A biomarker of opioid-induced respiratory toxicity in experimental studies
Marieke Hellinga, Marijke Hyke Algera, Rutger van der Schrier, Elise Sarton, Monique van Velzen, Albert Dahan, Erik Olofsen, Marieke Niesters
Abstract
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 PCO 2 (P ET CO 2 ) and the hypercapnic ventilatory response (HCVR) before and at 1-h intervals following intake of the opioid tapentadol. Pharmacokinetic/pharmacodynamic analyses that included CO 2 kinetics were applied to model the responses with focus on resting variables obtained without added CO 2 , HCVR slope and ventilation at an extrapolated P ET CO 2 of 55 mmHg ( V ˙ E 55). The HCVR, particularly V ˙ E 55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using V ˙ E 55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety.