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Insulin resistance measured with the surrogate marker hemoglobin (Hb)A1c was strongly associated with fibromyalgia in a small study, which may hold implications for the treatment of this poorly understood pain syndrome.

In a cohort of 23 patients with fibromyalgia, levels of HbA1c were significantly higher than in two independent groups of controls, being 0.59 units higher than for participants in the Framingham Offspring Study (P<0.001), and 0.39 units higher than for individuals in the National Health and Nutrition Examination Survey (NHANES) dataset (P=0.0002), according to Miguel A. Pappolla, MD, PhD, of the University of Texas Medical Branch in Galveston, and colleagues.

Moreover, among patients who were treated with the common diabetes medication metformin, 50% reported complete resolution of pain -- "a degree of improvement never observed before in such a large proportion of fibromyalgia patients subjected to any available treatment," the investigators wrote online in .

"I think this is going to be a breakthrough for the treatment of fibromyalgia because the data are very clear-cut," Pappolla told 番茄社区app.

However, "I think all one can say now is that these findings are very interesting and intriguing," commented Daniel J. Clauw, MD, director of the Chronic Pain and Research Center at the University of Michigan in Ann Arbor, who was not involved with the study.

"And as usual, such preliminary findings need to be replicated in future studies that are specifically designed to test these hypotheses," cautioned Clauw.

Fibromyalgia today is considered a disorder of pain sensitivity and aberrant processing of nociceptive stimuli, but understanding of the involved mechanisms has been limited. The impact is far from negligible, with an annual price tag of $120 billion in the U.S. alone, yet treatment has remained largely symptom-directed. Typical symptoms include multifocal pain, fatigue and sleep disturbances, gastrointestinal problems, and mood/cognitive difficulties.

"Prior observations indicate that insulin resistance causes dysfunctions in the brain microvasculature leading to focal cerebral hypoperfusion," the researchers explained. "Since similar brain perfusion abnormalities are present in patients with fibromyalgia, we hypothesized that insulin resistance may be the missing link in this disorder."

To explore this hypothesis, the team undertook a retrospective chart review of patients with fibromyalgia seen at a single subspecialty pain center, looking for potential laboratory abnormalities and comparing the results with those from 1,350 nondiabetic individuals in the Framingham group and 1,592 from NHANES.

The only abnormality they identified was elevated HbA1c in 23 patients, which had been included in a diagnostic panel for peripheral neuropathy.

Of the 23 patients, who ranged in age from 35 to 60, 21 were women, 11 were white, eight were Hispanic, and four were African-American.

An important aspect of the analysis was its correction for age, Pappolla explained. Age influences HbA1c levels, and "a value of 5.5%, for example (considered 'normal' by current criteria), may not be so in many young subjects," his team pointed out.

A subgroup of 16 patients underwent treatment with metformin, 500 mg twice daily, in addition to standard treatment, which consisted of norepinephrine reuptake inhibitors (NSRIs) and/or membrane stabilizing agents such as gabapentin or pregabalin. The remainder received standard treatment alone.

The median baseline pain score, calculated as the average of the worst pain in the week before assessment, was 8 (on an 11-point numeric pain rating scale). After exposure to metformin, with treatment duration ranging from 8 to 36 months, pain scores decreased to 4 for the standard treatment group -- but to 0.25 in the metformin group (P<0.0001).

"Interestingly, some patients responded only to metformin and not to standard treatment with NSRIs or membrane stabilizing agents," the investigators noted.

"Based on our data, we would like to propose that insulin resistance is pathogenetically linked to fibromyalgia," the team stated.

Moreover, the findings may hold implications for other types of chronic pain. "Many patients have markers of fibromyalgia such as multifocal pain associated with muscle pain but do not meet the established criteria. Those patients also may respond to this kind of treatment," Pappolla said.

Approximately 30% of patients who undergo knee replacement have persistent pain following the procedure. In conducted by Clauw's group at the University of Michigan that included more than 600 patients, those who had high scores on a fibromyalgia survey were more likely to fail to reach an improvement of at least 50% in pain post-surgery.

"The fibromyalgia survey score was predictive of failing to meet the threshold for improvement, with the odds increasing by 17.8% for every one-point increase on the scale," the researchers reported.

"And what we are finding now is that among those patients who do not respond to knee replacement, there is a very high incidence of insulin resistance," Pappolla said.

"So this is not only going to have an impact on fibromyalgia -- which in itself eats up a big chunk of the healthcare budget, but extends to other chronic pain conditions," he said. Similar findings on insulin resistance are also being observed by his group among patients with lumbar spine arthritis who don't respond to spine surgery, he added.

"If confirmed, our findings may translate not only into a radical paradigm shift for the management of fibromyalgia, but may also save billions of dollars to healthcare systems around the world," the researchers concluded.

Limitations of the study, Pappolla and co-authors said, included its small numbers, retrospective cross-sectional design, and the possibility that metformin has effects other than on insulin resistance.

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