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Small-fiber dysfunction may underlie pain.

BETHESDA, MD. -- A growing body of research suggests that dysfunction of the small-fiber axons that mediate pain sensation and autonomic function underlies complex regional pain syndrome, Dr. Anne Louise Oaklander said at a meeting sponsored by the National Institutes of Health's Pain Consortium.

Complex regional pain syndrome (CRPS) has been "one of the most mysterious of the pain disorders"--one with no known cause, leaving few physicians willing to treat it and many others believing the disorder to be psychosomatic, said Dr. Oaklander, a neurologist at Harvard Medical School and director of the nerve injury unit at Massachusetts General Hospital, Boston.

However, "we now understand the disease biology," she said. "It's time to abandon the dichotomy between CRPS I and CRPS II ... [and to] consider changing the name to 'posttraumatic neuralgia.'

"Small-fiber axonopathy is what causes this," Dr. Oaklander said.

Current diagnostic criteria for CRPS include the occurrence of a noxious event or other cause of immobilization; continuing or disproportionate pain, allodynia, or hyperalgesia; and edema, changes in skin blood flow, or abnormal sweating in the region of pain.

Most patients are classified as having CRPS-I (defined as having no known nerve injury); fewer than 10% receive a diagnosis of CRPS-II (having a known nerve injury). However, "seeing them in the clinic with the same presentation, it doesn't take a great leap of faith to believe these guys [with CRPS-I] have a nerve injury that wasn't discovered," she said.

CRPS is "what I call a focal 'pain-plus' syndrome. These patients have chronic pain but also vascular dysregulation and sometimes dystonia, contralesional 'mirror' pain ... osteopenia, [and focal changes in other innervated tissues]," Dr. Oaklander said. "[The disease] reflects pathological processes, not normal pain mechanisms."

Epidemiologic studies show that most patients diagnosed with CRPS are young (an average age of 39) and female (a 4:1 ratio), and that most patients recover spontaneously.

Skin biopsies done in Dr. Oaklander's lab of 18 CRPS-I patients show 30% fewer small-fiber nerve endings in painful CRPS-affected areas.

Results of ipsilateral and contralateral control biopsies discount a hypothesized effect of swelling on the number of nerve endings, and the fact that a control group of seven osteoarthritis patients with severe leg pain, edema, and disuse had no loss of nerve endings discounts the hypothesis that pain "burns out" nerve endings, Dr. Oaklander said. The identification of posttraumatic small-fiber loss in patients with CRPS has been validated by several other research groups, she noted.

There is good evidence that trauma disproportionately damages small fibers, probably because they lack protective myelin and saltatory conduction. Pain results when undamaged axons within the same nerve, as well as regenerating axon spouts, malfunction, firing without cause, for instance, triggering neurogenic edema and tissue ischemia.

"The problem isn't so much with the nociceptive fibers that are degenerated--it's with their neighbors," Dr. Oaklander said.

New animal models developed to prove causality, including her own laboratory's mouse model of distal nerve injury, have reproduced the symptoms of CRPS--from allodynia and dysautonomia to bone loss, dystonia, and a regional and mirror-like spread of symptoms--and have shown that long-lasting pain behaviors usually remit and that the prevalence of allodynia is independent of lesion size.

"We really can't assume that it takes a severe injury to leave someone with chronic pain--in fact, the opposite may be true," Dr. Oaklander said. "Most of those who have small-fiber damage, however, may be able to regenerate their axons, and those whose axons do not regenerate may have either mild or no degeneration of their vasa nervorum," she said.


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Title Annotation:Pain Medicine
Author:Kilgore, Christine
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Jul 1, 2007
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