Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression

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.

Keywords: Ventilatory response; analgesics; experimental model; hypercapnia; opioids; respiratory depression.