Michael Spaeth

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.

Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome

Researchers studying fibromyalgia strive to identify objective, measurable biomarkers that may identify susceptible individuals, may facilitate diagnosis, or that parallel activity of the disease. Candidate objective measures range from sophisticated functional neuroimaging to office-ready measures of the pressure pain threshold. A systematic literature review was completed to assess highly investigated, objective measures used in fibromyalgia studies. To date, only experimental pain testing has been shown to coincide with improvements in clinical status in a longitudinal study. Concerted efforts to systematically evaluate additional objective measures in research trials will be vital for ongoing progress in outcome research and translation into clinical practice.

Epidemiology, costs, and the economic burden of fibromyalgia

The assumption that fibromyalgia is associated with a major impact on the utilization of both healthcare and nonhealthcare resources has not been thoroughly supported by evidence-based data. Despite the differences between healthcare and sociopolitical systems in various countries, more recent results from epidemiological research now clearly demonstrate the socioeconomic burden of fibromyalgia and its comorbidities. The costs of the disease, calculated in single studies and countries, allow estimates for populations in other countries. The alarming results highlight the urgent need both for more research (including pathophysiology and epidemiology) and for the acceptance of emerging treatment challenges.

Neuropathic pain phenotyping as a predictor of treatment response in painful diabetic neuropathy: data from the randomized, double-blind, COMBO-DN study.

&NA; Duloxetine and pregabalin have different effects on neuropathic pain components. This might explain differential responses to these drugs when given either alone or in combination. &NA; Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO‐DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8‐week therapy with either duloxetine or pregabalin, and after subsequent 8‐week combination/high‐dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/d duloxetine, adding 300 mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120 mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/d duloxetine to 300 mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high‐dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high‐dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.

Estimation of minimum clinically important difference for pain in fibromyalgia

To estimate the minimum clinically important difference (MCID) for several pain measures obtained from the Brief Pain Inventory (BPI) for patients with fibromyalgia.

Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial

Background Fibromyalgia is characterised by chronic musculoskeletal pain and multiple symptoms including fatigue, multidimensional function impairment, sleep disturbance and tenderness. Along with pain and fatigue, non-restorative sleep is a core symptom of fibromyalgia. Sodium oxybate (SXB) is thought to reduce non-restorative sleep abnormalities. This study evaluated effects of SXB on fibromyalgia-related pain and other symptoms. Methods 573 patients with fibromyalgia according to 1990 American College of Rheumatology criteria were enrolled at 108 centres in eight countries. Subjects were randomly assigned to placebo, SXB 4.5 g/night or SXB 6 g/night. The primary efficacy endpoint was the proportion of subjects with ≥30% reduction in pain visual analogue scale from baseline to treatment end. Other efficacy assessments included function, sleep quality, effect of sleep on function, fatigue, tenderness, health-related quality of life and subjects impression of change in overall wellbeing. Results Significant improvements in pain, sleep and other symptoms associated with fibromyalgia were seen in SXB treated subjects compared with placebo. The proportion of subjects with ≥30% pain reduction was 42.0% for SXB4.5 g/night (p=0.002) and 51.4% for SXB6 g/night (p<0.001) versus 26.8% for placebo. Quality of sleep (Jenkins sleep scale) improved by 20% for SXB4.5 g/night (p≤0.001) and 25% for SXB6 g/night (p≤0.001) versus 0.5% for placebo. Adverse events with an incidence ≥5% and twice placebo were nausea, dizziness, vomiting, insomnia, anxiety, somnolence, fatigue, muscle spasms and peripheral oedema. Conclusion These results, combined with findings from previous phase 2 and 3 studies, provide supportive evidence that SXB therapy affordsimportant benefits across multiple symptoms in subjects with fibromyalgia.

Evaluation of Patient-Rated Stiffness Associated With Fibromyalgia: A Post-Hoc Analysis of 4 Pooled, Randomized Clinical Trials of Duloxetine

BACKGROUND Patients with fibromyalgia (FM) rate stiffness as one of the most troublesome symptoms of the disorder. However, there are few published studies that have focused on better understanding the nature of stiffness in FM. OBJECTIVES The primary objectives of these analyses were to characterize the distribution of stiffness severity in patients at baseline, evaluate changes in stiffness after 12 weeks of treatment with duloxetine, and determine which outcomes were correlated with stiffness. METHODS These were post-hoc analyses of 3-month data from 4 randomized, double-blind, placebo-controlled studies that assessed efficacy of duloxetine in adults with FM. Severity of stiffness was assessed by using the Fibromyalgia Impact Questionnaire (FIQ) on a scale from 0 (no stiffness) to 10 (most severe stiffness). The association between changes in stiffness and other measures was evaluated by using Pearsons correlation coefficient. The FIQ total score and items, the Brief Pain Inventory (BPI-modified short form), the Clinical Global Impression-Severity scale, the Multidimensional Fatigue Inventory, the 17-item Hamilton Depression Rating Scale, the Sheehan Disability Scale, the 36-item Short-Form Health Survey, and the EuroQoL Questionnaire-5 Dimensions were evaluated in the correlation analyses. Stepwise linear regression was used to identify the variables that were most highly predictive of the changes in FIQ stiffness. RESULTS The analysis included 1332 patients (mean age, 50.2 years; 94.7% female; and 87.8% white). The mean (SD) baseline FIQ stiffness score was 7.7 (2.0), and this score correlated with baseline BPI pain score and FIQ function. Duloxetine significantly improved the FIQ stiffness score compared with placebo (P < 0.001) and provided a moderate effect size (0.23 for the 60-mg dose and 0.38 for the 120-mg dose). Changes in stiffness were best correlated (range, 0.52-0.75; all, P < 0.001) with changes in BPI/FIQ pain and interference scores, FIQ nonrefreshing sleep, FIQ anxiety, 36-item Short-Form Health Survey bodily pain, and Sheehan Disability Scale total score. Variables related to severity of pain, pain interfering with daily activities, and physical functioning were predictors of change in stiffness. CONCLUSIONS Stiffness scores were high in this population with FM and best correlated at baseline with BPI pain score and FIQ function. Not unexpectedly, improvement in stiffness with duloxetine correlated with many of the other markers of FM severity, presumably a result of amelioration in FM comorbidities.

Long-term tolerability and maintenance of therapeutic response to sodium oxybate in an open-label extension study in patients with fibromyalgia

IntroductionThe long-term safety and therapeutic response of sodium oxybate (SXB) in fibromyalgia syndrome (FM) patients were assessed for a combined period of up to 1 year in a prospective, multicenter, open-label, extension study in patients completing 1 of 2 phase 3 randomized, double-blind, controlled, 14-week trials that examined the efficacy and safety of SXB 4.5 g, SXB 6 g, and placebo for treatment of FM.MethodsThis extension study comprised an additional 38 weeks of treatment and was carried out at 130 clinical sites in 7 countries. Initial entry criteria for the previous 2 double-blind clinical trials required that patients aged ≥ 18 years met the American College of Rheumatology 1990 criteria for FM, had a body mass index (BMI) < 40 kg/m2, and had a score ≥ 50 on a 100-mm pain visual analog scale (VAS) at baseline. All patients began treatment in the extension study with SXB 4.5 g/night (administered in 2 equally divided doses) for at least 1 week, followed by possible serial 1.5 g/night dose increases to 9 g/night (maximum) or reductions to 4.5 g/night (minimum).ResultsOf the 560 FM patients enrolled in this extension study, 319 (57.0%) completed the study. The main reason for early discontinuation was adverse events (AEs; 23.0% of patients). Patients were primarily middle-aged (mean 46.9 ± 10.8 years), female (91.1%), white (91.4%), with a mean duration of FM symptoms of 9.9 ± 8.7 years. Serious AEs were experienced by 3.6% of patients. The most frequently reported AEs (incidence ≥ 5% at any dose or overall) were nausea, headache, dizziness, nasopharyngitis, vomiting, sinusitis, diarrhea, anxiety, insomnia, influenza, somnolence, upper respiratory tract infection, muscle spasms, urinary tract infection, and gastroenteritis viral. Maintenance of SXB therapeutic response was demonstrated with continued improvement from controlled-study baseline in pain VAS, Fibromyalgia Impact Questionnaire (FIQ) total scores, and other measures. Responder analyses showed that 68.8% of patients achieved ≥ 30% reduction in pain VAS and 69.7% achieved ≥ 30% reduction in FIQ total score at study endpoint.ConclusionsThe long-term safety profile of SXB in FM patients was similar to that in the previously reported controlled clinical trials. Improvement in pain and other FM clinical domains was maintained during long-term use.Trial registrationClinicalTrials.gov NCT00423605.