A Phase I Placebo-Controlled Trial Comparing the Effects of Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride Administration on Respiratory Drive

Abstract

Introduction: Buprenorphine is a partial μ-opioid receptor agonist that, unlike full μ-opioid receptor agonists, has been shown to have a ceiling effect on respiratory depression. Buprenorphine buccal film (BBF) is approved by the US Food and Drug Administration for use in patients with chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for whom alternative treatment options are inadequate. This study was conducted to compare the effects of BBF and immediate-release oral oxycodone hydrochloride administration on respiratory drive, as measured by the ventilatory response to hypercapnia (VRH) after drug administration.

Methods: Subjects (N = 19) were men and women, ages 27-41 years, self-identifying as recreational opioid users who were not physically dependent on opioids as determined via a Naloxone Challenge Test. Respiratory drive was evaluated by measuring VRH through the assessment of the maximum decrease in minute ventilation (Emax) after administration of each treatment. The treatments utilized in this study included 300, 600, and 900 μg BBF; 30 and 60 mg orally administered oxycodone; and placebo (each separated by a 7-day washout period). Effects on respiratory drive were assessed using a double-blind, double-dummy, six-treatment, six-period, placebo-controlled, randomized crossover design. Statistical analyses were performed using a linear mixed-effects model.

Results: The least squares mean differences in minute volume Emax (L/min, versus placebo) were as follows: 300 μg BBF (+ 1.24, P = 0.529), 600 μg BBF (+ 0.23, P = 0.908), 900 μg BBF (+ 0.93, P = 0.637), 30 mg oxycodone (- 0.79, P = 0.687), and 60 mg oxycodone (- 5.23, P = 0.010).

Conclusions: BBF did not significantly reduce respiratory drive at any dose compared with placebo, including at the maximum available prescription dose of 900 μg. Administration of oxycodone resulted in a significant dose-dependent decrease in respiratory drive. These data suggest that BBF may be a safer treatment option than full μ-opioid receptor agonists for patients with chronic pain.

Trial registration: ClinicalTrials.gov identifier, NCT03996694.

Keywords: Buprenorphine; Buprenorphine buccal film; Hypercapnia; Oxycodone hydrochloride; Pain; Respiratory depression; Respiratory drive.

Figures

Fig. 1

Subjects were randomly assigned to 1 of 6 computer-generated treatment randomization sequences. BBF buprenorphine buccal film, Oxy oxycodone

Fig. 2

Study design and procedures. Blood pressure, heart rate, respiration rate, temperature, O2 saturation, and prior/concomitant medications were collected at all clinic visits; 12-lead ECG was performed at all clinic visits except day 1. BMI body mass index, ECG electrocardiogram, VRH ventilatory response to hypercapnia

Fig. 3

Ventilatory response to hypercapnia: experimental setting

Fig. 4

Effect of each drug treatment on respiratory drive as measured by minute ventilation LS mean difference from placebo (± 95% CI) at Emax. In the completer population (N = 15), only oxycodone 60 mg significantly reduced minute ventilation at Emax. Horizontal black bars represent the means. BBF buprenorphine buccal film, Emax maximum decrease in minute ventilation, LS least squares

Fig. 5

Effect of each drug treatment on respiratory drive: mean minute ventilation over time. In the partial completer population (N = 16), mean minute ventilation for BBF was not significantly different from placebo at any timepoint. BBF buprenorphine buccal film, Oxy oxycodone. *P < 0.05, **P < 0.01, ***P < 0.001

Fig. 6

Relationship between ventilation and PaCO2. Curve A represents the normal CO2 response of an awake individual. Line B represents the CO2 response following administration of a sedative or anesthetic medication (sufficient decrease in PaCO2 can result in apnea). Once apnea develops, PaCO2 must increase to approximately the resting value before ventilation restarts (line B′, a hysteresis loop). Curve C represents the carbon dioxide excretion hyperbola. Assuming constant CO2 production in the body, increasing ventilation will decrease PaCO2, whereas decreasing ventilation tends to increase PaCO2. In the awake state, point X defines the resting PaCO2 and ventilation, whereas point Y represents the values of PaCO2 and ventilation during sedation or anesthesia. PaCO2 partial pressure of CO2 Figure reproduced with permission from Jeffrey B. Gross; When You Breathe IN You Inspire, When You DON'T Breathe, You … Expire: New Insights Regarding Opioid-induced Ventilatory Depression. Anesthesiology 2003;99(4):767–770 [18]