48 - Benefit of Buprenorphine Buccal Film Versus Oral Oxycodone Hydrochloride on Respiratory Drive: A Phase 1 Placebo-Controlled Trial

¹PRA Health Sciences, Salt Lake City, UT, USA. ²BioDelivery Sciences International, Inc., Raleigh, NC, USA

Purpose
Respiratory depression is the primary cause of death related to opioid overdose. Buprenorphine is a partial μ-opioid receptor agonist that, unlike full μ-opioid receptor agonists (eg, morphine, oxycodone, fentanyl), has been shown to exhibit a ceiling effect for respiratory depression. Partial agonism refers to receptor-level activity and not analgesic efficacy, as buprenorphine has analgesic efficacy comparable to that of full μ-opioid receptor agonists. This partial agonism at the μ-opioid receptor, together with antagonism at the κ and Δ opioid receptors, and agonism at opioid-receptor like 1 may play a role in limiting common opioid-related adverse events such as respiratory depression. Respiratory depression is caused in part by inhibition of respiratory drive (ie, the ability of neuronal respiratory centers to control and regulate ventilation). The goal of this study was to compare the effects of buprenorphine buccal film (BELBUCA^®) and oral oxycodone (immediate release) on respiratory drive to distinguish the impact of a partial μ-opioid receptor agonist from that of a full μ-opioid receptor agonist.
Methods
The effect of buprenorphine buccal film and oxycodone (immediate release) on respiratory drive was assessed in healthy subjects (N=19) who self-identified as recreational opioid users and were not dependent on opioids (confirmed via a naloxone challenge test at day–1). The study had a single-center, double-blind, double-dummy, 6-treatment, 6-period, placebo-controlled, randomized crossover design. Treatments were 300 μg, 600 μg, and 900 μg buprenorphine buccal film; 30 mg and 60 mg oral oxycodone; and placebo. Each subject received every treatment once, following a computer-generated randomization treatment sequence, and all treatments were separated by a minimum 7-day washout period to avoid any potential carryover effects. This study design was chosen to minimize variability by allowing each subject to serve as their own control. Respiratory drive was evaluated by measuring the ventilatory response to hypercapnia through assessment of the maximum decrease in minute ventilation (E_max) after administration of each study drug (primary endpoint). Mean minute ventilation was measured pre-dose and at 0.5, 1, 2, 3, and 4 hours post-dose. Throughout the study, from the first dose up to 7±2 days after the last study dose was administered, patients were monitored for adverse events (AEs), which were recorded. Statistical analyses were performed using a linear mixed-effects model with treatment, period, and sequence as fixed effects and subject nested within sequence as a random effect; E_max was defined as the maximum effect for each subject after each study medication was administered. Least squares (LS) mean differences between each treatment were calculated, along with differences in LS means with 95% CIs and P values. A similar model was used to assess the difference between each treatment and placebo at each post-baseline timepoint (where the model also included a fixed effect term for timepoint).
Results
The difference between buprenorphine buccal film and placebo for minute ventilation at E_max (L/minute) was not significantly different for the 300 μg dose (+1.24 versus placebo, P=0.529), 600 μg dose (+0.23, P=0.908), or 900 μg dose (+0.93, P=0.637). In contrast, 30 mg oxycodone numerically reduced minute ventilation at E_max versus placebo (−0.79, P=0.687), and 60 mg oxycodone led to a significantly greater decrease in minute ventilation at E_max than did placebo (−5.23, P=0.010).
Oxycodone 30 mg produced a significantly greater decrease in mean minute ventilation than did placebo at the 1 hour post-dose timepoint (P=0.007), and oxycodone 60 mg led to significantly greater decreases than placebo did at 1 hour (P<0.001), 2 hours (P<0.05), and 4 hours (P<0.05) post-dose. Mean minute ventilation was similar for placebo and buprenorphine buccal film for all doses and timepoints.
No deaths or serious AEs were reported in this study. The most common treatment-emergent AEs with buprenorphine buccal film and oxycodone were nausea, vomiting, somnolence, euphoric mood, and pruritus; dizziness was also a common AE with buprenorphine buccal film. Only 1 subject discontinued owing to an AE likely related to the study drug (buprenorphine buccal film 600 μg, idioventricular rhythm).
Conclusions
Buprenorphine buccal film did not significantly reduce respiratory drive at any dose compared with placebo. Administration of oxycodone resulted in a significant dose-dependent decrease in respiratory drive. The tolerability profiles of both drugs were similar. No AEs related to respiratory depression have been reported in previous clinical studies of buprenorphine buccal film. Data from this study show that buprenorphine buccal film is well tolerated, and results from previous studies suggest that buprenorphine buccal film provides effective analgesia and may be a safer treatment option than a full μ-opioid receptor agonist for patients with chronic pain.