Eva Kosek, MD. PhD.

Fibromyalgia (FM) is a chronic pain syndrome, characterised by generalised pain, tenderness, morning stiffness, disturbed sleep and pronounced fatigue. The estimated prevalence of FM in the general population has been reported to be 2%, out of which 80-90% are women. The aetiology and pathophysiology is unknown, making the concept of FM controversial. The main source of controversy has been if FM, in the absents of specific objective physical signs, is truly a medical problem. Some argue that physicians have created a major health issue out of a “psychosocial syndrome”, simply by giving it a new name (i.e., FM) and elevated it in importance, thus medicalizing psychosocial problems and legitimising patients inappropriate sickness behaviour. However, emotional trauma in FM patients has been related to fatigue, functional disability and health care seeking, but not to pain severity or tenderness (Aaron et al. 1997). Furthermore, even though psychopathology has been associated with FM, it is not known whether it is a pain causing factor or a consequence of chronic pain. The latter is supported by the fact that many studies failed to reveal significant differences in psychopathology between FM patients and patients with rheumatoid arthritis. Unfortunately, a substantial part of the discussion regarding pathogenic mechanisms in FM has revealed a tendency to split body from mind by attributing pain to either organic (“ real disease”) or psychosocial (“ not a real disease”) causes, thus adding little to the understanding of the potential mechanisms by which psychosocial problems hypothetically could manifest themselves as pain and tenderness.

Although different sets of diagnostic criteria have been used, widespread pain in conjunction with tenderness have remained the hallmarks of FM. The currently used classification criteria for FM proposed by the American College of Rheumatology (ACR) include widespread pain and pain on palpation of 11 or more of 18 specified tender points (Wolfe et al. 1990). The pain in FM is mainly localised to the musculature, and exacerbation of pain and tenderness is seen during and following physical activity. However, results of studies concerning muscle morphology, metabolism and function in FM are conflicting ; discrete, non-specific abnormalities have been found and can most likely be explained as a consequence of ischemia and/or as a detraining effect (Henriksson and Mense 1994). Furthermore, the increased pressure pain sensitivity in FM patients is not restricted to the so called “tender points” (Tunks et al. 1988) nor to muscle tissue (Kosek et al. 1995). These findings support central nervous system mechanisms rather than muscle pathology as the cause of pain and tenderness in FM.

Central sensitisation and/or dysfunction of endogenous pain inhibition has been put forward as a plausible basis for aetiology and pathogenesis in FM. This is indirectly supported by findings of high levels of substance P (Vaerшy et al. 1988) as well as low levels of a serotonin metabolite (5-HIAA) (Houvenagel et al. 1990) in the cerebrospinal fluid of FM patients. Even though, SP may have analgesic effects, iontophoretical application of SP in the dorsal horn of the spinal cord in animals has been reported to have a prolonged excitatory effect selectively on nociceptive neurones, providing the basis for central sensitisation, whereas serotonin among other actions, has been implicated in inhibition of nociceptive transmission. Central sensitisation and/or disinhibition would be expected to cause a generalised, non-modality specific increase in pain sensitivity. In fact, increased sensitivity to various threshold and suprathreshold deep as well as cutaneous pain stimuli have been reported in FM (Lautenbacher et al. 1994, Kosek et al. 1996a).

Furthermore, an abnormal absence of pressure pain modulation during muscle contraction (Kosek et al. 1996b), as well as a lack of normal inhibition of pain sensitivity during heterotopic noxious conditioning stimulation (Kosek and Hansson 1997 ; Lautenbacher and Rollman, 1997) has been found in FM patients indicating a dysfunction of endogenous pain inhibition in FM. There is evidence that systems involved in sympathetic nervous system and cardiovascular regulation are functionally linked to endogenous pain regulatory systems. Diminished response to exercise by the sympathetic nervous system in FM patients, i. e., reduced exercise-induced increase of serum catecholamines and heart rate has been demonstrated (Van Denderen et al. 1992), and could contribute to increased ischemia in the contracting muscles. Thus, the exacerbation of pain and tenderness typically reported by FM patients during and following physical activity could result from a combination of peripheral mechanisms (i.e., sensitisation of mechanonociceptors due to muscle ischemia) and central mechanisms (i.e., dysfunction of endogenous pain modulation ; neuroendocrine abnormalities).

Neuroendocrine abnormalities, such as low concentrations of serum insulin-like growth factor - I (IGF-I) (Bennett et al. 1997) and a hyperreactive pituitary adrenocorticotropine hormone (ACTH) release with a relative hyporesponsiveness of adrenal corticosteroid secretion (Griep et al. 1993) have been reported in FM. The finding that FM patients, with initially normal levels of IGF-I often had a rapid decline of IGF-I over 1 to 2 years suggests that this is a secondary phenomenon (Bennett et al. 1997), which could be caused by disturbed sleep, reduced physical activity and/or chronic stress. The relationship between the reported abnormalities in hypothalamic-pituitary-adrenal axis and FM symptoms is unknown. However, the exaggerated ACTH response distinguishes FM patients from patients with chronic fatigue syndrome and post traumatic stress disorder, conditions that, just as FM, have been associated with chronic stress and that have many symptoms in common with FM, but in which pain is usually not such a prominent complaint.

As stated earlier, findings indicating central nervous system dysfunctions have been reported in FM. However, it is not clear whether these are a cause or a consequence of pain in FM, nor is it known whether they are specific for FM or if they are seen also in patients with other chronic pain conditions. Supporting the latter is the fact that generalised increase in pressure pain sensitivity (present outside the painful parts of the body) have also been reported in a number of other chronic pain conditions such as rheumatoid arthritis, osteoarthritis, localised myalgia, and temporomandibular disorder. Furthermore, a multimodal increase in pain sensitivity and a dysfunction of endogenous pain inhibition has also been reported in patients with temporomandibular disorder and patients with pain due to osteoarthritis of the hip. In the latter, these abnormalities had normalised when the patients were reassessed following hip replacement, indicating that they had been maintained by ongoing nociceptive barrage.

Thus, it has been shown that generalised sensibility changes as well as a dysfunction of endogenous pain inhibition can be found even in other chronic pain syndromes than FM. The majority of FM patients report localised pain for several years, before developing the generalised pain of FM. Furthermore, in several painful conditions pressure pain sensitivity has been found to increase with increased pain intensity and also with increased pain duration. In addition, the pressure pain sensitivity is more pronounced in FM patients when compared to patients with rheumatoid arthritis and localised myalgia. Therefore, it could be speculated, that in susceptible individuals chronic nociceptive localised pain, through mechanisms such as central sensitisation and/or disinhibition, spreads to involve larger parts of the body until finally a generalised pain and tenderness is present. This would make FM an extreme end in a continuum of chronic pain syndromes, rather than a discrete disorder. The high percentage of patients with whiplash trauma and chronic low back pain that develop FM could be interpreted in support of this hypothesis.

In conclusion, the pain in FM is most likely explained by a complex interaction between peripheral and central mechanisms. Even though multiple abnormalities have been found in FM patients, there are no known objective signs specific for FM. Furthermore, the important issue whether FM is a distinct medical entity or just an ultimate consequence of chronic pain in predisposed individuals remains unresolved.

References
Aaron, L. A. et al., Arthr. Rheum., 40 (1997) 453-460.
Bennett, R. M. et al., J. Rheumatol., 24 (1997) 1384-1389.
Griep, E. N. et al., J. Rheumatol., 20 (1993) 469-474.
Henriksson, K.-G., and Mense, S., Pain Rev., 1 (1994) 245-260.
Houvenagel, E. et al., Revue du Rheumatisme, 57 (1990) 21-23.
Kosek, E. et al., Pain, 63 (1995) 335-339.
Kosek, E. et al., Pain, 68 (1996a) 375-383.
Kosek, E. et al., Pain, 64 (1996b) 415-423.
Kosek, E. and Hansson, P., Pain, 70 (1997) 41-51.
Lautenbacher, S. et al., Pain, 59 (1994) 45-53.
Lautenbacher, S. and Rollman G. B., Clin. J. Pain, 13 (1997) 186-196.
Tunks, E. et al., Pain, 34 (1988) 11-19.
Vaerшy, H. et al., Pain, 32 (1988) 21-26.
Van Denderen, J. C. et al., Scand. J. Rheumatol., 21 (1992) 35-37.
Wolfe, F. et al., Arthr. Rheum., 33 (1990) 160-172.

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 57 - 59.