Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain

Figures & data

Figure 1. Study design: enriched-enrollment randomized-withdrawal study.

Figure 2. Flow diagram of patient disposition.

Table 1. Demographics and baseline characteristics in the open-label titration phase (safety population) and the double-blind treatment phase.

	Open-Label titration	Double-blind treatment
	Overall (N = 749)	Buprenorphine (n = 229)	Placebo (n = 232)	Overall (N = 461)
Age (years)
Mean ± SD	50.7 ± 13.0	51.2 ± 12.6	49.0 ± 13.1	50.1 ± 12.9
Median (range)	52.0 (19–82)	52.0 (22–82)	49.0 (19–78)	51.0 (19–82)
Age group, n (%)
18–64 years	634 (84.6)	199 (86.9)	203 (87.5)	402 (87.2)
65–75 years	106 (14.2)	26 (11.4)	28 (12.1)	54 (11.7)
>75 years	9 (1.2)	4 (1.7)	1 (0.4)	5 (1.1)
Gender, n (%)
Female	424 (56.6)	123 (53.7)	136 (58.6)	259 (56.2)
Race, n (%)
White	528 (70.5)	168 (73.4)	157 (67.7)	325 (70.5)
Black or African American	184 (24.6)	52 (22.7)	57 (24.6)	109 (23.6)
Asian	30 (4.0)	8 (3.5)	14 (6.0)	22 (4.8)
Other	7 (0.9)	1 (0.4)	4 (1.7)	5 (1.1)
Ethnicity, n (%)
Hispanic or Latino	106 (14.2)	38 (16.6)	37 (15.9)	75 (16.3)
Not Hispanic or Latino	643 (85.8)	191 (83.4)	195 (84.1)	386 (83.7)
Weight (kg)
Mean ± SD	91.5 ± 22.6	93.7 ± 23.6	90.9 ± 22.3	92.3 ± 23.0
Mean ± SD body mass index (kg/m^2)	31.9 ± 7.3	32.6 ± 7.7	31.8 ± 7.4	32.2 ± 7.6
Mean ± SD NRS average daily pain intensity score before open-label titration*	7.22 ± 1.09	7.21 ± 1.08	7.27 ± 1.06	7.24 ± 1.07
Mean ± SD NRS average daily pain intensity score at randomization baseline^†	NA	2.85 ± 1.00	2.81 ± 1.12	2.83 ± 1.06

NA: Not applicable; NRS: Numerical rating scale.

*NRS pain score before open-label titration is defined as the mean of pain intensity on the last 7 days before taking study medication before the open-label titration phase.

^†NRS pain score at baseline is defined as the mean of pain intensity on the last 7 days before taking study medication before the double-blind treatment phase.

Table 2. NRS of average daily pain intensity in double-blind treatment phase.*

Visit	Buprenorphine (n = 209)	Placebo (n = 211)
NRS of average daily pain intensity, mean ± SD
Before open-label titration^†	7.12 ± 1.06	7.18 ± 1.05
Randomization baseline^‡	2.82 ± 1.01	2.79 ± 1.12
Week 12^§	3.76 ± 1.94	4.39 ± 2.00
Change from baseline	0.94 ± 1.85	1.59 ± 2.04
Difference (95% CI) vs placebo	–0.67 (–1.07 to –0.26)
P value^||	0.0012

NRS: Numerical rating scale.

*One site excluded.

^†Before open-label titration is defined as the mean of pain intensity on the last 7 days before taking study medication before open-label titration phase.

^‡Baseline is defined as the mean of pain intensity on the last 7 days before taking study medication before the randomization date.

^§Patients with missing weekly patient diary data had their values imputed by multiple imputation methodology. Before multiple imputation, last observation carried forward was used to impute missing data for patients prematurely discontinued because of lack of efficacy, screening observation carried forward was used for patients prematurely discontinued because of adverse events and baseline observation carried forward was used for patients discontinued because of opiate withdrawal.

^||P value, treatment difference estimate and 95% CIs are calculated using PROC MIANALYZE (SAS Institute Inc., Cary, NC) by combining results from analysis of covariance model, performed with change from baseline as the dependent variable, treatment as a fixed effect, and screen and baseline values as covariates from 10 imputed data sets.

Figure 3. Mean (± SE) of weekly change from baseline in NRS pain intensity in double-blind treatment phase, observed cases only (ITT efficacy population; patients at one site excluded). ITT: Intent-to-treat; NRS: Numerical rating scale.

Figure 4. Sensitivity analyses of change from baseline to week 12 in NRS pain intensity. BOCF: Baseline observation carried forward; LCL: Lower confidence limit; LOCF: Last observation carried forward; MMRM: Mixed-effects model repeated measures; NRS: Numerical rating scale; PP: Per-protocol; SOCF: Screening observation carried forward; UCL: Upper confidence limit. *Missing values due to study discontinuation were imputed before the analysis as follows: (1) using the SOCF imputation if due to AEs/tolerability, (2) using the LOCF imputation if due to lack of efficacy, (3) using the BOCF imputation if due to opioid withdrawal and (4) using multiple imputation procedures for all other types of missing values. The SOCF, BOCF and LOCF imputations were implemented before multiple imputations. The sample size re-estimation was done at interim analysis and no change was made on sample size. Therefore, the unadjusted p value, estimate of treatment difference and its corresponding 95% two-sided CI were reported for the final primary analysis.

Figure 5. Proportion of responders with selected percentage pain reduction from before open-label titration to week 12 of the double-blind treatment phase.

Table 3. Patient-reported outcomes in double-blind treatment phase.

Visit	Buccal buprenorphine (n = 206)	Placebo (n = 201)
Patient Global Impression of Change
Randomization baseline, n	204	198
Mean (SD)	5.3 (1.22)	5.2 (1.28)
Median	6.0	6.0
Min, max	1, 7	1, 7
End of treatment/early termination, n	198	194
Mean (SD)	4.5 (1.75)	3.9 (1.99)
Median	5.0	4.0
Min, max	1, 7	1, 7
Difference (95% CI) vs placebo	0.6 (0.2−1.0)
P value*	0.0011
Roland Morris Disability Questionnaire
Before open-label titration,^† n	206	201
Mean (SD)	14.9 (4.44)	15.7 (4.21)
Median	15.0	15.0
Randomization baseline,^‡ n	197	189
Mean (SD)	10.5 (6.03)	10.9 (6.09)
End of treatment/early termination, n	193	189
Mean (SD)	11.0 (6.08)	11.9 (6.34)
Median	11.0	12.0
Change from randomization baseline to end of   treatment/early termination, n	187	179
Mean (SD)	0.6 (5.37)	1.2 (5.75)
Difference (95% CI) vs placebo	−0.75 (−1.77 to 0.27)
P value^§	0.1484

*P value is generated from analysis of variance model with observed value at week 12 as the dependent variable and treatment as a factor.

^†Before open-label titration is defined as the last assessment before taking study medication before open-label titration phase.

^‡Baseline is defined as the mean of pain intensity on the last 7 days before the randomization date.

^§P value is generated from analysis of covariance model with change from baseline as the dependent variable, treatment as a factor, and screen and baseline values as covariates.

Table 4. AEs during the open-label titration and double-blind treatment phases.

	Open-label titration	Double-blind treatment
Event, n (%)	Buccal buprenorphine (N = 749)	Buccal buprenorphine (n = 229)	Placebo (n = 232)
Any AE	540 (72.1)	94 (41.0)	101 (43.5)
Any treatment-related AE	451 (60.2)	38 (16.6)	40 (17.2)
Any severe AE	27 (3.6)	7 (3.1)	5 (2.2)
Death	0	0	0
Any serious AE	4 (0.5)	3 (1.3)	1 (0.4)
Any AE leading to discontinuation	112 (15.0)	14 (6.1)	7 (3.0)
Most commonly reported AEs (≥3%)
Gastrointestinal disorders
Nausea	373 (49.8)	23 (10.0)	17 (7.3)
Constipation	97 (13.0)	9 (3.9)	6 (2.6)
Vomiting	58 (7.7)	9 (3.9)	1 (0.4)
Dry mouth	28 (3.7)	1 (0.4)	0
Diarrhea	19 (2.5)	3 (1.3)	7 (3.0)
Nervous system disorders
Headache	60 (8.0)	5 (2.2)	8 (3.4)
Somnolence	52 (6.9)	2 (0.9)	1 (0.4)
Dizziness	48 (6.4)	4 (1.7)	1 (0.4)
General disorders
Fatigue	37 (4.9)	0	2 (0.9)
Infections and infestations
Upper respiratory tract infection	8 (1.1)	2 (0.9)	9 (3.9)

At each level of patient summarization, a patient is counted once if the patient reported ≥1 event (n). Percentages are based on the number of patients in the open label phase (N) or in each treatment group (n). AEs were coded by system organ class and preferred term using the Medical Dictionary for Regulatory Activities, version 16.0. AE: Adverse event.

Table 5. Treatment-related AEs occurring in ≥2 patients treated with buccal buprenorphine during the double-blind phase.

Treatment-related AE, n (%)	Buccal buprenorphine (n = 229)	Placebo (n = 232)
Nausea	17 (7.4)	12 (5.2)
Constipation	7 (3.1)	6 (2.6)
Vomiting	4 (1.7)	1 (0.4)
Dizziness	3 (1.3)	1 (0.4)
Headache	2 (0.9)	4 (1.7)
Somnolence	2 (0.9)	1 (0.4)
Drug withdrawal symptoms	2 (0.9)	6 (2.6)
Alanine aminotransferase increased	2 (0.9)	1 (0.4)

AE: Adverse event.