Esketamine counters opioid-induced respiratory depression.

Background: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression.

Methods: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO-chemosensitivity, or both.

Results: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO 6.5 kPa) by approximately 40% (from 20 to 12 litre min) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO sensitivity. The remifentanil concentration that reduced ventilatory CO sensitivity by 50% (C) was doubled at an esketamine concentration of 127 (84-191) ng ml [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression.

Conclusions: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO chemosensitivity.