Abstract
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.
Highlights
Boxed Warnings were added to the drug labeling of opioids and benzodiazepines after a Food & Drug Administration (FDA) review found that “combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system” can result in serious side effects including respiratory depression and death [1,2,3,4,5]
All animals treated with oxycodone alone or oxycodone with diazepam had notably reduced activity starting a few minutes after dosing with oxycodone, alone, or in combination with diazepam
The reductions in activity after combination treatment lasted for approximately 4 h after oxycodone dosing (4.5 h after diazepam dosing) compared to approximately 3 h in rats treated with oxycodone alone
Summary
Boxed Warnings were added to the drug labeling of opioids and benzodiazepines after a Food & Drug Administration (FDA) review found that “combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system” can result in serious side effects including respiratory depression and death [1,2,3,4,5]. Many nonbenzodiazepine sedating psychotropic drugs (SPDs) have long been in clinical use, but for some of these drugs there is little or no clinical or animal data on their potential to induce respiratory depression, either alone or in combination with an opioid [10]. Defining the effect of these and other classes of drugs on respiratory depression when used alone or in combination with an opioid would enhance the ability of regulators to make informed decisions on future regulatory actions on these drugs
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