Fibromyalgia

Fibromyalgia

Martin L. Pall, Professor Emeritus of Biochemistry and Basic Medical Sciences

Other web pages:

Main Web Page

Multiple Chemical Sensitivity

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Other Proposed NO/ONOO- Cycle Diseases

Therapy

Allergy Research Group Nutritional Support Protocol

Five Principles

Many properties of the NO/ONOO- cycle fit quite well with the properties of fibromyalgia (FM). Cases of FM are initiated by stressors including viral infections, physical trauma (especially head and neck trauma), bacterial infections, severe psychological stress and autoimmune diseases (especially lupus and rheumatoid arthritis). Each of these can initiate sequences that increase nitric oxide, either through iNOS induction (infection) or through NMDA stimulation followed by nNOS (and possibly eNOS) activation (psychological stress, physical trauma) (1,2). Thus at least two and possibly all three distinct nitric oxide synthases may have apparent roles in initiation of illness.

Many of the elements of the NO/ONOO- cycle have been studied in FM and each of these have been reported to be elevated. Such elevations in FM include (1,2):

* Eight studies reporting oxidative stress in FM

* Ten studies reporting mitochondrial/energy metabolism dysfunction

* Six studies reporting elevated levels of inflammatory cytokines

* Nine studies reporting or suggesting elevated levels of NMDA activity

* Two studies reporting elevated levels of nitric oxide; however a recent study did not find elevated nitric oxide levels (3). It should be noted that although there are several NO/ONOO- mechanisms that lead to increased nitric oxide production, the partial uncoupling of the nitric oxide synthases by BH4 depletion lowers nitric oxide production (4). Consequently, raised nitric oxide levels may not always be a consequence of the cycle (4).

* Three studies reporting elevated level of vanilloid (TRPV1) receptor activity as demonstrated by capsaicin-response activity

It can be seen from this that these results are consistent with predictions of chronic phase changes in fibromyalgia.

As was noted in my Therapy web page, observations of therapy are consistent with this mechanism, as are possible mechanisms for the generation of symptoms and signs shared by FM and the other multisystem illnesses (particularly CFS).

How Widespread Chronic Pain May Be Generated by a NO/ONOO- Cycle Mechanism

The most difficult challenge for this model in FM is how to explain the widespread chronic pain that is the characteristic feature of FM. The reason this is such a difficult challenge, is because of the local nature of the NO/ONOO- cycle. It is very unlikely that the pain in FM is generated locally in the painful tissues because if this were the case, we would expect that many patients would have pain over certain localized regions of their bodies, but not the widespread pain that is characteristic of FM. Such localized pain is common in the other multisystem illnesses and may be explained by local hyperalgesia mechanisms, but the widespread pain of FM is unlikely to be generated simply from a combination of many local effects. In fact, many scientists have suggested that pain generation in FM is due to central nervous system changes in pain processing (5-14) but the question is what region may be involved and how may its dysfunction generate such widespread chronic pain?

The studies of Staud and coworkers showing widespread pain processing up-regulation in the various dorsal horn regions up and down the spinal cord (10) provides another challenge for the NO/ONOO- cycle model. How can we generate such widespread pain processing change via a local mechanism?

A solution to these challenges comes from the reported involvement of changes in the thalamus in FM. Such thalamic involvement in FM has been proposed by Larson and Kovacs (12), by Henriksson (13) and also by Staud (14). The thalamus has descending neurons, known as lamina I neurons, that act primarily to inhibit pain processing in the various dorsal horn regions of the spinal cord (15-19). Consequently, thalamic dysfunction may be predicted to up-regulate pain processing in the dorsal horn regions throughout the spinal cord, as reported by Staud and coworkers (10), producing the widespread perception of excessive pain that is the cardinal symptom of FM. Such deficiency in descending pain processing inhibition in FM has been recently reported (20).

Several brain scan studies of FM have reported common thalamic involvement (21-24). Thalamic involvement is also suggested by the observations of Larson and coworkers (25), reporting mast cell activation in the thalamus in FM. Mast cell activation is stimulated by both TRPV1 and NF-kappa B activation, both elements of NO/ONOO- cycle biochemistry.

According to this view, people diagnosed with FM differ from others within the spectrum of multisystem illnesses by thalamic impact of their NO/ONOO- cycle biochemistry. Lowered thalamic activity leads to lower inhibition of pain processing via lamina I neurons, leading, in turn to the widespread excessive pain characteristic of FM.

References Cited:

1. Pall ML. 2007 Explaining “Unexplained Illnesses”: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others, Haworth Medical Press, in press.

2. Pall ML. 2006 The NO/ONOO- cycle as the cause of fibromyalgia and related illnesses: etiology, explanation and effective therapy. Chapter 2 in New Research in Fibromyalgia, John A. Pederson, Ed., Nova Science Publishers.

3. Sendur OF, Turan Y, Tastaban E, Yenisey C, Serter M. (2008) Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study. Rheumatol Int. 2008 Oct 14. [Epub ahead of print]

4. Pall ML. 2007 Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle. Med Hypotheses. 2007;69(4):821-825.

5. Lidbeck J. 2002 Central hyperexcitability in chronic musculoskeletal pain: a conceptual breakthrough. Pain Res Manag 7:81-92.

6. Clauw DJ, Crofford LJ. 2003 Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol 17:685-701.

7. Desmeules JA, Cedraschi C, Rapiti E, et al. 2003 Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum 48:1420-1429.

8. Staud R, 2002 Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Curr Rheumatol Rep 4:299-305.

9. Bradley LA, McKendree-Smith NL, Alarcon GS, Cianfrini LR. 2002 Is fibromyalgia a neurologic disease? Curr Pain Headache Rep 6:106-114.

10. Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. 2004 Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared with normal controls. Pain 110:689-696.

11. Yunus MB. 2001 Central sensitivity syndromes: a unified concept for fibromyalgia and other similar maladies. Fibromyalgia Frontiers 9(3):3-8.

12. Larson AA, Kovacs KJ. 2001 Nociceptive aspects of fibromyalgia. Curr Pain Headache Rep 5:338-346.

13. Henriksson KG. 2003 Hypersensitivity in muscle pain syndromes. Curr Pain Headache Rep 7:426-432.

14. Staud R. 2004 Evidence of involvement of central neural mechanisms in generating fibromyalgia pain. Current Science 4:299-305.13.

15. Markenson JA. 1996 Mechanisms of chronic pain. Am J Med 101:6S-18S.

16. Simone DA, Zhang X, Li J, et al. 2004 Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J Neurophys 91:213-222.

17. Mantyh PW, Hunt SP. 2004 Setting the tone: superficial dorsal horn projection neurons regulate pain sensitivity. Trends Neurosci 27:582-584.

18. Saab CY, Park YC, Al-Chaer ED. 2004 Thalamic modulation of visceral nociceptive processing in adult rats with neonatal colon irritation. Brain Res 1008:186-192.

19. Gauriau C, Bernard JF. 2004 A comparative reappraisal of projections from the superficial luminae of the dorsal horn of the rat: the forebrain. J Comp Neurol 468:24-56.

20. Julien N, Goffaux P, Arsenault P, Marchand S. 2005 Widespread pain in fibromyalgia is related to a deficit in endogenous pain inhibition. Pain 114:295-302.

21. Mountz JM, Bradley LA, Modell JG, et al. Fibromyagia in women. Abnormalities in regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels. Arthritis Rheum 38:926-938.

22. Wik G, Fischer H, Bragee B, Finer B, Fredrikson M. 1999 Functional anatomy of hypnotic analgesia: a PET study of patients with fibromyalgia. Eur J Pain 3:7-12.

23. Lekander M, Fredrikson M, Wik G. 2000 Neuroimmune relations in patients with fibromyalgia: a positron emission tomography study. Neurosci Lett 282:193-196.

24. Kwiatek R, Barnden L, Tedman R, et al. 2000 Regional cerebral blood flow in fibromyalgia: a single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 43:2823-2833.

25. Anon. 2003 A possible cause of fibromyalgia. The American Fibromyalgia Syndrome Association, Inc., 2003 Special Update Edition, pp.14-18.