Fibromyalgia: A Distinct Entity

The University of Sydney Faculty of Medicine
Postgraduate Diploma in Physical Medicine (Musculskeletal)

ESSAY 1997: Fibromyalgia: A Distinct Entity
Dr D W Allen

Introduction

After 150 years of controversy and a mountain of research, the very existence of an entity with a reported incidence of 2-5%, one in four of which receive disability payments, is still the subject of intense medical debate?. Even among those who accept fibromyalgia as a distinct entity, there is disagreement as to whether the abnormality is central (in the nervous system) or peripheral (in the muscles). This essay will examine the evidence, reviewing the literature relating to pathology, aetiology, therapy and prognosis, and explore connections, if any, with myofascial pain syndrome (MPS), chronic fatigue syndrome (CFS) and depression.

The all too common presentation of chronic widespread muscular aches and pains, tenderness and stiffness, was once variably termed muscular (or soft-tissue or non-articular) rheumatism or, where fatigue was a prominent feature, neurasthenia. In 1904, when an Edinburgh pathologist, Ralph Stockman, documented inflammation in fibrous intermuscular septa in biopsies of tender muscles from these patients, the neurologist, Sir William Gower, coined the term fibrositis. A later variation was fibromyositis. When repeated attempts to reproduce Stockman’s findings met with failure, the misnomer fibrositis fell into disrepute and subsequent neglect, being replaced by synonyms, based on unproven theories, such as psychogenic rheumatism , tension rheumatism or muscle-tension pain syndrome. After Lewis and Kellgren, demonstrated referred pain patterns on injecting hypertonic saline into normal muscles in the 1930s, and Travell developed the concept of myofascial trigger points and MPS, the two conditions became confused. This confusion is still evident in some rheumatology texts.

A new era began when Moldofsky and his co-workers described distinct electroencephalographic (EEG) sleep abnormalities in patients with chronic diffuse musculoskeletal pain and multiple tender points in 1975; reported induction of the condition in healthy volunteers by selective sleep stage deprivation in 1976; and proposed diagnostic criteria in 1977. They stimulated a cascade of interest and research papers that led to increasing clinical acceptance of fibromyalgia, a term suggested by Yunus in 1981. The fibromyalgia syndrome (FMS) then received the official imprimatur of the American College of Rheumatology, which published classification criteria in 1990, and official recognition by the World Health Orgainzation in 1992.

Classification Criteria

As interest grew, various centres evolved their own diagnostic criteria, based on unblinded studies and often imprecise clinical features. Although useful, the varying definitions tended to be circular and tautological. While most researchers focused on the presence of chronic widespread pain and multiple tender points, others emphasised associated symptoms, such as disturbed or non-restorative sleep, and modulating factors. 15. Most, but not all, accepted secondary or concomitant fibromyalgia in the presence of other medical disorders. 16. There was diagnostic uncertainty regarding the degree and extent of pain, the number and distribution of tender points and placebo points, the degree of tenderness, and the applied pressure required. The authoritative Textbook of Rheumatology, for instance, listed 14 points in 1985 and 16 (requiring 7 to be tender) in 1989. 11.

A consortium of centres interested in fibromyalgia therefore formed a committee in 1986 to provide a consensus definition and establish new criteria for the classification of FMS.16 Sixteen centres participated in the study of 558 consecutive patients, interviewed and examined by trained and blinded assessors. There were 158 patients with primary fibromyalgia, 135 matched controls with regional tendinitis or pain syndromes; 135 secondary fibromyalgia patients (35% with inflammatory arthritis, 37% with osteoarthritis of the knee or hip, and 28% with axial skeletal pain syndromes) and 130 matched controls with the same conditions but without fibromyalgia. They analysed 11 symptom variables previously shown to differ among primary fibromyalgia patients and controls, and 10 modulating factor variables, including noise, stress, activity, heat, cold, humidity, and weather changes.

Symptoms. Sleep disturbance, fatigue, and morning stiffness were found to be the most common symptoms, present in 73-85% (but all three in only 56%) of the patients. Pain all over, paraesthesias, frequent headaches, and anxiety were moderately common, occurring in 45-69%. Prior depression, irritable bowel syndrome, urinary urgency, dysmenorrhoea, Raynaud’s phenomenon, and sciatic symptoms were less common (<35%). Patients and controls differed for these symptoms at the 0.001 level. There was no significant difference between primary and secondary-concomitant fibromyalgia patients, except that irritable bowel syndrome was more common in the former.

Modulating factors were found in 60-79% of fibromyalgia patients, but in nearly as many controls.

Widespread pain. Pain for at least three months on both sides of the body, above and below the waist, and including axial skeletal pain, was present in 97.6% of patients and 70% of controls, giving a specificity of 30.9%.

Tender points (TP) were palpated manually by examiners trained to apply a consistent pressure of 4 kg, with the pulp of the thumb, index or middle fingers, at 24 actived sites (12 pairs) and 6 control sites (3 pairs), recording 5 grades of tenderness. Dolorimeters (spring-loaded gauges capped with a 1.54cm2 stopper, advanced at approximately 1 kg/second until pain occurred or 6.5 kg) were also used at 6 active and 3 control sites, on the right side of the body only, as shown in Table 1.

Table 1. SITES OF ACTIVE & CONTROL TENDER POINTS FOR MANUAL PALPATION & DOLORIMETRY

Manual Palpation (R & L) Dolorimetry
Active sites:
1. Occiput: Suboccipital muscle insertions (R)
2. Trapezius: Midpoint of upper border (R)
3. Supraspinatus: Above medial border of scapular spine
4. Paraspinous: Mid-scapula 3 cm lateral to midline (R)
5. Low cervical: Anterior aspect of intertransverse space of C5-7
6. Second rib: Upper lateral costochondral junction(R)
7. Lateral pectoral: 4th rib at anterior axillary line
8. Lateral epicondyle: 2 cm distal to epicondyle (R)
9. Medial epicondyle: over epicondyle
10. Gluteal: Upper outer quadrant of buttocks
11. Greater trochanter: Posterior to trochanteric prominence
12. Knee: Medial fat pad proximal to joint line (R)
Control Sites: 1. Forearm: Junction of middle and distal dorsal thirds (R)
2. Thumbnail (R)
3. Midfoot: Midpoint of dorsal third metatarsal (R)


Dolorimetry was not found to be superior to manual palpation. Indeed, the most discriminating and least variable measure of tenderness was mild or greater tenderness as determined by palpation. To reduce the number of TP to a manageable level, the committee eliminated three pairs of TP (the lateral pectorals, medial epicondyles, and paraspinous points) which had the lowest discriminating power, leaving 18 sites (Table 1. Bold face).

Skinfold tenderness, assessed by skin rolling over the upper trapezius, was significantly present in 60% of patients and 16.7 % of controls. Reactive hyperaemia (49.8%) and reticular skin abnormality (14.6%), however, had little discriminatory power.

ACR-90 Criteria. Various combinations of TP levels and groups of symptoms (as in previous criteria) were tested, but none proved to be as sensitive (88.4%), specific (81.1%), and accurate (84.9%) as the combination of:

1. History of widespread pain (and)
2. Pain in 11 of 18 tender points on digital palpation with a force of 4 kg.
Primary and secondary-concomitant fibromyalgia were essentially indistinguishable using these criteria, and the committee suggested abolishing this distinction. While the ACR-90 classification criteria does not include other frequently encountered symptoms or signs, it does not preclude them.
The Controversy
The ACR-90 classification criteria has been attacked from two sides, each focusing on peripheral pathology. Firstly, the sceptics, such as Awerbuch 3, argue that a distinct disease entity must be a discrete homogeneous disorder and that tender points are as non-specific as widespread pain.. . and the sites of the tender points have no discriminating value, based on the following evidence:
a) Tender points (sometimes more than 11) are found in people not complaining of pain.
b) FMS patients are more tender everywhere (i.e. at control sites) than are controls.
c) Since 90% of experienced examiners could not consistently determine when they were
d) applying 4 kg of pressure by palpation?, and there is only moderate inter-rater reliability
e) with both digital examination (kappa = 0.51) and dolorimetry (kappa = 0.62), the latter
f) resulting in significantly fewer points being classified as tender?, the prevalence of
g) fibromyalgia might vary as a function of examination technique.
h) No serious attempt has been made to define the tender point. There is almost unanimous
i) agreement that the tender point cannot be defined in patho-anatomical terms.3
j) Secondly, the true believers in a peripheral pathology deny any association with central symptoms or overlap with other syndromes4. Some investigators, convinced of the uniqueness of tender points, have attempted to refine the examination of these points (Figure 1). Intensively trained examiners, using only the thumb pad, specific patient/examiner positioning for each site, a numerical order of survey sites, detailed soft tissue and bony landmarks to achieve more precise locations, and re-introduction of pain ratings (on a scale of 0 to 10) found that 70 fibromyalgia patients reported significantly higher pain severity than did 70 patients with chronic headache for all TP sites and 2 of the 3 control sites. There was no difference at the mid-forehead control point. They interpreted the finding that fibromyalgia patients rated control sites (none of which were over muscle) as significantly less painful than active sites, as supporting the uniqueness of the TP. The inter-rater reliability of these examiners, however, was not tested.
Pathology and Pathophysiology of a Tender Point
As previously mentioned, muscle biopsy studies? in the 1920s and 1930s failed to confirm Stockman’s findings of inflammation. In 1940, Collins put the final nail in the fibrositis coffin with further negative studies and a review of Stockmaní’ original biopsy photographs, which scarcely show more variation in fibrous tissue structure than can be encountered normally.
Ultrastructural findings of abnormal mitochondria and moth-eaten muscle fibres, in unblinded uncontrolled muscle biopsy studies, were first reported by Fassbender in 1975, and subsequently by Hendriksson et al, who also described ragged-red fibres and histochemical evidence of reduced high energy phosphates, suggestive of tissue anoxia. Blood flow studies in resting trapezius muscles by Klemp, using 133xenon clearance, detected no difference between patients and controls. Bennett, finding that over 80% of FMS patients had below average levels of aerobic fitness, respiratory quotient during exercise, and blood flow (133xenon clearance) in exercising muscles, and that even moderate physical activity exacerbated their muscle symptoms, postulated that FMS patients have a heightened susceptibility to muscle hypoxia and microtrauma. These studies, however, failed to account for deconditioning in patients with FMS.
Yunus, employing sedentary controls, blinded reading and graded systems, failed to confirm Fassbenderís and Hendrikssonís histological findings. In a study that fully accounted for the possible effects of deconditioning on muscle in FMS, Simms, using highly sophisticated magnetic resonance spectroscopy (31P-MRS) over TPs in FMS patients and sedentary controls, found no significant difference in levels of phosphocreatine (PCr), inorganic phosphate (Pi), and PCr/Pi ratios. Nor did he find any correlation between overall or local pain severity and the principal muscle metabolic parameter, PCr/Pi in patients with FMS. Patients and sedentary controls also had similar levels of VO2max and of maximum voluntary contraction of the upper trapezius and tibialis anterior muscles. Also using 31P-MRS, Jubrias and Bennett found unchanged PCr/Pi ratios and dolorimetry scores in FMS patients following acute exercise, providing evidence against their earlier hypothesis that FMS patients are more susceptible to activity-induced muscle damage than are healthy controls. They did, however, find a 3-fold higher rate of phosphodiester resonance among FMS patients than among controls. As they point out, phosphodiester peaks may be seen in some normal muscles, and the significance of their findings is unclear.
Electromyographic (EMG) studies of TPs, by both surface and needle EMG, have revealed no abnormalities or evidence to support the belief that fibromyalgia pain is the result of constant muscle tension or defective sympathetic nervous dysfunction. The EMG has also been used to demonstrate that early studies showing reduced muscle strength in FMS can be explained by lack of voluntary effort.38
In conclusion, therefore, the pathology and pathophysiology of the tender point remains elusive. Muscle tenderness in fibromyalgia cannot be explained on the basis of primary muscle abnormalities, either structural or functional, general or focal. The same cannot be said, however, about myofascial trigger points.
Distinction Between Tender Points in FMS and Trigger Points in MPS
Myofascial trigger points (TrP) have been defined by Travell and Simons as self-sustaining hyperirritable foci located in skeletal muscle or its associated fascia, characterized clinically by discrete tenderness, usually over a palpable nodule within a taut band of muscle, reproducing the patients referred pain, a jump sign, and a twitch response to stimulation by vigorous snapping palpation of and/or needling the taut band at the TrP. There is usually functional shortening and inhibitory weakness of the involved muscle. Active trigger points refer pain at rest or with normal activity, whereas latent trigger points produce referred pain only on stimulation. They can become activated by chilling or overloading the muscle.
In monopolar needle EMG studies of trigger points, Hubbard and Berkoff found spontaneous electrical activity (SEA) to occur only when the needle was precisely located within the TrP, so as to reproduce the subjects referred pain. The SEA persisted for as long as the needle remained in the nidus of the TrP, but would disappear if the needle was moved as little as 1 mm. Simons also found regular high-amplitude spike potentials, superimposed on a background of SEA, in close proximity to end plate zones, suggestive of excessive acetycholine release from dysfunctional motor end plates.
Hong examined the twitch response with a surface EMG electrode over a TrP and a needle within the taut band, and found it to be quite distinct from a voluntary contraction of the muscle (Figure 2). In studies on rabbits, he found that transection of the spinal cord did not ablate the twitch response, but transection of the ventral nerve root did, implicating the motor neuron at the spinal cord level.
Simons describes large round myofibrils in cross section histological examinations of trigger points, and contraction knots of bunched up sarcomeres in some fibres adjacent to motor end plates in longitudinal sections under electron microscopy. Bruckle probed trigger points with an oxygen sensor and found elevated pO2 levels immediately surrounding an hypoxic nidus within TrP nodules, leading Simons to postulate a self-perpetuating energy crisis, with reduced ATP production and calcium reuptake, resulting in sustained contraction of that part of the fibre adjacent to the motor end plate.
Unlike tender points in FMS, trigger points respond well to spray and stretch techniques, to injection with a wide range of agents, and to dry needling 39, probably by disruption of the contraction knots. Differences between FMS and MPS are summarized in Table 2. Although quite distinct clinical and pathological entities, they are not mutually exclusive. In a study of 96 chronic pain patients referred to a community pain centre, Gerwin found that 74% had MPS, 7% had FMS and 19% had both.
Table 2. DISTINCTIVE DIFFERENCES IN HISTORY, EXAMINATION AND RESPONSE TO TREATMENT IN MPS & FMS
Myofascial Pain (MPS) / Fibromyalgia (FMS)
Sex M / F - M:F = 1:7 (1)
Family History+/++ (?)
Fatigue / Poor Sleep+/+++
Psychological Distress+/++++ (1)
Mechanical Factors++ +/-
Site of Pain: Regional / Local /Widespread / Diffuse
Tenderness Focal (TrP) Generalized (11/18 TP)
Referred Pain Yes No
Jump Sign Yes No
Twitch Response Yes (usually) No
Muscle Compliance Normal / Reduced (8)
Range of Movement Reduced (affected muscle) / Normal
Response to Injection Excellent/Poor
When trigger points are found in FMS patients, they respond differently and less well to injection or needling than do trigger points in patients without FMS (Figure 3). A fibromyalgia patient having a TrP injected, therefore, should be warned that they will have more pain for several days before a gradual relief of symptoms over the following two weeks. Response over time to injection of a TrP in patients with and without FMS. Those with MPS only had rapid pain relief, while those with FMS had more pain initially. (From Hong et al.)
Evidence for a Central Mechanism: Perceptual Amplification in Fibromyalgia
It is now quite evident that, unlike MPS, there is no peripheral pathology to account for the pain of FMS. Fibromyalgia patients have widespread pain and hyperalgesia, extending well beyond the tender points; and the pain is not reproduced by pressure on a TP, nor relieved by anaesthetizing it. This is very suggestive of a central pain mechanism, as is the qualitative difference in response to injecting a TrP in FMS.
Further evidence that nociception is qualitatively altered in patients with FMS has recently been provided by Bendtsen et al. They took 25 women with FMS and 25 healthy women, and asked them to record their pain response on a visual analogue scale as their trapezius muscles were subjected to seven different intensities of pressure. As expected, the FMS patients experienced more pain at all levels of pressure. But, unlike the logarithmic response of the healthy controls, their response was almost perfectly linear. Interestingly, the response to pressure over the temporalis muscle in both groups conformed to a near perfect power function, indicating that nociception is not universally altered in patients with FMS.
The question is whether these changes can be linked to peripheral nerve endings, the spinal cord, or to higher-order neurons. Unless an unidentified class of silent nociceptors exists, it is unlikely that sensitization of peripheral nociceptors would induce a qualitative as well as quantitative change in the stimulus-response curve.
The authors suggest, as a more likely explanation, an alteration in the synaptic connections between the low-threshold mechanosensitive (LTM) neurons and the high-threshold mechanosensitive (HTM) neurons in the dorsal horn of the spinal cord, so that the linear response of the LTM neurons to innocuous stimuli is transmitted to the HTM neurons, which normally posses a positively accelerating stimulus-response to nociceptive input. In this way, the LTM afferents can mediate pain, probably via N-methyl-D-aspartic acid (NMDA) receptor activation. NMDA receptor-blockade with intravenous ketamine has been shown to reduce pain in FMS. Torebjork et al demonstrated similar changes in the central processing of input from LTM afferents following intradermal injection of capsaicin. The next question is whether this sensitization in the dorsal horn is the primary pathology, or secondary to changes higher up in the central nervous system.
Sensations other than pain are also amplified in FMS. McDermid et al examined pain threshold, pain tolerance, and noise tolerance in 20 patients (19 female and 1 male) with FMS, 20 patients with rheumatoid arthritis (RA) and 20 healthy controls, all carefully matched. Using a Fischer dolorimeter at a non-TP near each wrist, the pressure was increased at 1 kg/sec until the subjects first experienced pain (threshold) and then continued until the pain became intolerable. The FMS group had significantly lower pain thresholds and tolerance (mean = 1.51 kg & 2.78 kg respectively) than did the RA group (2.89 & 4.59) and the healthy controls (5.50 & 8.05). Noise tolerance, measured three times using white noise through a headset, increasing by 5 dB every 3 seconds until intolerable, was also lower in the FMS group (mean = 66.17 dB) than in the RA group (75.98) and normal controls (100.48). These findings correlated closely with responses to questionnaires assessing current and recent pain on visual analogy scales, the Noise Sensitivity Scale, the Kohn Reactivity Scale and the Pennebaker Inventory of Limbic Languidness.
They concluded that FMS patients have a generalized hypervigilance or perceptual amplification that may explain their frequent somatic complaints, such as swelling feelings in soft tissues, paraesthesias, irritable bowel syndrome, primary dysmenorrhoea, and irritable bladder syndrome, and the aggravation of their symptoms by noise, lights, stress and weather changes. Smythe described these patients as having an exquisite hypersensitivity to a variety of external and internal stimuli and has referred to fibromyalgia as the irritable everything syndrome.
In a controlled study using CO2 laser stimulation to the hands, Gibson et al? found that FMS patients had altered temperature thresholds, with associated abnormal electroencephalographic (EEG) changes. PET scans have revealed abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus, associated with low pain threshold levels, in women with FMS.? Bennett? suggested that ìsomatic distress and functional disability may result from a true enhancement of pain through a reduction in the descending inhibitory pathways of pain.
The cerebrospinal fluid in FMS patients has been found to contain a 3-fold elevation in levels of substance P, which facilitates pain transmission, and lower than normal levels of serotonin, norepinephrine, and dopamine metabolites. Serum concentrations of serotonin (5-HT) and tryptophan (a 5-HT precursor) are lower and the level of free serum tryptophan is inversely correlated with the severity of pain in FMS patients. Serotonin, an important neurotransmitter, appears to modulate pain perception, sleep, energy and mood. Amitriptyline, a serotonin re-uptake inhibitor, has been shown to improve sleep quality in FMS, and reduce morning stiffness, fatigue, pain, and tender point scores. The 5-Hydroxytryptamine type 3 receptor (5-HT-3R) antagonist, ondansteron (Zofran), has been shown to provide marked and rapid improvement in pain intensity and pain threshold in a double blind crossover trial of 21 patients with FMS. It is known that 5-HT-3R is present in various brain areas critical to nociception processing, including the dorsal horn and C fiber primary afferents?, and that 5-HT-3R antagonists inhibit the evoked release of substance P, neurokinin, and calcitonin gene related peptide neurotransmitters from the primary afferent neurons.67
There is also evidence of disturbance of the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis, characterized by an exaggerated adreocorticotropin (ACTH) response to corticotropin-
releasing hormone (CRH) during stress, but an impaired subsequent adrenal cortisol response, and blunting of the normal diurnal fluctuation. Growth hormone and Somatomedin C levels are also significantly lower. These findings lead one to question the role of stress and sleep disturbance in fibromyalgia.
Relationship of FMS to Stress, Trauma, and Sleep Disturbance
Psychological distress is a common feature of FMS.1 Whether this is a consequence of chronic pain or a reflection of underlying predisposing psychopathology is open to debate. According to Carette, there are arguments for both views but relatively little solid data to support them. Psychologic tests are of limited value to assess patients once they have developed the all the features of the syndrome. Case-control studies, in a tertiary care setting, have shown that FMS patients have a higher pre-morbid prevalence of depression, sexual and physical abuse (53-65%), drug abuse and eating disorders than do matched rheumatic disease controls. Psychological stressors appear to be very high prior to the development of FMS in children and adolescents.
Although most patients report that their FMS symptoms began gradually in adulthood, several studies have documented an acute onset in nearly 40% of patients: 24% following events perceived as physically traumatic, such as motor vehicle accidents, work injuries, surgery and viral illnesses, and 14% after events perceived as emotionally traumatic; the latter being valid independently of demographics, physical trauma, and physical/sexual abuse. Physical trauma was associated with more inactivity, disability, unemployment, and compensation78,79 than was emotional trauma, and the latter was associated with a greater utilization of medical services.80
How might physical or emotional trauma lead to FMS. Is the hyper-responsiveness to sensory stimuli seen in FMS a consequence of the symptoms associated with pain; a type of vicious circle Granges and Littlejohn? suggest that stress, anxiety, sleep disturbance, and psychological factors may lead to a central modulation change and pattern of amplification. Certainly, the RA patients in McDermidís study54 were more hypervigilant than the healthy controls. For many pain disorders, however, patients are not hypervigilant to noxious stimuli. Rather, their pain threshold and tolerance are significantly higher than those of controls.
Trauma to the axial skeleton has been suggested as a possible aetiologic factor in FMS.77 Buskila et al followed up 102 patients with neck injury and 59 patients with leg fractures, all of whom were employed. They found FMS was 13 times more frequent, and more severe, following injury to the neck (21.6%) than to the lower extremity (1.7%), the latter incidence being no different from that reported in the general population. Other studies, however, have found no increase in incidence of FMS following whiplash injury.
Despite reports of FMS following non-specific viral infections, an extensive search for infectious agents has failed to provide conclusive evidence of a direct link between viruses and FMS.
Although few immunologic studies have been done, no differences have been observed between FMS patients and community volunteers, with the exception of a higher CD4+ lymphocytes and CD4/CD8 ratio in one study.84 Might viral infections occasionally evoke FMS via sleep disturbance.
Sleep disturbance is reported by 75% of FMS patients16. They have more mini-arousals and transitional sleep and spend less time in stage 1 and rapid-eye-movement (REM) sleep. Many studies have shown that patients with FMS often display intrusion of a-wave sleep through all stages of non-REM sleep.
Other investigations, however, have found this EEG pattern, considered to be an objective index of arousal, only slightly (not significantly) more often in fibromyalgia than in healthy controls, equally frequently in patients with major depression?, and commonly in patients with RA without FMS. Moldofskyís 1976 experimental induction of fibromyalgia by selective deprivation of non-REM sleep13 has not been repeated. Although sleep disturbance may precede and aggravate fibromyalgia, it is probably comorbid rather than causative.85
FMS, Chronic Fatigue Syndrome and Depression
Hudson and Pope have reviewed the literature and list seven types of studies linking fibromyalgia with major depressive disorder (MDD):
1. Pnenonenology
Patients with FMS commonly experience depressed mood, sleep disturbance, fatigue, poor concentration, and other symptoms overlapping with those of a major depressive disorder.15,16
1. High rates of musculoskeletal pain are reported in patients with MDD.
2. Psychological tests and rating scales - High rates of psychiatric symptomatology similar to that found in MDD reported in FMS.1
3. Lifetime prevalence of major depressive disorder. High rates (20-70%) of MDD found in individuals with FMS in the majority of studies74, and a four-fold incidence of FMS in patients with lifetime history of MDD.1
4. Patterns of comorbidity. High lifetime rates of migraine, atypical facial pain, irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS) in FMS patients?; high rates of MDD found in patients with migraine, IBS and CFS.
5. Family history. High rates of MDD found in the relatives of individuals with FMS.1
6. Response to antidepressant medications FMS reported to respond partially to some antidepressant medications.95
7. Laboratory tests FMS and MDD share some neurotransmitter, neuroendocrine and polysomnographic features.
Because FMS, MDD and their comorbid conditions appear in no particular temporal sequence,74,94 Hudson concludes that neither can be said to cause the other. Rather, he proposes the concept that all of these conditions belong to a wider affective spectrum disorder sharing a common etiologic abnormality: probably some form of hypothalamic dysfunction, limbic system dysfunction, serotonin deficit, or a general disturbance in modulation of nervous system tone. 92
Aaron and his co-workers, however, strongly dispute an intrinsic association between these disorders. They compared FMS patients from a tertiary care setting with community residents with FMS who had not sought medical care for their FMS symptoms (FMS non-patients), and with healthy controls; and found that, while FMS patients did have a significantly higher lifetime psychiatric diagnoses than the controls, FMS non-patients did not. They found that patients reported significantly higher levels of anxiety, depression and fatigue, and displayed significantly lower pain threshold levels than did non-patients and controls, and that the differences in psychological distress between patients and non-patients were eliminated after controlling for pain threshold and fatigue. They concluded that psychological distress in persons with FMS is strongly associated with symptom severity. Psychiatric disorders are not intrinsically related to the FMS syndrome (sic.). Instead, multiple lifetime diagnoses may contribute to the decision to seek medical care for FMS in tertiary care settings ... and ... the onset of mood disorders after the development of FMS may be related to poor coping strategies among some patients in response to development of a chronic pain syndrome.
Although FMS is associated with serotonin deficits and responds to tricyclic antidepressants65, only low doses are tolerated, and the response is poor and temporary. The selective serotonin reuptake inhibitor (SSRI), fluoxetine, has not been shown to be superior to placebo. While some comorbid conditions, such as atypical facial pain and irritable bowel syndrome, respond well to anti- depressants, chronic fatigue syndrome exhibits a poor response, similar to that of fibromyalgia.94
Abnormalities in the HPA axis in FMS also differ from those found in both MDD and CFS. The similarities and differences between these conditions is reviewed by Crofford and Demitrack and summarized in Table 3. A number of studies have shown inconsistent and sometimes contradictory results, however, and HPA axis function in these conditions cannot be said to be fully understood at present.92 A distinctive feature of FMS appears to be an increased release of arginine vasopressin (AVP) from the hypothalamus in response to postural change.70 Plasma levels of neuropeptide Y (NPY) are reduced in FMS, consistent with hypofunction of the sympathetic nervous system,70 and elevated in depression.?

Table 3. HPA-AXIS PERTURBATIONS IN FMS, CFS ________________________________________________________________________________

FMS CFS MDD
Basal
24 hour urine free cortisol Decreased Decreased Increased
Peak (AM) plasma cortisol Normal Increased
Trough (PM) plasma cortisol Elevated Decreased
Circadian change Blunted Normal
Trough (PM) plasma ACTH Normal Elevated
Cerebrospinal CRH levels Normal
Plasma AVP Normal/elevated Decreased Normal
Provocative
ACTH release: CRH stimulation Exaggerated Blunted Blunted
Cortisol response to CRH Blunted Normal Increased to dexamethazone Suppressed Suppressed Nonsuppressed

Finally, Buskila et al48 examined the offspring of mothers with FMS and found a tenfold increase in the prevalence (28%) of FMS, consistent with autosomal dominant inheritance, but no difference in psychological factors in children with and without FMS. Interestingly, they also found that 81% of the children with FMS also had hypermobility, that girls had lower pain thresholds than boys, and that children of different ethnic origins had remarkably different pain thresholds.

Therapy and Prognosis

Fibromyalgia is a chronic condition with a very low remission rate, in the order of 5% over 3 years in one study. The treatment of FMS is notoriously difficult. Single modalities are relatively ineffective, and more than half fail to respond to numerous pharmaclogical and non-pharmacological therapies.

Medications that have been shown to be effective, although no more so than analgesics in the long term, include amitiptyline (10-50mg daily)66, clomipramine, dothiepin (75mg daily), cyclobenzaprine (not available in Australia), alprazolam and S-adenosylmethionine (an antidepressant with anti-inflammatory properties)92. Not all tricyclics (eg imipramine) are effective, and they are poorly tolerated.103 Fluoxetine, ineffective on its own, appears to enhance the effect of amitriptyline.92 Steroids and NSAIDS are ineffective, although one study showed ibuprofen to enhance the modest benefit from alprazolam. Hypnotics, such as Zolpidem and Zopiclone, may improve sleep and energy but not pain parameters.

Nonpharmacologic therapies have been shown to be much more beneficial, especially in combination. Cardiovascular fitness training, even a modest 20-minute walk three times a week, is most effective in reducing psychological distress, pain and tender point scores. Many patients, however, experience more pain initially with exercise, and it usually takes at least 12 and up to 20 weeks of exercise before benefit is seen.103 Significantly, perhaps, the few subjects in whom Moldofksy13 failed to induce fibromyalgia symptoms by selective sleep deprivation were endurance athletes. Other effective modalities include EMG biofeedback training, electroacupuncture, hypnotherapy, and cognitive behavioural therapy, including:

1.Social persuasion of capacity to be more functional

2.Mastery experiences: actually performing a previously off-limits activity

3.Modeling of other patients being successful in performing the desired activity

4.Physiologic feedback: listening to ones body to optimise the timing of new activities.

The Portland Program combined these in a multidisciplinary 6-month group therapy program - the most comprehensive and effective reported to date. At the end of six months, 70% of the 104 FMS patients had <11 TP (mean reduction from 16 to 9) and fibromyalgia impact questionnaire (FIQ) scores had improved by 25%. After two years, 33 patients continued to show improvement, whereas the control group showed no significant improvement. Two of the greatest changes were a reduction of catastrophizing and an increased aerobic fitness.

Modalities not shown to be effective include: Ice or heat, massage, TENS, interferential current, iotophoresis, laser therapy, postisometric relaxation, myofascial release, local injection or dry needling (except for trigger points rather than tender points).103

Conclusion

Fibromyalgia is a real and distinct entity or syndrome affecting around 2% of the population, predominantly middle aged women with a genetic predisposition. It is diagnosed on the basis of widespread pain for more than 3 months and the presence of 11 or more of a possible 18 tender points. FMS usually has a gradual onset, but may be precipitated or aggravated by certain physical or emotional traumas, and results in perceptual amplification associated with characteristic but as yet poorly understood changes in the central nervous and neuroendocrine systems. It may be associated with other symptoms (eg unrefreshing sleep) and syndromes (eg chronic fatigue syndrome) and related to, but is distinct from, major depressive disorder. There is no evidence of any peripheral pathology or inflammation, and the term fibrositis should not be used. I anticipate that the name will again be changed when we have a more precise understanding of the pathology of this condition, which is currently disappointingly difficult to treat.

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