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 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.

FIGURE 1

Comparison of arterial partial pressure of carbon dioxide (pCO₂). Changes between oxycodone alone and paroxetine (a) or Quetiapine (b) co‐administered with oxycodone. Plots of mean pCO₂ at each timepoint following administration shows a significant increase in pCO₂ with co‐administration of oxycodone (150 mg/kg) with (a) paroxetine (50 mg/kg) and (b) quetiapine (250 mg/kg) compared to oxycodone alone (150 mg/kg). Values are mean ± SD; significant difference (p < 0.05) was determined by analysis of variance across the entire experimental times series for both paroxetine and quetiapine; n = 6 per experimental group. Paroxetine was given 3 h prior to time zero when oxycodone was administered. Quetiapine and oxycodone were given concurrently

FIGURE 2

Effects of oxycodone (Oxy) alone (a) versus combined effects of oxycodone with diazepam (b), paroxetine (c), quetiapine (d), ramelteon (e), and trazodone (f) on change from baseline arterial partial pressure of carbon dioxide (pCO₂). Shown are the univariate (a) and multivariate (b–f) linear regression results using data from the animal experiments with oxycodone alone, the sedative psychotropic drug (SPD) alone, and the SPD combined with oxycodone. The univariate linear regression for oxycodone (dark gray with 95% confidence interval [light gray]) is shown to display model‐predicted effects on change from baseline arterial pCO₂ from oxycodone alone. Multivariate linear regression models were developed for each combination of oxycodone and SPD. The resulting oxycodone relationship from the multivariate linear regression is shown on each plot for comparison with the effects from oxycodone combined with the SPD. Shown in blue are the mean change from baseline arterial pCO₂ with 95% confidence for the SPD and oxycodone combination arms (amount administered is labeled on each figure). Each point is represented on the x‐axis based on the geometric maximum concentration of all rats at that dose and/or combination. If the combination treatment is less than or overlaps with the mean effect of oxycodone alone (dark gray), this would suggest oxycodone alone could explain the observed effects on change from baseline arterial pCO₂. Likewise, if the combination effect is greater, this would suggest the drug combination is having an additional effect, which could be due to the SPD alone or synergy