Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat

Abstract Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be...

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Autores principales:	Lin Xu, Ashok Krishna, Sharron Stewart, Katherine Shea, Rebecca Racz, James L. Weaver, Donna A. Volpe, Nageswara R. Pilli, Suresh Narayanasamy, Jeffry Florian, Vikram Patel, Murali K. Matta, Marc B. Stone, Hao Zhu, Michael C. Davis, David G. Strauss, Rodney Rouse
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/47f7303872624d87ada0be77ae52f79d
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spelling	oai:doaj.org-article:47f7303872624d87ada0be77ae52f79d2021-11-19T17:51:34ZEffects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat1752-80621752-805410.1111/cts.13080https://doaj.org/article/47f7303872624d87ada0be77ae52f79d2021-11-01T00:00:00Zhttps://doi.org/10.1111/cts.13080https://doaj.org/toc/1752-8054https://doaj.org/toc/1752-8062Abstract Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.Lin XuAshok KrishnaSharron StewartKatherine SheaRebecca RaczJames L. WeaverDonna A. VolpeNageswara R. PilliSuresh NarayanasamyJeffry FlorianVikram PatelMurali K. MattaMarc B. StoneHao ZhuMichael C. DavisDavid G. StraussRodney RouseWileyarticleTherapeutics. PharmacologyRM1-950Public aspects of medicineRA1-1270ENClinical and Translational Science, Vol 14, Iss 6, Pp 2208-2219 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270
spellingShingle	Therapeutics. Pharmacology RM1-950 Public aspects of medicine RA1-1270 Lin Xu Ashok Krishna Sharron Stewart Katherine Shea Rebecca Racz James L. Weaver Donna A. Volpe Nageswara R. Pilli Suresh Narayanasamy Jeffry Florian Vikram Patel Murali K. Matta Marc B. Stone Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
description	Abstract Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2). The current study used that model to assess the impact on respiration of non‐benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone‐paroxetine co‐administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug‐drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co‐administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.
format	article
author	Lin Xu Ashok Krishna Sharron Stewart Katherine Shea Rebecca Racz James L. Weaver Donna A. Volpe Nageswara R. Pilli Suresh Narayanasamy Jeffry Florian Vikram Patel Murali K. Matta Marc B. Stone Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse
author_facet	Lin Xu Ashok Krishna Sharron Stewart Katherine Shea Rebecca Racz James L. Weaver Donna A. Volpe Nageswara R. Pilli Suresh Narayanasamy Jeffry Florian Vikram Patel Murali K. Matta Marc B. Stone Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse
author_sort	Lin Xu
title	Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
title_short	Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
title_full	Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
title_fullStr	Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
title_full_unstemmed	Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
title_sort	effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/47f7303872624d87ada0be77ae52f79d
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Effects of sedative psychotropic drugs combined with oxycodone on respiratory depression in the rat

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