Effect of midazolam co-administered with oxycodone on ventilation: a randomised clinical trial in healthy volunteers

British Journal of Anaesthesia, vol. 134, pp. 1170–1180

Abstract

Background Benzodiazepines can exacerbate opioid-induced respiratory depression by furthering the decrease in central respiratory drive and causing loss of upper airway patency potentially leading to airway obstruction. This study aimed to determine if co-administration of benzodiazepines and opioids significantly decreases hypercapnic ventilation compared with opioids alone. Methods We conducted a randomised, double-blind, four-period crossover trial in 20 healthy participants to assess whether i.v. midazolam (0.0375 mg kg −1 in the first five participants; 0.075 mg kg −1 in 15 participants) plus oral oxycodone (10 mg), compared with oxycodone alone, decreases minute ventilation at an end-tidal carbon dioxide ( P co 2 ) of 7.3 kPa using modified Read rebreathing methodology. Results Midazolam administered with oxycodone, compared with oxycodone alone, did not significantly decrease minute ventilation at an end-tidal P co 2 of 7.3 kPa (23.5 vs 25.2 L min −1 ; mean difference –1.7 L min −1 , one-sided 95% confidence interval –∞ to 1.6; P =0.21). However, midazolam plus oxycodone increased resting end-tidal P co 2 compared with oxycodone alone (5.8 vs 5.6 kPa; mean difference 0.2 kPa, 95% confidence interval 0.0–0.4). Nine of 15 (60%) participants fell asleep or snored on midazolam plus oxycodone, compared with 0 of 15 (0%) on oxycodone alone. Conclusions Midazolam co-administered with oxycodone did not decrease hypercapnic ventilation, compared with oxycodone alone, but did affect tidal volume, ventilatory frequency, and resting end-tidal P co 2 . These findings support the hypothesis that benzodiazepines influence ventilation by inducing relaxation of the respiratory muscles and highlight the need for additional investigations to elucidate the potential for upper airway obstruction when benzodiazepines and opioids are co-administered. Clinical trial registration NCT 04310579.

Authors 19

1. Victoria Gershuny

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

2. Jeffry A. Florian

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

3. Rutger M. van der Schrier Aachen Department of Anesthesiology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

4. Pablo A. Salcedo

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

5. Celine Wang

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

6. Keith Burkhart

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

7. Kristin Willner Prentice

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; Booz Allen Hamilton, McLean, VA, USA

8. Aanchal Shah

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; Booz Allen Hamilton, McLean, VA, USA

9. Rebecca Racz

   United States Food and Drug Administration · Center for Drug Evaluation and Research

   Affiliation as printed

   Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

10. Vikram P. Patel

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

11. Murali Krishna Matta

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

12. Omnia A. Ismaiel

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

13. Rodney Boughner
    Affiliation as printed

    KCAS Bioanalytical Services, Shawnee, KS, USA

14. Kevin A. Ford

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

15. Rodney L. Rouse

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

16. Marc B. Stone

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Psychiatry, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

17. Carlos R. Sanabria

    Spaulding Clinical Research (United States)

    Affiliation as printed

    Spaulding Clinical Research, West Bend, WI, USA

18. Albert Dahan Aachen Department of Anesthesiology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

19. David G. Strauss corresponding

    United States Food and Drug Administration · Center for Drug Evaluation and Research

    Affiliation as printed

    Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. Electronic address: Jeffry.Florian@fda.hhs.gov