Knowledge Grows About Puzzling Disorder

It has only been two decades since fibromyalgia—a baffling mix of chronic pain throughout the body variously coupled with anxiety, depression, fatigue, insomnia, and difficulty thinking clearly—was officially recognized as an illness by the American College of Rheumatology (ACR).

The ACR developed research classification criteria for fibromyalgia that required not only a history of chronic widespread pain, but the physical finding of widespread pain points in the body.

Since then, scientists have made considerable progress toward understanding fibromyalgia and finding treatments for it.

Credit: Lesley Arnold, M.D.

"It is a familial disorder, so we do believe that there is a genetic component to it," Lesley Arnold, M.D., a professor of psychiatry at the University of Cincinnati who treats and researches fibromyalgia, said in an interview. "In addition, there are environmental influences, and studies suggest they are varied. It could be a viral infection, physical trauma, even emotional distress. Research is supporting a strong central nervous system component that largely becomes independent of more peripheral pain inputs.... It's as if a volume-control setting for pain is abnormally high in fibromyalgia."

Or to put it another way, such patients have an abnormally low pain threshold, I. Jon Russell, M.D., Ph.D., a San Antonio rheumatologist and fibromyalgia expert, told Psychiatric News. For example, if a subject with fibromyalgia and a healthy subject are exposed to a painful stimulus, neuroimaging shows that the same brain areas are activated in both subjects. But it takes much less of a painful stimulus to produce such activation in the subject with fibromyalgia than in the healthy subject.

The basic central nervous system mechanisms of fibromyalgia also include some neurochemical abnormalities, Russell continued. Whereas the metabolite levels of two neurotransmitters—serotonin and norepinephrine—are abnormally low in the spinal fluid of such patients, the level of substance P in their spinal fluid is abnormally high—about three times higher than in healthy individuals.

"Since substance P is a known amplifier of pain messaging, there is suspicion that elevated levels of it may be responsible for the patients' low pain threshold," he said. Moreover, "this elevation seems to be unique to people with fibromyalgia, because patients with some other painful conditions have been examined, and they don't exhibit such high levels."

Three Medications Approved

The Food and Drug Administration (FDA) has approved three medications to treat fibromyalgia pain—the anticonvulsant pregabalin and the SNRIs duloxetine and milnacipran. (Although duloxetine has also been approved by the FDA for treating depression, milnacipran has been approved only as an antidepressant by Europe's drug regulatory agency.) Clinical trials have shown that all three compounds can reduce fibromyalgia pain by at least 30 percent, Arnold said.

Credit: I. Jon Russell, M.D., Ph.D.

Furthermore, clinical trials have shown in fibromyalgia subjects that pregabalin can improve sleep and that duloxetine and milnacipran can lessen fatigue, Arnold noted. And she and her colleagues found in a trial with fibromyalgia subjects that duloxetine relieved pain regardless of whether subjects had a major depressive disorder.

"Unfortunately, there is a paucity of data regarding the use of pregabalin and duloxetine or pregabalin and milnacipran in combination for fibromyalgia," Russell said.

"Yet the combinations that I have found make sense in my practice are combining pregabalin and duloxetine or pregabalin and milnacipran," Binit Shah, M.D., a psychiatrist and pain specialist at University Hospitals Case Medical Center, said.

Some nondrug regimens can also help fibromyalgia patients, Arnold pointed out. Ample evidence has shown that aerobic exercises can improve patients' overall function, and some evidence has also suggested that yoga and the Chinese martial art tai chi can do so as well. Cognitive-behavioral therapy (CBT) has been found to lessen patients' pain and improve their function even if it is offered online and not in person. Arnold has her patients use a CBT Web site designed for fibromyalgia patients called <www.fibroguide.com>. "I think it's excellent," she said.

More May Be Coming

Some new medications for fibromyalgia are also in the works, Russell said. He likewise foresees nerve growth factor being a possible target for future fibromyalgia medications since production of a purported major culprit in fibromyalgia—substance P—is facilitated by nerve growth factor in the central nervous system.

And E. Baron Short, M.D., an assistant professor of psychiatry at the Medical University of South Carolina, found in a randomized, controlled pilot study of 20 fibromyalgia subjects that 10 sessions of repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex, over a two-week period, significantly reduced pain from baseline, whereas the sham treatment did not. The results were reported on July 20 in the journal Pain.

"Moreover," Short and his group wrote, "the rapid onset of pain reduction in this pilot trial approximates that of pregabalin and duloxetine, although with markedly fewer side effects."

Short and his colleagues will now be applying for funding to conduct a larger rTMSm/fibromyalgia trial, he told Psychiatric News.

The FDA approved rTMS for treating major depression in 2008.

An abstract of Short's paper, "Ten Sessions of Adjunctive Left Prefrontal rTMS Significantly Reduces Fibromyalgia Pain: A Randomized, Controlled Pilot Study," is posted at <www.sciencedirect.com/science/article/pii/S0304395911003769>.