Home

Current Issue

Archives

Guidelines for Authors

Classified Ads

Links

Search PubMed

Subscriptions

Subscriber Registration

Guidelines for Website Users

JRheum Update Service

Contact Info

Fibromyalgia Is a Neuropathic Pain Syndrome

To the Editor:

I was startled when I saw an entire issue devoted to a symposium on fibromyalgia (FM) as a neuropathic pain syndrome¹! Since this has been precisely our proposal over the years, I read the issue eagerly. However, I was taken aback by the fact that there was no discussion of our arguments favoring the notion that FM is a neuropathic pain syndrome^2-4. Most of our articles dealing with this proposal were published before the symposium, which convened in September 2003. So, I would like to summarize our reasoning for considering FM a sympathetically-maintained neuropathic pain syndrome.

The International Association for the Study of Pain defines neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction of the nervous system"⁵. The clinical features of neuropathic pain are the presence of stimuli-independent pain accompanied by allodynia and paresthesias⁶. These are precisely the features of pain in FM. FM is a stimulus-independent pain state because there is no underlying structural damage, and inflammatory signs are conspicuously absent. Most patients with FM have paresthesias, as demonstrated in the original study that led to the American College of Rheumatology criteria showing that more than 80% of patients with FM had such sensory alteration⁷. Simms and Goldenberg⁸ corroborated the extremely high prevalence of paresthesias. We used a questionnaire that is part of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale. This instrument was developed to recognize neuropathic pain and set it apart from nociceptive pain. Our study showed that most patients with FM give assenting responses to questions pertaining to dysesthetic, evoked, paroxysmal, and thermal domains. This response rate was markedly different from that given by patients with active rheumatoid arthritis⁹. Several groups of investigators have said that the typical FM tender points reflect a state of generalized allodynia¹⁰. It would be difficult to ascribe allodynia and paresthesias to a pathogenesis different from an intrinsic nervous system alteration.

A more restrictive definition has been proposed that suggests neuropathic pain should be diagnosed only when there is evidence of nervous system damage¹¹. Nevertheless, the clinical importance of neuropathic pain resides, not in the nerve lesion itself, but in the resulting nerve dysfunction. There are other clinical syndromes classified as neuropathic pain in which no nervous system damage is obvious (e.g., trigeminal neuralgia or reflex sympathetic dystrophy). Another argument for considering FM a neuropathic pain syndrome comes from reports of central nervous system sensitization. Patients with FM have abnormal temporal summation of pain¹² and abnormal spinal cord reflexes¹³. Central sensitization is expression of neuroplasticity and is the major cause of hypersensitivity to pain after injury⁶.

We propose that, among neuropathic pain etiologies, FM is sympathetically maintained: Controlled studies show that patients with FM display signs of relentless sympathetic hyperactivity¹⁴, FM pain is responsive to sympathetic blockade¹⁵, and FM pain is rekindled by norepinephrine injections¹⁶.

The concept of sympathetically maintained pain has strong and ample foundations in the animal model. After nerve injury, sympathetic sprouting at the dorsal root ganglia becomes apparent and forms basket-like structures around large-diameter, axotomized sensory neurons; sympathetic stimulation can activate such neurons repetitively¹⁷. Another site of abnormal post-traumatic connections occurs in the dorsal horn of the spinal cord where there is an A-fiber sprouting into the superficial layers, thus provoking tactile stimuli to be felt as painful. This mechanism may explain allodynia.

Emerging genomic investigations support this paradigm: catecholamines are the sympathetic neurotransmitters. The major systemic transformation of catecholamines is catalyzed by the enzyme catechol-O-methyltransferase (COMT). There are different single-nucleotide polymorphisms (SNP) in the COMT gene that induce important functional alterations of the enzyme. The best studied mutation occurs in codon 158 with valine to methionine transition (val-158-met polymorphism). Val-158-val genotype gives rise to an effective enzyme whereas met-158-met genotype produces a "lazy" enzyme unable to effectively clear catecholamines from the system. Zubieta, et al demonstrated that healthy individuals with val-158-val genotype are pain-resistant; the opposite occurs in persons with met-158-met genotype. The authors speculate that this association could be due to high levels of catecholamines interfering with endorphin interactions with mu-opioid receptors in the central nervous system¹⁸. Gursoy, et al found an association between FM and val-158-met COMT polymorphism¹⁹. Our investigations published in an abstract form concur with Gursoy's findings²⁰. We are currently probing other SNP of the COMT gene in subjects with FM.

The above collection of data supports the notion that FM is a sympathetically maintained neuropathic pain syndrome. This different perspective on FM opens new avenues for research and treatment.

MANUEL MARTINEZ-LAVIN, MD, Chief, Rheumatology Department, National Institute of Cardiology, Mexico City, Mexico. E-mail: mmlavin@infosel.net.mx

REFERENCES

1. Dworkin RH, Fields HL. Fibromyalgia from the perspective of neuropathic pain. J Rheumatol 2005;32 Suppl 75:1-5.

2. Martinez-Lavin M, Hermosillo AG. Autonomic nervous system dysfunction may explain the multisystem features of fibromyalgia. Semin Arthritis Rheum 2000;29:197-9.

3. Martinez-Lavin M. Is fibromyalgia a generalized reflex sympathetic dystrophy? Clin Exp Rheumatol 2001;19:1-3.

4. Martinez-Lavin M. Fibromyalgia as a sympathetically maintained pain syndrome. Curr Pain Headache Rep 2004;5:385-9.

5. Merskey H, Bogduk N. Classification of chronic pain. In: Merskey H, Bogduk N, editors. IASP Task Force on Taxonomy. Seattle: IASP Press; 1994.

6. Woolf CJ, Mannion RJ. Neuropathic pain: etiology, symptoms, mechanisms, and management. Lancet 1999;353:1959­64.

7. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the Multicenter Criteria Committee. Arthritis Rheum 1999;33:160­71.

8. Simms RW, Goldenberg DL. Symptoms mimicking neurologic disorders in fibromyalgia syndrome. J Rheumatol 1988;15:1271­3.

9. Martinez-Lavin M, Lopez S, Medina M, Nava A. Use of the Leeds assessment of neuropathic symptoms and signs questionnaire in patients with fibromyalgia. Semin Arthritis Rheum 2003;32:407­11.

10. Russell J. Advances in fibromyalgia: possible role for central neurochemicals. Am J Med Sci 1998;315:377­84.

11. Hansson PT, Lacerenza M, Marchettini P. Aspects of clinical and experimental neuropathic pain: the clinical perspective. In: Hansson PT, Fields HL, Hill RG, Marchettini P, editors. Neuropathic pain: pathophysiology and treatment. Seattle: IASP Press; 2001:1­19.

12. Staud R, Cannon RC, Mauderli AP, et al. Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome. Pain 2003;102:87­95.

13. Desmeules JA, Cedraschi C, Rapiti E, et al. Neurophysiologic evidence of central sensitization in patients with fibromyalgia. Arthritis Rheum 2003;48:1420-9.

14. Martinez-Lavin M, Hermosillo AG, Rosas M, Soto ME. Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis. Arthritis Rheum 1998;42:1966­71.

15. Bengtsson A, Bengtsson M. Regional sympathetic blockade in primary fibromyalgia. Pain 1988;33:161­7.

16. Martinez-Lavin M, Vidal M, Barbosa RE, et al. Norepinephrine-evoked pain in fibromyalgia: a randomized pilot study ISCRTN 70707830. BMC Musculoskelet Disord 2002;3:2. Epub 2002 Jan 16

17. McLachlan EM, Jäning W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993;363:543­6.

18. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val-158-met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003;299:1240-3.

19. Gursoy S, Erdal E, Herken H, et al. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int 2003;23:104-7.

20. Martinez-Lavin M, Ramos-Kuri M, Hernández F, et al. Exploring a genomic basis for fibromyalgia's dysautonomic nature: Catechol-O-methyl transferase (COMT) val-158-met polymorphism [abstract]. Arthritis Rheum 2004;50 Suppl:S249.