14 - Buprenorphine Buccal Film in Patients With Chronic Low Back Pain: A Pooled Subgroup Analysis of Two Double-Blind, Placebo-Controlled, Randomized Withdrawal Trials by Baseline Pain Severity

¹BioDelivery Sciences International, Inc., Raleigh, NC, USA. ²University of Alabama at Birmingham School of Public Health, Department of Biostatistics, Birmingham, AL, USA. ³Pythagoras, Inc., Birmingham, AL, USA

Purpose
Buprenorphine is a Schedule III opioid with partial agonistic activity at the mu-opioid receptor, antagonist activity at the delta- and kappa-opioid receptors, and agonist activity at the opioid-receptor-like 1 (ORL-1) receptor. Buprenorphine is a unique opioid with demonstrated efficacy as an analgesic and favorable safety properties that may provide an improved risk-benefit profile relative to other opioids.
As with Schedule II long-acting opioids, buprenorphine buccal film (BELBUCA^®, BioDelivery Sciences International, Inc.) is approved by the US Food and Drug Administration for the management of pain severe enough to require daily, around-the clock, long-term opioid treatment and for which alternative treatment options are inadequate. Two previous phase 3 clinical trials established the efficacy of buprenorphine buccal film for treating chronic low back pain in opioid-naïve and opioid-experienced subjects (ClinicalTrials.gov NCT01633944 and NCT01675167, respectively). Both studies used an enriched enrollment, randomized withdrawal design that consisted of an open-label buprenorphine buccal film titration phase followed by a randomized, double-blind phase in which subjects either continued treatment with buprenorphine buccal film or were switched to placebo. After 12 weeks of double-blind treatment, results of the primary efficacy analysis showed that mean average daily pain scores increased (worsened) significantly less from baseline in subjects who continued use of buprenorphine buccal film than in those who switched to placebo. Subjects in the buprenorphine buccal film group also had significantly lower pain scores than subjects in the placebo group at week 1 and at all subsequent time points through week 12. This post hoc analysis pools data from both clinical trials to further characterize the efficacy of buprenorphine buccal film on the basis of baseline pain severity scores.
Methods
Both studies enrolled adults aged ≥18 years who had chronic low back pain as their primary source of pain for ≥6 months. To enter the open-label titration phase, subjects had to have an average pain intensity score of ≥5 on an 11-point numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain imaginable) during the last week of screening. Opioid-experienced subjects with well controlled pain (average pain intensity <5) were also permitted to enroll, provided that their pain scores were at ≥5 for at least 3 consecutive days during taper of their previous opioid. After titration to their optimal buprenorphine buccal film dose during the open-label phase, eligible subjects were randomly assigned (1:1 ratio) to receive buprenorphine buccal film or placebo buccal film twice daily for 12 weeks. Subjects assigned to receive buprenorphine buccal film continued the same optimal dose established during the open-label phase.
Post hoc analyses combined data for subjects from both studies and evaluated the mean difference in average daily NRS scores from baseline (the start of double-blind treatment) in 10-day intervals through day 80. Subjects were stratified by average pain severity in the 7 days before the start of open-label titration, with mild pain defined as an average NRS of ≤4, moderate pain as an average NRS of 5 or 6, and severe pain as an average NRS ≥7. A linear mixed-effects model was used to assess differences between the groups in individual NRS pain scores. The mean pain score over time adjusted for baseline was used to assess the change in pain intensity scores from baseline to week 12. Estimates of mean treatment differences were calculated using a quadratic model that provided a conservative estimate of the difference as the model was adjusted to fit excess differential dropouts over time in the placebo arm; p values were calculated using the least squares means at each time point from the model.
Results
Across both studies, 971 subjects were randomly assigned to buprenorphine buccal film (n=483) and placebo buccal film (n=488). Mean (SD) pain scores before open-label titration were 7.0 (1.2) in the buprenorphine buccal film group and 6.9 (1.2) in the placebo group; scores improved to 2.9 (1.0) and 2.8 (1.1), respectively, at the start of the double-blind period. Overall, mean differences between treatment groups suggested significantly lower pain scores in the buprenorphine buccal film group than in the placebo group at every 10-day interval assessed; the greatest difference was observed at day 60 (mean difference, −0.8 [95% CI, −1.1 to −0.6]; p<0.0001). At most time points, greater decreases in pain scores for buprenorphine buccal film than for placebo were observed in subjects with moderate pain at entry (n=102 and 94, respectively) and severe pain at entry (n=366 and 371) than in subjects with mild pain at entry (n=15 and 23). For both the moderate and severe pain subgroups, mean differences between groups suggested significantly lower pain scores in the buprenorphine buccal film group than the placebo group for every 10-day interval assessed. The greatest difference in pain scores between the buprenorphine buccal film and placebo group was observed at day 50 for the moderate pain subgroup (mean difference, −1.0 [95% CI, −1.5 to −0.6]; p<0.0001) and at day 60 and day 70 for the severe pain subgroup (mean difference for both, −0.8 [95% CI, −1.1 to −0.5]; p<0.0001). Mean differences in pain scores between the buprenorphine buccal film group and the placebo group were the same or greater for subjects in the moderate pain subgroup than for those in the severe pain subgroup at every 10-day interval assessed.
Conclusions
Buprenorphine buccal film has demonstrated analgesic efficacy for the treatment of chronic low back pain in opioid-naïve and opioid-experienced patients. The results of this post hoc analysis indicate that treatment with buprenorphine buccal film results in greater reductions in pain than does placebo; similar reductions in pain were observed regardless of whether subjects had moderate or severe pain at study entry. Given the favorable risk-benefit profile of buprenorphine, buprenorphine buccal film should be considered a treatment option for patients who require long-term opioid treatment for which alternative treatment options are inadequate, even when their pain levels are considered severe.