Copyright © 2017, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. <zdoi;10.1097/ALN.0000000000001505> Anesthesiology, V 126 • No 3 534 March 2017 O PIOIDS produce potentially life-threatening respi- ratory depression through their action at μ-opioid receptors present in brainstem respiratory centers. 1,2 Numerous studies have shown that exogenous opioids decrease the ventilatory responses to hypercapnia and hypoxia, cause irregular breathing and at high dose cause the complete cessation of rhythmic respiratory activity. 1,2 Recent studies indicate that a large number of visits to the emergency department are because of abuse or misuse of legally prescribed opioids (e.g., the use of higher doses than prescribed, the use of prescription opioids in sometimes opioid-naive individuals who are not pain patients) that involved concomitant ethanol consumption. 3,4 Addition- ally, data from the forensic literature indicate that the com- bined use of opioids and ethanol is a frequent observation in postmortem blood analysis. 5,6 Tese data suggest a pos- sibly contributing role of ethanol in the deleterious respira- tory efects of (prescription) opioids, possibly due to the enhancement of sedation. 7 Ethanol is a legal substance that afects various physiologic processes including arousal, cognition, and motor skills. 7,8 What We Already Know about This Topic • Many visit the emergency department because of misuse or abuse of legally prescribed opioids that involve concomitant ethanol consumption, suggesting that opioid-induced respiratory depression may be exacerbated by simultaneous ethanol intake What This Article Tells Us That Is New • Oxycodone (oral 20 mg immediate release) signifcantly reduced baseline minute ventilation, the slope of the hypercapnic ventilatory response curve, and minute ventilation at an end-tidal partial pressure of carbon dioxide of 55 mmHg in healthy young and elderly opioid-naive volunteers • Baseline minute ventilation and minute ventilation at an end-tidal partial pressure of carbon dioxide of 55 mmHg were further impaired by the concomitant administration of ethanol, independent of dose • Elderly subjects were especially likely to have repeated apneic events produced by the ethanol–oxycodone combination, resulting in frequent episodes of oxygen desaturation Copyright © 2017, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2017; 126:534-42 ABSTRACT Background: Respiratory depression is a potentially fatal complication of opioid use, which may be exacerbated by simulta- neous ethanol intake. In this three-way sequential crossover dose-escalating study, the infuence of coadministration of oral oxycodone and intravenous ethanol was assessed on resting ventilation, apneic events and the hypercapnic ventilatory response in healthy young and older volunteers. Methods: Twelve young (21 to 28 yr) and 12 elderly (66 to 77 yr) opioid-naive participants ingested one 20 mg oxyco- done tablet combined with an intravenous infusion of 0, 0.5, or 1 g/l ethanol. Resting respiratory variables and the primary outcome, minute ventilation at isohypercapnia (end-tidal partial pressure of carbon dioxide of 55 mmHg or VE55), were obtained at regular intervals during treatment. Results: Oxycodone reduced baseline minute ventilation by 28% (P < 0.001 vs. control). Ethanol caused a further decrease of oxycodone-induced respiratory depression by another 19% at 1 g/l ethanol plus oxycodone (P < 0.01 vs. oxycodone). Ethanol combined with oxycodone caused a signifcant increase in the number of apneic events measured in a 6-min window with a median (range) increase from 1 (0 to 3) at 0 g/l ethanol to 1 (0 to 11) at 1 g/l ethanol (P < 0.01). Mean (95% CI) VE55 decreased from 33.4 (27.9 to 39.0) l/min (control) to 18.6 (15.6 to 21.6) l/min (oxycodone, P < 0.01 vs. control) and to 15.7 (12.7 to 18.6) l/min (oxycodone combined with ethanol, 1 g/l; P < 0.01 vs. oxycodone). Conclusions: Ethanol together with oxycodone causes greater ventilatory depression than either alone, the magnitude of which is clinically relevant. Elderly participants were more afected than younger volunteers. (ANESTHESIOLOGY 2017; 126:534-42) This article is featured in “This Month in Anesthesiology,” page 1A. Submitted for publication May 31, 2016. Accepted for publication December 7, 2016. From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Influence of Ethanol on Oxycodone-induced Respiratory Depression A Dose-escalating Study in Young and Elderly Individuals Rutger van der Schrier, M.D., Margot Roozekrans, M.D., Erik Olofsen, M.Sc., Leon Aarts, M.D., Ph.D., Monique van Velzen, Ph.D., Merijn de Jong, B.Sc., Albert Dahan, M.D., Ph.D., Marieke Niesters, M.D., Ph.D. PAIN MEDICINE Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/126/3/534/488122/20170300_0-00029.pdf by guest on 29 November 2021