Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression
Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label war...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Toxicology Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750019303804 |
| _version_ | 1818644718729297920 |
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| author | Lin Xu Ashok Chockalingam Sharron Stewart Katherine Shea Murali K. Matta Suresh Narayanasamy Nageswara R. Pilli Donna A. Volpe James Weaver Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse |
| author_facet | Lin Xu Ashok Chockalingam Sharron Stewart Katherine Shea Murali K. Matta Suresh Narayanasamy Nageswara R. Pilli Donna A. Volpe James Weaver Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse |
| author_sort | Lin Xu |
| collection | DOAJ |
| description | Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs. |
| first_indexed | 2024-12-17T00:19:18Z |
| format | Article |
| id | doaj.art-b52b833fe4214e969df8c6926f6d031f |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-12-17T00:19:18Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-b52b833fe4214e969df8c6926f6d031f2022-12-21T22:10:37ZengElsevierToxicology Reports2214-75002020-01-017188197Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depressionLin Xu0Ashok Chockalingam1Sharron Stewart2Katherine Shea3Murali K. Matta4Suresh Narayanasamy5Nageswara R. Pilli6Donna A. Volpe7James Weaver8Hao Zhu9Michael C. Davis10David G. Strauss11Rodney Rouse12Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USADivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Silver Spring, Maryland, USA; Corresponding author at: U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Translational Science, Office of Clinical Pharmacology, Division of Applied Regulatory Science, White Oak Federal Research Center, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA.Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150 mg/kg) and with diazepam (2, 20, 200 mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150 mg/kg and diazepam 20 mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.http://www.sciencedirect.com/science/article/pii/S2214750019303804Animal modelOpioidsSedating psychotropic drugsRespiratory depressionArterial partial pressure of oxygenArterial partial pressure of carbon dioxide |
| spellingShingle | Lin Xu Ashok Chockalingam Sharron Stewart Katherine Shea Murali K. Matta Suresh Narayanasamy Nageswara R. Pilli Donna A. Volpe James Weaver Hao Zhu Michael C. Davis David G. Strauss Rodney Rouse Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression Toxicology Reports Animal model Opioids Sedating psychotropic drugs Respiratory depression Arterial partial pressure of oxygen Arterial partial pressure of carbon dioxide |
| title | Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression |
| title_full | Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression |
| title_fullStr | Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression |
| title_full_unstemmed | Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression |
| title_short | Developing an animal model to detect drug–drug interactions impacting drug-induced respiratory depression |
| title_sort | developing an animal model to detect drug drug interactions impacting drug induced respiratory depression |
| topic | Animal model Opioids Sedating psychotropic drugs Respiratory depression Arterial partial pressure of oxygen Arterial partial pressure of carbon dioxide |
| url | http://www.sciencedirect.com/science/article/pii/S2214750019303804 |
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