I. Jon Russell

The American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and Measurement of Symptom Severity

To develop simple, practical criteria for clinical diagnosis of fibromyalgia that are suitable for use in primary and specialty care and that do not require a tender point examination, and to provide a severity scale for characteristic fibromyalgia symptoms.

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.

Auranofin therapy and quality of life in patients with rheumatoid arthritis. Results of a multicenter trial

In a six-month, randomized, double-blind study at 14 centers, auranofin (3 mg twice daily) was compared with placebo in the treatment of patients with classic or definite rheumatoid arthritis. All patients had unremitting disease for at least the previous six months and at least three months of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs, oral steroids, and analgesics were allowed throughout the trial. Efficacy was analyzed in 154 patients who received auranofin and 149 who received placebo. To reflect an expanded view of outcome assessment, the measures used included some 20 nontraditional measures of functional performance, pain, global impression, and utility (worth or value) in addition to five standard clinical measures of rheumatoid synovitis (e.g., number of tender joints). The nontraditional measures were mainly in the form of structured questionnaires administered by trained interviewers. To minimize the statistical problem of multiple comparisons, most of the measures were grouped into four composites--clinical (standard measures), functional, global, and pain--and the treatment effect for each composite was tested at the 0.0125 level of significance. Auranofin was superior to placebo in the clinical (p = 0.003), functional (p = 0.001), and global (p = 0.007) composites and trended similarly in the pain composite (p = 0.021). Individual measures within the composites consistently favored auranofin. Other measures, not part of the composites, also favored auranofin, including a patient utility measure designed for this study, the PUMS (p = 0.002). Results confirm the hypothesis that the favorable effect of auranofin on clinical synovitis is accompanied by improvements across a range of outcomes relevant to the patients quality of life.

A 14-week, Randomized, Double-Blinded, Placebo-Controlled Monotherapy Trial of Pregabalin in Patients With Fibromyalgia

UNLABELLED The purpose of the study was to assess the efficacy and safety of pregabalin monotherapy in patients with fibromyalgia in a randomized, double-blinded, placebo-controlled trial. After 1 week of single-blinded administration of placebo, 750 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to pregabalin (300 mg/d, 450 mg/d, 600 mg/d) or placebo, administered twice daily for 14 weeks. The primary outcome variable was comparison of end point mean pain scores, derived from daily diary ratings of pain intensity (0 to 10 scale), between each of the pregabalin groups and the placebo group. If positive, additional primary efficacy parameters included the Patient Global Impression of Change (PGIC) and the Fibromyalgia Impact Questionnaire (FIQ) total score. Compared with placebo-treated patients, mean changes in pain scores at the end point in pregabalin-treated patients were significantly greater (P < .001: 300 mg/d, -0.71; 450 mg/d, -0.98; 600 mg/d, -1.00). Compared with placebo, significantly more pregabalin-treated patients reported improvement on PGIC (P < .01 for all 3 pregabalin doses) and significant improvements in total FIQ score for the 450 mg/d (P = .004) and the 600 mg/d (P = .003) doses. Compared with placebo, all 3 doses of pregabalin were associated with significant improvement in sleep. The most commonly reported pregabalin-related adverse events were dizziness and somnolence, which tended to be dose-related. PERSPECTIVE This randomized, placebo-controlled trial of 300, 450, and 600 mg/d of pregabalin monotherapy demonstrated that all 3 doses were efficacious for up to 14 weeks for the treatment of fibromyalgia and were well tolerated by most patients. These results provide evidence that pregabalin is an important treatment option for patients with fibromyalgia.

Identifying the clinical domains of fibromyalgia: Contributions from clinician and patient delphi exercises

OBJECTIVE In evaluating the effectiveness of fibromyalgia (FM) therapies, it is important to assess the impact of those therapies on the full array of domains considered important by both clinicians and patients. The objective of this research was to identify and prioritize the key clinically relevant and important domains impacted by FM that should be evaluated by outcome assessment instruments used in FM clinical trials, and to approach consensus among clinicians and patients on the priority of those domains to be assessed in clinical care and research. METHODS Group consensus was achieved using the Delphi method, a structured process of consensus building via questionnaires together with systematic and controlled opinion feedback. The Delphi exercises involved 23 clinicians with expertise in FM and 100 patients with FM as defined by American College of Rheumatology criteria. RESULTS The Delphi exercise revealed that the domains ranked most highly by patients were similar to the domain rankings by clinicians. Pain was consistently ranked highest by both panels. Fatigue, impact on sleep, health-related quality of life, comorbid depression, and cognitive difficulty were also ranked highly. Stiffness was ranked highly by patients but not clinicians. In contrast, side effects was important to clinicians but was not identified as important in the patient Delphi exercise. CONCLUSION The clinician and patient Delphi exercises identified and ranked key domains that need to be assessed in FM research. Based on these results, a conceptual framework for measuring patient-reported outcomes is proposed.

Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia : implications for nitric oxide pathways

&NA; Substance P (SP), a putative nociceptive transmitter, is increased in the CSF of patients with fibromyalgia syndrome (FMS). Because excitatory amino acids (EAAs) also appear to transmit pain, we hypothesized that CSF EAAs may be similarly involved in this syndrome. We found that the mean concentrations of most amino acids in the CSF did not differ amongst groups of subjects with primary FMS (PFMS), fibromyalgia associated with other conditions (SFMS), other painful conditions not exhibiting fibromyalgia (OTHER) or age‐matched, healthy normal controls (HNC). However, in SFMS patients, individual measures of pain intensity, determined using an examination‐based measure of pain intensity, the tender point index (TPI), covaried with their respective concentrations of glutamine and asparagine, metabolites of glutamate and aspartate, respectively. This suggests that re‐uptake and biotransformation mask pain‐related increases in EAAs. Individual concentrations of glycine and taurine also correlated with their respective TPI values in patients with PFMS. While taurine is affected by a variety of excitatory manipulations, glycine is an inhibitory transmitter as well as a positive modulator of the N‐methyl‐D‐asparate (NMDA) receptor. In both PFMS and SFMS patients, TPI covaried with arginine, the precursor to nitric oxide (NO), whose concentrations, in turn, correlated with those of citrulline, a byproduct of NO synthesis. These events predict involvement of NO, a potent signaling molecule thought to be involved in pain processing. Together these metabolic changes that covary with the intensity of pain in patients with FMS may reflect increased EAA release and a positive modulation of NMDA receptors by glycine, perhaps resulting in enhanced synthesis of NO.

Advances in fibromyalgia : Possible role for central neurochemicals

The neurophysiologic term allodynia has been applied to fibromyalgia because people with that disorder experience pain from pressure stimuli which are not normally painful. The nociceptive neurotransmitters of animal studies are now relevant to this human model of chronic, widespread pain. Evidence is presented to implicate several chemical pain mediators (including serotonin, substance P, nerve growth factor, and dynorphin A) in the pathogenesis of fibromyalgia. This perception is hopeful because it offers many new options for the development of innovative therapy.

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.

Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study.

&NA; This 14‐week, phase 3, double‐blind, randomized, controlled trial evaluated sodium oxybate (SXB) 4.5 and 6 g per night versus placebo in patients with fibromyalgia (FM). SXB is the sodium salt of γ‐hydroxybutyrate (GHB). GHB is an endogenous compound, synthesized from γ‐aminobutyric acid (GABA) and found broadly in the central nervous system and body. Among 548 randomized patients, a ⩾30% reduction in pain was experienced by 54.2% and 58.5% of patients treated with SXB 4.5 and 6 g, respectively, versus 35.2% for placebo with a 100‐mm Visual Analog Scale (VAS) (P < 0.001 for both comparisons). Relative to placebo, both SXB doses significantly reduced fatigue (with a 100‐mm VAS; P < 0.001) and sleep disturbance (with the Jenkins Sleep Scale; P < 0.001), and resulted in significant improvements in function as measured by the FM Impact Questionnaire (P = 0.003 and P = 0.001 for 4.5 and 6 g per night, respectively). On the Short‐Form 36 Health Survey, SXB‐related improvement was significant on the Physical, but not the Mental, Component Scale. The proportion of patients who reported a global improvement of “much” or “very much” better on the Patient Global Impression of Change was significantly greater in both SXB groups versus placebo (P < 0.001). Headache, nausea, dizziness, vomiting, diarrhea, anxiety, and sinusitis were the most commonly reported adverse events, with an incidence at least twice that of placebo. These results expand the evidence from previous clinical trials suggesting that SXB is effective and safe in FM. This study expands evidence from previous trials that sodium oxybate provides safe, effective treatment for multiple symptoms experienced by patients with fibromyalgia.

Neurophysiopathogenesis of Fibromyalgia Syndrome: A Unified Hypothesis

The characteristic presenting complaint of patients with fibromyalgia syndrome (FMS) is chronic widespread allodynia. Research findings support the view that FMS is an understandable and treatable neuropathophysiologic disorder. The pain of FMS is often accompanied by one or more other manifestations, such as affective moods, cognitive insecurity, autonomic dysfunction, or irritable bowel or bladder. Growing evidence suggests that this is a familial disorder with many underlying genetic associations. New findings from brain imaging and polysomnography imply that FMS may be a disorder of premature neurologic aging. A conceptual model at the molecular level is proposed to explain many of the observed features of FMS. The model can also explain anticipated responses to FDA approved pharmacologic therapies.