Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords ''fibromyalgia'', ''treatment or management'' and ''trial''. Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and ''other pharmacological'' and exercise, cognitive behavioural therapy, education, dietary interventions and ''other non-pharmacological''. In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.Fibromyalgia syndrome (FMS) is a common rheumatological condition characterised by chronic widespread pain and reduced pain threshold, with hyperalgesia and allodynia. Associated features include fatigue, depression, anxiety, sleep disturbance, headache, migraine, variable bowel habits, diffuse abdominal pain and urinary frequency. Although effective treatments are available 12-14 no guidelines exist for the management of FMS. The objectives were to ascertain the strength of the research evidence on the effectiveness of treatment of FMS and develop recommendations for its management based on the best available evidence and expert opinion to inform healthcare professionals. METHODS ParticipantsA multidisciplinary taskforce was formed consisting of 19 experts in FMS representing 11 European countries. Search strategyA systematic search of Medline, PubMed, EmBASE, PsycINFO, CINAHL, Web of Sciences, Science Citation Indices, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews using the keywords: ''fibromyalgia'', ''treatment or management'' and ''trial'' for all publications till the end of December 2005 was carried out. A manual search of the bibliographies of trials was undertaken to...

Central mechanisms related to referred muscle pain and temporal summation of muscular nociceptive activity are facilitated in fibromyalgia syndrome (FMS) patients. The present study assessed the effects of an NMDA-antagonist (ketamine) on these central mechanisms. FMS patients received either i.v. placebo or ketamine (0.3 mg/kg, Ketalar((R))50% decrease in pain intensity at rest by active drug on two consecutive VAS assessments). Fifteen out of 17 ketamine-responders were included in the second part of the study. Before and after ketamine or placebo, experimental local and referred pain was induced by intramuscular (i.m.) infusion of hypertonic saline (0.7 ml, 5%) into the tibialis anterior (TA) muscle. The saline-induced pain intensity was assessed on an electronic VAS, and the distribution of pain drawn by the subject. In addition, the pain threshold (PT) to i.m. electrical stimulation was determined for single stimulus and five repeated (2 Hz, temporal summation) stimuli. The pressure PT of the TA muscle was determined, and the pressure PT and pressure pain tolerance threshold were determined at three bilaterally located tenderpoints (knee, epicondyle, and mid upper trapezius). VAS scores of pain at rest were progressively reduced during ketamine infusion compared with placebo infusion. Pain intensity (area under the VAS curve) to the post-drug infusion of hypertonic saline was reduced by ketamine (-18. 4+/-0.3% of pre-drug VAS area) compared with placebo (29.9+/-18.8%, P<0.02). Local and referred pain areas were reduced by ketamine (-12. 0+/-14.6% of pre-drug pain areas) compared with placebo (126.3+/-83. 2%, P<0.03). Ketamine had no significant effect on the PT to single i.m. electrical stimulation. However, the span between the PT to single and repeated i.m. stimuli was significantly decreased by the ketamine (-42.3+/-15.0% of pre-drug PT) compared with placebo (50. 5+/-49.2%, P<0.03) indicating a predominant effect on temporal summation. Mean pressure pain tolerance from the three paired tenderpoints was increased by ketamine (16.6+/-6.2% of pre-drug thresholds) compared with placebo (-2.3+/-4.9%, P<0.009). The pressure PT at the TA muscle was increased after ketamine (42.4+/-9. 2% of pre-drug PT) compared with placebo (7.0+/-6.6%, P<0.011). The present study showed that mechanisms involved in referred pain, temporal summation, muscular hyperalgesia, and muscle pain at rest were attenuated by the NMDA-antagonist in FMS patients. It suggested a link between central hyperexcitability and the mechanisms for facilitated referred pain and temporal summation in a sub-group of the fibromyalgia syndrome patients. Whether this is specific for FMS patients or a general phenomena in painful musculoskeletal disorders is not known.

Background: This population study based on a representative sample from a Swedish county investigates the prevalence, duration, and determinants of widespread pain (WSP) in the population using two constructs and estimates how WSP affects work status. In addition, this study investigates the prevalence of widespread pain and its relationship to pain intensity, gender, age, income, work status, citizenship, civil status, urban residence, and health care seeking.

Muscle biopsies from the descending portion of the trapezius muscle were studied in 9 healthy subjects and in 10 patients with localized chronic myalgia related to static load during repetitive assembly work for 16 (10-31) years, with 10 (4-26) months of sick leave at the time of biopsy. Both categories showed isolated atrophic muscle fibers and occasional abnormal fibers with internally situated nuclei, some variation in fiber diameter, and fiber splitting. Fibers with a "moth-eaten" appearance due to a multifocal loss of oxidative enzyme activity were frequent both in the healthy and in the myalgic individuals. In contrast, isolated pathologic "ragged red" fibers were only found in the cases with myalgia (8 of 10), strongly suggesting mitochondrial damage. The phenomenon was confined to the Type 1 fibers. The frequency of Type 1 fibers was increased. Levels of adenosine triphosphate and adenosine diphosphate were reduced in myalgia patients, whereas lactate, pyruvate, and glycogen levels were normal, as well as phosphoryl creatine and total creatine.

Myosin constitutes the major part of the thick filaments in the contractile apparatus of striated muscle. MYH7 encodes the slow/beta-cardiac myosin heavy chain (MyHC), which is the main MyHC isoform in slow, oxidative, type 1 muscle fibers of skeletal muscle. It is also the major MyHC isoform of cardiac ventricles. Numerous missense mutations in the globular head of slow/beta-cardiac MyHC are associated with familial hypertrophic cardiomyopathy. We identified a missense mutation, Arg1845Trp, in the rod region of slow/beta-cardiac MyHC in patients with a skeletal myopathy from two different families. The myopathy was characterized by muscle weakness and wasting with onset in childhood and slow progression, but no overt cardiomyopathy. Slow, oxidative, type 1 muscle fibers showed large inclusions consisting of slow/beta-cardiac MyHC. The features were similar to a previously described entity: hyaline body myopathy. Our findings indicate that the mutated residue of slow/beta-cardiac MyHC is essential for the assembly of thick filaments in skeletal muscle. We propose the term myosin storage myopathy for this disease.

Pain intensity, muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and control points were assessed in 31 patients with fibromyalgia (FM), before and after intravenous administration of morphine (9 patients), lidocaine (11 patients), and ketamine (11 patients). The three different studies were double-blind and placebo-controlled. The patients were classified as placebo-responders, responders (decrease in pain intensity by > 50%) and non-responders. The morphine test did not show any significant changes. The lidocaine test showed a pain decrease during and after the infusion. The ketamine test showed a significant reduction in pain intensity during and after the test period. Tenderness at tender points decreased and endurance increased significantly, while muscle strength remained unchanged. The present results support the hypothesis that the NMDA receptors are involved in pain mechanisms in fibromyalgia. These findings also suggest that central sensitization is present in FM and that tender points represent secondary hyperalgesia.

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We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39±5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (V02) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v 02 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7±2.1) despite normal oxygen carrying capacity and Hgb-02 PSO. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Q..: patient = 303 ml/min per kg, normal men 238±36) and the slope of increase in Q relative to V02 (i.e., A&Q/AVO2) from rest to exercise was exaggerated (A&Q/AVO2, patient = 29, normal men = 4.7±0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex H in skeletal muscle was confirmed by the finding ofdeficiency ofsuccinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle. (J. Clin.