Fabrication of topical metered dose film forming sprays for pain management.

Topical film-forming metered dose spray formulations were designed for management of pain. Ropivacaine, a local anesthetic is explored for its topical efficacy in alleviating pain. Metered dose spray containers, organic solvents, film forming polymers and permeation enhancers were utilized to fabricate the Metered Dose topical spray. Factors like viscosity, spray pattern, spray angle, volume of actuation, droplet size distribution of the metered dose spray formulation and drying time, flexibility and wash-ability of the film formed after spraying were assessed. Permeation of the drug into the porcine skin was observed based on ex-vivo diffusion studies and confocal microscopy. The results indicated a high level of drug concentration in the skin layers. Anti-nociceptive efficacy of the formulations was assessed on Wistar rats by hot plate and tail flick tests, based on the response to pain perception. The results were comparable to the conventional lidocaine gel. Topical film forming sprays have the ability to provide an accurate, long lasting and patient compliant delivery of drugs on the skin as compared to conventional gels.

The analgesic efficacy and safety of a novel intranasal morphine formulation (morphine plus chitosan), immediate release oral morphine, intravenous morphine, and placebo in a postsurgical dental pain model.

BACKGROUND: Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (i.n.) morphine to i.v. and oral morphine and placebo. METHODS: Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were randomized to receive a single dose of i.n. morphine 7.5 mg or 15 mg, i.v. morphine 7.5 mg, oral morphine 60 mg or placebo. Pain intensity was assessed using visual analog and categorical scales, and pain relief using a categorical scale. Outcomes included total pain relief, pain intensity difference, summed pain intensity difference, time to analgesic onset, time to requesting rescue medication, and patients' global evaluation of their treatment. Safety assessments included adverse event recording and nasal examinations. RESULTS: Across the various efficacy outcomes, both i.n. morphine doses were statistically similar to the positive comparators (i.v. and oral morphine), and all four morphine treatments were statistically superior to placebo. Overall, i.n. morphine 15 mg presented an efficacy profile similar to i.v. morphine 7.5 mg; both treatments demonstrated rapid onset of efficacy, generally persistent throughout the 6-h assessment period. The lower dose of i.n. morphine, 7.5 mg, was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated, with no withdrawals due to adverse events or other safety concerns, and no serious adverse events reported. The most frequently reported adverse events were typical systemic opioid effects. CONCLUSIONS: I.n. morphine offers a noninvasive alternative to i.v. morphine for postoperative analgesia.

Extended-release opioids for the management of chronic non-malignant pain.

Recent clinical trials have documented the use of extended-release (ER) opioids in the management of chronic non-malignant pain. This manuscript reviews the clinical pharmacology of investigational and current marketed ER opioids. Recent randomised clinical trials of ER opioids that document the efficacy and safety of opioid therapy for chronic pain are reviewed. Finally, the abuse liability of ER opioids is discussed. Current technologies aimed at defeating the abuse of ER opioids will also be presented.

Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: results of a randomized, double-blind, placebo- and active-controlled phase III trial.

OBJECTIVE: To compare oxymorphone extended release (ER) and placebo on indices of pain, function, and safety in patients with chronic osteoarthritis (OA) pain. DESIGN: In this multicenter, double-blind, placebo- and active-controlled, parallel-group, dose-ranging study, patients were randomized to oxymorphone ER 20 mg (N = 121), oxymorphone ER 40 mg (N = 121), oxycodone controlled release 20 mg (N = 125), or placebo (N = 124) every 12 hours. The primary efficacy end point was change in arthritis pain intensity (visual analog scale, 0-100) from baseline to week 3 for the oxymorphone ER 40 mg group versus placebo. RESULTS: The primary end point was achieved: the week 3 oxymorphone ER least squares mean difference (LSMD) from placebo was -9.0 (95% confidence interval [CI]: -16.2 to -1.8; P = 0.015). Secondary efficacy analysis showed similar improvements at week 4 (LSMD from placebo, -10.3 [95% CI: -17.7 to -2.8]; P = 0.007) and with oxymorphone ER 20 mg at week 3 (LSMD from placebo, -7.7 [95% CI: -15.0 to -0.4]; P = 0.039) and week 4 (LSMD from placebo, -7.5 [95% CI: -15.0 to 0.0]; P = 0.050). Weeks 3 and 4 pain intensity decreased by approximately 30-40%. Oxymorphone ER 20 and 40 mg improved from baseline on the Western Ontario and McMaster Universities Osteoarthritis Composite Index and pain and physical function subscales at week 4. Adverse events in all opioid groups included mild to moderate nausea, constipation, and somnolence. CONCLUSIONS: In this short-term study, oxymorphone ER was superior to placebo for relieving pain and improving function in patients with moderate to severe chronic OA pain, and is an alternative to other sustained-release opioids.

Efficacy of oxymorphone extended release in postsurgical pain: a randomized clinical trial in knee arthroplasty.

Patients with moderate or severe pain following knee arthroplasty and washout from standard patient-controlled analgesia (PCA) were randomized to receive 20 mg of an extended-release (ER) oxymorphone formulation (n = 65) or placebo (n = 61) q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER provided significant improvements over placebo for most standard single-dose analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12 hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple-dose (24-h) efficacy assessments. Oxymorphone-treated patients used significantly less rescue PCA than those who received placebo (p < 0.02). Adverse events such as nausea and constipation were typical of opioids, and laboratory and physical findings were similar between groups. Oxymorphone ER was effective and generally well tolerated. A single dose was active from 2 hours until > or = 12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery.

Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee.

The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride (tramadol ER) was evaluated in patients with moderate to severe chronic pain of osteoarthritis (OA). This was a randomized, double-blind, placebo-controlled, parallel-group, 12-week study. Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria, defined by knee pain and presence of osteophytes, plus at least age >50 years, morning stiffness <30 minutes in duration, and/or crepitus, entered a 2-7 day washout period during which all analgesics were discontinued. When pain at the index knee joint reached > or =40 mm (0-100 mm VAS), patients were randomized to tramadol ER or placebo. Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment. After the first week, further increases to tramadol ER 300 mg or 400 mg QD were allowed. Outcome measures included Arthritis Pain Intensity Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Arthritis Scale (WOMAC) Pain, Stiffness, Physical Function VAS subscales, Patient and Physician Global Assessment of Therapy, Sleep, dropouts due to insufficient therapeutic effect, and adverse events. Two hundred forty-six patients were randomized (tramadol ER 124, placebo 122). There were no baseline differences between the two treatments. The mean age was 61 years, mean duration of OA 12.9 years, and the mean tramadol ER dose was 276 mg QD. All efficacy outcome measures favored tramadol ER over placebo. On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks, tramadol ER was superior to placebo (least squares mean change from baseline: 30.4 mm vs. 17.7 mm, P < 0.001). Significant differences from placebo were evident at week 1, the first post-treatment visit. Similarly, outcomes on the WOMAC Pain, Stiffness and Physical Function subscales, the WOMAC Composite Scale, dropouts due to insufficient therapeutic effect, Patient and Physician Global Assessment of Therapy, and Sleep were all significantly better with tramadol ER than placebo (P < 0.001 to < 0.05). Treatment with tramadol ER results in statistically significant and clinically important and sustained improvements in pain, stiffness, physical function, global status, and sleep in patients with chronic pain. A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep and improved compliance.

Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery.

BACKGROUND: The AERx Pain Management System (Aradigm Corporation, Hayward, CA) is a novel pulmonary delivery system for the systemic administration of morphine. The authors compared the relative analgesic efficacy and safety of the AERx Pain Management System with those of placebo and intravenous morphine in an orthopedic postsurgical pain model. METHODS: Eighty-nine male and female PS-1 to PS-3 patients underwent standardized bunionectomy surgery and received multiple doses of inhaled or intravenous placebo, inhaled morphine (one inhalation [2.2 mg] or three inhalations [6.6 mg]), or intravenous morphine (4 mg) in a blinded fashion. Open-label rescue morphine (2 mg) was also available as needed. Pain intensity, pain relief, and time to pain relief were measured after the first dose. Global evaluation, morphine consumption, vital signs, and adverse events were monitored for 8 h after treatment. Blinded study personnel performed all treatment administrations and pain assessments. RESULTS: Three inhalations of morphine and 4 mg intravenous morphine provided comparable single- and multiple-dose analgesia. One inhalation of morphine was statistically indistinguishable from placebo. Three inhalations of morphine and 4 mg intravenous morphine both consistently demonstrated significantly greater analgesic efficacy than did placebo and one inhalation of morphine. CONCLUSIONS: Comparable analgesic efficacy was demonstrated between a carefully matched dose of inhaled and intravenous morphine in a postsurgical pain model.

Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial.

A randomized, 4-week, double-blind trial followed by an open-label extension trial assessed the efficacy and safety of a once-daily, extended-release morphine formulation (Avinza (previously referred to as Morphelan)) in 295 patients with chronic, moderate-to-severe osteoarthritis pain who had failed to obtain adequate pain relief with NSAIDs and acetaminophen. Participants received one of four treatments: Avinza 30 mg once daily (QAM or QPM), MS Contin(R) 15 mg twice daily, or placebo twice daily. Patients (n =181) received Avinza QAM or QPM during the 26-week open-label extension trial and could increase their dose to optimize pain control. Avinza and MS Contin reduced pain and improved several sleep measures versus placebo. Analgesic efficacy was comparable between Avinza and MS Contin; however, Avinza QAM demonstrated greater improvements in overall quality of sleep. The most common adverse events were constipation and nausea. The majority of AEs occurred at a similar incidence among the active treatment groups.

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.