Effect of Paroxetine or Quetiapine Combined With Oxycodone vs Oxycodone Alone on Ventilation During Hypercapnia

Abstract

ImportanceOpioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects.ObjectiveTo study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia.Design, Setting, and ParticipantsRandomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021.InterventionsOxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo.Main Outcomes and MeasuresVentilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary).ResultsAmong 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], −4.9 L/min [1-sided 97.5% CI, −∞ to −0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, −10.2 L/min [1-sided 97.5% CI, –∞ to –6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, −1.2 L/min [1-sided 97.5% CI, −∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, −0.6 L/min [1-sided 97.5% CI, −∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, −9.3 L/min [1-sided 97.5% CI, −∞ to −3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, −∞ to 6.4]; P = .67). No drug-related serious adverse events were reported.Conclusions and RelevanceIn this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04310579

Oral Oxycodone‐Induced Respiratory Depression During Normocapnia and Hypercapnia: A Pharmacokinetic‐Pharmacodynamic Modeling Study

“…To obtain the HCVR, the subjects breathed through a face mask placed over the mouth and nose that was connected to a pneumotachograph and pressure transducer system (Hans Rudolph) to measure minute ventilation 9,10 . Oxygen, carbon dioxide, and nitrogen were delivered to the subject through three mass flow controllers (Bronkhorst Nederland BV, Veenendaal, The Netherlands).…”

New science, drug regulation, and emergent public health issues: The work of FDA’s division of applied regulatory science

“… In this preliminary study involving healthy participants over 5 days, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia ( 30 ), whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.…”

“…While significant progress has been made in engineering biological products, the human immune system may still produce an unexpected or exaggerated immune response to a drug product resulting in poor efficacy or life-threatening adverse reactions. DARS is comparing the ability of different In this preliminary study involving healthy participants over 5 days, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia (30), whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings.…”

“…This DARS-led clinical study assessed whether combining the selective serotonin reuptake inhibitor paroxetine or the atypical antipsychotic quetiapine with the opioid oxycodone, compared to oxycodone alone, decreased ventilation during hypercapnia (elevated carbon dioxide). The study found that paroxetine combined with oxycodone decreased ventilation ( Figure 4 ), indicating the need for further study of the clinical implications ( 30 ).…”

Safety and efficacy of etomidate in combination with oxycodone in painless gastroscopic procedures in the elderly: A prospective randomized controlled trial study

“…[ 4 , 5 ] It can agonize both μ- and κ-opioid receptors and has the advantages of rapid onset of action, better analgesia, and fewer adverse effects such as respiratory depression. [ 4 , 5 ] Oxycodone is an optional agent for the clinical management of acute pain, [ 6 ] chronic pain, [ 7 ] postoperative pain, [ 5 , 8 ] cancer-related pain, [ 9 ] visceral pain, [ 10 ] osteoarthritis-related pain, [ 5 ] and neuropathic pain. [ 10 ] Researchers believe it can be used as effectively as morphine in selected patients at the doses studied, with fewer side effects.…”