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

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 (Pco₂) 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 Pco₂ 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 Pco₂ 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 Pco₂. 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.