EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

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.

Evaluation of four outpatient educational programmes for patients with longstanding fibromyalgia.

OBJECTIVE: Four programmes based on educational and cognitive principles but with a variation in total length and number of staff/patient contact hours were compared in order to gain further insight into the importance of the format of the programme for the final outcome. DESIGN: A prospective non-randomized intervention study with 191 persons with fibromyalgia. Data were collected before, after and at 1-year follow-up. Participants served as their own controls. Results within and between the programmes were calculated. METHODS: Clinical investigations before and after intervention. Questionnaires were answered before, after and at 1-year follow-up. RESULTS: Most instruments showed no significant improvements after the programme. However, some improvements were found in important variables such as attitudes, self-efficacy, vitality and "days feeling well". Results were unchanged at the 1-year follow-up and 16 persons had started working. Seven had ceased working. Participants reported frequent use of coping strategies in everyday life. No major differences could be found between the programmes. CONCLUSIONS: More comprehensive programmes did not produce better results at group level. Also short and less costly interventions based on educational and cognitive principles were valuable for persons with longstanding fibromyalgia. More attention must be given to evaluating the clinical effect of programmes.

The expression of adhesion molecules in muscle biopsies: the LFA-1/VLA-4 ratio in polymyositis.

OBJECTIVES: The expression of three pairs of adhesion receptors and ligands was examined in 22 consecutive muscle biopsies showing morphological signs of inflammation. MATERIAL AND METHODS: The following groups were studied: patients with polymyositis (PM) (n=7), patients with myositis that did not fulfil criteria for PM, i.e. suspected PM (n=5), patients with other diseases, with no clinical signs of inflammatory myopathy (n=6), and a small group of non-PM inflammatory myopathies (n=4). The endothelial expression of ICAM-1, VCAM-1 and E-selectin was evaluated, as was the cellular expression of LFA-1, VLA-4 and SLex. In addition, the expression of MHC class I and II was studied. RESULTS: The ratio between the number of cells expressing LFA-1 and VLA-4 showed significant differences between the groups, with the lowest values in PM. CONCLUSION: The LFA-1/VLA-4 ratio should be suitable for diagnostic purposes. Our findings also indicate that the VLA-4/VCAM-1 system is important for chronic T cell inflammation in muscle, in line with findings in other "hidden" organs like joints and the central nervous system.

The prevalences of cytochrome c oxidase negative and superpositive fibres and ragged-red fibres in the trapezius muscle of female cleaners with and without myalgia and of female healthy controls.

The association of cytochrome c oxidase negative fibres (COX-negative) and ragged-red fibres (RR-fibres) with work related trapezius myalgia has been proposed. Hitherto studies have been small or without control groups. The aim of the present study was to investigate the prevalences of RR-fibres and COX-negative fibres in female cleaners with (n=25) and without (n=23) trapezius myalgia and in clinically healthy female teachers (n=21). The cleaners did mainly floor cleaning requiring monotonous loading on the trapezius muscle. A questionnaire covering background data and aspects of pain (prevalence, duration, intensity and influence on daily living) was answered. Biopsies were obtained from the trapezius muscle by an open surgical technique. The three groups did not differ in prevalence of COX-negative or COX-superpositive (i.e. type-I fibres with extremely strong brownish reaction in both the COX and SDH/COX stainings) fibres. The prevalence of COX-negative fibres was age dependent. Two subgroups of RR-fibres were present when stained for COX; COX-negative (73%) and COX-superpositive (26%) fibres. Forty-two percent of the COX-negative fibres were RR-fibres and 79% of the COX-superpositive were RR-fibres. A significantly (P=0.002) higher proportion of the COX-superpositive fibres in the cleaners were RR-fibres compared to the teachers. Multivariate regression analysis revealed that age, occupation as cleaner and a tender point in the trapezius were significantly associated with increased prevalences of RR-fibres; a cleaner with a tender point had a 4.35 higher prevalence of RR-fibres compared to a teacher without a tender point. No correlations between other pain related variables and prevalence of RR-fibres were noted. In conclusion, RR-fibres but not COX-negative or COX-superpositive fibres were correlated with cleaning work tasks and with a tender point in the trapezius.

A pilot study of body awareness programs in the treatment of fibromyalgia syndrome.

OBJECTIVE: To compare in a pilot study the effect of two physical therapies, the Mensendieck system (MS) and body awareness therapy (BAT) according to Roxendal, in fibromyalgia patients and to investigate differences in effect between the two interventions. METHODS: Twenty female patients were randomized to either MS or BAT in a program lasting 20 weeks. Evaluations were tender point examination and questionnaires, including visual analog scales (pain intensity at worst site, muscular stiffness, evening fatigue, and global health), Fibromyalgia Impact Questionnaire (FIQ), Coping Strategies Questionnaire, Quality of Life Scales, Arthritis Self-Efficacy Scale (ASES), and disability before, immediately after, and at 6 and 18 months follow-up. RESULTS: The BAT group had improved global health at 18 months follow-up, but lower results than the MS group. The MS group had improved FIQ, ASES other symptoms, and pain at worst site at 18 months follow-up. CONCLUSION: In the present pilot study, MS was associated with more positive changes than BAT.

Is fibromyalgia a distinct clinical entity? Pain mechanisms in fibromyalgia syndrome. A myologist's view.

The cause of muscle pain and allodynia may not be the same in all persons fulfilling the American College of Rheumatology (ACR) criteria for fibromyalgia syndrome. In the majority of patients the generalized pain is preceded by localized or regional pain, usually in the musculoskeletal system. In many patients with fibromyalgia there are findings compatible with tissue injury pain with pain mechanisms involving both the primary afferent neuron and the nociceptive system in the central nervous system. Evidence for these mechanisms is described.

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome.

Levels of substance P were determined in the cerebrospinal fluid (CSF) in 15 patients with chronic fatigue syndrome (CFS). All values were within normal range. This is in contrast to fibromyalgia (FM). The majority of patients with FM have increased substance P values in the CSF. The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

Hyperexcitability in fibromyalgia.

OBJECTIVE: Spontaneous chronic widespread pain in combination with hyperalgesia to pressure stimuli is the hallmark of fibromyalgia (FM). We tested whether muscular hyperalgesia can exist in a muscle without spontaneous pain, which could indicate a generalized hyperexcitability of the nociceptive system in patients with FM. METHODS: Twelve women with FM and 12 age matched female controls participated in this blind study. Patients had no spontaneous pain in the anterior tibial (AT) muscle. The pressure pain threshold was tested on the AT muscle. The pain threshold to electrical single and repeated stimulations of the skin and of the right AT muscle was assessed. Pain was evoked in the left AT muscle by infusion of sterile hypertonic saline (5.7%, 2.8 ml over 480 s). The saline induced muscle pain intensity and duration were assessed by continuous recordings on an electronic visual analog scale (VAS), and the distribution of pain was assessed on drawings. The sequence of electrical sensibility tests and the infusion of hypertonic saline was randomized. RESULTS: Pressure pain thresholds were lower (p < 0.02) in patients with FM compared to controls. Thresholds for pain evoked by electrical stimulation at the skin were not significantly different in the 2 groups. The pain threshold to repeated intramuscular stimulation was significantly (p = 0.02) lower for the patients with FM compared to the control group, indicating that the temporal nociceptive summation was more pronounced in patients with FM. This is an indication of central sensitization (hyperexcitability). Infusion of hypertonic saline evoked muscle pain with a longer duration (p = 0.01) in patients with FM, and referred pain that spread to a larger area (p = 0.002) than in controls. This is an indication of central hyperexcitability. CONCLUSION: There is a state of central hyperexcitability in the nociceptive system in FM. This hyperexcitability can be revealed by excitation of intramuscular nociceptors in a muscle with no spontaneous pain.

Fibromyalgia--are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs.

OBJECTIVE: Pain was analyzed in patients with fibromyalgia (FM) in a randomized, double blind, crossover study using intravenous (i.v.) administration of different drugs. METHODS: In 18 patients with FM muscle pain to i.v. administration of morphine (0.3 mg/kg), lidocaine (5 mg/kg), ketamine (0.3 mg/kg), or saline was studied. Spontaneous pain intensity, muscle strength, static muscle endurance, pressure pain threshold, and pain tolerance at tender points and non-tender point areas were followed. Drug plasma concentrations and effects on physical functioning ability score (FIQ) were recorded. A personality inventory (KSP) was used to related pain response to personality traits. RESULTS: Thirteen patients responded to one or several of the drugs, but not to placebo. Two patients were placebo responders responding to all 4 infusions. Three were nonresponders responding to no infusions. Seven of the responders had a reduction in pain for 1-5 days. Pressure pain threshold and pain tolerance increased significantly in responders. Plasma concentrations were similar in responders and nonresponders. FIQ values improved significantly after the ketamine infusion. Responders scored higher on KSP scales for somatic anxiety, muscular tension, and psychasthenia compared with healthy controls. CONCLUSION: FM diagnosed according to the American College of Rheumatology criteria seems to include patients with different pain processing mechanisms. A pharmacological pain analysis with subdivision into responders and nonresponders might be considered before instituting therapeutic interventions or research.

Muscle-nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism.

Sixteen members of a family with a history of autosomal dominant progressive external ophthalmoplegia (adPEO) with hypogonadism were examined. The muscular involvement commenced cranially and descended in relation to increasing disease duration. The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyogram (EMG) was myopathic in facial and proximal limb muscles. Neurogenic involvement was suspected in a few tibial anterior muscles. Neurography showed signs of axonal neuropathy correlated to clinical signs. F-responses were reduced in number or absent in peroneal nerves, and did not correlate to clinical signs or disease duration. Muscle biopsies in advanced cases had structural abnormalities of mitochondria, ragged-red fibers, and focal cytochrome c oxidase deficiency. A combination of muscle-nerve involvement with PEO, Achilles tendon areflexia, distal vibration sensory impairment, myopathic EMG, and abnormally low sural nerve responses seems to be typical of this type of mitochondrial disorder.

Chronic regional muscular pain in women with precise manipulation work. A study of pain characteristics, muscle function, and impact on daily activities.

Pain characteristics, muscle function and impact on daily activities were studied in 39 women with chronic regional muscular pain (RMP). They were all blue-collar workers in work involving precise manipulations. The main location of the pain was in the neck-shoulder region. Nineteen age-matched women with fibromyalgia (FM) were studied in the same way as the RMP patients. Thirty-seven women with no pain and with the same age and weight as the RMP patients served as reference group with respect to muscle strength and endurance. A follow-up study was done with respect to pain distribution and other pain characteristics 20 months after the initial examination. The findings were of the same nature in the RMP and the FM groups. The intensity of pain, the lowering of pain threshold for pressure, and the degree of sleep disturbance were greater in the FM than in the RMP group. Isometric muscle strength and static muscular endurance were reduced in both FM and RMP compared to reference values. The reduction in strength and endurance was greater in FM than in RMP. Even if the impact on everyday activities were greater in FM than in RMP, the impact was substantial in RMP patients also, for example with regard to work capacity. There were no transitions from RMP to FM during the 20 months to follow-up. Three FM patients, however, did not meet the ACR criteria for FM at follow-up.

Phospholipase A2 activity in dystrophinopathies.

Phospholipase A2 activity in human muscle with or without dystrophin abnormality was studied. The results showed an increased phospholipase A2 activity in Duchenne muscular dystrophy (DMD) patients (1160 +/- 160, P < 0.01) compared to controls (< 200 U mg-1). DMD fetal muscle showed normal levels, but levels then increased dramatically postnatally. Highest levels were found at 5 yr of age (10 times normal) and then declined to 1.5-2 times normal by age 10. Steroid treatment did not change the phospholipase A2 levels significantly. In patients with abnormal dystrophin, i.e. Becker muscular dystrophy, phospholipase A2 activity was increased in the age group 3-15 (920 +/- 230 U mg-1, P < 0.01), while older patients (17-49) showed a non-significant (220 +/- 60 U mg-1) increase. The lack of phospholipase A2 activation in fetuses with DMD, indicates that activation is not a direct consequence of dystrophin deficiency. Phospholipase A2 activity has been shown to be connected to the formation of several inflammatory mediators such as prostaglandins, leukotriens, platelet activating factor and lysophospholipids. Phospholipase A2 activation may therefore play an important role in the development of inflammation and necrosis, with subsequent fibrosis and massive loss of muscle function, which develops in Duchenne and Becker muscular dystrophy.

Malignant hyperthermia susceptibility without central core disease (CCD) in a family where CCD is diagnosed.

Central Core Disease (CCD) is a myopathy closely linked to malignant hyperthermia (MH) susceptibility. We present a family with a girl suffering from CCD. Due to the CCD diagnosis, all available relatives were investigated for MH-susceptibility. No other family member has CCD. In vitro contracture tests revealed that several relatives are MH-susceptible. Thus our results suggest that healthy members of families with CCD could be at risk for being malignant hyperthermia susceptible.

Fibromyalgia and disability. Report of the Moss International Working Group on medico-legal aspects of chronic widespread musculoskeletal pain complaints and fibromyalgia.

The present article is the result of a working group conference held in Moss, Norway, in June 1993, financed by the Royal Norwegian Ministry of Health and Social Affairs. Its purpose was to review and focus upon problems and needs related to the medico-legal aspects of fibromyalgia and chronic widespread musculoskeletal complaints: thus to define directions for future work on issues which have generally not been addressed within the medical community. Our report describes specific problems in this area in regard to definition, evaluation and recommendation, and in currently available work and disability statistics. We have recommended international efforts to establish research programs through organizations such as the International Social Security Association and the World Health Organization. While our recommendations call for research into medico-legal interactions, causes and pathogenic mechanisms, prevention and treatment are also key and relevant concerns in the medico-legal setting.

Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine.

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.

Chronic muscular pain: aetiology and pathogenesis.

The conclusion is that no one single mechanism can explain FMS and is thus in that sense a compromise. FMS in some patients may start in the muscle, in other patients in the brain. The combination of peripheral and central factors is the key to the pathogenesis of FMS as long as FMS is defined as a pain syndrome.

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Recently, we described a patient with severe exercise intolerance and episodic myoglobinuria, associated with marked impairment of succinate oxidation and deficient activity of succinate dehydrogenase and aconitase in muscle mitochondria (1). We now report additional enzymatic and immunological characterization of mitochondria. In addition to severe deficiency of complex II, manifested by reduction of succinate dehydrogenase and succinate:coenzyme Q oxidoreductase activities to 12 and 22% of normal, respectively, complex III activity was reduced to 37% and rhodanese to 48% of normal. Furthermore, although complex I activity was not measured, immunoblot analysis of complex I showed deficiency of the 39-, 24-, 13-, and 9-kD peptides with lesser reductions of the 51- and 18-kD peptides. Immunoblots of complex III showed markedly reduced levels of the mature Rieske protein in mitochondria and elevated levels of its precursor in the cytosol, suggesting deficient uptake into mitochondria. Immunoreactive aconitase was also low. These data, together with the previous documentation of low amounts of the 30-kD iron-sulfur protein and the 13.5-kD subunit of complex II, compared to near normal levels of the 70-kD protein suggest a more generalized abnormality of the synthesis, import, processing, or assembly of a group of proteins containing iron-sulfur clusters.