Research led by scientists at the University of Texas Medical Branch (UTMB) at Galveston has found that fibromyalgia (FM) pain can be reduced dramatically by treating patients using the antidiabetic drug metformin. The researchers’ studies, reported in PLOS One, point to a previously unrecognized pathogenetic link between insulin resistance and fibromyalgia. They claim that if validated through additional clinical trials, their findings could completely change how this poorly understood pain disorder is perceived, diagnosed, and treated.

“If confirmed, our findings may translate not only into a radical paradigm shift for the management of FM but may also save billions of dollars to healthcare systems around the world,” concluded UTMB professor of neurology Miguel Pappolla, PhD, and colleagues in their published paper, which is titled, “Is insulin resistance the cause of fibromyalgia? A preliminary report.”

Fibromyalgia is a generalized pain disorder that is estimated to affect 2.7% of the general population. Three times as many women as men are affected, the authors explained. Patients typically experience chronic, widespread pain, and may also report extreme fatigue, poor sleep, gastrointestinal problems, and cognitive or mood issues. The underlying causes and neurobiology of fibromyalgia aren’t understood.

As one of the most common conditions causing chronic pain and disability, fibromyalgia represents a huge global economic burden, the authors continued. “In the United States alone, the healthcare cost is around $100 billion/year; comparable to reports in European countries.” Unfortunately, while a number of hypotheses have attempted to explain the wide range of symptoms associated with FM, “… none of these propositions has led to practical advances beyond symptomatic treatment.”

Prior studies have identified changes to the tiny blood vessels in the brains of FM patients, which can affect blood flow. Dysfunction of brain microvasculature is also a feature of insulin resistance, and this prompted the team to hypothesize whether IR may be the “missing link” in FM. “Earlier studies discovered that insulin resistance causes dysfunction within the brain’s small blood vessels,” said Pappolla, who headed the research team, which included collaborating scientists at the National Institutes of Health’s National Institute on Aging. “Since this issue is also present in fibromyalgia, we investigated whether insulin resistance is the missing link in this disorder.”

The researchers evaluated data from 23 FM patients who had been referred to a pain medicine clinic for myofascial pain. The patients had all undergone routine blood tests, including measurements of HbA1c, which is widely used as a biomarker for insulin resistance. Patients with mildly raised HbA1c levels are considered pre-diabetic, and have an increased risk of developing peripheral neuropathies, cardiovascular disorders, and neurological disease, and an elevated risk of all-cause mortality.

The team compared HbA1c values from the 23 FM patients with mean HbA1c values from two independent control populations. The results showed that while the HbA1c values for many FM patients were in the normal range, when the HbA1c data were stratified for age, there was an obvious association with FM. “… a clear-cut difference between the groups (patients with FM versus controls) came to light … The results showed a highly significant association between FM and HbA1c levels,” the scientists stated. “We showed that most—if not all—patients with fibromyalgia can be identified by their A1c levels, which reflects average blood sugar levels over the past two to three months,” Pappolla noted.

While the investigators were initially puzzled that the same finding hadn’t been reported through previous research, they suggest the reason may be that their study was the first to analyze the data in an age-stratified manner. “This is important, considering the effect of aging on HbA1c levels,” they noted. “Therefore, a value of 5.5%, for example (considered “normal” by current criteria), may not be so in many young subjects.”

The health risks associated with pre-diabetes mean that clinic patients who developed IR were routinely offered early treatment with metformin. The investigators found that those IR patients who had been treated using metformin in addition to standard treatment (ST) for their FM experienced a “dramatic” reduction in reported pain scores. Eight of 16 patients who had been treated using metformin plus ST reported complete resolution of pain, which the team stated is “a degree of improvement never observed before in such a large proportion of FM patients subjected to any available treatment.” Some of the patients, in fact, responded only to metformin and not to STs. In contrast, patients receiving standard treatment alone experienced only some improvements to their pain.

The team acknowledged that while their initial results are compelling and suggest that IR may present as a “pathological substratum in FM,” the reported study had limitations, and a causal link between FM and IR will have to be validated through additional research in patients. “Based on our data, we would like to propose that IR is pathogenetically linked to FM,” they concluded. “However, there are several caveats to our proposition which must be carefully considered in the design of future clinical trials attempting to confirm this hypothesis … Our data provides preliminary evidence suggesting that IR may be a pathological substratum in FM and sets the stage for future studies to confirm these initial observations.”

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