Amy S. Chappell

Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial

&NA; The primary objectives of this study were to assess the efficacy and safety of duloxetine for reducing pain severity in fibromyalgia patients with or without current major depressive disorder. This was a 6‐month, multicenter, randomized, double‐blind, placebo‐controlled study. In total, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20‐mg/day group titrated to 60 mg/day). The co‐primary outcome measures were the Brief Pain Inventory (BPI) average pain severity score and Patient Global Impressions of Improvement (PGI‐I) score. Safety was assessed via treatment‐emergent adverse events, and changes in vital sign, laboratory, and ECG measures. Compared with placebo‐treated patients, those patients treated with duloxetine 120 mg/day improved significantly more on the co‐primary outcome measures at 3 months (change in BPI score [−2.31 vs −1.39, P < 0.001] and PGI‐I [2.89 vs 3.39, P = 0.004]) and at 6 months (change in BPI [−2.26 vs −1.43, P = 0.003] and PGI‐I [2.93 vs 3.37, P = 0.012]). Compared with placebo, treatment with duloxetine 60 mg/day also significantly improved the co‐primary measures at 3 months and BPI at 6 months. Duloxetine was efficacious in patients both with and without major depressive disorder. There were no clinically significant differences between treatment groups in changes in vital signs, laboratory measures, or ECG measures. Study results demonstrated that duloxetine at doses of 60 mg/day and 120 mg/day appears to be safe and efficacious in patients with fibromyalgia.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

&NA; There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial.

ABSTRACT Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. Herein, we report the results of a 13‐week, randomized, double‐blind, placebo‐controlled trial of duloxetine (60–120 mg/day) versus placebo in the treatment of knee pain in 231 patients meeting clinical and radiographic criteria for osteoarthritis of the knee. Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24‐h pain scores) beginning at Week 1 and continuing through the treatment period (P ⩽ .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse‐event rates did not differ significantly between treatment groups (49.5% for duloxetine 60–120 mg/day, and 40.8% for placebo).

A Double‐blind, Randomized, Placebo‐controlled Study of the Efficacy and Safety of Duloxetine for the Treatment of Chronic Pain Due to Osteoarthritis of the Knee

Objective:  To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee.

Efficacy and safety of duloxetine in patients with chronic low back pain.

Study Design. This was a randomized, double-blind, placebo-controlled clinical trial. Objective. To assess the efficacy and safety of duloxetine in the treatment of chronic low back pain (CLBP). Summary of Background Data. Imbalance of serotonin and norepinephrine within modulatory pain pathways has been implicated in the development and maintenance of chronic pain. Duloxetine, a selective reuptake inhibitor of serotonin and norepinephrine, has demonstrated clinical efficacy in 3 distinct chronic pain conditions: diabetic peripheral neuropathic pain, fibromyalgia, and chronic pain because of osteoarthritis. Methods. In this randomized double-blind trial, adult nondepressed patients with a non-neuropathic CLBP and a weekly mean of the 24-hour average pain score ≥4 at baseline (0–10 scale) were treated with either duloxetine or placebo for 13 weeks. The dose of duloxetine during first 7 weeks was 60 mg once daily. At week 7, patients reporting <30% pain reduction had their dose increased to 120 mg. The primary outcome measure was the Brief Pain Inventory (BPI) 24-hour average pain rating. Secondary measures included Roland-Morris Disability Questionnaire-24; Patients Global Impressions of Improvement; Clinical Global Impressions-Severity (CGI-S); BPI-Severity and -Interference (BPI-I); and weekly means of the 24-hour average pain, night pain, and worst pain scores from patient diaries. Quality-of-life, safety, and tolerability outcomes were also assessed. Results. Compared with placebo-treated patients (least-squares mean change of −1.50), patients on duloxetine (least-squares mean change of −2.32) had a significantly greater reduction in the BPI 24-hour average pain from baseline to endpoint (P = 0.004 at week 13). Additionally, the duloxetine group significantly improved on Patients Global Impressions of Improvement; Roland-Morris Disability Questionnaire-24; BPI-Severity and average BPI-Interference; weekly mean of the 24-hour average pain, night pain, and worst pain. Significantly more patients in the duloxetine group (13.9%) compared with placebo (5.8%) discontinued because of adverse events (P = 0.047). The most common treatment-emergent adverse events in the duloxetine group included nausea, dry mouth, fatigue, diarrhea, hyperhidrosis, dizziness, and constipation. Conclusion. Duloxetine significantly reduced pain and improved functioning in patients with CLBP. The safety and tolerability were similar to those reported in earlier studies.

A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia

Objective: Assess the efficacy of duloxetine 60/120 mg (N = 162) once daily compared with placebo (N = 168) in the treatment of patients with fibromyalgia, during six months of treatment. Methods: This was a phase-III, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of duloxetine. Results: There were no significant differences between treatment groups on the co-primary efficacy outcome measures, change in the Brief Pain Inventory (BPI) average pain severity from baseline to endpoint (P = 0.053) and the Patient’s Global Impressions of Improvement (PGI-I) at endpoint (P = 0.073). Duloxetine-treated patients improved significantly more than placebo-treated patients on the Fibromyalgia Impact Questionnaire pain score, BPI least pain score and average interference score, Clinical Global Impressions of Severity scale, area under the curve of pain relief, Multidimensional Fatigue Inventory mental fatigue dimension, Beck Depression Inventory-II total score, and 36-item Short Form Health Survey mental component summary and mental health score. Nausea was the most common treatment-emergent adverse event in the duloxetine group. Overall discontinuation rates were similar between groups. Conclusions: Although duloxetine 60/120 mg/day failed to demonstrate significant improvement over placebo on the co-primary outcome measures, in this supportive study, duloxetine demonstrated significant improvement compared with placebo on numerous secondary measures.

A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis.

Abstract Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.

Efficacy of duloxetine in patients with fibromyalgia: Pooled analysis of 4 placebo-controlled clinical trials

OBJECTIVE To investigate the efficacy of duloxetine in the treatment of pain and improvement in functional impairment and quality of life in patients with fibromyalgia from a pooled analysis of 4 placebo-controlled, double-blind, randomized trials. METHOD Patients were eligible for inclusion in the studies if they were at least 18 years of age, met criteria for fibromyalgia as defined by the American College of Rheumatology, and had specified minimum pain severity scores. Across all studies, 797 patients received duloxetine 60-120 mg/d and 535 patients received placebo. Pain was assessed by the Brief Pain Inventory (BPI) 24-hour average pain severity score; other efficacy measures included the Clinical Global Impressions-Severity of Illness scale (CGI-S), Patient Global Impressions-Improvement scale (PGI-I), 17-item Hamilton Depression Rating Scale (HDRS-17), Fibromyalgia Impact Questionnaire (FIQ) total score, BPI pain interference items, Sheehan Disability Scale (SDS), and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) mental and physical components. Changes from baseline to endpoint (last observation carried forward) for most of the above efficacy measures were analyzed using an analysis-of-covariance model. RESULTS After 12 weeks of treatment, pain was significantly reduced in patients treated with duloxetine (P < .001) compared with placebo. In addition, duloxetine was superior to placebo in improving CGI-S (P < .001); PGI-I (P < .001); FIQ total (P < .001); HDRS-17 total (P = .003); SDS global functioning (P < .001), work/school (P = .018), and family life (P < .001); SF-36 mental (P < .001) and physical (P = .026) component; and BPI pain interference (P < .001) scores. Treatment-by-subgroup interactions were not significant for sex (P = .320), age (P = .362), or race (P = .180). CONCLUSIONS This pooled analysis provides evidence that 12 weeks of treatment with duloxetine 60-120 mg/d effectively improves fibromyalgia symptoms and may offer benefits beyond pain relief.

A 1-year Safety and Efficacy Study of Duloxetine in Patients With Fibromyalgia

ObjectivesEvaluate the efficacy and safety of duloxetine at doses up to 120 mg once daily in patients with fibromyalgia. MethodsThis was a phase 3, 60-week study, which included an 8-week open-label period followed by a 52-week, randomized, double-blind period. Patients received duloxetine 30 mg daily for 1 week and duloxetine 60 mg daily for 7 weeks and were then randomized to receive either 60 or 120 mg daily (1:2 ratio). ResultsEnrolled patients (N=350, 95.7% female) exhibited moderate disease symptoms at study entry (Brief Pain Inventory average pain=6.7, Clinical Global Impression of Severity=4.1, and Patients Global Impression of Severity=4.1). Significant pain reduction in patients was observed during the open-label study phase. This pain reduction continued during the 52-week double-blind study phase, as demonstrated by additional mean decreases in the Brief Pain Inventory average pain score within both duloxetine groups. The most common (≥15%) treatment-emergent adverse events (overall phase) were nausea, headache, insomnia, dizziness, constipation, and dry mouth. Seventy-four (21.1%) patients reported adverse events as a reason for discontinuation [most common (>1%) were insomnia, vomiting, diarrhea, dizziness, and nausea]. The mean change (SD) in sitting systolic blood pressure (mm Hg) was −0.1 (14.4), in sitting diastolic blood pressure was −0.2 (9.6), in sitting pulse rate was 1.9 (10.4) bpm, and in weight was 0.7 (4.3) kg. DiscussionThe profile of duloxetine for the long-term treatment of fibromyalgia was consistent with that seen in other indications for which the drug is currently marketed.

Long-Term Safety, Tolerability, and Efficacy of Duloxetine in the Treatment of Fibromyalgia

OBJECTIVES To assess the long-term safety, tolerability, and efficacy of duloxetine in patients with fibromyalgia. METHODS We report results from the 6-month extension phases of 2 randomized, double-blind, placebo-controlled clinical trials having 6-month placebo-controlled phases. In Study 1, all patients received duloxetine 120 mg/d after 28 weeks on placebo or duloxetine 60 or 120 mg/d. In Study 2, patients taking placebo were titrated to duloxetine 60 mg/d after 27 weeks on treatment, while duloxetine-treated patients remained on their dosages of 60 or 120 mg/d. Safety and tolerability were assessed via discontinuation rates, treatment-emergent adverse events (TEAEs), and changes in vital signs and laboratory measures. The primary efficacy measure was the Brief Pain Inventory average pain severity score. RESULTS The percentage of patients entering and completing the extension phase was 56% (156/278) for Study 1 and 69% (140/204) for Study 2. Groups titrating from placebo to duloxetine showed the highest discontinuation rates due to an adverse event (Study 1, 25%; Study 2, 19%) and TEAE rates (Study 1, 82%; Study 2, 77%). The most common TEAEs were nausea and dry mouth. No significant within-group changes in blood pressure occurred in any group. Significant within-group mean increases in pulse (bpm) were observed in the placebo/duloxetine 120 mg group in Study 1 (3.7 [SD = 11.2], P <or= 0.01) and the placebo/duloxetine 60 mg group in Study 2 (4.8 [SD = 10.2], P <or= 0.001). Most treatment groups showed small mean change improvements in the Brief Pain Inventory average pain severity score. CONCLUSIONS These findings support a positive risk/benefit profile for duloxetine in the long-term treatment of fibromyalgia.