A biomarker of opioid-induced respiratory toxicity in experimental studies

Summary: Opioids are commonly used painkillers and drugs of abuse and have serious toxic effects including potentially lethal respiratory depression. It remains unknown which respiratory parameter is the most sensitive biomarker of opioid-induced respiratory depression (OIRD). To evaluate this issue, we studied 24 volunteers and measured resting ventilation, resting end-tidal PCO2 (PETCO2) and the hypercapnic ventilatory response (HCVR) before and at 1-h intervals following intake of the opioid tapentadol. Pharmacokinetic/pharmacodynamic analyses that included CO2 kinetics were applied to model the responses with focus on resting variables obtained without added CO2, HCVR slope and ventilation at an extrapolated PETCO2 of 55 mmHg (V˙E55). The HCVR, particularly V˙E55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using V˙E55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety.