50 - Secondary Outcomes of a Phase 1 Placebo-Controlled Trial Comparing the Effects of Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride on Respiratory Drive
Lynn Webster1, Jacqueline Cater1, Thomas Smith2
1PRA Health Sciences, Salt Lake City, UT, USA. 2BioDelivery Sciences International, Inc, Raleigh, NC, USA
Purpose Buprenorphine is a Schedule III atypical opioid with partial mu-opioid receptor agonist activity, which is thought to contribute to its decreased risk of respiratory depression relative to that of full mu-opioid receptor agonists (eg, fentanyl, morphine, oxycodone). Buprenorphine also has functions at other opioid receptors, including antagonism at the delta- and kappa-opioid receptors and agonism at opioid receptor-like 1. The unique receptor activation profile of buprenorphine translates to effective analgesia and potentially greater safety than Schedule II opioids for the management of chronic pain. As the primary cause of opioid-related death is suppression of respiratory drive, leading to respiratory depression, this phase 1 study was conducted to directly compare the effects of buprenorphine buccal film (BELBUCA®, BioDelivery Sciences International, Inc.) and the full mu-opioid receptor agonist oxycodone hydrochloride (immediate release) on respiratory drive (clinicaltrials.gov, NCT03996694). The primary outcome of the study evaluated respiratory drive by observing the maximum decrease in minute ventilation after the administration of each study drug via the ventilatory response to hypercapnia and showed that buprenorphine buccal film did not impact respiratory drive at any of the doses tested relative to placebo, whereas oxycodone did in a dose-dependent fashion. Presented here are additional secondary outcomes that were assessed throughout the study, including changes in minute ventilation, peak expiratory flow rate, and oxygen saturation over time. Methods This study was a randomized, double-blind, double-dummy, 6-period, 6-treatment, placebo-controlled, crossover trial that compared the effects of 300, 600, and 900 μg buprenorphine buccal film; 30 and 60 mg oral immediate-release oxycodone hydrochloride; and matching placebo on respiratory drive in recreational opioid users. Before randomization, subjects were determined not to be dependent on opioids with a Naloxone Challenge Test. Each subject received every treatment and acted as their own control, and the treatments were separated by 7-day washout periods to avoid any potential carryover effects. During the ventilatory response to hypercapnia test, minute ventilation, peak expiratory flow rate, and oxygen saturation were observed at each specific post-dose time point. These parameters were continuously recorded as the hypercapnic gas mixture (72% N2, 21% O2, and 7% CO2) was administered. For minute ventilation, least-squares (LS) mean differences were calculated for each treatment, and statistical analysis was performed using a linear mixed-effects model with treatment, period, sequence, and time point as fixed effects and subject as a random effect. For peak expiratory flow rate, statistical analysis was performed using a linear mixed-effects model with treatment, period, and sequence as fixed effects and timepoint and treatment-by-timepoint interaction as repeated fixed effects. These analyses compared each study drug to placebo at each post-dose time point. Other endpoints of the study included assessments of pupil diameter, change in the ratio of minute ventilation over end-tidal CO2, vital signs, the number of reported adverse events, and results from 12-lead electrocardiograms and laboratory safety tests. Any observed clinically significant abnormalities were also reported. Results A total of 19 subjects were enrolled (18 [94.7%] men, 1 [5.3%] woman), and 15 (78.9%) completed the study. For all doses of buprenorphine buccal film (300, 600, and 900 μg) across all time points (0.5, 1, 2, 3, and 4 hours), mean minute ventilation remained similar to that seen with placebo. However, oxycodone 30 mg resulted in a significant LS mean (95% CI) decrease (–4.9 [–8.6, –1.2] L/min; P < 0.05) in minute ventilation at 1-hour post-dose relative to placebo. Oxycodone 60 mg resulted in the largest overall decrease in minute ventilation, including significant LS mean (95% CI) decreases at hours 1, 2, and 4 (–6.5 [–10.3, –2.8], –4.0 [–7.6, –0.3], and –4.5 [–8.1, –0.8] L/min, respectively; P < 0.05 for each time point) relative to placebo. Oxycodone 60 mg also caused the largest sustained decrease in peak expiratory flow rate, with a maximum and significant LS mean (95% CI) decrease relative to placebo at 1-hour post-dose (–18.6 [–29.5, –7.7]; P < 0.05). Oxycodone 30 mg resulted in an initial LS mean (95% CI) decrease in peak expiratory flow rate, which was significant at 1-hour post-dose (–14.9 [–25.8, –4.0]; P < 0.05), whereas rates for buprenorphine buccal film remained similar to that of placebo throughout all post-dose time points. Mean oxygen saturation levels remained fairly stable (≥95%) after treatment with each study drug. However, one subject had an oxygen saturation level of 86% approximately 1.5 hours after receiving oxycodone 60 mg, which was considered by the investigator as a moderate adverse event likely related to the study drug. Conclusions None of the buprenorphine buccal film doses (300, 600, or 900 μg) decreased minute ventilation or peak expiratory flow rate over time or caused an adverse reaction related to a decrease in oxygen saturation levels, whereas oxycodone did. These secondary outcomes further support the primary results of this study by confirming the enhanced safety profile of buprenorphine buccal film compared with that of the full mu-opioid receptor agonist oxycodone. Overall, buprenorphine buccal film may be a safer treatment option and should be considered before the use of a full mu-opioid receptor agonist for the management of chronic pain.