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).

Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain.

OBJECTIVE: The present randomized, double-blinded, crossover study compared the efficacy and safety of a seven-day buprenorphine transdermal system (BTDS) and placebo in patients with low back pain of moderate or greater severity for at least six weeks. METHODS: Prestudy analgesics were discontinued the evening before random assignment to 5 microg/h BTDS or placebo, with acetaminophen 300 mg/codeine 30 mg, one to two tablets every 4 h to 6 h as needed, for rescue analgesia. The dose was titrated to effect weekly, if tolerated, to 10 microg/h and 20 microg/h BTDS. Each treatment phase was four weeks. RESULTS: Fifty-three patients (28 men, 25 women, mean [+/- SD] age 54.5+/-12.7 years) were evaluable for efficacy (completed two weeks or more in each phase). Baseline pain was 62.1+/-15.5 mm (100 mm visual analogue scale) and 2.5+/-0.6 (five-point ordinal scale). BTDS resulted in lower mean daily pain scores than in the placebo group (37.6+/-20.7 mm versus 43.6+/-21.2 mm on a visual analogue scale, P=0.0487; and 1.7+/-0.6 versus 2.0+/-0.7 on the ordinal scale, P=0.0358). Most patients titrated to the highest dose of BTDS (59% 20 microg/h, 31% 10 microg/h and 10% 5 microg/h). There were improvements from baseline in pain and disability (Pain Disability Index), Pain and Sleep (visual analogue scale), Quebec Back Pain Disability Scale and Short-Form 36 Health Survey scores for both BTDS and placebo groups, without significant differences between treatments. While there were more opioid-related side effects with BTDS treatment than with placebo, there were no serious adverse events. A total of 82% of patients chose to continue BTDS in a long-term open-label evaluation, in whom improvements in pain intensity, functionality and quality of life were sustained for up to six months without analgesic tolerance. CONCLUSION: BTDS (5 microg/h to 20 microg/h) represents a new treatment option for initial opioid therapy in patients with chronic low back pain.

A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediate-release tramadol taken as needed for chronic noncancer pain.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of controlled-release (CR) tramadol and immediate-release (IR) tramadol in patients with moderate or greater intensity chronic noncancer pain. METHODS: A total of 122 patients underwent washout from all opioids 2 to 7 days before randomization to 1 of 2 groups: active CR tramadol 200 mg every morning plus placebo IR tramadol 50 mg every 4 to 6 hours PRN rescue, or placebo CR tramadol 200 mg every morning plus active IR tramadol 50 mg every 4 to 6 hours PRN rescue. After 2 weeks, the doses were increased to CR tramadol 400 mg or placebo and IR tramadol 100 mg every 4 to 6 hours PRN or placebo, as rescue. After 4 weeks in the first phase, patients crossed over to the alternative treatment for another 4 weeks. Pain intensity (100-mm visual analog scale [VAS] and 5-point ordinal scales) was assessed twice daily in diaries. Pain intensity, Pain and Disability Index (PDI; 0-10 ordinal scale), Pain and Sleep Questionnaire (100-mm VAS), and analgesic effectiveness (7-point ordinal scale) were assessed at biweekly clinic visits. RESULTS: Sixty-five patients (35 men, 30 women) completed the study. Mean (SD) age was 56.5 (12.7) years; mean (SD) weight was 82.0 (18.5) kg. Daily diary pain intensity (mean [SD]) was significantly lower in the CR tramadol group than in the IR tramadol group in the last 2 weeks of each phase (completers: VAS, 29.9 [20.5] vs 36.2 [20.4] mm, P < 0.001; ordinal scale, 1.41 [0.7] vs 1.64 [0.6], P < 0.001; intent-to-treat [ITT] population: VAS, 32.5 [22.9] vs 38.6 [21.2] mm, P < 0.003; ordinal scale, 1.50 [0.8] vs 1.72 [0.7], P < 0.002). The overall pain intensity scores from the daily diary were also significantly better with CR tramadol for both the completers and ITT. Similar results were obtained on the biweekly VAS pain intensity questionnaire. No differences were found between treatments in total PDI or overall Pain and Sleep scores in either population. For the completers, both patients and investigators rated effectiveness higher for CR tramadol than for IR tramadol (P < 0.004 and P < 0.008 for patients and investigators, respectively). CONCLUSION: This study reports significant improvement in pain intensity with CR tramadol as compared with IR tramadol.

Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain.

The efficacy, safety, and pharmacokinetics of a novel once-daily morphine formulation (OAD morphine) and a 12-hourly formulation (twice-daily CR morphine) were compared in a double-blind, multi-centered crossover study. Chronic cancer pain patients (n=25) were randomized to OAD morphine (mean 238 +/- 319 mg q24h) or twice-daily CR morphine (mean 119 +/- 159 mg q12h) for one week. They then crossed over to the alternate drug, which also was taken for one week. There was no difference between treatments for evaluations of overall pain intensity, analgesic efficacy, or adverse events. However, whereas pain scores increased during the day on twice-daily CR morphine (P=0.0108), they remained stable on OAD morphine. Most patients (68%) chose once-daily dosing for continuing pain management (P=0.015). The AUC ratio was 100.3%, indicating equivalent absorption. Fluctuation indices were 93.5 +/- 28.8% and 179.3 +/- 41.3% (P=0.0001) for OAD morphine and twice-daily CR morphine, respectively. OAD morphine provides analgesia similar to twice-daily CR morphine with reduced fluctuation in plasma morphine concentration and more stable pain control.

Evaluation of dosing guidelines for use of controlled-release codeine in chronic noncancer pain.

OBJECTIVE: The clinical utility of guidelines for conversion of patients from a combination analgesic preparation of acetaminophen 300 mg plus codeine 30 mg every 4h to 6h as needed to scheduled controlled-release (CR) codeine every 12h was evaluated. METHODS: Adult patients with chronic noncancer pain underwent a two-week evaluation on acetaminophen plus codeine, followed by eight weeks of treatment with CR codeine. Patients taking four to six tablets of acetaminophen plus codeine per day were transferred to 50 mg CR codeine every 12 h; those on seven to nine tablets were transferred to 100 mg every 12 h; those on 10 to 12 tablets were transferred to 150 mg every 12 h; and those on greater than 12 tablets were transferred to 200 mg every 12 h. Subsequent dose adjustments were permitted. Acetaminophen (325 mg) was available for rescue. Pain intensity (five-point categorical and 100 mm visual analog scale), pain related disability, adverse events and acceptability were assessed. RESULTS: Of the 140 patients enrolled, 95 completed eight weeks of treatment with CR codeine. During month 1 and month 2, the mean CR codeine daily doses were 295.7+/-119.1 mg and 390.3+/-163.4 mg, respectively. Pain scores during both CR codeine month 1 and 2 were significantly lower than on acetaminophen plus codeine (53.6+/-20.9 mm and 49.7+/-23.7 mm versus 59.6+/-17.5 mm; P=0.0003, P=0.0001, respectively). CR codeine treatment was rated as moderately or highly acceptable by 82% of patients compared with 50% for acetaminophen plus codeine (P=0.001). Only seven patients (5.9%) discontinued CR codeine treatment because of adverse events. CONCLUSION: The results confirm the safety, efficacy and patient acceptability of the initial conversion and maintenance dosing recommendations for CR codeine from a combination opioid/nonopioid analgesic.

Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy.

BACKGROUND: Painful neuropathy is one of the most common long-term complications of diabetes mellitus and often proves difficult to relieve. METHODS: Patients with diabetic neuropathy with moderate or greater pain for at least 3 months, were evaluated for efficacy, safety and health-related quality of life (QOL) while receiving controlled-release (CR) oxycodone (OxyContin) or active placebo. Patients underwent washout from all opioids 2-7 days before randomization to 10 mg CR oxycodone or active placebo (0.25 mg benztropine) q12h. The dose was increased, approximately weekly, to a maximum of 40 mg q12h CR oxycodone or 1 mg q12h benztropine, with crossover to the alternate treatment after a maximum of 4 weeks. Acetaminophen, 325-650 mg q4-6h prn was provided as rescue. RESULTS: Thirty-six patients were evaluable for efficacy (21 men, 15 women, mean age 63.0+/-9.4 years). CR oxycodone resulted in significantly lower (P=0.0001) mean daily pain (21.8+/-20.7 vs. 48.6+/-26.6 mm VAS), steady pain (23.5+/-23.0 vs. 47.6+/-30.7 mm VAS), brief pain (21.8+/-23.5 vs. 46.7+/-30.8 mm VAS), skin pain (14.3+/-20.4 vs. 43.2+/-31.3 mm VAS), and total pain and disability (16.8+/-15.6 vs. 25.2+/-16.7; P=0.004). Scores from 6 of the 8 SF-36 domains and both summary scales, Standardized Physical Component (P=0.0002) and Standardized Mental Component (P=0.0338) were significantly better during CR oxycodone treatment. The number needed to treat to obtain one patient with at least 50% pain relief is 2.6 and clinical effectiveness scores favoured treatment with CR oxycodone over placebo (P=0.0001). CONCLUSION: CR oxycodone is effective and safe for the management of painful diabetic neuropathy and improves QOL.