Title:Ventilatory Response to Hypercapnia as Experimental Model to Study Effects
of Oxycodone on Respiratory Depression
Volume: 17
Issue: 1
Author(s): Lynn R. Webster*, Erik Hansen, Gregory J. Stoddard, Austin Rynders, David Ostler and Harley Lennon
Affiliation:
- Early Development Services, PRA Health Sciences, Salt Lake City, Utah UT 84122 USA
Keywords:
Ventilatory response, hypercapnia, respiratory depression, experimental model, opioids, analgesics.
Abstract: Background: Opioid analgesics used to treat pain can cause respiratory depression.
However, this effect has not been extensively studied, and life-threatening, opioid-induced respiratory
depression remains difficult to predict. We tested the ventilatory response to hypercapnia for
evaluating the pharmacodynamic effect of a drug on respiratory depression.
Methods: We conducted a randomized, placebo-controlled, double-blind, crossover study on 12
healthy adult males. Subjects received 2 treatments (placebo and immediate-release oxycodone 30
mg) separated by a 24-hour washout period. Subjects inhaled a mixture of 7% carbon dioxide, 21%
oxygen, and 72% nitrogen for 5 minutes to assess respiratory depression. Minute ventilation, respiratory
rate, tidal volume, flow rate, end-tidal CO2, and oxygen saturation were recorded continuously
at pre-dose and 30, 60, 120, and 180 minutes post-dose. The primary endpoint was the effect on
the ventilatory response to hypercapnia at 60 minutes post-dose, as assessed by the slope of the linear
relationship between minute ventilation and end-tidal CO2.
Results: At 60 minutes post-dose, subjects had a mean slope of 2.4 in the oxycodone crossover period,
compared to 0.1 in the placebo period (mean difference, 2.3; 95% CI: 0.2 to 4.5; p = 0.035).
Statistical significance was likewise achieved at the secondary time points (30, 120, and 180 minutes
post-dose, p <0.05).
Conclusions: This model for testing ventilatory response to hypercapnia discriminated the effect
of 30 mg of oxycodone vs. placebo for up to 3 hours after a single dose. It may serve as a method
to predict the relative effect of a drug on respiratory depression.
