Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase.

Background: Buprenorphine is a mixed-activity, partial mu-opioid agonist. Its lipid solubility makes it well suited for transdermal administration.

Objective: This study assessed the efficacy and safety profile of a 7-day buprenorphine transdermal system (BTDS) in adult (age >18 years) patients with moderate to severe chronic low back pain previously treated with > or =1 tablet daily of an opioid analgesic.

Methods: This was a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. After a 2- to 7-day washout of previous opioid therapy, eligible patients were randomized to receive BTDS 10 microg/h or matching placebo patches. The dose was titrated weekly using 10- and 20-microg/h patches (maximum, 40 microg/h) based on efficacy and tolerability. After 4 weeks, patients crossed over to the alternative treatment for another 4 weeks. Patients who completed the double-blind study were eligible to enter the 6-month open-label phase. Rescue analgesia was provided as acetaminophen 325 mg to be taken as 1 or 2 tablets every 4 to 6 hours as needed. The primary outcome assessments were daily pain intensity, measured on a 100-mm visual analog scale (VAS), from no pain to excruciating pain, and a 5-point ordinal scale, from 0 = none to 4 = excruciating. Secondary outcome assessments included the Pain and Sleep Questionnaire (100-mm VAS, from never to always), Pain Disability Index (ordinal scale, from 0 = no disability to 11 = total disability), Quebec Back Pain Disability Scale (categorical scale, from 0 = no difficulty to 5 = unable to do), and the 36-item Short Form Health Survey (SF-36). Patients and investigators assessed overall treatment effectiveness at the end of each phase; they assessed treatment preference at the end of double-blind treatment. After implementation of a precautionary amendment, the QTc interval was measured 3 to 4 days after randomization and after any dose adjustment. All assessments performed during the double-blind phase were also performed every 2 months during the open-label extension. Adverse events were collected by non-directed questioning throughout the study.

Results: Of 78 randomized patients, 52 (66.7%) completed at least 2 consecutive weeks of treatment in each study phase without major protocol violations (per-protocol [PP] population: 32 women, 20 men; mean [SD] age, 51.3 [11.4] years; mean weight, 85.5 [19.5] kg; 94% white, 4% black, 2% other). The mean (SD) dose of study medication during the last week of treatment was 29.8 (12.1) microg/h for BTDS and 32.9 (10.7) microg/h for placebo (P = NS). During the last week of treatment, BTDS was associated with significantly lower mean (SD) pain intensity scores compared with placebo on both the VAS (45.3 [21.3] vs 53.1 [24.3] mm, respectively; P = 0.022) and the 5-point ordinal scale (1.9 [0.7] vs 2.2 [0.8]; P = 0.044). The overall Pain and Sleep score was significantly lower with BTDS than with placebo (177.6 [125.5] vs 232.9 [131.9]; P = 0.027). There were no treatment differences on the Pain Disability Index, Quebec Back Pain Disability Scale, or SF-36; however, BTDS was associated with significant improvements compared with placebo on 2 individual Quebec Back Pain Disability Scale items (get out of bed: P = 0.042; sit in a chair for several hours: P = 0.022). Of the 48 patients/physicians in the PP population who rated the effectiveness of treatment, 64.6% of patients (n = 31) rated BTDS moderately or highly effective, as did 62.5% of investigators (n = 30). Among the 50 patients in the PP population who answered the preference question, 66.0% of patients (n = 33) preferred the phase in which they received BTDS and 24.0% (n = 12) preferred the phase in which they received placebo (P = 0.001), with the remainder having no preference; among investigators, 60.0% (n = 30) and 28.0% (n = 14) preferred the BTDS and placebo phases, respectively (P = 0.008), with the remainder having no preference. The mean placebo-adjusted change from baseline in the QTc interval ranged from -0.8 to +3.8 milliseconds (P = NS). BTDS treatment was associated with a significantly higher frequency of nausea (P < 0.001), dizziness (P < 0.001), vomiting (P = 0.008), somnolence (P = 0.020), and dry mouth (P = 0.003), but not constipation. Of the 49 patients completing 8 weeks of double-blind treatment, 40 (81.6%) entered the 6-month, open-label extension study and 27 completed it. Improvements in pain scores achieved during the double-blind phase were maintained in these patients.

Conclusions: In the 8-week, double-blind portion of this study, BTDS 10 to 40 microg/h was effective compared with placebo in the management of chronic, moderate to severe low back pain in patients who had previously received opioids. The improvements in pain scores were sustained throughout the 6-month, open-label extension. (Current Controlled Trials identification number: ISRCTN 06013881).