Muscle function and origin of pain in fibromyalgia

2 Muscle function and origin of pain in fibromyalgia R O B E R T M. BENNETT SOREN JACOBSEN

The complaints of fibromyalgia (FM) patients, besides muscle pain, are sensations of increased fatiguability and low muscular endurance. Characteristically the intensity of the pain in FM increases after physical activity. Light physical activity generally does not have any acute effects on muscle pain, whereas strenuous activity clearly results in worsening of the pain (Bengtsson et al, 1986a; van Denderen et al, 1992; Jacobsen et al, 1993). Exercise intolerance, poor work tolerance, complaints of weakness and functional disability (Bennett, 1981; Bengtsson et al, 1986a; Cathey et al, 1988; Hawley et al, 1988; Mason et al, 1989; MYOPAIN '92 Consensus Committee, 1993) clearly indicate impaired muscle function or perceived dysfunction in the majority of FM patients. ASSESSMENT OF MUSCLE FUNCTION IN FM Isometric muscle strength During an isometric contraction the muscle does not shorten. Measurement of maximal voluntary isometric muscle strength is one of the oldest methods for assessing muscle contractions. Several tests have been developed (Asmussen and HeebN1-Nielsen, 1961; Edwards et al, 1977) and are relatively easy to perform with inexpensive equipment. Isokinetic muscle strength During an isokinetic contraction the muscle shortens at a constant speed. Isokinetic muscle strength testing requires the use of an isokinetic dynamometer (Gransberg and Knutsson, 1983), which controls movement by keeping the joint angular velocity at a constant preset speed. This method has the advantage that more detailed information on the muscle contraction can be obtained throughout the range of motion, and has been shown to be more reliable than isometric measurements in FM (Jacobsen et al, 1991c). However, this method requires expensive equipment and is thus restricted to certain centres. Bailli~re's ClinicalRheumatology-Vol. 8, No. 4, November 1994 ISBN 0-7020-186%8

72 t Copyright 9 1994, by Bailli~re Tindall All rights of reproduction in any form reserved

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Muscular endurance

The outcome of measurements of muscular endurance is highly dependent on how endurance is defined and on specific details in the measurement procedure. For example, with regard to static endurance, outcome varies greatly with the level of contraction required during the test. Dynamic endurance also depends on the contraction level, the length of contraction and the length of pause between contractions. Standardized measures for endurance are not generally agreed upon and have to be carefully defined for each experiment. Stimulated muscle contractions

The above mentioned methods use maximal voluntary muscle performance as a measure of muscle function. Thus, central activation and pain restriction of muscular outcome are relevant issues, particularly in FM patients. Electrically stimulated contractions allow more standardized settings for strength measurements and can yield information about speed of relaxation and rate of force fatigue (Edwards et al, 1977). However, this requires easy access to a motor nerve, which is not always possible. In such cases, muscle may be directly stimulated by transcutaneous electrical impulses. This method may provide information about the degree of central activation during muscle contraction (Jacobsen and H0ydalsmo, 1993). Magnetic resonance spectroscopy

Topical magnetic resonance (MR) spectroscopy allows non-invasive investigation of the metabolism of skeletal muscle. Phosphorus-31 (31p) MR spectroscopy provides data about the bioenergetics of muscles at rest as well as during exercise (Edwards et al, 1982; Radda et al, 1983). This method is limited to very few centres because of the expensive equipment and considerable experience which is required to obtain good quality 31p spectra. CONTRACTILE PROPERTIES OF FM MUSCLE Voluntary muscle strength

Maximal voluntary muscle strength (MVS) of FM patients measured during isometric contraction of the quadriceps muscle is reduced to 34-56% of the values obtained in healthy controls (Jacobsen and Danneskiold-Sams0e, 1987; Jacobsen et al, 1991c). Isokinetic MVS is reduced to 49-59% of the expected values (Jacobsen and Danneskiold-Sams0e, 1987; Jacobsen et al, 1991c). These data have been confirmed by the finding of comparable reductions in isokinetic MVS in other FM patient groups (Jacobsen and Holm, 1992; Lindh et al, 1992). Low MVS has also been observed for other muscle groups in FM patients, including forearm flexor muscles (B~ckman et al, 1988).

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Isokinetic MVS and the number of tender points in FM patients are negatively correlated. Patients with nine or more out of 14 possible tender points had significant decreases in isokinetic MVS, whereas patients with fewer tender points did not differ significantly from healthy controls (Jacobsen and Danneskiold-Samsc~e, 1989). This negative correlation has been confirmed in another sample of FM subjects in which the effects of sex, age and physical activity were taken into account (Nr et al, 1993). Furthermore, isokinetic MVS correlated with the cumulated number of subjective symptoms (Jacobsen and Danneskiold-Samsr 1989). An expected correlation between muscle strength and height (Asmussen and Heebr 1961) was not seen in FM (Jacobsen and DanneskioldSamsr 1989) due to the existence of confounding factors, as has also been demonstrated in rheumatoid arthritis (Danneskiold-Samsc~e, 1988). Isokinetic MVS correlated well with aerobic capacity, whereas this was not so for isometric MVS (Jacobsen and Holm, 1992). An uncontrolled followup study of isokinetic MVS spanning 4 years showed no significant further decline, nor was it possible to identify any subgroups demonstrating accelerated decline in muscle strength (NOrregaard et al, 1993). Low MVS is not specific for FM and may be seen in most diseases affecting the musculoskeletal system, including chronic myofascial pain syndromes and rheumatoid arthritis (Danneskiold-SamsCe, 1988; Jacobsen et al, 1991a). A Swedish study found normal strength and endurance of shoulder flexors both in patients with FM and in those with mild work-related myalgia (Elert et al, 1992); however, this study did not provide a description of the degree of muscle pain or the cumulated load of symptoms. Measurement of MVS has thus no diagnostic significance in FM; however, when FM has been clinically diagnosed, isokinetic MVS may reflect the impact of the disease on the individual patient. It still remains to be determined whether this method is useful to detect changes over time corresponding to other measures of disease activity in FM. However, significant changes in tender point score over time were not accompanied by corresponding changes in isokinetic MVS (Jacobsen et al, 1991b). When measuring muscle strength in FM, high speed isokinetic quadriceps dynamometry is recommended due to its high reproducibility in these patients (Jacobsen et al, 1991c). Electrical stimulation of muscle

The ability to add transcutaneously electrically elicited twitches during maximum voluntary contraction points towards a submaximal effort during contraction. This was found in 65% of FM patients and 15% of healthy subjects. Three subjects, all healthy, had different outcomes in the two tests with regard to the presence of interpolated twitches. In all cases the isometric strength achieved during contraction was lowest in the test where the interpolated twitches occurred (Jacobsen et al, 1991c). A preliminary report using the same technique confirmed these findings (Lindh et al, 1992). Maximal contraction of the adductor pollicis muscle was obtained by stimulating the ulnar nerve in FM patients (Bfickman et al, 1988). The

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reduced MVS in FM may thus be due to central mechanisms and/or failure of peripheral neuromuscular transmission. Electromyographic studies have shown no signs of specific myo/neuropathic disease or reduced signal propagation (McBroom et al, 1988; Zidar et al, 1990; Roy et al, 1992), so failure of peripheral neuromuscular transmission is thus not likely. Afferent activity from the musculoskeletal system may cause reflex inhibition of muscle performance (Stokes and Young, 1984; Woods et al, 1987). However, MVS in FM was not related to local tenderness, even though it was related to the cumulated number of tender points (Jacobsen and Danneskiold-Sams0e, 1989). Pain inhibition on a conscious level or reflex mediated may partly be responsible for low MVS in FM. The twitch interpolation technique has important pathophysiological implications. By superimposing transcutaneous electrical impulses to a muscle during submaximal voluntary contraction, extra force is generated, showing as twitches. The more a muscle is contracted, the less the extra generated force; when voluntary contraction is maximal no extra force is generated (Chapman et al, 1984). The twitch interpolation technique may thus provide a basis for estimating the degree of central activation during voluntary muscle contraction (Lloyd et al, 1991) or the maximal strength potential (Jacobsen and H0ydalsmo, 1993). The clinical significance of electrical muscle stimulation tests has been stressed by Mills and Edwards (1983). These techniques are currently being elaborated, and for the present the twitch interpolation technique is a reproducible method for testing if full contraction capacity is being used. A and I band Donnan potentials

The structural composition of the contractile proteins in skeletal and heart muscle produces the phenomenon of cross-striation by the presence of A bands (dark) and I bands (light). By measuring Donnan potentials using microelectrodes it is possible to estimate the fixed electric charges on the A and I bands of the striated muscle fibres (Bartels and Elliott, 1985). These electrical charges reflect the integrity of the contractile proteins. In polymyositis the inflammatory process causes degenerative changes in the muscle fibres, including the contractile proteins, resulting in abnormal electrical charges on the A and I bands (Bartels et al, 1989). Such measurements in FM patients showed no differences from healthy controls, indicating that the contractile filaments in FM muscle are normal (Bartels and Danneskiold-Sams0e, 1986). E N D U R A N C E AND RESPONSE TO EXERCISE Muscle endurance

The easy fatiguability which is seen in FM may be expected to influence muscular endurance. To quantify this symptom voluntary dynamic muscular endurance (DME) was measured in patients with FM and patients with

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chronic myofascial pain (CMP). A significantly lower DME was found in the FM patients than in CMP patients. This was also found when compared with data on healthy controls from the literature (Jacobsen and DanneskioldSams0e, 1992) and when directly studied (Jacobsen and Holm, 1992). There are conflicting reports as to whether FM patients have reduced muscular endurance (Bengtsson and B~ickman, 1992; Elert et al, 1992; van Denderen et al, 1992); these may stem from the use of different methodologies and fatigue definitions, which are critical for the study outcome (BiglandRitchie, 1984). Total work delivered until exhaustion was significantly lower in FM patients than in healthy controls using a bicycle test, a step test and repeated plantar flexions (Jacobsen et al, 1992; van Denderen et al, 1992). Elert et al (1992) have reported that FM patients were able to carry out 100 maximal repetitive shoulder flexions, which contrasts highly with the previously described findings. Subjects were encouraged to relax between contractions, which may have resulted in submaximal efforts allowing subjects to carry on for longer than when contracting maximally. Data on pretest maximum strength were not provided. DME in FM patients was related to the score of daily physical activity, but not to the cumulated number of subjective symptoms. The relation of D M A to scores of physical activity was substantiated by the fair correlation between total work during the endurance test and aerobic capacity in FM (Jacobsen and Holm, 1992). There are currently no prospective studies on endurance in FM. In the light of the varying findings on muscle endurance in FM, the feasibility of this parameter for describing FM patients has not been fully investigated. Fatigue mechanisms

Localized fatigue during muscle work results in a reduction in the median surface electromyographic frequency (Eberstein and Beattie, 1985). This phenomenon has been studied in the anterior tibialis and upper trapezius muscles in FM patients, showing no evidence of abnormal fatigue mechanisms in these patients (Elert et al, 1989; Roy et al, 1992). Perceived exertion

The local (lower extremity), central and overall exertion perceived during a bicycle aerobic fitness test at both low and high exercise intensity was rated equally by FM patients and sedentary controls (Skrinar et al, 1992). The rate of perceived exertion during maximal volitional exhaustion was also equal in FM patients and sedentary controls matched with regard to maximum oxygen uptake (Bennett et al, 1989; Clark et al, 1992). These findings indicate that FM is not a general symptom amplification disorder. Muscle enzyme response to exercise

Resting levels of creatine kinase have in several studies been found to be normal, which is a requirement for the condition to be primary. Blood levels

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of creatine kinase and myoglobin in FM patients have been found not to rise excessively after work, as can be seen in myopathies. In fact, these compounds were found not to increase as much in FM patients as in the controls, probably due to the lower work level of the FM patients (van Denderen et al, 1992). Muscle blood flow

Several authors have proposed that alterations in muscle blood flow (MBF) may be of importance in the pathophysiology of both FM and myofascial pain syndrome (Klemp et al, 1982; Lund et al, 1986; Bennett, 1989b). Clinical correlations of this notion are th~ beneficial effects of heat, massage, light exercise, shortwave diathermy and ultrasound, particularly on myofascial pain, since these forms of therapy all increase MBF. MBF may be determined by using the local xenon-133 (133Xe) clearance method as described in a study on chronic localized trapezius pain (Klemp et al, 1982). It was hypothesized that the resting MBF would be lower in the fibromyotic muscles as part of the pathophysiology of the myofascial pain syndrome. This hypothesis was not supported for this form of localized muscle pain. However, if only a small part of the muscle is ischaemic, this method may not detect this due to the averaging effect with the surrounding normally supplied muscle. In FM the exercising MBF of the peroneal muscles has been determined by measuring the clearance of 133Xe after a standardized exercise programme (Bennett et al, 1989). The exercise-induced MBF in FM patients was significantly lower than in sedentary controls matched for age, sex, weight and aerobic capacity. The exercise MBF was even lower when compared with trained controls. It was concluded that the reduced exercising MBF in FM may be due to a peripheral detraining effect. One would expect this to be reflected by a reduced capillary density. However, this was not found in the muscle biopsy study by Bengtsson and coworkers (1986b). Bioenergetics of muscle

A single preliminary report suggested changes in the ratio between inorganic phosphate and phosphocreatine (Pi/Pcr) of resting FM muscle (Mathur et al, 1988) as seen in certain mitochondrial myopathies (Matthews et al, 1991). This has not been confirmed by several other studies (de B16court et al, 1991; Jacobsen et al, 1992; Joos et al, 1992; Simms et al, 1992; Wigers et al, 1992), nor have several other studies been able to detect changes in the resting pH in FM muscle (de B16court et al, 1991; Jacobsen et al, 1992; Joos et al, 1992; Krapf et al, 1992; Simms et al, 1992; Wigers et al, 1992). The importance of also examining the muscle response to exercise has been pointed out by Kushmerick (1989). This was investigated in twelve patients and seven controls (Jacobsen et al, 1992). The maximum power output tolerated by the patients was significantly reduced compared with the healthy controls. When comparing Pi/Pcr ratios and pH at the highest

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possible submaximal level reached by all subjects, no differences could be detected between the patients and the controls. In addition, the recovery of the Pi/Pcr ratio was similar in the two groups. Other research teams have made similar observations (Simms et al, 1992; Wigers et al, 1992). These findings indicate that patients with FM do not have a generalized abnormality of muscle metabolism but, due to the relatively large volume of the sensitive coil, they do not exclude focal changes. If dispersed muscle fibres are in metabolic crisis, as suggested by Henriksson and Bengtsson (1990), 31p MR spectroscopy at its present stage would probably not be able to detect these focal alterations of biochemical activity due to the averaging effect with the surrounding normal muscle. When measuring aerobic capacity by respiratory gas exchange, information about the anaerobic threshold and respiratory quotient may also be obtained. In FM patients, these additional parameters were not indicative of excessive work-induced lactic acidosis as would be expected in a generalized energy crisis (Bennett et al, 1989; Clark et al, 1992). PHYSICAL DECONDITIONING FM patients have a lower level of rated daily physical activity compared with healthy controls (Jacobsen et al, 1993). This may explain why the majority of FM patients are aerobically unfit. Approximately 85% of the patients have been found to have a physical fitness below average (Bennett et al, 1989; Jacobsen and Holm, 1992). This finding is undoubtedly of great relevance to muscle research in FM as skeletal muscle displays extreme plasticity regarding its ability to adjust to physiological demands. The effects of training and exercise have been studied extensively, whereas research into the effects of disuse and inactivity has been patchy. It has been shown that FM patients have a lower daily physical activity compared with healthy controls (Jacobsen et al, 1993) and that their maximal oxygen uptake is subnormal (Bennett et al, 1989). Disuse of skeletal muscle may be one of the key issues in the aetiology of the pain in FM, as previously suggested (Bennett, 1989b). The basic adaptive responses to use and disuse of skeletal muscle will be briefly described and related to findings in FM before discussing the possible pathophysiology of pain in FM. During the initial phases of training the resulting increased strength does not correlate with a corresponding increase in the cross-sectional area of the trained muscle (Sattin and Gollnick, 1983). This may be due to an increased central recruitment of motor units. Furthermore, it is known that immobilization reduces the number of recruited motor units (Fuglsang-Frederiksen and Scheel, 1978). FM patients have been shown not to recruit their full contractile capacity, which may partly be explained by a lower rate of motor unit recruitment (Jacobsen et al, 1991c). Muscle mass and cross-sectional area are closely related to muscle strength and the training condition of the muscle. Variation of these factors with training/detraining is accomplished by a change in the total crosssectional area of the individual fibres (Saltin and Gollnick, 1983). The

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clinical impression of muscle in FM patients is not that of atrophy, neither is there a reduction in muscle fibre size (Bengtsson et al, 1986b). The distribution of slow and fast twitch fibres has also been found to be comparable to healthy controls (Bengtsson et al, 1986b). The metabolic capacity of muscle is determined by the supply of substrates and the activity of the enzymes. It has still not been determined if the size of the phosphagen stores, i.e. adenosine triphosphate (ATP) and creatine phosphate (CP), is related to the training condition of muscle. The effect of immobilization on the phosphagen stores of muscle is small and has been suggested not to be of biological importance (Saltin and Gollnick, i983). The levels of phosphagens in FM has been shown to be reduced in particularly painful muscle (Bengtsson et al, 1986c). Reduced levels of ATP and CP have also been found in muscle biopsies from patients with rheumatoid arthritis (Nordemar et al, 1974). This suggests that inactivity may reduce the muscle phosphagen content. The levels of pyruvate and glycogen in FM muscle have been shown not to differ from healthy muscle (Bengtsson et al, 1986c). No studies have investigated the activity of the glycolytic enzymes (phosphofructokinase, lactate dehydrogenase, phosphorylase), the mitochondrial enzymes or calcium ATPase in FM. MUSCLE BIOPSY FINDINGS Since the pain in FM is mainly felt in the muscles, much attention has been focused on the possible existence of changes in the striated muscle that may relate to the pathophysiology. Parameters such as muscle fibre composition and size, muscle size and muscle metabolic capacity are highly dependent on the training condition of the investigated muscle (Sargeant et al, 1977; Saltin and Gollnick, 1983). To obtain reasonable conclusions from studying these parameters in muscle biopsies, the degree of physical activity should be considered in both patients and control subjects. This has not been done in any of the published studies described below. Interpretation of these studies may therefore be difficult, and sometimes impossible, particularly since most FM patients are physically unfit (Bennett et al, 1989; Jacobsen and Holm, 1992). Furthermore, most of these studies have been performed on biopsies from the trapezius muscle, which also has many of the described changes in healthy subjects (Bengtsson et al, 1986b; Yunus et al, 1989a). Routine light microscopic evaluation Three studies have not been able to detect any signs of inflammation (Kalyan-Raman et al, 1984; Drewes et al, 1993; Schr0der et al, 1993), and in one study (Bengtsson et al, 1986b) only discrete infiltrates of lymphocytes were seen in some patients. Variable findings of hyalinized fibres, split fibres and central nuclei seem quite unspecific for FM as they are also found in healthy controls and in patients with work-related chronic myalgia

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(Bengtsson et al, 1986b; Larsson et al, 1988). Capillary density was not found to differ between patients and healthy controls (Bengtsson et al, 1986b). Morphology of skinned fibres Bartels and Danneskiold-SamsOe (1986) demonstrated two not previously described muscle changes in patients with FM, one called 'rubber band' morphology and the other presenting as an interfibriUar network of connective tissue different from collagen. These changes were not seen in healthy subjects. A subsequent blinded study reproduced the finding of 'rubber band' morphology in FM patients using this technique. However, with a control group consisting of chronic myofascial pain patients this finding turned out to be non-specific, even though a statistical difference between the two groups was achieved (Jacobsen et al, 1991a). Another controlled and blinded study also identified these morphological changes, but with the same frequency in patients and healthy controls (J. NCrregaard, M. Harreby, K. Amris, B. Kiens, E. Bartels and B. Danneskiold-SamsOe, unpublished results). Detraining effects, including a reduction in muscle ATP (Bengtsson et al, 1986c), may influence the contractile properties of the muscle, resulting in a reduced rate of relaxation (B~ckman et al, 1988) or neuromuscular hyperexcitability (Vitali e t a ! , 1989) due to increased intracellular calcium. 'Rubber band' morphology has thus been hypothesized to be related to focal hypercontraction of several contiguous sarcomeres, but it may also be a procedure-induced artifact (Jacobsen et al, 1991a). Histochemistry Bengtsson et al (1986b) were not able to detect differences between patients and controls with regard to fibre type distribution, fibre size or variation in fibre size. This is contrasted by the finding of type II atrophy in 7 out of 12 patients in an uncontrolled study by Kalyan-Raman et al (1984) and in 23 out of 25 patients in a controlled study by Schr~der et al (1993). Type II atrophy may also be found in chronic work-related myalgia (Dennett and Fry, 1988; Larsson et al, 1988) and in immobilized muscle (Sargeant et al, 1977). Histochemical staining for reduced nicotinamide adenine dinucleotide (NADH)-tetrazolium reductase demonstrates the distribution and qualitative activity of this mitochondrial enzyme. Using this technique Henriksson et al (1982) reported the presence of muscle fibres with a moth-eaten appearance and a ragged-red appearance in FM. A controlled study on a larger sample confirmed this report, but also found that the moth-eaten appearance was non-specific compared with healthy subjects (Bengtsson et al, 1986b). The finding of moth-eaten fibres antedates the ragged-red appearance during ischaemia (Heffner and Barron, 1978). Ragged-red fibres have also been found in patients with work-related chronic myalgia (Larsson et al, 1988). Another study was not able to detect any abnormalities in N A D H staining in 25 FM patients: (SehrCder et al, 1993), neither

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was there any immunohistochemical staining for an antineuronal cell adhesive molecule seen in denervated muscle fibre membranes. Ultrastructure

Papillary projections of sarcolemma suggestive of hypercontraction were found in 11 of 12 patients in the trapezius muscle (Kalyan-Raman et al, 1984). A subsequent controlled and blinded study of trapezius muscle reproduced these and other findings, but they turned out to be non-specific (Yunus et al, 1989a). Atrophy and basal lamina excess were also reported by Drewes et al (1993). Biochemistry

The level of ATP in healthy trapezius muscle was higher than in painful FM trapezius muscle, but was not different from pain-free anterior tibialis muscle from FM patients (Bengtsson et al, 1986c). Similar changes have been found in patients with rheumatoid arthritis (Nordemar et al, 1974) and work-related chronic myalgia (Larsson et al, 1988). The possibility of disuserelated changes in the phosphagen pools cannot be ruled out, even though these pools seem quite stable (Saltin and Gollnick, 1983). Increased intracellular calcium in FM, as hypothesized above, may also result in a depletion of ATP via overwork of cytoplasmic ATP-dependent calcium pumps. Substrate and carnitine levels do not seem to be affected in FM (Bengtsson et al, 1986c, 1990). Glycolytic enzyme activities have not been studied as yet.

PERIPHERAL MECHANISMS OF PAIN IN FM Muscle nociception

Muscle pain is mediated by slowly conducting thin-myelinated and nonmyelinated afferent nerve fibres (Mense, 1986). The receptors at the end of these fibres are named free nerve endings due to the lack of a visible receptor structure (Stacey, 1969). These free nerve endings are concentrated in the regions of tendons and connective tissue in the muscle (Stacey, 1969; Kumazawa and Mizumura, 1977). The receptive endings are stimulated by mechanical forces and normally have a high mechanical threshold. However, several endogenous substances such as bradykinin, histamine, potassium, prostaglandins and substance P may lower this threshold, resulting in the sensation of pain when the muscle is contracted or pressed upon (Dorpat and Holmes, 1955; Mense, 1990). Some of the endogenous substances mentioned are seen in relation to inflammation. However, inflammatory responses are not always present in sore or painful muscle, especially not in FM (Drewes et al, 1993). The lack of pain-relieving effects in controlled studies of non-steroidal anti-inflammatory drugs (Goldenberg et al, 1986;

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Yunus et al, 1989b) and prednisone (Clark et al, 1985b) in FM further discards the existence of an inflammatory process. Furthermore, muscle inflammation does not always produce pain, as in the case of polymyositis (Bohan and Peter, 1975). This directs attention towards non-inflammatory agents such as potassium, which has been shown to leak out to the interstitium and subsequently to the plasma during muscle work (Sjcgaard, 1990). Exercise-induced muscle pain and microtrauma

Muscle pain as an acute effect of unaccustomed exercise is a well-known phenomenon, and may be attributable to accumulation of metabolites in the muscle (Dorpat and Holmes, 1955). This pain normally disappears rapidly, but hours to days after exercise, stiffness and soreness of the exercised muscles may become prominent again (delayed onset of muscle soreness; DOMS). Asmussen reported in 1956 how eccentric work is particularly responsible for the development of DOMS in contrast to concentric work. Eccentric muscle work is less expensive in terms of energy than concentric muscle work for the same tension developed (Asmussen, 1952) due to recruitment of fewer muscle fibres (Newham, 1988). This results in a higher tension per recruited muscle fibre in eccentric contractions than in concentric contractions. Exercise-induced muscle fibre injury has been verified in extensive studies by Frid6n et al, with the most prominent microtraumas being streaming or disruption of the Z discs (Frid6n et al, 1981, 1988; Frid6n, 1984). However, biochemical factors within the muscle may play a role in the development of muscle pain and ultrastructural changes, as suggested by Armstrong (1984). Structural damage to the sarcolemma or alterations in the permeability of the cell membrane resulting from mechanical forces may result in an increased intracellular calcium content. This has deleterious effects on mitochondria, sarcolemma, Z discs, troponin and tropomyosin due to calcium-dependent proteases and phospholipases (Dayton et al, 1976; Jackson et al, 1984). Microtrauma of the sarcolemma would result in the diffusion of intracellular components into the interstitium. The efflux of potassium during work induces muscle fatigue, and has been considered to be a protective mechanism against muscle overload (Sj0gaard, 1990), but an increase in extracellular potassium may also sensitize muscle nociceptors (Kniffki et al, 1978). Pain mechanisms in DOMS and FM are probably not the same since pain in DOMS correlates with a raise in serum levels of muscle enzymes (Fleckenstein et al, 1989) which, by definition, are normal at rest in FM and do not rise excessively after exhaustive work (van Denderen et al, 1992). However, work-induced potassium efflux may constitute a peripheral pain stimulus that could account for the acute worsening of pain after physical activity which is characteristic in FM (Jacobsen et al, 1993). Further evidence for a peripheral origin of the pain in FM is the finding of tender point reduction by epidural blockade (Bengtsson et al, 1989).

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Focal muscle energy crisis

A series of Swedish studies indicate that there is a muscle energy deficiency in FM (Henriksson and Bengtsson, 1990). This hypothesis is based on the following findings in resting, painful FM muscle: signs of disturbed microcirculation and hypoxia (Lund et al, 1986), histochemical signs of mitochondrial dysfunction (Bengtsson et al, 1986b), reduced high-energy phosphate content (Bengtsson et al, 1986c) and decreased muscle relaxation rate (indicative of energy depletion) (B~ickman et al, 1988). These studies have not all been repeated, but no evidence for hypoxia was found in FM muscle by Brfickle et al (1990). SchrCder et al (1993) did not find ragged-red fibres in FM, and the finding of low levels of high'energy phosphates was not reproduced (J. N0rregaard, M. Harreby, K. Amris, B. Kiens, E. Bartels and B. Danneskiold-Sams0e, unpublished results). However, if these findings are related to physical activity, the differences may relate to selection of patients. Unfortunately, such data are not available. Studies using 31p MR spectroscopy and respiratory gas exchange did not support the concept of a generalized abnormality of muscle metabolism. But, as stated by Henriksson and Bengtsson (1990), the energy deficiency may be restricted to single muscle fibres. Such energy-deficient fibres would constitute a possible source of noxious substances such as potassium and lactate. If these changes are secondary to disuse, these mechanisms would also apply in other chronic diseases affecting physical fitness. The common coexistence of FM and rheumatoid arthritis (Wolfe and Cathey, 1983; Wolfe et al, 1984a) might partly be explained in this way. C E N T R A L M E C H A N I S M S OF PAIN IN FM Disturbed pain modulation

The involvement of the central nervous system (CNS) in FM was indicated by Smythe (1979) when introducing the theory of pain amplification. Within recent years increasing evidence has emerged that pain modulation is disturbed in FM. FM patients are more tender over the so-called tender point areas compared with control points and when compared with healthy normals they are somewhat more tender over control points (Scudds et al, 1987; Quimby et al, 1988; Simms et al, 1988; Tunks et al, 1988; Wolfe et al, 1990; Kroeling et al, 1992; Mau et al, 1992). One interpretation of these findings is that FM patients over-react to normal bodily sensations, a notion that is the foundation of the somatization concept. On the other hand, somatic distress and functional disability may result from a true enhancement of pain through a reduction in the descending inhibitory pathways of pain. CNS evoked responses of cutaneous heat stimulation were abnormally increased in FM and were correlated with the severity of FM (Granges et al, 1993). CNS evoked responses were also correlated with the degree of cutaneously induced flares, which previously were reported to be increased in FM after chemical induction (Littlejohn et al, 1987). These findings may be interpreted as increased activity of polymodal nociceptors in FM.

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Several neuropeptides responsible for the modulation of afferent pain have been investigated. Studies of serum and cerebrospinal fluid (CSF) levels of [3-endorphin have not revealed abnormalities (Yunus et al, 1986; Va~re~y et al, 1988b). Markers for pro-enkephalin and pro-dynorphin, two other major opioid systems, were found to be increased in CSF from FM patients (Va~rCy et al, 1991). Endorphin deficiency is thus not likely, but whether receptor sensitivity is reduced is unknown. Moldofsky and Warsh (1978) noted that there was a weak but definite association with symptomatology at low levels of plasma tryptophan and suggested that abnormal serotonin metabolism may be relevant to the pathophysiology of the FM syndrome. Tryptophan is the precursor of serotonin, which in turn is an important neurotransmitter in the pathways serving stage 4 sleep as well as the inhibitory descending pain pathways (Russell et al, 1986; Jones, 1989). Yunus and coworkers (i992) have described normal levels of plasma tryptophan in FM patients compared with healthy controls, but FM patients had a significantly reduced transport ratio of tryptophan (the transport ratio is the molar concentration of tryptophan divided by the sum of the molar concentrations of other plasma amino acids). On the other hand, Russell et al (1989) reported that the concentration of serum tryptophan, as well as nine other amino adds, was significantly lower in 20 FM patients compared with 20 matched controls. An upregu lation of 3H-imipramine binding to platelets in FM patients may reflect low levels of serotonin (Russell et al, 1992a), as imipramine binds to platelet receptors and an increased density of binding sites would be consistent with an upregulation of serotonin receptors resulting from low plasma levels. Further support for the 'serotonin hypothesis' comes from the finding of low CSF concentrations of 5-hydroxyindoleacetic acid (Houvenagel et al, 1990; Houvenagel et al, 1992; Russell et al, 1992b), a metabolic byproduct of tryptophan metabolism. Serotonergic CNS activity is closely related to pain modulation, depression and sleep physiology (Beitz, 1990; Weil-Fugazza, 1990), which are all important issues in FM. In a related vein Va~rCyand coworkers (1988a) have found higher levels of substance P in the CSF of patients with FM compared with healthy controls and other chronic pain patients. A large proportion of the substance P synthesized in the dorsal horn is transported antidromically to the peripheral terminations of afferent pain fibres. Littlejohn and coworkers (1987) have shown an enhanced response in FM patients to capsaicin, the active ingredient of the red pepper, which stimulates the release of substance P from afferent nerve terminals. However, the concept of enhanced perception of minor nociceptive stimuli in FM is far from proven; in fact, there are persuasive arguments to the contrary (Bengtsson and Bengtsson, 1988; Bengtsson et al, 1989; Bennett, 1990, 1993a). Besides disturbed pain modulation, CNS dysfunction may also involve autonomic dysfunction. Many of the subjective symptoms that are described in FM may be vegetative, indicating an increased sympathetic drive. Uncontrolled preliminary studies on plasma and urinary catecholamines indicate increased levels for at least noradrenaline (Russell et al, 1986; Hamaty et al, 1989). Bennett et al (1991) have shown increased cold-induced

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vasospasm which correlated with elevated levels of a2-adrenergic receptors in FM patients. These studies both indicate increased sympathetic discharge and increased responsiveness to efferent sympathetic activity. Improved skin microcirculation related to reduction in pain as an effect of regional sympathetic blockade further indicates the significance of sympathetic activity in the pathophysiology of FM (B~ickman et al, 1988; Bengtsson and Bengtsson, 1988). Low postural control and failure to relax during short pauses indicate reduced motor coordination (Elert et al, 1989; Thoumie et al, 1992). This could be due to low muscular fitness, but eye motility dysfunction as described by Rosenhall et al (1987) and Odkvist et al (1986) indicate poor central control. Abnormal auditory evoked brainstem responses also direct attention to the possibility of intracranial CNS lesions, as previously described in a smaller group of patients (Jacobsen et al, 1989).

Psychological and psychiatric aspects Although the core symptoms of FM are widespread musculoskeletal pain and multiple tender points, many patients present with a syndrome of generalized somatic complaints (Yunus et al, 1981; Bengtsson et al, 1986a; Dinerman et al, 1986; Bennett, 1989a; Wallace, 1990; Wolfe et al, 1990; Bennett et al, 1991). Common symptoms include tension headaches, migraine headaches, irritable bowel syndrome, Raynaud's phenomenon, premenstrual tension, jaw pain, irritable bladder, paraesthesiae, excessive fatigue, anxiety, depression and sicca symptoms. It has been suggested that these symptoms are not distinct but represent a pattern of generalized somatic distress suggestive of a somatoform disorder (Kirmayer et al, 1988). To quote from the Diagnostic and Statistical Manual of Mental Disorders (DSM IIIR) (American Psychiatric Association, 1987), 'the essential features of this group of disorders are symptoms suggesting a physical disorder (hence, somatoform) for which there are no demonstrable organic findings or no physiological mechanisms and for which there is positive evidence or a strong presumption that the symptoms are linked to psychological factors or conflicts'. In other words, although the symptoms are 'physical' in the absence of a generally agreed upon pathophysiological derangement, they are most readily conceptualized by means of psychological constructs. There are seven categories of somatoform disorder; the one most applicable to FM is somatoform pain disorder. This is defined as a preoccupation with pain for at least 6 months plus either (i) appropriate evaluation uncovers no organic pathology or pathophysiological mechanism (e.g. a physical disorder or the effects of injury to account for the pain) or (ii) if there is related organic pathology, the complaint of pain or resulting social or occupation impairment is grossly in excess of what would be expected from the physical findings. The latter notion embodies the idea that, although symptoms may have a peripheral locus, their perception is magnified at a central level; Yunus (1992) has hypothesized that such a mechanism is at work in FM patients. If there is an enhanced responsiveness to painful stimuli in FM, it may

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only involve a small subset of patients. Some support for this notion has been advanced by Clark et al (1993) in a study of perceived discomfort when exercised to volitional exhaustion. Most FM patients could push themselves to exercise beyond the anaerobic threshold (a respiratory quotient > 1.0) and could also accurately estimate their level of exertion. However, approximately one quarter of the patients did overestimate their degree of work; this subset failed to reach the anaerobic threshold on account of pain. Interestingly another subset, all of whom reached the anaerobic threshold, underestimated their degree of work. This result may be an explanation for the finding that the core features of FM (tender points, fatigue and poor sleep) were independent of psychological status, but pain severity was correlated with the level of psychological distress (Yunus et al, 1991). In general, numerous studies of FM patients have failed to establish any consistent psychological profile (Ahles et al, 1984, 1991; Wolfe et al, 1984b; Clark et al, 1985a; Bengtsson et al, 1986a). Many patients suffer from a lot of somatic and psychological distress (Robbins et al, 1990; Uveges et al, 1990), but this may be the result of a markedly reduced quality of life (Henriksson et al, 1992; Burckhardt et al, 1993) and/or the fact that most such studies have been done on patients seen in academic centres, with a resulting referral bias, Birnie et al (1991) examined psychological aspects of patients with FM and compared them with patients with chronic pain and concluded that many of the psychological aspects of FM are the psychological sequelae of chronic pain. A study comparing FM patients with rheumatoid patients and patients without pain found no differences in the lifetime history of any psychiatric disorder (Ahles et al, 1991). However, FM patients did have an elevation on the somatization scale which correlated with a history of psychiatric disorder. The idea that FM may be a 'depressive equivalent' has had many proponents. This has resurfaced under the title of 'affective spectrum disorder' (Hudson and Pope, 1989; Hudson et al, 1992), The conditions encompassed by this diagnosis include FM, panic disorder, depression, obsessive/compulsive disorder, attention deficit disorder, bulimia nervosa, migraine and irritable bowel syndrome. The justification for placing these conditions into one diagnostic category is based on the common denominators of: (a) an association with depression; (b) a high comorbidity with one another; (c) a tendency to familial aggregation; and (d) a beneficial response to antidepressants. This hypothesis should be interpreted in the light of widely differing reports on the extent of depression in FM and equivocal results with the dexamethasone suppression test (Hudson et al, 1984; McCain and Tilbe, 1989), although this test is only abnormal in melancholic depression. In summary, the contemporary evidence does not support the notion that FM is a psychological disease; however, in a subset of patients, psychological factors may modulate the severity of perceived distress and demand appropriate recognition and treatment. Sleep disturbances and the neuroendocrine axis

Virtually all FM patients report awakening in the morning feeling as if they had never slept, or even if they did sleep 6-10 h they feel unrefreshed on

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arising (Campbell et al, 1983; Wolfe et al, 1985; Yunus and Masi, 1985). Many FM patients say that they are light sleepers and are easily awakened by minor noises or disruptive thoughts. Furthermore, they often perceive the diurnal intensity of their symptoms to be positively correlated to having a 'good' or 'bad' night. The mechanism whereby a sleep disorder could modulate the symptoms of muscle pain and other sensations is not immediately apparent unless it merely reflects the effects of fatigue on coping abilities. The finding of a distinctive but not unique sleep disturbance in the majority of the FM patients by Moldofsky et al (1975) was a seminal milestone in the renewed interest in this condition in the early 1980s. It was noted that FM patients had an alpha rhythm (7.5 to 11.0 Hz) on electroencephalographic recordings of non-rapid eye movement (NREM) sleep. This was found to be present over the central and prefrontal areas of the scalp, whereas the alpha rhythm seen during quiet wakefulness predominates over the posterior scalp. This sleep anomaly was not specific for FM, having been first described by Hauri and Hawkins (1973) in a small group of psychiatric patients who all shared the symptoms of malaise and fatigue-they termed this abnormal rhythm the alpha-delta sleep anomaly. Furthermore, the ability to cause a FM-like state in healthy volunteers by the artificial induction of alpha-delta NREM sleep suggested that abnormal sleep may play an important role in the pathogenesis of the syndrome (Moldofsky and Scarisbrick, 1976). Subsequent reports have linked conditions that result in alpha-delta NREM sleep with the clinical syndrome of FM; these include nocturnal myoclonus (Moldofsky et al, 1986), sleep apnoea (Molony et al, 1986), rheumatoid arthritis (Moldofsky et al, 1983), osteoarthritis (Moldofsky et al, 1987), physical trauma (Saskin et al, 1986) and viral illnesses (Moldofsky et al, 1988). Other links between disturbed sleep and FM-like symptoms can be found in references to the stress of combat in World War II (Boland, 1947), Israeli soldiers involved in combat duties (Solomon et al, 1987) and the disruptive effect of aircraft noise (Tarnapolsky et al, 1980). On the other hand, the occurrence of alpha-delta sleep is not invariably associated with the development of FM (Dumermuth et al, 1972; Scheuler et al, 1983; Scheuler et al, 1988), suggesting that the pathogenesis is multifactorial (Bennett, 1989b, 1993a). Nevertheless, medications that improve the quality of sleep have provided modest but definite benefit in controlled trials (Carette et al, 1986; Goldenberg et al, 1986; Bennett et al, 1988; V~erOyet al, 1989; Jacobsen et al, 1991b). The manner in which alpha-delta sleep could play a part in the pathogenesis of FM symptoms is not readily apparent. However, it may be relevant that the pulsatile secretion of several pituitary hormones is closely linked to the chronobiology of different sleep stages (Van Coevorden et al, 1991). This is especially notable in the secretion of cortisol, prolactin and growth hormone (GH). Several recent studies have described changes in the secretion of these three hormones. McCain and Tilbe (1989) initially reported that FM patients had less variation between peak and trough values of plasma cortisol levels compared with rheumatoid arthritis patients. A careful analysis of the hypothalamic-pituitary-adrenal (HPA) axis in FM has indicated the

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following changes: (a) insulin-induced hypoglycaemia and corticotrophinreleasing hormone stimulation induced an exaggerated secretion of adrenocorticotrophic hormone (ACTH) in FM compared with controls; (b) there was no escape from suppression in either FM or controls on administration of 1 mg of dexamethasone; and (c) despite the heightened secretion of ACTH in FM there was no concomitant increase in plasma cortisol (Griep et al, 1993). These results were interpreted to indicate that FM patients have a hyperactive pituitary ACTH response and a relative adrenal hyporesponsiveness. This pattern of reactivity is different from that described in melancholic depression (Gold et al, 1988) and the chronic fatigue syndrome (Demitrack et al, 1991). Whether these differences are 'real' or whether they relate to the complex feedback loops, diurnal variability and overall plasticity of the H P A axis must await further investigation. The similarity between many FM symptoms and hypothyroidism has made evaluation of thyroid hormone secretion a standard baseline test for FM patients. Interestingly, even when a diagnosis of hypothyroidism has been made and adequately treated, the FM symptoms do not improve (Wilke et al, 1981; Trommer, 1982; Carette and LeFrancois, 1988). Neeck and Riedel (1992) have recently reported a suboptimal response of thyroidstimulating hormone and thyroid hormones to stimulation with thyrotrophin-releasing hormone (TRH); it was also noted that there was an exaggerated response of prolactin to TRH. Ferraccioli (1991) also reported a hyperprolactinaemic response after stimulation with T R H in one third of FM patients. Bennett et al (1992) have reported significantly lower levels of somatomedin C in the serum of FM patients compared with healthy controls. Somatomedin C is produced by the liver in response to the pulsatile secretion of GH and is the major mediator of GH's anabolic actions. The secretion of G H is tightly linked to NREM sleep, and approximately 80% of GH is produced during stage 4 sleep (Holl et al, 1991). Total disruption of sleep by staying awake all night almost completely abolishes the secretion of GH (Davidson et al, 1991). Furthermore, the other major stimulus for GH secretion is strenuous exercise (Weltman et al, 1992), which is usually lacking in most FM patients (Bennett et al, 1989). It is tempting to link low levels of somatomedin C in FM with the alpha-delta sleep anomaly; however, such a conclusion must await studies that periodically measure G H levels throughout the night in FM patients and relate them to the different stages of sleep and in particular the occurrence of alpha-delta sleep. Many of the symptoms of adult GH deficiency are mirrored by FM patients (Cuneo et al, 1990, 1992). In particular, they have an impaired quality of life (Bjork et al, 1989) which is improved by treatment with recombinant human GH (McGauley et al, 1990). From the point of view of musculoskeletal pain, low levels of somatomedin C may be especially relevant as G H has important anabolic effects on muscle (Salomon et al, 1989; Lundeberg et al, 1991; Fryburg et al, 1992) and supplemental GH given to GH-deficient adults improves muscle performance (Cuneo et al, 1991a,b; Yarasheski et al, 1992). A hypothesis has been forwarded that links the musculoskeletal pain experienced by FM patients to the muscle microtrauma that occurs after

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unaccustomed exercise, and suggests that a relative GH deficiency might be a factor in the perpetuation of a vicious cycle of pain-inactivity-deconditioning and increased susceptibility to muscle microtrauma (Bennett, 1990, 1993a,b).

SUMMARY

It may be concluded that both peripheral and central mechanisms may operate in the pathophysiology of both impaired muscle function and pain in FM. These mechanisms may in part be attributable to physical deconditioning and disuse of muscle secondary to the characteristic pain and fatigue so often seen in FM. Most likely the initiation of this condition is multifactorial and the combination of peripheral and central factors that constitute a vicious circle may perpetuate the condition into a chronic state.

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