51 - Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride Effects on Pupillometry in a Phase I Placebo-Controlled Trial

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

Purpose
Opioid overdose is a serious health issue, with approximately 450,000 deaths from overdose of prescription and illicit opioids reported in the US between 1999 and 2018. Owing to the rising number of opioid overdoses, the safety of these drugs has been increasingly scrutinized. Of particular concern is the abuse liability of opioids, which can lead to accidental overdose. However, whether in the context of misuse and abuse or legitimate prescription use of these drugs, most opioid-related deaths are caused by respiratory depression.
Buprenorphine is a partial μ-opioid receptor agonist analgesic that has been shown to have a limited effect on respiratory drive when compared with full μ-opioid agonists. In previous studies, a ceiling effect on respiratory depression has been demonstrated with intravenous buprenorphine. Buprenorphine may induce euphoria in subjects who are not physically dependent on opioids and may be positively reinforcing; however, buprenorphine is considered to have lower abuse potential than full μ-opioid agonists and is therefore classified as a Schedule III drug.
A phase 1 placebo-controlled study was recently conducted to compare the effects of buprenorphine buccal film on respiratory drive with those of oxycodone hydrochloride (a full μ-opioid receptor agonist). In addition, since previous opioid studies have demonstrated a relationship between drug “liking” and pupil diameter, we also compared the effects of buprenorphine buccal film and oxycodone on pupil diameter. Both buprenorphine buccal film and oxycodone would have pupillary-constricting effects, with oxycodone having more prominent effects.
Methods
Subjects were healthy individuals who self-identified as recreational opioid users, which was confirmed with a Naloxone Challenge Test. Study treatments were placebo; 300 μg, 600 μg, and 900 μg buprenorphine buccal film; and 30 mg and 60 mg oxycodone. Each treatment was separated by a 7-day washout period to avoid any potential carryover effects. The effect of each treatment on respiratory drive and pupil diameter was assessed using a double-blind, double-dummy, 6-treatment, 6-period, placebo-controlled, randomized crossover design. Respiratory drive was evaluated by measuring the ventilatory response to hypercapnia through assessment of the maximum decrease in minute ventilation (E_max). Pupil diameter was determined with standard pupillometry at the following time points: pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours post-dose. Statistical analyses were performed using a mixed-effects model with treatment, period, and sequence as fixed effects, and time point and treatment by time point interaction as repeated fixed effects.
Results
A total of 19 subjects were enrolled, and 15 subjects completed the study. Of the 19 subjects enrolled, there were 18 men and 1 woman, ranging in age from 27 to 41 years. Most (73.7%) of the subjects were white. For the measurement of respiratory depression, only oxycodone 60 mg significantly decreased E_max minute ventilation relative to placebo. For pupillometry, statistically significant miosis was slower to develop with buprenorphine buccal film than with oxycodone. The initial onset of miosis that was significant relative to that seen with placebo occurred at 2 hours, 1.5 hours, and 1 hour after dosing with buprenorphine buccal film 300 μg, 600 μg, and 900 μg, respectively; and at 0.5 hours after dosing with oxycodone 30 mg or 60 mg. In addition, the miosis observed with buprenorphine buccal film 300 μg was significantly less than that seen with oxycodone 30 mg (at all time points except 4 hours post-dose) and oxycodone 60 mg (at all time points). Compared with both oxycodone doses (30 mg and 60 mg), administration of buprenorphine buccal film 600 μg resulted in significantly less miosis for up to 2 hours post-dose. Similarly, buprenorphine buccal film 900 μg led to significantly less miosis than either oxycodone doses did, for up to 1.5 hours post-dose.
Conclusions
In this study involving healthy volunteers, administration of oxycodone resulted in respiratory depression in a dose-dependent manner, whereas buprenorphine buccal film (at all doses) did not. In addition, the decrease in pupil diameter that is typically associated with opioid administration, occurred earlier after oxycodone use than after buprenorphine buccal film use. Since previous studies have shown a relationship between pupil constriction and opioid drug liking, the delayed miosis found with buprenorphine buccal film, relative to that seen with oxycodone, may be indicative of a lower risk of drug liking and abuse potential, at least in the time period immediately following drug administration. This is also in agreement with the abuse quotient (C_max/T_max) for buprenorphine buccal film, which is much lower than that for oral oxycodone. Together, these results suggest that buprenorphine buccal film, at these doses, may be a safer treatment option than full μ-opioid agonists for the treatment of chronic pain.