Andrew C. Darke

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).

Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: A randomized controlled trial

OBJECTIVE The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration.

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.

Clinical efficacy and safety of a novel controlled-release morphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation.

PURPOSE A significant number of cancer patients will require an alternate route of morphine administration at some point during their illness. This study compared the clinical efficacy and safety of a novel morphine sulfate controlled-release suppository (MS-CRS) and subcutaneous (SC) morphine in patients with cancer pain. METHODS Thirty patients with cancer pain were randomized in a double-blind crossover study to MS-CRS every 12 hours or SC morphine every 4 hours for 4 days each, using a 2.5:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Evaluations were made by the patient at 8 AM, noon, 4 PM, and 8 PM and rescue morphine consumption recorded. RESULTS Twenty-three patients completed the study (13 men and 10 women; mean age, 64.0 +/- 2.0 years) and were treated with mean daily MS-CRS and SC morphine doses of 326 +/- 69 mg and 138 +/- 28 mg, respectively. There was a small but significant difference in overall ordinal pain-intensity scores in favor of MS-CRS (0.7 +/- 0.1 v 0.9 +/- 0.1, P = .0459). There were no significant differences between MS-CRS and SC morphine in overall VAS scores for pain intensity (13 +/- 3 v 13 +/- 3 mm), sedation (23 +/- 3 v 25 +/- 4 mm), and nausea (8 +/- 2 v 9 +/- 2 mm). The mean daily rescue analgesic consumption during MS-CRS and SC morphine did not differ significantly (1.2 +/- 0.4 v 1.2 +/- 0.4 doses/d). CONCLUSION MS-CRS, administered every 12 hours, provides analgesia comparable to SC morphine and represents a reliable, noninvasive alternative method of pain control for patients unable to take oral morphine.

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.

Single‐Dose Pharmacokinetics of Multilayer‐Release Methylphenidate and Immediate‐Release Methylphenidate in Children With Attention‐Deficit/Hyperactivity Disorder

The objective of this study was to compare the single‐dose pharmacokinetics of multilayer‐release and immediate‐release methylphenidate in children with attention‐deficit/hyperactivity disorder. Patients 6‐ to 12‐years‐old with a DSM‐IV diagnosis of attention‐deficit/hyperactivity disorder were randomized to receive multilayer‐release methylphenidate (qd) or immediate‐release methylphenidate (bid) at equivalent doses, with a 14‐day washout between treatments. Plasma samples were collected predosing and 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours postdose. Pharmacokinetic analysis was conducted on 14 patients (1 female, 13 male; mean age: 9.6 ± 2.5 years [range, 6–12]). The mean dose of methylphenidate received by these patients in both phases of the study was 38.6 mg/d (range, 20–80 mg/d). The relative AUC0–t and Cmax 0–4 ratios for multilayer‐release compared with immediate‐release methylphenidate were 100.8% and 78.8%, respectively. Multilayer‐release methylphenidate produces a biphasic concentration‐time profile, with a rapid initial increase in plasma concentration that is maintained throughout the school day.

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

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).

Efficacy of 12 Hourly Controlled-Release Condeine Compared with as Required Dosing of Acetaminophen Plus Codeine in Patients with Chronic Low Back Pain

OBJECTIVE: To compare pain relief and stability of pain control in patients with chronic low back pain treated with scheduled 12 hourly doses of controlled-release codeine or as required doses of a fixed combination of acetaminophen and codeine.

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

PurposeFollowing 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 cholecystectomyMethodsEligible patients were randomized to CC or A/C in a double-blind, double-dummy parallel group study. Unrelieved pain in hospital was treated with fentanyliv bolus. Rain [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.ResultsEighty-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.ConclusionsControlled-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.RésuméObjectifEn chirurgie ambulatoire, les analgésiques postopératoires d’action prolongée peuvent avoir des avantages sur les analgésiques d’action brève. Nous comparons la codéine à libération contrôlée (CC) et une combinaison d’acétaminophène et de codéine (A/C; 300 mg/30 mg) comme analgésique pendant 48 h après une cholécystectomie laparoscopique.MéthodeDes patients admissibles à l’expérimentation ont reçu de la CC ou de l’A/C lors d’une étude à double insu, à double placebo en contrôle parallèle. A l’hôpital, la douleur tenace a été traitée avec des bolus iv de fentanyl. La douleur [échelle visuelle analogique (EVA) de 100 mm] a été évaluée avant la première dose de médicament; à 0,5, une, deux, trois et quatre heures après la dose; au moment du départ et trois fois par pur pendant 48 h. Les événements indésirables ont été notés et des mesures de la satisfaction du patient ont été faites à la fin de l’étude.RésultatsLétude a été réalisée auprès de 84 patients: 42 dans chaque groupe. Il n’y a pas eu de différence statistiquement significative entre les traitements à la CC ou à l’A/C. La douleur initiale moyenne a été similaire dans les deux groupes (P = 0,49) et il n’y a pas eu de différence significative de temps précédant le début de l’analgésie (P = 0,17). À 0,5 h, le score de douleur moyen à l’EVA était significativement réduit dans les deux groupes (P = 0,0001). Les scores à l’EVA au départ de l’hôpital ont été respectivement réduits de 59 % et de 56 % par rapport aux mesures initiales de la douleur (P = 0,61). Aucune différence intergroupe dans l’incidence d’événements indésirables n’a été notée et la satisfaction des patients était comparable d’un groupe à l’autre.ConclusionLa codéine à libération contrôlée offre un délai d’installation de l’analgésie, une réduction de la douleur postopératoire et un niveau de satisfaction équivalents à une combinaison d’acétaminophène et de codéine pendant 48 h après une cholécystectomie, et ce, avec l’avantage d’un dosage moins fréquent.

Pharmacokinetics and Pharmacodynamics of Once‐Daily Controlled‐Release Oxybutynin and Immediate‐Release Oxybutynin

Oxybutynin is used to treat patients with urinary urgency, frequency, and urge incontinence. In this 2‐way, multiple‐dose, crossover study, the pharmacokinetics and pharmacodynamics of once‐daily controlled‐release oxybutynin were compared with immediate‐release oxybutynin. Eighteen healthy male volunteers received one 15‐mg controlled‐release oxybutynin tablet once daily for 5 days or one 5‐mg immediate‐release oxybutynin tablet every 8 hours for 5 days. The washout period between treatments was ≤7 days. The mean steady‐state AUC for oxybutynin following controlled‐release oxybutynin treatment was higher (73.0 ng·h/mL) than following immediate‐release oxybutynin treatment (53.6 ng·h/mL) (P = .0001). The mean Cmax was lower for controlled‐release oxybutynin (5.7 ng/mL) than for immediate‐release oxybutynin (7.5 ng/mL) (P = .0051), with a smaller fluctuation in oxybutynin plasma concentration for controlled‐release oxybutynin (135.6%) than for immediate‐release oxybutynin (319.3%) (P = .0001). Mean stimulated saliva output was greater for controlled‐release oxybutynin, and mean dry mouth severity was less than immediate‐release oxybutynin.