OBJECTIVES:To evaluate the efficacy and safety of duloxetine 30 mg/d in adults with fibromyalgia.
METHODS:This 12-week, randomized, double-blind, placebo-controlled study was conducted in the United ...States, Mexico, Argentina, and Israel and enrolled patients meeting the criteria for primary fibromyalgia as defined by the American College of Rheumatology. The primary endpoint was the average pain severity item from the Brief Pain Inventory (BPI)-Modified Short Form, assessed by an analysis of covariance model using change from baseline to the modified baseline-observation-carried-forward endpoint. Secondary endpoints included the Patient Global Impression of Improvement (PGI-I) score and the Fibromyalgia Impact Questionnaire (FIQ) total score and those measuring pain, depression, anxiety, health outcomes, and safety.
RESULTS:Patients (mean age, 51 y; 95% female; 87% White; 22% with major depressive disorder) received duloxetine 30 mg/d (N=155) or placebo (N=153). Duloxetine-treated patients did not have a statistically significant BPI-Modified Short Form average pain severity reduction versus placebo-treated patients (−2.04 vs. −1.70; P=0.202). There was a significant difference between duloxetine-treated and placebo-treated patients (P<0.05) for the PGI-I endpoint score (2.97 vs. 3.35) and the changes in FIQ total score (−14.62 vs. −9.75) and the Short-Form Health Survey (SF)-36 mental component score. Discontinuations due to adverse events did not differ significantly between treatment groups; nausea and dry mouth were the only adverse events with a significantly higher incidence with duloxetine versus placebo.
DISCUSSION:Duloxetine 30 mg/d did not significantly reduce pain severity in patients with fibromyalgia. However, duloxetine-treated patients reported global improvement in symptoms and function. Safety findings were consistent with the known duloxetine safety profile.
Sleep disturbance is a common experience in fibromyalgia (FM). The field lacks a sleep specific patient reported outcome (PRO) measure developed and validated in a FM population. The study objective ...is to gain an in-depth understanding of sleep in FM and to develop a PRO measure of it.
Research involved the following stages: 1) A literature review conducted to identify key concepts associated with FM patient experience of sleep and PRO measures that have been used to assess this; 2) Qualitative interviews with therapeutic area experts; 3) Focus groups with FM patients who experienced sleep disturbance; 4) Development of a conceptual framework and the Fibromyalgia Sleep Diary (FMSD); and 5) Cognitive interviews with patients to explore content validity of the FMSD.
The literature review and expert interviews supported sleep disturbance being an important aspect of the FM patient experience, and underscored the need for a new FM specific sleep PRO measure. Results from the focus groups demonstrated that FM patients experience sleep disturbances that they attribute to their FM symptoms, such as pain and stiffness, confirming the importance of understanding more about sleep changes. Aspects of sleep raised by FM patients included poor sleep quality and insufficient quantity including difficulty with falling asleep, getting comfortable, and staying asleep; restlessness; light sleep; not feeling rested upon awakening; and difficulty starting the day. Cognitive interview results showed that the 8-item FMSD, developed to reflect the concepts identified above, was relevant to FM patients with content that was interpreted as intended.
The FMSD was developed in line with the recommendations of the FDA PRO guidance and ISPOR PRO Task Force. The qualitative evidence generated thus far strongly supports the content validity of the FMSD as a PRO measure of sleep disturbance in FM populations. Psychometric evaluation of the FMSD to demonstrate reliability, validity and sensitivity to change is recommended as a next step.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE: Binge eating disorder is associated with obesity. Topiramate is an antiepileptic agent associated with weight loss. The objective of this study was to evaluate topiramate in the treatment ...of binge eating disorder associated with obesity. METHOD: For this 14-week, double-blind, flexible-dose (25-600 mg day) topiramate trial, 61 outpatients (53 women, eight men) with binge eating disorder who were obese (body mass index ≥30 kg m2) were randomly assigned to receive topiramate (N=30) or placebo (N=31). The primary efficacy measure was binge frequency. The primary analysis of efficacy was a repeated-measures random regression with treatment-by-time as the effect measure. RESULTS: Compared with placebo, topiramate was associated with a significantly greater rate of reduction in binge frequency, binge day frequency, body mass index, weight, and scores on the Clinical Global Impression severity scale and the Yale-Brown Obsessive Compulsive Scale (modified for binge eating). Topiramate was also associated with significantly greater reductions in binge frequency (topiramate: 94%, placebo: 46%) and binge day frequency (topiramate: 93%, placebo: 46%) and with a significantly higher level of response than placebo. The mean weight loss for topiramate-treated subjects who completed the study was 5.9 kg. Median topiramate dose was 212 mg day (range=50-600). Nine patients (three receiving placebo, six given topiramate) discontinued because of adverse events. The most common reasons for discontinuing topiramate were headache (N=3) and paresthesias (N=2). CONCLUSIONS: Topiramate was efficacious and relatively well tolerated in the short-term treatment of binge eating disorder associated with obesity.
Fibromyalgia syndrome Mease, Philip J; Clauw, Daniel J; Arnold, Lesley M ...
Journal of rheumatology,
11/2005, Letnik:
32, Številka:
11
Journal Article
Recenzirano
The objectives of the first OMERACT Fibromyalgia Syndrome (FM) Workshop were to identify and prioritize symptom domains that should be consistently evaluated in FM clinical trials, and to identify ...aspects of domains and outcome measures that should be part of a concerted research agenda of FM researchers. Such an effort will help standardize and improve the quality of outcomes research in FM. A principal assumption in this workshop has been that there exists a clinical syndrome, generally known as FM, characterized by chronic widespread pain typically associated with fatigue, sleep disturbance, mood disturbance, and other symptoms and signs, and considered to be related to central neuromodulatory dysregulation. FM can be diagnosed using 1990 American College of Rheumatology criteria. In preparation for the workshop a Delphi exercise involving 23 FM researchers was conducted to establish a preliminary prioritization of domains of inquiry. At the OMERACT meeting, the workshop included presentation of the Delphi results; a review of placebo-controlled trials of FM treatment, with a focus on the outcome measures used and their performance; a panel discussion of the key issues in FM trials, from both an investigator and regulatory agency perspective; and a voting process by the workshop attendees. The results of the workshop were presented in the plenary session on the final day of the meeting. A prioritized list of domains of FM to be investigated was thus developed, key issues and controversies in the field were debated, and consensus on a research agenda on outcome measure development was reached.
Increasing research interest and emerging new therapies for treatment of fibromyalgia (FM) have led to a need to develop a consensus on a core set of outcome measures that should be assessed and ...reported in all clinical trials, to facilitate interpretation of the data and understanding of the disease. This aligns with the key objective of the Outcome Measures in Rheumatology (OMERACT) initiative to improve outcome measurement through a data driven, interactive consensus process.
Through patient focus groups and Delphi processes, working groups at previous OMERACT meetings identified potential domains to be included in the core data set. A systematic review has shown that instruments measuring these domains are available and are at least moderately sensitive to change. Most instruments have been validated in multiple languages. This pooled analysis study aims to develop the core data set by analyzing data from 10 randomized controlled trials (RCT) in FM.
Results from this study provide support for the inclusion of the following in the core data set: pain, tenderness, fatigue, sleep, patient global assessment, and multidimensional function/health related quality of life. Construct validity was demonstrated with outcome instruments showing convergent and divergent validity. Content and criterion validity were confirmed by multivariate analysis showing R square values between 0.4 and 0.6. Low R square value is associated with studies in which one or more domains were not assessed.
The core data set was supported by high consensus among attendees at OMERACT 9. Establishing an international standard for RCT in FM should facilitate future metaanalyses and indirect comparisons.
OBJECTIVES:To evaluate the effects of long-term milnacipran treatment in fibromyalgia patients.
METHODS:Patients completing a previous milnacipran study were eligible to participate in this long-term ...(up to 3.25 y), open-label study. After washout, dose escalation, and 8 weeks of stable-dose treatment (100 mg/d), patients received flexible doses of milnacipran (50 to 200 mg/d) for the remainder of the study. Safety evaluations included adverse events and vital signs. Clinical measures included weekly recall pain (visual analog scale VAS), Patient Global Disease Status (PGDS), and the Short Form-36 Health Survey (SF-36, including the Physical Component Summary PCS and Mental Component Summary scores). Cohort analyses were conducted to assess the effects of milnacipran over varying periods of time.
RESULTS:Of 1227 patients entering the study, 585 (47.7%) were classified as completers, including 379 (30.9%) patients who were currently enrolled when the study was administratively terminated. Mean duration of treatment was 19 months, with 206 patients reaching the final visit and receiving 36 to 38 months of study treatment. The percentage of patients with ≥1 treatment-emergent adverse event was 88.3%, with nausea (25.9%) and headache (13.4%) being the most common events. Discontinuations due to adverse events occurred in 20.9% of patients. Potentially clinically significant increases in blood pressure or heart rate occurred in ≤1.1% of patients. Mean improvement from baseline in weekly recall VAS pain was 17.6; improvements in global status (PGDS) and physical functioning (SF-36 PCS) were also observed. In all patient cohorts, these improvements were observed by month 3 and remained relatively constant over time. At final study visit in the 3-year cohort, 70.3% of patients rated their overall fibromyalgia as “much improved” or “very much improved.”
DISCUSSION:No new safety concerns were identified in this long-term study. Sustained symptom improvements were found in fibromyalgia patients who received up to 3.25 years of milnacipran treatment.
Objective
To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia.
Design
A post hoc analysis of four 8‐ to ...14‐week phase 2–3, placebo‐controlled trials of fixed‐dose pregabalin (150–600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms.
Patients
A total of 2,747 patients with fibromyalgia, aged 18–82 years.
Methods
Pain and sleep quality scores, recorded daily on 11‐point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1‐point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported “much improved” or “very much improved” on the Patient Global Impression of Change (PGIC) at endpoint.
Results
Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo.
Conclusions
Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo.
Fatigue is one of the most disabling symptoms associated with fibromyalgia that greatly impacts quality of life. Fatigue was assessed as a secondary objective in a 2-phase, 24-week study in ...outpatients with American College of Rheumatology-defined fibromyalgia.
Patients were randomized to duloxetine 60-120 mg/d (N = 263) or placebo (N = 267) for the 12-week acute phase. At Week 12, all placebo-treated patients were switched to double-blind treatment with duloxetine for the extension phase. Fatigue was assessed at baseline and every 4 weeks with the Multidimensional Fatigue Inventory (MFI) scales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Activity, and Reduced Motivation. Other assessments that may be associated with fatigue included Brief Pain Inventory (BPI) average pain, numerical scales to rate anxiety, depressed mood, bothered by sleep difficulties, and musculoskeletal stiffness. Treatment-emergent fatigue-related events were also assessed. Changes from baseline to Week 12, and from Week 12 to Week 24, were analyzed by mixed-effects model repeated measures analysis.
At Week 12, duloxetine versus placebo significantly (all p < .05) reduced ratings on each MFI scale, BPI pain, anxiety, depressed mood, and stiffness. Improvement in ratings of being bothered by sleep difficulties was significant only at Weeks 4 and 8. At Week 24, mean changes in all measures indicated improvement was maintained for patients who received duloxetine for all 24 weeks (n = 176). Placebo-treated patients switched to duloxetine (n = 187) had significant within-group improvement in Physical Fatigue (Weeks 16, 20, and 24); General Fatigue (Weeks 20 and 24); Mental Fatigue (Week 20); and Reduced Activity (Weeks 20 and 24). These patients also experienced significant within-group improvement in BPI pain, anxiety, depressed mood, bothered by sleep difficulties, and stiffness. Overall, the most common (> 5% incidence) fatigue-related treatment-emergent adverse events were fatigue, somnolence, and insomnia.
Treatment with duloxetine significantly improved multiple dimensions of fatigue in patients with fibromyalgia, and improvement was maintained for up to 24 weeks.
ClinicalTrials.gov registry NCT00673452.
Abstract Background: Esreboxetine is an investigational, highly selective norepinephrine reuptake inhibitor that has been reported to have antinociceptive effects in preclinical pain models. ...Objective: This study assessed the efficacy and safety profile of esreboxetine in the management of fibromyalgia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial in patients aged ≥18 years who met American College of Rheumatology criteria for fibromyalgia. Eligible patients were required to have a score ≥40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization, and a mean score ≥4 on an 11-point pain rating scale (from 0 = no pain to 10 = worst possible pain) based on the weekly mean pain score in the week before randomization. After a 1-week baseline period and a 2-week, single-blind, placebo run-in period, patients were randomized to receive esreboxetine or placebo for 8 weeks, followed by a 1-week follow-up period. Esreboxetine dosing was started at 2 mg/d and was escalated by 2 mg/d every 2 weeks until attainment of a dose of 8 mg/d or the maximum tolerated dose. The primary efficacy outcome was the change from baseline to week 8 in weekly mean pain scores, as derived from patients' daily pain ratings on the 11-point scale. Additional primary efficacy outcomes included changes in the Fibromyalgia Impact Questionnaire (FIQ) total score and the Patient Global Impression of Change (PGIC). The safety profile was evaluated based on observed and spontaneously reported adverse events, laboratory tests, and other safety measures. Results: One hundred thirty-four patients were randomized to each study group, but 1 patient in the placebo group did not receive treatment. Thus, the study population consisted of 267 patients (89.5% female; 88.4% white; mean age, ∼50 years range, 20–84 years). Twenty-seven patients in each group discontinued the study. Adverse events were the most common reason for discontinuation in the esreboxetine group (11 patients), compared with 3 discontinuing due to adverse events in the placebo group. Patient default (withdrawal of consent and loss to follow-up) was the most common reason for discontinuation in the placebo group (13 patients), compared with 10 in the esreboxetine group. The esreboxetine group had significantly greater improvement in the weekly mean pain score compared with the placebo group (mean SE change from baseline: −1.55 0.16 vs −0.99 0.16, respectively; P = 0.006). A significantly greater percentage of patients in the esreboxetine group reported a ≥30% reduction in pain scores compared with the placebo group (37.6% 50/133 vs 22.6% 30/133; P = 0.004). Esreboxetine was associated with significant improvement compared with placebo in the FIQ total score (mean change from baseline: −15.63 1.56 vs −8.07 1.54; P < 0.001). On the PGIC, significantly more patients in the esreboxetine group than in the placebo group reported their condition much or very much improved (odds ratio = 2.42; 90% CI, 1.549-3.786; P < 0.001). Esreboxetine also was associated with significant improvements in secondary outcomes compared with placebo. These included fatigue, as reflected in scores on the Multidimensional Assessment of Fatigue (mean SE change from baseline: −6.39 0.75 vs −2.82 0.75, respectively; P < 0.001), and scores on measures of patient function and health-related quality of life, including the 36-item Short Form Health Survey (SF-36) Physical Component Summary (mean change from baseline: 4.36 0.59 vs 1.86 0.59; P = 0.002), the SF-36 Mental Component Summary (mean change from baseline: 4.25 0.83 vs 1.81 0.83; P = 0.019), and the Sheehan Disability Scale total score (mean change from baseline: −6.50 0.64 vs −2.79 0.61; P < 0.001). Numerically more patients in the esreboxetine group than in the placebo group reported at least one adverse event (71.6% vs 57.1%), most commonly constipation (17.2% vs 5.3%), insomnia (15.7% vs 3.0%), dry mouth (15.7% vs 2.3%), and headache (10.4% vs 2.3%). Conclusions: In this 8-week trial in patients with fibromyalgia, esreboxetine was associated with significant reductions in pain scores compared with placebo. It was also associated with improvements in outcomes relevant to fibromyalgia, including the PGIC, function, and fatigue. ClinicalTrials.gov identifier: NCT00357825.
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