 of 55 mm Hg.

Results: There was alignment between ventilation and pupil diameter for subjects administered just oxycodone (Pearson’s r=0.74, 95% CI: 0.16 to 0.94). At the primary timepoint, oxycodone decreased minute ventilation at 55 mm Hg by 6.2 L/min (CV=136%) and pupil diameter by 1.2 mm (CV=62%) compared to placebo. Midazolam and quetiapine did not have significant effects on minute ventilation but decreased pupil diameter whereas paroxetine decreased minute ventilation while increasing pupil diameter both alone compared to placebo and in combination with oxycodone compared to oxycodone alone.

Conclusion: On their own, midazolam and quetiapine decreased pupil diameter but did not affect minute ventilation whereas paroxetine increased pupil diameter while decreasing ventilation. In combination with oxycodone, psychotropic drug effects were generally additive, leading to combination-dependent relationships between pupil diameter and minute ventilation.