COMMENTARY

Finding the Etiology of Chronic Widespread Pain

The Right Diagnostic Tool Adds Precision to This Often Imprecise Diagnosis

Charles E. Argoff, MD

Disclosures

February 04, 2015

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This is Dr Charles Argoff, professor of neurology at Albany Medical College and director of the Comprehensive Pain Center at Albany Medical Center in Albany, New York.

Today I want to discuss some emerging concepts regarding chronic widespread pain. Certainly, we think of fibromyalgia as the prototypical chronic widespread pain condition, but most of this discussion will not be focused on fibromyalgia. The differential diagnosis regarding chronic widespread pain can include a variety of rheumatologic causes such as osteoarthritis, polymyalgia rheumatica, myopathy, various collagen vascular and autoimmune disorders such as lupus and other connective tissue disorders, Sjögren syndrome, etc. More recently, the British Pain Society has established guidelines[1] noting that chronic widespread pain is very prevalent and that the differential includes fibromyalgia, for example, but that the diagnosis should be based on the presence and distribution of signs and symptoms in the absence of another pathologic process.

That last point is extremely important, and I want to focus on this a bit more. Again, the diagnosis should be based on the presence and distribution of signs and symptoms in the absence of another defined pathologic process.

Standard Diagnostic Tools Measure the Wrong Things

Diagnosing the cause of chronic widespread pain can be quite challenging in medicine in general, but especially in pain management. We do blood work, CT, MRI, x-rays, and other radiographic procedures. We also conduct electrophysiologic testing to measure the role of various neuropathic or nerve-related conditions and problems that may contribute to chronic widespread pain. Quite often, we use electromyography (EMG) and nerve conduction velocity testing, but here is the problem: EMG, and specifically nerve conduction velocity testing, measures assess the nerve fibers that that are involved in nonpainful sensation (eg, position sense, light touch), not those that are ultimately responsible for facilitating pain. The bottom line is that a normal EMG and nerve conduction velocity study, which is not uncommon in someone with chronic widespread pain, may miss the abnormalities because it is measuring large, myelinated nerve fiber function rather than the population of fibers that are involved in pain transmission, which are the small, weakly myelinated or unmyelinated fibers. Thus, the EMG and nerve conduction velocity assessment approach may result in a large number of false negatives.

That is very important because our patients are often told that there is "nothing wrong" with them; or they have been diagnosed as having a nonneuropathic disorder; or they may have been characterized as having fibromyalgia when, in fact, they may have a more specific condition. Similarly, blood work does not always uncover the underlying cause; and x-ray, CT, and MRI do not confirm that a person is experiencing pain, nor does any other evaluation of structure.

Quantitative sensory testing may be able to provide more information about the population of smaller nerve fibers that is responsible for chronic widespread pain, but this tool is often only available in facilities involved in academic research. What has recently emerged as a useful diagnostic approach is skin biopsy. A 3-mm skin punch biopsy performed at characteristic locations, most often in the lower extremities, may give clues about the small-fiber neuropathic nature of a patient's complaints. Generally, such a biopsy will show the reduction of intraepidermal nerve fiber density, which indicates small-fiber polyneuropathy.

Small-Fiber Polyneuropathy and Chronic Widespread Pain

Three important studies highlight how individuals previously diagnosed as having fibromyalgia were found to have a small-fiber polyneuropathy. Anne Louise Oaklander and colleagues[2] compared 27 patients who had satisfied the American College of Rheumatology (ACR) criteria for fibromyalgia with 30 matched controls. In all, 41% of skin biopsies from patients with fibromyalgia were diagnostic for small-fiber peripheral neuropathy or polyneuropathy, compared with 3% from controls.

In a second study,[3] 25 patients with fibromyalgia were compared with 10 patients with depression but no pain and a group of healthy controls. To evaluate small nerve fibers, participants underwent quantitative sensory testing, pain-related evoked potentials, quantified intraepidermal nerve fiber density, and evaluation of regeneration of intraepidermal nerve fibers of the lower leg and upper thigh.

Compared with healthy controls and patients with depression, patients with a diagnosis of fibromyalgia had impaired small-fiber function. Skin biopsy findings demonstrated that the total and regenerating intraepidermal nerve fibers of the lower leg and upper thigh were reduced in patients with fibromyalgia compared with controls. A reduction in unmyelinated nerve fiber bundles was seen in patients with fibromyalgia vs depressed and control subjects. The authors concluded that these results support the concept that fibromyalgia is neuropathic in nature.

In a third study,[4] presented by Todd Levine and David Saperstein at the 2012 ACR meeting, 56 patients who had met the 2010 ACR diagnostic criteria for fibromyalgia underwent skin punch biopsies at the proximal and distal lower limb sites. In 61% of these biopsies, findings were consistent with small-fiber neuropathy.

These three studies show that a significant percentage of individuals who had a diagnosis of fibromyalgia in fact had findings consistent with a small-fiber polyneuropathy process. This does not mean that fibromyalgia is a neuropathic condition in all people. Fibromyalgia may well be a separate condition from small-fiber neuropathy. However, it also means that people who previously have been diagnosed as having fibromyalgia may, in fact, have a small-fiber neuropathy process.

Important Treatment Implications

Clarifying this pathologic process is important because there are recognized causes of small-fiber neuropathy, including glucose intolerance, Sjögren syndrome, celiac disease, and exposure to certain chemotherapeutic agents, among others. If you follow the adage of treating the treatable, then identifying the etiology of a condition—in this case, painful small-fiber neuropathy—generally should lead to better treatment.

Of course, we have a long way to go; however, it is instructive and important to point out that many people previously diagnosed with fibromyalgia may, in fact, have been incorrectly or incompletely diagnosed and may be experiencing a small-fiber neuropathy.

An Unanswered Question

Chronic widespread pain has also been associated with opioid-induced hyperalgesia. We have limited literature about this phenomenon, but it has been observed that some individuals who are receiving chronic opioid therapy have developed increased sensitivity to pain. We do not know to what extent that is due to the opioid itself; moreover, multiple molecular and cellular mechanisms have been proposed, but very few have been proved.

The US Food and Drug Administration has mandated that the nine manufacturers of extended-release and long-acting opioids study this phenomenon, and a study will soon be initiated that we hope will address this very important scientific question.

Real-World Examples

I want to conclude by describing four patients from my own practice who have been diagnosed with small-fiber neuropathy. The first is a 67-year-old man who had a history of Sjögren syndrome, progressively severe burning pain in both lower extremities, and less severe complaints in his upper body. His neurologic examination was otherwise completely normal except for mild allodynia upon palpation of his feet. We performed 3-mm skin-punch biopsies of his left leg and thigh, which demonstrated reduced intraepidermal nerve fiber density.

The second patient is a 50-year-old woman who complained of chronic widespread pain following a cholecystectomy 1 year before. Initially, her complaints involved only her right upper quadrant, but after the cholecystectomy she began to experience pain throughout her body. Detailed evaluation, blood work, and radiographic testing revealed no specific etiology, but skin-punch biopsies demonstrated reduced intraepidermal nerve fiber density.

The third patient is a 48-year-old woman with a 10-year history of fibromyalgia whose symptoms flared while she was being treated for a localized thoracic reticular complaint. Skin-punch biopsies revealed reduced intraepidermal nerve fiber density at both lower extremity sites.

The last patient is a 29-year-old woman who developed chronic widespread pain and chronic pelvic pain after undergoing multiple surgical procedures for the treatment of endometriosis. Skin-punch biopsies revealed reduced intraepidermal nerve fiber density in her lower extremities, supporting the diagnosis of painful small-fiber neuropathy.

In summary, as you evaluate people with chronic widespread pain and especially when you consider patients you have been treating for fibromyalgia, realize that certain individuals who present with chronic widespread pain may be experiencing symptoms due to small-fiber neuropathy. It is in the best interest of these patients and their treatment that the diagnosis be as clear and precise as possible. This is not to say that fibromyalgia is a separate entity but that small-fiber neuropathy should be considered in patients with widespread pain symptoms.

I hope that these comments have been helpful to you. I am Dr Charles Argoff, professor of neurology at Albany Medical College and director of the Comprehensive Pain Management Center at Albany Medical Center in Albany, New York.

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