The Pain and Sleep Questionnaire three-item index (PSQ-3): a reliable and valid measure of the impact of pain on sleep in chronic nonmalignant pain of various etiologies.

BACKGROUND: Sleep disturbance is among the more common complaints reported by chronic pain patients. Because pain-related sleep disturbance may serve as a marker for the assessment of responses to treatment for chronic pain, inclusion of a measure designed to assess the impact of pain on sleep in clinical trial protocols is important, if not necessary. Measures typically used for this purpose lack scales specifically designed for the assessment of the impact of pain on sleep or are based on a single item. Single-item scales lack reliability and, therefore, validity. OBJECTIVES: To investigate the psychometric properties of the five-item Pain and Sleep Questionnaire (PSQ) Index, which is embedded in the eight-item inventory, by applying an accepted methodology using retrospective analyses in controlled clinical trials in which the measure had been administered among patients with chronic nonmalignant pain. METHODS: Data were pooled from nine independent, single-site, double-blind, randomized placebo-controlled clinical trials conducted over a period of approximately 10 years, the majority of which were cross-over designs. A cross-validation approach was adopted with exploratory and confirmatory factor analyses conducted to evaluate the underlying structure and dimensionality of the measure. Internal consistency reliability was evaluated using Cronbach's alpha coefficient. Mean score differences were used to assess the ability of the index to detect important treatment changes. Correlation coefficients were calculated between index scores and scores from other health-related outcome measures to evaluate the criterion validity of the index. Finally, predictive validity was assessed using multiple regression analyses. RESULTS: Pooling the data resulted in a sample of 605 patients (65.5% female; mean age 55.7 years). Findings suggested a revised three-item PSQ Index (PSQ-3). The PSQ-3 demonstrated high internal consistency across samples (ranging from 0.82 to 0.93) and was sensitive to detecting meaningful treatment effects within different chronic pain categories. Moderate to strong correlations (r>0.40) between the PSQ-3 and other health-related outcome measures provided preliminary evidence for criterion-related validity. Results of multiple regression analyses demonstrated that the PSQ-3 accounted for between 29% and 40% of the variance in scores from other health-related outcome measures. CONCLUSIONS: Results support the scoring of a revised three-item index for the assessment of the impact of pain on sleep. The revised index demonstrated acceptable levels of internal consistency and preliminary support for the structural, criterion-related and predictive validity of the index was achieved.

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.

Cognitive and behavioral effects of multilayer-release methylphenidate in the treatment of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The aim of this study was to compare the pharmacodynamics of a new multilayer-release (MLR) formulation methylphenidate (MPH; Biphentin) with immediate-release (IR) MPH (Ritalin) in a double-blind, cross-over, placebo-controlled study in patients with attention-deficit/hyperactivity disorder (ADHD). METHOD: Patients were randomized to equivalent doses of MPH as MLR (once per day), IR (twice per day) or placebo. Each treatment was taken for 1 week prior to repeated behavioral and cognitive laboratory evaluations on a single day in each phase of the crossover. RESULTS: Two girls and 15 boys 6.8-15.3 years old (mean age 11.3 +/- 2.2 years) participated. Both MLR and IR MPH significantly reduced the Stop Signal Reaction Time (p = 0.0001, p = 0.0005), the Errors of Omission on the Continuous Performance Task (p = 0.0039, p = 0.0001), the IOWA-Conners Inattention/Overactivity Index (p = 0.0001, p = 0.0001), and increased the Clinical Global Impressions (CGI) Efficacy Index (p = 0.0001, p = 0.0017) and reduced the CGI Global Improvement Index (p = 0.0001, p = 0.0006) compared to placebo. Mild adverse events were experienced by 4, 6, and 3 patients on placebo, IR, and MLR MPH, respectively. CONCLUSIONS: MLR MPH given once daily produces equivalent improvements in behavioral and cognitive measures, and has a duration of effect at least as long as that of IR MPH given twice daily.

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.

Once-daily multilayer-release methylphenidate in a double-blind, crossover comparison to immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to evaluate the comparative efficacy and safety of a novel long-duration multilayer-release (MLR) methylphenidate (MPH) formulation and immediate-release (IR) MPH in attention-deficit/hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: This study was a randomized, double-blind, crossover comparison of once-daily MLR and twice-daily IR-MPH in home and school settings in children with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of ADHD. Patients completed a 1-week baseline followed by two active medication titration phases. Each phase of treatment was 1-4 weeks of titration with an additional stable dose week. The final dose was based on efficacy and adverse events for each patient. Efficacy measures included Clinical Global Impressions (CGI) and Conners' Parent and Teacher Rating Scales (CPRS and CTRS). The Clinical Assessment of Side Effects (CASE) scale assessed frequency of adverse events. RESULTS: Of the 90 enrolled patients, aged 6.4-17.5 years, 79 (88%) completed the study. Stable daily doses were 32.0 and 32.5 mg for MLR and IR-MPH, respectively. All efficacy parameters were significantly improved from baseline. A total of 73.2% and 81.0% of patients on MLR and IR-MPH were rated as "much" or "very much improved" on the CGI. A total of 77.4% and 81.1% of patients were normalized on the CPRS-R and 78.9 and 90.4% of patients were normalized on the CTRS-R for MLR and IR-MPH, respectively. The mean CASE score was not different from baseline for either treatment.

Opioid use following the introduction of an extended-release oxycodone formulation with tamper-resistant properties: Prospective historical chart review in methadone-maintained patients.

OBJECTIVE: Emerging data are demonstrating that tamper-resistant opioids may play an important role in changing prescription opioid abuse behaviors. This study was a chart review to examine if the reformulation of OxyContin® into a version with tamper-resistant properties (OxyNEO®) had an impact on oxycodone-positive urine drug screens (UDSs) in opioid-dependent patients receiving methadone maintenance therapy (MMT). DESIGN: The historical element of this study examined 250 eligible charts from patients on MMT who had data during the time periods when only OxyContin was available (baseline period), during the transition to OxyNEO, and when only OxyNEO was available. The prospective element included an exploratory questionnaire regarding retrospective opioid use. SETTING: The study was conducted at three methadone clinics, in Oshawa, Peterborough, and Scarborough in Ontario, Canada. PARTICIPANTS: Male and female patients were eligible if they had a diagnosis of opioid dependency, received MMT, and had at least one oxycodone-positive UDS during the baseline period. INTERVENTION: This was a noninterventional study. MAIN OUTCOME MEASURE: The main outcome was the number of oxycodonepositive UDSs. RESULTS: The results demonstrated a marked reduction in oxycodone-positive UDSs that showed stepwise, statistically significant decreases during the transition and post-OxyContin periods relative to baseline. While the oxycodone-positive UDS results were decreasing, morphine-related-positive UDSs remained relatively stable during the same periods. There were no significant gender differences noted. CONCLUSIONS: The introduction of OxyNEO was associated with a statistically significant reduction in oxycodone exposure in a population of methadone-maintained patients.

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.

Efficacy of controlled-release codeine in chronic non-malignant pain: a randomized, placebo-controlled clinical trial.

Treatment decisions for the use of opioid analgesics in chronic non-malignant pain are based primarily on survey data, as evidence from well-controlled clinical trials has been lacking. Forty-six patients with chronic non-malignant pain were enrolled in a randomized, double-blind, placebo-controlled evaluation of controlled-release (CR) codeine. Following a 3-7-day diary familiarization period, patients were randomly assigned to 7 days of treatment each with CR codeine q12h or placebo. The CR codeine dose was determined from the consumption of acetaminophen+codeine in the 7 days preceding the study. During both phases, breakthrough pain was treated with acetaminophen+codeine every 4 h as required. Pain intensity was assessed at 08:00 h and 20:00 h using a visual analogue scale (VAS) and a 5-point categorical scale, and rescue analgesic consumption was recorded at the time of use. Thirty patients (17 female, 13 male; mean age: 55.1 +/- 13.4 years) completed the study and were treated with a mean daily CR codeine dose of 273 +/- 78 mg (range: 200-400 mg). CR codeine treatment resulted in significantly lower overall VAS pain intensity scores (35 +/- 18 vs. 49 +/- 16, P = 0.0001), categorical pain intensity scores (1.7 +/- 0.6 vs. 2.2 +/- 0.6, P = 0.0001), and in pain scores by day of treatment and by time of day. Daily rescue analgesic consumption was significantly lower on CR codeine, relative to placebo treatment (3.6 +/- 3.5 vs. 6.1 +/- 3.2 tablets/day, P = 0.0001). There was also a significant reduction in the Pain Disability Index (PDI) on CR codeine, compared to placebo (25.0 +/- 7.7 vs. 35.1 +/- 8.2, P = 0.0001). Patients' and investigators' blinded treatment preference was significantly in favor of CR codeine, relative to placebo (73% vs. 10%, P = 0.0160 and 80% vs. 7%, P = 0.0014, respectively). The incidence of nausea was significantly higher on CR codeine than on placebo (32.6% vs. 11.9%, P = 0.013). Ninety-three percent of patients completing the study requested long-term, open-label treatment with CR codeine. Pain intensity scores at the completion of 19 weeks of long-term evaluation were comparable to those during the double-blind CR codeine treatment. We conclude that treatment with CR codeine results in reduced pain and pain-related disability in patients with chronic non-malignant pain.

A randomized, double-blind, parallel-group comparison of controlled- and immediate-release oxybutynin chloride in urge urinary incontinence.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of a new PO controlled-release (CR) QD oxybutynin tablet relative to PO immediate-release (IR) TID oxybutynin in patients with urge urinary incontinence (UI). METHODS: In this multicenter, double-blind trial, patients with UI (> or = 7 episode/wk) and frequency (> or = 8 micturitions/d) were randomized to CR or IR oxybutynin for 6 weeks. Patients initiated treatment at 15 mg/d and the dose was adjusted (in 5-mg/d increments) over 2 weeks according to tolerability. Efficacy (UI episodes, voids, absorbent pads used, urgency, and volume voided per micturition) was assessed during the final 2 weeks of treatment. Tolerability was assessed by evaluating adverse events and treatment withdrawals. RESULTS: Of the 125 patients randomized, 94 (75%) were evaluable for efficacy; tolerability was assessed in all patients. In the CR group, 48 patients (91%) were women and 5 (9%) were men; the mean (SD) age was 58.0 (12.4) years (range, 26-78 years). In the IR group, 37 patients (90%) were women and 4 (10%) were men; the mean (SD) age was 60.6 (14.8) years (range, 26-83 years). Both CR and IR oxybutynin significantly reduced the mean number of total UI episodes per week (both P < 0.001 vs baseline). Both treatments produced equivalent reductions in mean voiding frequency and urinary urgency (all P < 0.001 vs. baseline). Significantly more patients rated CR oxybutynin tolerable on the initial dose of 15 mg/d (P = 0.020) and completed the study at a dose of > or = 15 mg/d (P = 0.018). Dry mouth was the most common adverse event, reported by 68% and 72% of patients in the CR and IR oxybutynin groups, respectively. CONCLUSIONS: Among the patients with urge UI included in this study, CR oxybutynin was as effective as IR oxybutynin for improving primary symptoms, with the additional benefit of QD administration.

Preliminary evaluation of a new controlled-release oxybutynin in urinary incontinence.

OBJECTIVE: To conduct a preliminary evaluation of a new oral formulation of controlled-release (CR) oxybutynin tablet taken once-daily in patients with urinary urge incontinence. RESEARCH DESIGN AND METHODS: A single-centre, open-label, 8-week study was conducted. Patients with urodynamically-confirmed detrusor instability, micturition frequency (>/= 8 voids/day) and/or urinary incontinence (>/= 2 incontinence periods/day) were enrolled. The study duration was 8 weeks: patients received IR oxybutynin (2.5-5 mg bid) for 2 weeks, followed by a 2-week washout/baseline period to avoid carryover effects, and oral CR oxybutynin (15 mg OD) for 4 weeks. Daily void frequency, fluid intake, urinary incontinence episodes, and spontaneously reported adverse events were recorded in a daily diary for five consecutive days in each treatment period. RESULTS: Of 12 enrolled patients, 9 patients efficacy; all patients were evaluable for safety. completed the study and were evaluable for Compared to baseline/washout, CR oxybutynin reduced UI episodes/day by 45% (p = 0.13) and micturitions/day by 15% (p = 0.07). Treatment with IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day) reduced UI episodes/day from baseline by 7% (p = 0.58) and voids/day by 6% (p = 0.29). Fluid intake remained consistent at approximately 2 litres/day during all study periods. The most common adverse event was dry mouth. CONCLUSIONS: Based on the reductions in daily frequency of incontinence and micturition following 4-weeks treatment, CR oxybutynin (15 mg OD) was at least as effective as the patients' previous dose of IR oxybutynin (mean dose: 6.7 +/- 2.5 mg/day). These improvements were achieved without restriction of fluid intake. Initial 15 mg doses of CR oxybutynin appear to be well tolerated.

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.

Long-term safety and clinical effectiveness of controlled-release metoclopramide in cancer-associated dyspepsia syndrome: a multicentre evaluation.

Patients with cancer frequently report gastrointestinal symptoms such as anorexia, early satiety, nausea, vomiting, and bloating. A reduction of the severity of some of these symptoms would benefit the patient by enhancing quality of life and improving their treatment. Forty-eight patients (25 female and 23 male; mean age 63 +/- 11 years) with a minimum two-week history of cancer-associated gastrointestinal symptoms were assigned to a single, open-label treatment group and received controlled-release metoclopramide 20 mg-80 mg q12h for a maximum period of 12 weeks (mean 46 +/- 35 days). There was a 40%-60% decrease in the severity of nausea over the first two weeks of treatment, and an approximate 50% reduction in severity of vomiting over the first four weeks of treatment. Appetite and bloating also improved, although smaller and less consistent changes were observed. Patient ratings of overall clinical effectiveness with respect to relief from symptoms and tolerability of side effects indicated that controlled-release metoclopramide was highly and moderately effective in 36% and 30% of the patients, respectively. Controlled-release metoclopramide is a useful treatment for the management of gastrointestinal symptoms associated with the cancer-associated dyspepsia syndrome including nausea, vomiting, loss of appetite, and bloating.

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).

Efficacy of a novel biphasic controlled-release methylphenidate formula in adults with attention-deficit/hyperactivity disorder: results of a double-blind, placebo-controlled crossover study.

OBJECTIVE: To evaluate the efficacy and safety of a new biphasic multilayer-release (MLR) methylphenidate formulation in a double-blind, placebo-controlled crossover study of adults with attention-deficit/hyperactivity disorder (ADHD). METHOD: Adults 18 to 60 years of age with a DSM-IV diagnosis of ADHD entered a no-medication baseline week and were then randomly assigned to once-daily MLR methylphenidate or matching placebo. Patients were titrated to optimal effect over 1 to 3 weeks followed by 2 weeks of treatment on a stable dose. The same titration protocol was repeated with the alternate treatment. Clinical Global Impressions scale (CGI) and Conners' Adult ADHD Rating Scales (Self-rated, CAARS-S, and Observer-rated, CAARS-O) were collected at weekly clinic visits. The study was conducted between October 2003 and April 2004. RESULTS: Fifty patients were randomly assigned to treatment, and 39 were analyzed in a per-protocol population (23 men, 16 women; mean age = 37.9 years). CGI-Improvement scores of subjects taking MLR methylphenidate were significantly improved compared with placebo (Global Improvement: 2.6 vs. 3.7; p = .0015). MLR methylphenidate produced improvements over placebo on the ADHD Index T scores of the CAARS-S (12.2 vs. 5.4 [change from baseline score]; p = .0083) and the CAARS-O (10.9 vs. 6.6 [change from baseline score]; p = .1404). The most frequent adverse events for MLR methylphenidate and placebo were headache (26% and 24%, respectively), anorexia (22% and 6%), insomnia (22% and 8%), nervousness (20% and 4%), and nausea (16% and 8%). There were no serious adverse events. CONCLUSIONS: Once-daily MLR methylphenidate produces significant improvements in ADHD symptoms and situational behavior in adult patients with ADHD, with a prolonged duration of effect and minimal side effects, thus having the potential to improve compliance and, therefore, treatment outcomes in routine clinical use.

A double-blind randomized dose-response study comparing daily doses of 5, 10 and 15 mg controlled-release oxybutynin: balancing efficacy with severity of dry mouth.

OBJECTIVE: To assess the efficacy, incidence of dry mouth and overall satisfaction with initial doses of 5, 10 and 15 mg of a new, once-daily, controlled-release (CR) form of oxybutynin for treating urge urinary incontinence (UUI). PATIENTS AND METHODS: Patients who reported urinary incontinence (UI) (one or more episodes/diary) and voiding frequency (eight or more voids/day) or urgency (one or more episodes/diary) during a 2-week baseline were randomized to once-daily 5, 10 or 15 mg CR oxybutynin for 4 weeks. Daily episodes of UI, voids, urgency, adverse events, dry mouth and satisfaction were recorded in a 3-day diary at baseline and after 4 weeks of treatment. In all, 237 patients were randomized and evaluated. RESULTS: Episodes of UI, voids and urgency were significantly reduced over the study period at all doses. Daily UI episodes were significantly lower with 15 mg/day than 5 and 10 mg/day. Dry mouth symptoms were similar in the 10 and 15 mg/day groups, and higher than in the 5 mg/day group. However, significantly greater overall satisfaction was reported with 15 than 5 mg/day. CONCLUSIONS: There were significant dose-response relationships with CR oxybutynin for both UI episodes and dry mouth. The greatest satisfaction was with 15 mg/day, and the severity of dry mouth was comparable at 10 mg/day, indicating that greater efficacy at the higher dose did not compromise tolerability.

Efficacy and safety of controlled-release oxycodone and standard therapies for postoperative pain after knee or hip replacement.

BACKGROUND: Standard therapy (ST) for postoperative pain after knee and hip replacement at the Hamilton Health Sciences Henderson Hospital consists of epidural analgesia or patient-controlled analgesia for the first 48 hours, followed by oral or parenteral analgesics, or both, on an as-needed basis. We compared the efficacy and safety of scheduled controlled-release (CR) oxycodone hydrochloride (OxyContin; Purdue Pharma, Pickering, Ont.) and ST for postoperative pain 48 hours after primary knee and hip replacement. METHODS: In 2 separate 3-week studies of similar design, pain intensity, pain relief, length of hospital stay, analgesic use and side effects of CR oxycodone (n = 70) and ST (n = 101) were evaluated. In the CR oxycodone trial, a dose de-escalation protocol was used. RESULTS: At the time of discharge from hospital, patients in the CR oxycodone group recorded lower mean (and standard deviation) pain intensity scores than the ST group (20.2 [17.9] v. 27.7 [21.5] mm on a 100-mm visual analogue scale; p = 0.021). Length of hospital stay was 5.5 and 6.4 days for the CR oxycodone and ST groups respectively (p < 0.001). CR oxycodone patients used less opioid (morphine equivalent) while in hospital than ST patients (p < 0.001), and the average number of daily administrations of analgesics in hospital was 2.1 and 3.5 for CR oxycodone and ST patients respectively (p < 0.001). ST patients reported more nausea and vomiting, pruritus and fever than the CR oxycodone patients, but less somnolence, constipation, dizziness, confusion and tachycardia. CONCLUSIONS: CR oxycodone every 12 hours is as effective as ST in treating postoperative pain but length of hospital stay was shorter and analgesic administration in the hospital was used less frequently, providing potential hospital cost savings and reduced use of health care resources.

Controlled-release codeine is equivalent to acetaminophen plus codeine for post-cholecystectomy analgesia.

PURPOSE: Following ambulatory surgery, long-acting analgesics may provide advantages over short-acting analgesics. This study compared controlled-release codeine (CC) and acetaminophen plus codeine (A/C; 300 mg/30 mg) for pain control in the 48-hr period following laparoscopic cholecystectomy. METHODS: Eligible patients were randomized to CC or A/C in a double-blind, double-dummy parallel group study. Unrelieved pain in hospital was treated with fentanyl i.v. bolus. Pain [100 mm visual analogue scale (VAS)] was assessed before the first dose of medication; at 0.5, one, two, three, and four hours post-dose; at discharge; and three times a day for 48 hr. Adverse events were recorded and measures of patient satisfaction were assessed at the end of the study. RESULTS: Eighty-four patients were enrolled in the study; 42 patients in each group. There were no statistically significant differences between CC and A/C treatment. Mean VAS baseline pain was similar in both groups (P = 0.49) and there was no significant difference in the time to onset of analgesia (P = 0.17). At 0.5 hr, the mean VAS pain score was significantly reduced from baseline in both groups (P = 0.0001). The VAS pain scores at discharge were reduced 59% and 56% from baseline, respectively (P = 0.61). There was no difference between treatments in the incidence of adverse events and patients reported similar levels of satisfaction. CONCLUSIONS: Controlled-release codeine provides an equivalent onset of analgesia, reduction in postoperative pain, and level of patient satisfaction, to acetaminophen plus codeine, over 48 hr following cholecystectomy, with the advantage of less frequent dosing.