Letters to the Editor: Feedback from the Readers

No Such Thing as Fibromyalgia

The October issue of The Rheumatologist featured an article on fibromyalgia by Daniel Clauw. Fibromyalgia does not exist. What is called fibromyalgia is part of the spectrum of chronic pain. The tender points are tender in everyone. Fibrous tissue and muscle are not involved. In other words, fibromyalgia is a misnomer. Like silicone breast implant syndrome and other now-forgotten diseases, it will disappear.

George E. Ehrlich, MD
Master, ACR

Dr. Clauw Responds:

To Dr. Ehrlich, thank you for your comments. I am quite aware that some people refuse to change their minds even in the face of overwhelming data.

Daniel J. Clauw, MD
Professor of Anesthesiology and Medicine (Rheumatology)
University of Michigan in Ann Arbor

Fibromyalgia Controversy

I read Dr. Clauw’s recent review of the pathogenesis and therapy of fibromyalgia (FM) with a good deal of interest.^1,2 While his description of FM as an example of “central [nervous system] sensitization (CS)” resulting in pain amplification has appeal on a heuristic basis, I believe that it fails to identify a fundamental pathophysiologic explanation for the initiation and perpetuation of pain in the FM syndrome.

Dr. Clauw’s construct suggests the presence of certain “environmental stressors” that “trigger” FM in the susceptible individual, but then disappear (at least from that individual’s immediate environment), while leaving a mysteriously self-perpetuating CS/FM in its wake. This “non-nociceptive” form of CS (see Table 2 in Reference 1) is deemed to be self-evident since there are, Dr. Clauw says, no—or very few—peripheral indicators of tissue damage in FM. Supporting evidence for these assertions includes abnormal brain functional imaging studies (showing areas of hyperactive pain integration), and a clinical, pain-lessening effect for centrally acting pharmacological therapies, such as amitrptyline and pregabalin.

Dr. Clauw’s review is worthy of comment for a number of reasons. First, he has nicely sensitized rheumatologists, who are better known for their appreciation of the immune system and for being students of inflammation than for being neurophysiologists, to the role of CS in rheumatic disease pain production. I am afraid, however, that he has left the impression that FM is a disorder primarily of the central nervous system. He does not, for example, point out that many, and probably most, CS syndromes require constant peripheral nociceptive input in order to be maintained,^3,4 though this maintenance may require only low levels of continuing nociceptive stimulation.⁵ The larger question for the rheumatologist may, therefore, revolve around determining from where and how that nociceptive input continues to arise in FM.

Second, Dr. Clauw repeatedly points out that there is no peripheral tissue lesion in FM [admittedly, this is left a bit ambiguous by his Table 2 in Reference 1 and Figure 1 in Reference 2]. In fact, over the last 25 years, there have been numerous demonstrations of peripheral pathology involving cutaneous, muscular, and neuronal tissue in FM. Interestingly, many of these tissue findings have involved, either directly or indirectly, an aberrancy of the immune system.^6-16

Third, I and others have recently been able to show electrophysiologic and microscopic evidence of peripheral nerve injury in FM.^17-19 These changes have included evidence of a polyneuropathy involving large nerves in 47% of FM patients, and peripheral nerve demyelination, akin to that seen in chronic inflammatory demyelinating polyneuropathy (CIDP), in 33% of FM patients.¹⁷ We have also reported preliminary evidence of diminished epidermal, nerve fiber density in FM patients suggestive of a small fiber neuropathy (SFN).²⁰ These latter findings are of particular interest since SFN is known to be a painful disorder, and chronic C-fiber stimulation is thought by most, though not by all, to be a major component to the induction of CS.^21-23 SFN could thus form one source of the necessary peripheral nociceptive input required for the production of “wind up” and CS in FM. In our earliest FM series, none of these peripheral nerve changes could be explained by any other mechanism but peripheral immunologically mediated injury, and suggested to us a role for immunotherapy in selected FM patients.¹⁷ Staud et al have recently pointed out the potential importance of significant muscular injury patterns in FM and demonstrated their potential for a role in CS maintenance.⁴ In everyday rheumatologic practice (rather than during clinical research), it is also likely that other peripheral factors, including metabolic, mechanical, endocrine, and neoplastic ones, to name a few, are important in the enhanced central pain production in FM.

These considerations regarding the importance of peripheral nociceptive input in FM for the maintenance of CS are of more than academic interest. It is known, for example, that extinguishing peripheral nociceptive input effectively eliminates spinal cord “wind up” and, in the setting of dorsal horn hyperexcitability (i.e., CS), abolishes CS.^24-26 This degradation of CS may be somewhat gradual in my experience (days to weeks), presumably due to the long-term neuroplastic changes associated with CS.5,22 On the other hand, there is no experimental or practical evidence that I am aware of that shows that control of CS with “centrally acting [medicinal] agents” such as amitrptyline or pregabalin ever leads to the extinction of peripheral nociceptive input. At best, therefore, such centrally acting agents might serve as temporary or “bridge” therapy while the true nature of the peripheral, perpetuating factor(s) is uncovered and treated in FM. Borg-Stein has alluded to this strategy recently.²⁷

Dr. Clauw, then, has presented us with a rather comprehensive review of FM, and stressed the role of CS in this disorder. Understanding this component of the FM syndrome does indeed seem worthwhile.²³ I do think, however, that he has not provided sufficient balance for the very area of FM best addressed and studied by the rheumatologist—that is, the peripheral tissue injury in FM and its implications for the pathophysiology of this disorder. His conservative view of FM (i.e., that FM is a disorder primarily of CS) has led some to question whether the rheumatologist should even be involved in the treatment of FM.²⁸ Such a view is likely to limit future clinical and experimental insight into the proper therapy of the FM patient.

In the final analysis, it remains to be seen whether recognizing and treating the peripheral component of FM will be of equal or even greater importance to the rheumatologist than understanding “enhanced central pain processing.” There is, however, no reason to think, at this point at least, that addressing the importance of CS and addressing the importance of peripheral tissue injury in FM are mutually exclusive endeavors.

Xavier J. Caro, MD
Associate Clinical Professor of Medicine
David Geffen School of Medicine at UCLA

Dr. Clauw Responds:

To Dr. Caro, I agree with many of your assertions. I suspect we will eventually find that nearly all chronic pain states are “mixed” pain states, with variable degrees of peripheral and central input. In the article in The Rheumatologist, I tried to highlight the central features of fibromyalgia and the fact that these are present to variable degrees across all rheumatic diseases, rather than give an exhaustive review of fibromyalgia.

Daniel J. Clauw, MD

References

1. Clauw DJ. Turn down the pain volume. Fibromyalgia’s evolution from discrete entity to prototypical central pain syndrome. The Rheumatologist. 2009; 3(10):1, 20-23.
2. Clauw DJ. Neurological piece of the fibromyalgia puzzle. Exploring the peripheral and central elements of pain in FM. The Rheumatologist. 2009; 3(11):1, 18-20.
3. Meyer RA, Ringkamp M, Campbell JN, Raja SN. Peripheral mechanism of cutaneous nociception. In: McMahon SB, Koltenburg M, editors. Wall and Melzack’s Textbook of Pain. Philadelphia: Elsevier Churchill Livingstone; 2006. 3-34.
4. Staud RN, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain. 2009; 145:96-104.
5. Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain. 2004; 110:689-696.
6. Caro XJ. Immunofluorescent detection of IgG at the dermal-epidermal junction inpatients with apparent primary fibrositis syndrome. Arthritis Rheum. 1984;27:1174-1179.
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