Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE).

BACKGROUND: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval. PATIENTS AND METHODS: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales. RESULTS: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, antidiarrheals, and antiemetics. Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco. CONCLUSIONS: Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these events.

Evaluation of the depth and duration of anesthesia from heated lidocaine/tetracaine (Synera) patches compared with placebo patches applied to healthy adult volunteers.

BACKGROUND: The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability. METHODS: This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation. RESULTS: A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P < 0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P < 0.001). Light touch and pinprick were detectable by most subjects. CONCLUSIONS: The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application.

Long-term tolerability and effectiveness of oxymorphone extended release in patients with cancer.

OBJECTIVE: To evaluate the long-term safety, tolerability, and effectiveness of oxymorphone extended release (ER) in patients with cancer-related pain. DESIGN: Post hoc analysis of two-1-year open-label extension studies. SETTING: Multiple US cancer treatment facilities. PATIENTS: Patients with cancer pain who had participated in two short-term crossover comparator trials of oxymorphone ER: one open-label and one double-blind randomized. INTERVENTIONS: Patients who had been taking oxymorphone ER continued the dose established in the previous study. Patients who had been taking a comparator opioid were switched to an equianalgesic dose of oxymorphone ER. All patients underwent individualized oxymorphone ER dose titration to optimize effectiveness and tolerability. ASSESSMENTS: Current, average, worst, and least pain scores were normalized to a 100-point scale. Patients rated treatment on a five-point global assessment of study medication (Poor = 1 to Excellent = 5). All adverse events (AEs) were recorded. RESULTS: Of the 80 patients who entered the extension trials, 26 completed 52 weeks, 7 discontinued owing to loss of effectiveness, and 20 discontinued owing to AEs, most of which were unrelated to study drug. No significant increase in mean (standard deviation [SDD average pain intensity was observed from baseline (30.5 [19.6], 100-point scale) to final visit (35.9 [21.1], p = 0.37). The most common AEs were concomitant disease progression (28.8 percent, n=23), nausea (22.5 percent, n=18), dyspnea (16.3 percent, n=13), fatigue (16.3 percent, n=13), and edema of the lower limb (15 percent, n=12). CONCLUSIONS: In these patients with pain related to cancer, oxymorphone ER was generally well tolerated and provided stable long-term pain control.

Titration with oxymorphone extended release to achieve effective long-term pain relief and improve tolerability in opioid-naive patients with moderate to severe pain.

OBJECTIVE: Assess the effectiveness and tolerability of a program of gradual dose titration with oxymorphone extended release (ER) for treatment of moderate to severe chronic pain in opioid-naive patients. DESIGN: Open-label, nonrandomized 6-month study with a titration/stabilization period of 50%) reductions of pain interference with quality-of-life measures. There was minimal dose escalation over the 5 months and low use of rescue medication. CONCLUSIONS: Oxymorphone ER provided effective pain relief from moderate to severe chronic pain in opioid-naive patients. Gradual titration was well tolerated, with a low rate of discontinuations caused by AEs.

Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial.

BACKGROUND: Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. OBJECTIVE: This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. METHODS: This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged >or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). RESULTS: Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. CONCLUSION: In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain.

A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain.

OBJECTIVE: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP). DESIGN AND METHODS: Patients > or = 18 years of age were titrated with oxymorphone ER (5- to 10-mg increments every 12 h, every 3-7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12 h for 12 weeks. Oxymorphone immediate release was available every 4-6 h, as needed, for the first 4 days and twice daily thereafter. RESULTS: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4 mm at screening to 22.7 mm (p < 0.0001). After randomization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 +/- 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 +/- 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group. CONCLUSIONS: Stabilized doses of oxymorphone ER were generally safe and effective over a 12-week double-blind treatment period in opioid-naive patients with CLBP.

Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study.

UNLABELLED: Opioid-experienced (N = 250) patients with chronic, moderate to severe low back pain (LBP) were converted from their prestudy opioid(s) to an approximately equianalgesic dose of OPANA ER (oxymorphone extended release). Patients continued slow titration, with 56% stabilized within 1 month to a dose of OPANA ER that reduced average pain to <40 mm on a visual analog scale with good tolerability. Stabilized patients (n = 143) were randomized to placebo or their stabilized dose of OPANA ER every 12 hours for a 12-week double-blind period. Pain intensity increased significantly more for patients randomized to placebo than for patients who continued their stabilized dose of OPANA ER; the increase from baseline (at randomization) to final visit was 31.6 mm for placebo versus 8.7 mm with OPANA ER (P < .0001). During double-blind treatment, placebo patients were approximately 8-fold more likely than OPANA ER patients to discontinue because of lack of efficacy (P < .001). Discontinuations as a result of adverse events were similar between groups, 10% with placebo and 11% with OPANA ER. Opioid-related adverse events included constipation (6%), somnolence (3%), and nausea (3%). Fifty-seven percent of opioid-experienced patients with chronic, moderate to severe LBP achieved a stable dose of OPANA ER that was efficacious and generally well-tolerated for up to 12 weeks. PERSPECTIVE: In a 12-week, double-blind, randomized, placebo-controlled trial in opioid-experienced patients with chronic, moderate to severe LBP, OPANA ER provided efficacious, long-term analgesia and was generally well-tolerated. OPANA ER may provide clinicians with a new treatment option for patients experiencing suboptimal analgesic responses or poor tolerability with other opioids.

Efficacy and safety of oxymorphone immediate release for the treatment of mild to moderate pain after ambulatory orthopedic surgery: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the analgesic efficacy and safety of 5 mg of oxymorphone immediate release (IR) for mild to moderate pain. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Ambulatory surgical centers. PARTICIPANTS: Outpatients (age, > or = 18 y) undergoing knee arthroscopy. INTERVENTION: Randomization to 5 mg of oxymorphone IR or placebo hourly as needed for up to 8 hours. MAIN OUTCOME MEASURE: Sum of pain intensity difference (SPID) from baseline to 8 hours. RESULTS: Among 122 patients randomized, 70.5% and 28.7% had moderate or mild postsurgical pain at baseline, respectively. The mean SPID score was significantly greater in the oxymorphone IR group, showing greater pain relief, compared with the placebo group (least squares mean difference +/- standard error, 76.9+/-28.09; 95% confidence interval, 21.26-132.59; P=.007). More placebo patients (48.4%) required rescue medication than oxymorphone IR patients (16.7%), with median times to use of rescue medication of 6 hours 54 minutes and more than 8 hours, respectively (P<.001). More patients (47.4%) rated oxymorphone IR "very good" or "excellent" for pain relief versus placebo (25.0%). No oxymorphone IR-treated patients discontinued because of adverse events (AEs) or experienced serious AEs. CONCLUSIONS: Five milligrams of oxymorphone IR was well tolerated and effective at relieving mild or moderate postsurgical pain after outpatient knee surgery.

MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance.

While many pre-clinical and clinical studies have suggested that the addition of N-methyl-D-aspartate (NMDA) receptor antagonists, such as dextromethorphan (DM), to opioid analgesics, such as morphine (MS), may enhance the analgesic effects and prevent the tolerance that may result from chronic opioid administration, others have not. The potential for reduced doses, enhanced opioid analgesia, and decreased analgesic tolerance associated with the MS/DM combination were evaluated in a series of three large, randomized, double-blind, parallel group, phase 3, multicenter trials each of 3 months duration in patients with chronic, non-malignant, non-neuropathic pain. To evaluate these unique endpoints, novel study designs were employed. In Study A, patients received fixed doses of MS or MS/DM, based on the stable dose of MS/DM attained during a Run-in period; changes from baseline in average daily pain intensity were compared. In Studies B and C, patients self-titrated doses of MS or MS/DM, based on stable doses of MS or other opioids attained during Run-in periods, to maintain pain relief; percentage changes from baseline in MS (or MS-equivalent) doses were compared. No statistically significant differences between treatment groups in any primary or secondary efficacy variables were demonstrated in any trial. These results suggest that adding the NMDA antagonist, dextromethorphan, to opioids does not add any clinical benefit.

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.

Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain.

This randomized, controlled trial compared the analgesic efficacy and safety of the new oxycodone 10-mg/acetaminophen 325-mg formulation (Percocet) for the treatment of acute pain following oral surgery with double the dose of oxycodone alone (controlled-release [CR] oxycodone 20 mg [OxyContin]). A total of 150 male and female patients with > or = 2 full or partial bone-impacted mandibular molars, at least moderate persistent pain, and moderate trauma received a single dose of combination agent, CR oxycodone, or placebo following oral surgery and rated pain intensity and pain relief over the next 6 hours. The intent-to-treat population comprised 141 patients (55 on combination agent, 56 on oxycodone, and 30 on placebo). Combination agent and CR oxycodone were significantly superior to placebo for all efficacy measures. Combination agent was statistically superior to CR oxycodone in four of five outcome measures of pain intensity and pain relief (PPID, PPAR, SPID, and SPRID). It also provided a faster onset and 24% reduction in the number of patients reporting treatment-related adverse events compared with twice the dose of opioid alone. This new formulation offers the combination of two analgesic drugs with complementary mechanisms of action, which results in enhanced analgesia, an "opioid-sparing" effect, and an improved side effect and safety profile.

The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale.

BACKGROUND: Several controlled clinical trials have demonstrated the efficacy and safety of the lidocaine patch 5% (LP) for the treatment of postherpetic neuralgia (PHN). OBJECTIVE: To assess the effects of the LP on distinct neuropathic pain qualities common to all neuropathic pain conditions, the authors analyzed data from one of the vehicle-controlled trials in which the Neuropathic Pain Scale (NPS), the only assessment tool specifically designed to measure the distinct components of neuropathic pain, was administered. METHODS AND RESULTS: To improve the sensitivity of the NPS to treatment effects, only patients who, at the time of enrollment in the study, reported moderate-to-severe pain on the NPS (as defined by a score > or =4/10 reported for at least 6 of the 10 individual NPS items) were included in the analysis. Thus, 96 patients were included in this analysis. After a 3-week, vehicle-controlled study, LP improved all assessed pain qualities to a greater extent than the placebo patch, as measured by the NPS 10, a sum score including all 10 NPS item scores ( = 0.043), and an NPS 8 score, which included scores for all 8 pain descriptors, excluding "unpleasantness" and "global intensity" ( = 0.042). Separate analysis of all 8 items believed not to reflect allodynia (NPS NA; excluding "skin sensitivity" and "surface pain") also demonstrated superiority ( = 0.022), as did analysis of the subitems that are believed not to be primarily related to peripheral pathophysiological events (the "NPS 4": "sharp," "hot," "dull," and "deep" pains; = 0.013). CONCLUSIONS: This study demonstrates that LP reduces the intensity of all common neuropathic pain qualities and thus may be of potential benefit for nonallodynic neuropathic pain states. Furthermore, these findings suggest that peripheral mechanisms may play a role in the pathophysiological development of pain qualities that heretofore have been assumed not to involve peripheral mechanisms, such as "dull," "deep," "sharp," and "burning" pains.