Effect of subcutaneous methylnaltrexone on patient-reported constipation symptoms.

BACKGROUND: Methylnaltrexone, a selective peripheral acting mu-opioid receptor antagonist, alleviates the constipating effects of opioids without affecting centrally mediated analgesia. OBJECTIVES: To assess the effect of subcutaneous (SC) methylnaltrexone injection on patient-reported constipation symptoms and pain scores. METHODS: A total of 469 subjects on opioids for chronic non-malignant pain with opioid-induced constipation were randomized to methylnaltrexone SC with once daily (QD) or every other day (QOD) dosing or placebo for 4 weeks. Constipation symptoms and pain were assessed using the patient assessment of constipation-symptoms (PAC-SYM) questionnaire and a 11-point scale, respectively, at baseline, Day 14 and Day 28. Change from baseline in PAC-SYM and pain scores were compared between methylnaltrexone and placebo arms at Day 28 using analysis of covariance, with treatment group as factor and baseline score as covariate. RESULTS: A majority of patients were women (60%), average age was 49 years old, and back pain (60%) was the primary pain condition. At Day 28, the methylnaltrexone SC QD group showed a significant improvement over placebo for rectal symptoms (-0.56 vs. -0.30; P < 0.05), stool symptoms (-0.76 vs. -0.43; P < 0.001) and global scores (-0.62 vs. -0.37; P < 0.001). Improvement in stool symptoms (-0.69 vs.-0.43; P < 0.05) and the global scores (-0.52 vs. -0.37; P < 0.05) were significantly greater than placebo in the methylnaltrexone QOD group. Differences in change from baseline in abdominal symptoms and pain scores between the methylnaltrexone SC QD or QOD dosing arms and placebo were not significant. CONCLUSION: The results of our study indicate significant improvement in constipation symptoms with methylnaltrexone QD or QOD dosing compared to placebo without a significant effect on pain scores.

Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder.

OBJECTIVE: To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD). RESEARCH DESIGN AND METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. The primary efficacy measure was the HAM-D(17). Changes from baseline in HAM-D(17) scores were analyzed using analysis of covariance. The final on-therapy evaluation was the primary endpoint for efficacy analyses, using last-observation-carried-forward data. MAIN OUTCOMES MEASURES AND RESULTS: The intent-to-treat population included 447 patients. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018); the 100-mg dose group (-11.0) did not achieve statistical significance (p=0.065). The 100-mg dose group experienced significant improvements compared with placebo on several secondary efficacy measures, including the 6-item Hamilton Depression Rating Scale (p=0.038) and the Visual Analog Scale-Pain Intensity total score (p=0.041). Both desvenlafaxine doses were generally well-tolerated. The most common adverse events (incidence > or =10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness. CONCLUSIONS: These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. The significant findings on secondary measures support the efficacy of desvenlafaxine 100 mg, as seen in other trials. Conclusions may be limited by the exclusion of MDD patients with comorbid conditions and the short-term desvenlafaxine treatment duration.

A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder.

OBJECTIVE: This study evaluated the efficacy and safety of desvenlafaxine succinate extended-release in major depressive disorder (MDD). METHOD: Adult outpatients with DSM-IV-defined MDD were randomly assigned to desvenlafaxine 100 mg/day (N = 114), 200 mg/day (N = 116), or 400 mg/day (N = 113) or placebo (N = 118) for 8 weeks. Efficacy variables included change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D(17), the primary efficacy measure), Clinical Global Impressions-Improvement scale (CGI-I), Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness scale (CGI-S), rates of response (> or = 50% decrease from baseline HAM-D(17) score) and remission (HAM-D(17) score < or =7), and Visual Analog Scale-Pain Intensity overall score. The study was conducted from November 2003 to November 2004. RESULTS: At the final on-therapy evaluation, the mean HAM-D(17) scores for desvenlafaxine 100 mg/day (12.75) and 400 mg/day (12.50) were significantly lower than for placebo (15.31; p = .0038 and p = .0023, respectively); for desvenlafaxine 200 mg/day, the mean score was 13.31 (p = .0764). CGI-I and Montgomery-Asberg Depression Rating Scale results were significant for all groups; CGI-S results were significant with 100 mg/day and 400 mg/day. Response rates were significantly greater for desven-lafaxine 100 mg/day (51%) and 400 mg/day (48%) versus placebo (35%; p = .017 and p = .046, respectively); the response rate for desvenlafaxine 200 mg/day was 45% (p = .142). Remission rates were significantly greater for desvenlafaxine 400 mg/day (32%) versus placebo (19%; p = .035); remission rates were 30% for desvenlafaxine 100 mg/day (p = .093) and 28% for desvenlafaxine 200 mg/day (p = .126). Visual Analog Scale-Pain Intensity results were significant for desvenlafaxine 100 mg/day versus placebo (p = .002), but not for the higher doses. The most commonly reported adverse events were nausea, insomnia, somnolence, dry mouth, dizziness, sweating, nervousness, anorexia, constipation, asthenia, and abnormal ejaculation/orgasm. CONCLUSIONS: Desvenlafaxine is effective and well tolerated in the short-term treatment of MDD.