Fw: Subject Reference: The muscle in fibromyalgia

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Subject: Subject Reference: The muscle in fibromyalgia

EditorialThe muscle in fibromyalgia A. Bengtsson Rheumatology Unit, University Hospital, 581 85 Linköping, Sweden The main symptoms in fibromyalgia are muscle pain, stiffness and musclefatigue. In 1981, when we started our fibromyalgia studies, we had a lotof patients with such symptoms at our clinic. None of them had arthritisor laboratory signs of inflammation, which is the key that opens thedoor to the rheumatology unit. Fibromyalgia patients inour own studies were all diagnosed according to the Yunus criteria from1981 to 1990 and according to the ACR criteria since 1990 [1, 2]. The first questions that should be asked are these: When do we feel painin the muscles? What kind of changes in the muscle tissue produce pain?Is there any evidence that such changes exist in the muscle infibromyalgia? Muscle fibres are not provided with nociceptors [for reviews see 3–5].Chronic degenerative muscle disorders are not painful. Inflammation cancause sensitization of pain receptors, but on the other handpolymyositis can exist without pain. Hypoxia in combination with musclework causes pain as well as energy depletion. In the late 1980s we carried out several studies to find out if therewas any peripheral contribution to the pain of fibromyalgia. An epiduralcatheter was inserted in the patients.According to the method introduced by Cherry et al. [6], the patientswere given physiological saline twice followed by an opioid, givennaloxone intravenously, and finally a local anaesthetic (lidocaine) [6].The nine patients were placed on a bicycle ergometer and were asked toexercise to an intensity of 40 and 80% of their maximal oxygen uptake[7]. These studies showed that the patients did not respond to placebo,they were able to work without any increase in pain duringadministration of the opioid, and when they were given the localanaesthetic they were all free of pain. The conclusion was that thereprobably is a peripheral component in fibromyalgia. Because the main symptoms in fibromyalgia (pain, stiffness and fatigue)are located in the muscles—at least according to the patients—musclebiopsies, mostly from the trapezius muscle, have been studied [8].Biopsies have also been taken from the deltoid, the brachioradial,anterior tibial and quadriceps muscles. Light microscope, histochemicaland electron microscope studies have been done, as well as specificanalyses of, for example, the content of substance P in muscle biopsies,which is increased in fibromyalgia muscle. Serotonin has been measuredby the use of microdialysis in the masseter muscle and found to behigher in patients with fibromyalgia than in controls. Muscle biopsy studies have been made by our group as well as by Yunus etal. [9], Bartels and Danneskiold-Samsoe [10], Kalyan Raman et al. [11],Pongratz and Spath [12] and Drewes et al. [13]. Drewes et al. studiedthe quadriceps muscle by electron microscopy, and in most cases theyfound empty sleeves of basement membrane, cellulardamage manifested as lipofuchsin inclusions, and mitochondria withirregular patterns of cristae. Electron microscope studies have alsobeen done by Kalyan Raman et al. [11], Fassbender and Wegner [14], Yunuset al. [15] and Lindman et al. [16, 17], and these studies have shownminor mitochondrial abnormalities. In general, there has been no sign of degeneration or regeneration orinflammation. Atrophy of type 2 fibres has been reported in severalstudies. The frequencies of type 1 and type 2 fibres have beendetermined in patients and controls, as has mean cross-sectional area ofthe fibres, and no differences have been found. Most of the studies havebeen made in the upper part of the trapezius muscle. Studies of thenormal trapezius indicate a relatively poor supply of capillaries aswell as low mitochondrial volume density compared with limb muscles[17]. In the normal trapezius there are some differences between men andwomen, females having smaller cross-sectional areas of both type-1and type-2 fibres. As the mitochondrial volume density of a muscle isdirectly related to its endurance capacity, our results might indicate arelatively low oxidative capacity of the muscle fibres and thus littleability for endurance work. The presence of moth-eaten and ragged-red fibres indicates unevendistribution and proliferation of mitochondria. Accumulation ofmitochondria is seen in Gomori trichrome staining, and this gives theragged appearance. Mitochondrial proliferation may be a compensatoryphenomenon in disorders or pathophysiological states affecting oxidativemetabolism. Ragged red fibres appear to be related to insufficient bloodsupply, as shown by Heffner and Barron in 1978 [18]. Ragged red and moth-eaten fibres are not specific to fibromyalgia, butare often seen in chronic neuromuscular disorders. They have also beenfound in controls. Ragged red fibres are also found in localized chronicshoulder pain, predominantly on the painful side and if the patient hasbeen exposed to static loading. They can also be found inpolymyalgia rheumatica, mitochondrial diseases and experimentalischaemia. Muscle microcirculation can be measured in different ways. Lund et al.[19] used an oxygen multipoint electrode on the muscle surface in 10patients and eight controls. The trapezius and brachioradial muscleswere studied. A pathological distribution of tissue oxygen pressurevalues was found in all patients but in only one of the controls. Theseresults indicate abnormal capillary microcirculation, at least in thetender point area. Blood flow in the tender point area has also beenexamined using an intramuscular needle electrode, and lower values werefound in the patients. Capillary density was examined in the trapezius muscle in 10 patientsand nine controls, and no differences were found between the two groups[8]. Lindh et al. [20] examined the vastus lateralis muscle and found alower density of capillaries (numbers of capillaries per fibre and permm2) in fibromyalgia patients. Lindman et al. [21] founda greater thickness of the endothelium of the capillaries offibromyalgia patients. Similar changes had been observed by Fassbenderand Wegner in 1973 [14]. These changes are either caused by or are thecause of localized hypoxia. These findings are similar to those ofGidlöf et al. [22], who observed derangement of limb muscle capillariesafter tourniquet-induced ischaemia. The endothelial changes were alsofound in controls, but they were more frequent in fibromyalgia. Muscleblood flow has also been examinedby et al. [23] using xenon 133 clearance, and lower values werefound in fibromyalgia. The microcirculation in the muscle is controlled by locally producedmetabolites, the sympathetic nervous system and humoral factors. Wheneight patients received a stellate ganglion blockade with the localanaesthetic bupivacaine, patients with total sympathetic blockade werefree from pain and tender points in the arm. Sham blockade did nothave this effect [24]. Larsson et al. [25] studied blood flow with alaser Doppler technique in the trapezius muscle in patients withshoulder pain on only one side. On the pain-free side there was anincrease in blood flow as the load increased. On the painful side,however, blood flow did not increase on increasing the load. This alsoindicates disturbed local regulation of the microcirculation. Levels of ATP and phosphocreatine were analysed in muscle biopsies fromthe trapezius [26] and the tibialis anterior muscle in patients withfibromyalgia and in the trapezius muscle of healthy controls, and lowervalues were found in the patients than in the controls. Studies using magnetic resonance spectroscopy (MRS) have producedresults different from studies of muscle biopsies. The MRS studies wereall carried out under different circumstances and in different muscles. At our clinic, fibromyalgia patients and controls were studied duringrest and under different work loads. At rest and under submaximalloading there were no differences between the two groups, but undermaximal load the patients produced only half as much work as thecontrols (A. Bengtsson et al., submitted for publication). The pHreduction was the same in controls and patients, as, for example,Vestergaard-Poulsen et al. have also found [27]. The patients thusreached the level of pH reduction at which pain and fatigue inhibit workafter a much shorter time and under a lesser work load compared with thecontrols. Park et al. found lower ATP values at rest in patients withfibromyalgia [28]. Oxidative enzymes were studied by Lindh et al. [20],who found that 3-hydroxy CoA dehydrogenase and citrate synthase werelower in patients than in controls. Maximal voluntary contraction has been examined in fibromyalgia inseveral studies, and all of these found a reduction in muscle strength,but when the muscle was stimulated electrically normal values werefound. sen et al. [29] found a significant reduction in isometricand isokinetic strength in the quadriceps muscle. Mengshoel et al. [30]tested grip strength in the dominant hand and found a significantreduction in muscle endurance, tested by repeated maximal grip pressure,dynamic endurance work and staticendurance work. Bäckman et al. [31] presented evidence that the reduced strength was dueto an impaired central activation of motor units. In one study by Elertet al. [32], patients and controls were asked to do 100 repeatedshoulder flexions. EMG was controlled simultaneously. Pain andperception of effort were not recorded. However, this study showedthat patients with fibromyalgia had EMG activity between musclecontractions. One hypothesis is that this was due to the prolongedrelaxation time recorded in fibromyalgia [31]. When the muscle is notrelaxed between contractions, the microcirculation of the muscle mightbe affected. When the microcirculation and metabolism of the muscle are affected,muscle pain can arise in work, but fibromyalgia patients have pain atrest as well as widespread pain and allodynia that cannot be explainedby the results of muscle biopsies. Pain cannot be explained by thefindings of muscle biopsies if a state of central sensitization does notexist [33]. Pharmacological analyses of pain in fibromyalgia showed that patientswere all pain-free after epidural blockade [7]. Resting paindisappeared, as did the tender points. The effects of intravenous infusion of morphine, lidocaine, ketamine andplacebo were analysed in 18 patients. Only two patients responded toplacebo [34]. Thirteen responded to one or several drugs but not toplacebo. Only three patients did not respond to any drug or to placebo.Thirteen patients responded to ketamine, which blocksNMDA (N-methyl-D-aspartate) receptors. This points to centralsensitization as an important factor in fibromyalgia and the likelihoodthat different fibromyalgia patients probably have different painmechanisms [35]. Sörensen et al. [33] studied experimentally induced muscle pain byinfusion of hypertonic saline and showed that hyperalgesia infibromyalgia is present in fibromyalgia muscle without pain. In thecerebral fluid, the concentration of substance P is higher infibromyalgia patients than in controls, and these findings have beenconfirmed by [36]. The muscle biopsy studies show that there are no specific changesconclusively for fibromyalgia. However, moth-eaten fibres, ragged redfibres and type 2 fibre atrophy indicate that the muscles are involvedin the pathogenesis of fibromyalgia. The studies mentioned aboveindicate that the regulation of the microcirculation is disturbed infibromyalgia in a way that might lead to sensitization of theintramuscular nociceptors. My conclusion from the studies on musclemetabolism in fibromyalgia is that there is a defect that is not seen atrest and when the patient is working at a submaximal load, but is seenunder maximal loading and under static contraction. The mechanisms of pain are not the same in all patients withfibromyalgia. It may be that this confuses us all because differentfibromyalgia patients are seen according to whether we work in arheumatology unit, a general practice or a psychiatric clinic. However, in the majority of patients there is a state of centralsensitization. In these patients, changes in the muscles, such asmitochondrial changes, a change in the microcirculation and/or a changein muscle metabolism, might sensitize muscle nociceptors and therebycause pain, fatigue and muscle weakness. It is important for us to understand the influences of other chronicpain mechanisms, such as pain-inhibitory and pain-facilitating pathways,and the cortical and subcortical processes involved in the establishmentof chronic pain. Studies of both peripheral and central factors will benecessary before we achieve a full understanding of pain infibromyalgia. References1.Yunus M, Masi AT, Calabro JJ et al. Primary fibromyalgia (fibrositis):clinical study of 50 patients with matched normal controls. SeminArthritis Rheum1981;11:151–71.[Medline] 2.Wolfe F, Smythe HA, Yunus MB et al. The American College ofRheumatology 1990 criteria for the classification of fibromyalgia:report of the Multicenter Criteria Committee. ArthritisRheum1990;33:160–72.[Medline] 3.Henriksson KG. Pain mechanisms in fibromyalgia syndrome. A myologist'sview. Baillière's Clin Rheumatol1999;13:77–83. 4.Mense S. Nociception from skeletal muscle in relation to clinicalmuscle pain. Pain1993;54:241–89.[Medline] 5.Henriksson KG. 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