A biomarker of opioid-induced respiratory toxicity in experimental studies

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 (P_ETCO₂) 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 P_ETCO₂ of 55 mmHg ( $$ 55). The HCVR, particularly $$ 55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using $$ 55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety.