Important Points:

Fibromyalgia
Chronic pain
hemoglobin A1c
insulin resistance

Insulin Resistance and Chronic Pain

An estimated 10 million adults in the United States live with fibromyalgia — a condition that causes pain throughout the body often to the point where it’s difficult to function. Could the key to understanding and treating fibromyalgia and other chronic pain involve insulin resistance? We will shed some light on current research on this topic.

So, what is Fibromyalgia?

Characterized by chronic and widespread pain, increased sensitivity to pain, and heightened feelings of fatigue, brain fog, etc., fibromyalgia remains poorly understood. The condition is also hard to diagnose, difficult to manage, and diminishes the quality of life for those struggling with it. It is reported that there’s an estimated global prevalence of 2.7%, with females outnumbering males nearly three to one. In addition, a couple of studies have noted that fibromyalgia seems to be more prevalent among individuals with Type 2 diabetes (T2d) suggesting a link between the two conditions that is worthy of further study. While experts agree that genetics and environmental factors are at play with fibromyalgia, little is known regarding how and why the syndrome develops.

Diagnostic criteria for fibromyalgia comes from the American College of Rheumatology (ACR) guidelines. The Widespread Pain Index measures pain or tenderness felt in the week prior to the appointment in 19 different body regions. The Severity Scale is deduced by the patient’s reporting the severity of symptoms like fatigue and brain fog on a scale from 0 to 3. ACR guidelines combine these two measurements using a rating scale from 0 to 31, and according to them, a score of 13 or higher corresponds to a diagnosis of fibromyalgia.

The global economic impact of FM is enormous. In the United States alone, the healthcare cost is around $100 billion/year and is comparable to reports in European countries. Due to lower pain thresholds, patients with FM also have a higher incidence of symptomatic musculoskeletal and spinal disorders which in themselves contribute to the financial burden of managing this disorder.

Many hypotheses have been advanced to explain the extensive array of symptoms including inherited abnormalities, dysfunction of neurotransmitter pathways such as substance P, immune dysregulation, and several others. Unfortunately, none of these propositions has led to practical advances beyond symptomatic treatment. In fact, recent reviews of FM published in 2016 and 2017 have concluded that there have been no substantive advances in our understanding of this disease.

2. What are the Similarities Between Fibromyalgia and Insulin Resistance?

Although more recent reviews of fibromyalgia research do not make mention of the purported link between the syndrome and insulin resistance or diabetes, the two conditions affect brain vasculature in strikingly similar ways.

According to Miguel Pappolla, MD, PhD, a professor of neurology at the University of Texas Medical Branch and medical director of St. Michael’s Pain and Spine Clinics in Houston, insulin resistance is known to impair brain microcirculation leading to slowed blood flow and oxygenation (hypo-perfusion) in certain brain regions. “What is very interesting,” he said, “is that patients with fibromyalgia also have hypo-perfusion in several brain areas.” The question remains, however, whether insulin resistance may be behind these similar decreases in blood flow experienced by those with fibromyalgia.

Research into these Similarities

To investigate this question, Dr. Pappolla led a retrospective, cross-sectional study, reviewing medical records from 23 patients (21 females, 2 males; 11 White, 8 Hispanic, 4 African American; ages 35 to 60) at St. Michael’s Pain and Spine Clinics.⁷ All 23 patients met the ACR criteria for diagnosis with fibromyalgia.

As a measure of insulin resistance, the team selected the hemoglobin A1c, in which values between 5.7 and 6.4 define prediabetes and values of 6.5 or more constitute diabetes. They compared the A1cs on record for the 23 patients with fibromyalgia to those of two separate control groups: the non-diabetic subset (1,350 people) from the Framingham Offspring Study characterized by normal glucose tolerance (FOS NGT) and the non-diabetic subset (1,592 people) from the National Health and Nutrition Examination Survey (NHANES).

When the investigators compared the A1c test results of the people with fibromyalgia with those of age-matched controls, they found that the former group had significantly higher levels of hemoglobin A1c than the latter indicating a measure of insulin resistance.

“[People with prediabetes] with slightly elevated A1c values carry a higher risk of developing central (brain) pain, a hallmark of fibromyalgia and other chronic pain disorders,” notes Dr. Pappolla, pointing out that this link between insulin resistance and fibromyalgia has been around for a long time. Surprisingly, this link went unnoticed. “Considering the extensive research on fibromyalgia, we were puzzled that prior studies had overlooked this simple connection,” the first author says.

“The main reason for this oversight is that about half of fibromyalgia patients have A1c values currently considered within the normal range. However, this is the first study to analyze these levels normalized for the person’s age, as optimal A1c levels do vary throughout life,” the researcher continues.

“Adjustment for the patients’ age was critical in highlighting the differences between patients and control subjects,” he explains.

As part of the study, the researchers administered metformin — a drug that people typically take to treat insulin resistance — to the participants with fibromyalgia and muscular or connective tissue pain.

Metformin successfully reduced pain in this cohort, prompting the researchers to suggest that this common drug could be a viable and less expensive treatment option for some people with this chronic pain condition.

“In the [U.S.] alone, the healthcare cost is around $100 billion [per] year; comparable to reports in European countries,” the researchers write in the study paper.

“Earlier studies discovered that insulin resistance causes dysfunction within the brain’s small blood vessels. Since this issue is also present in fibromyalgia, we investigated whether insulin resistance is the missing link in this disorder.”

First author Dr. Miguel Pappolla

“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 2 to 3 months,” Dr. Pappolla adds.

The A1c test is a blood test that allows doctors to measure a person’s blood sugar levels by looking at “hemoglobin A1c,” a blood cell protein that binds to the simple sugar glucose. Doctors use this test to diagnose prediabetes and type 2 diabetes

In order to supplement this finding, the evolution of the pain scores of patients with FM who had had their Insulin Resistance treated pharmacologically was also reviewed. This subgroup of patients reported dramatic improvements of their myofascial pain after treatment with metformin.

Do these findings offer hope for the future for Chronic Pain Treatment?

This evidence, although preliminary, suggests a pathogenetic relationship between Fibromyalgia and Insulin Resistance, which may lead to better treatment plans. Along with this, Metformin, a drug commonly used to treat diabetes patients by targeting insulin resistance, has shown promise with treating pain from fibromyalgia; it 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.

That said more research is needed to better understand the link between insulin resistance and fibromyalgia and other types of chronic pain.

References:

NCBI (2016): A Correlative Relationship Between Chronic Pain and Insulin Resistance in Zucker Fatty Rats: Role of Downregulation of Insulin Receptors. Retrieved from

https://www.ncbi.nlm.nih.gov/pubmed/26705975

Science Daily (2019): Does insulin resistance cause fibromyalgia? Retrieved from

https://www.sciencedaily.com/releases/2019/05/190507145523.htm

MedicalNewsToday (2019): Fibromyalgia: Is insulin resistance ‘the missing link?’ Retrieved from

https://www.medicalnewstoday.com/articles/325155.php#1

Plos One (2019): Is insulin resistance the cause of fibromyalgia? A preliminary report. Retrieved from

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216079

Practical Pain Management (2019): Fibromyalgia and Insulin Resistance: Correlational or Causal Relationship? Retrieved from

https://www.practicalpainmanagement.com/pain/myofascial/fibromyalgia-insulin-resistance-correlational-causal-relationship

Healthline (2019): Drug Used to Treat Diabetes May Be Effective Against Fibromyalgia. Retrieved from

https://www.healthline.com/health-news/does-insulin-resistance-cause-fibromyalgia

Dr. Gurpreet Padda is an interventional pain physician who treats patients with profound, chronic, severe pain that is unrelenting. Over time he worked out that there was more to these people’s pain than just the physical source of it and that it was also a systemic or metabolic inflammatory issue and that hyperinsulinemia was at the root of it. He found that the majority of his patients were obese and either pre-diabetic or diabetic. He found that the majority of them also had leaky gut as well. This was all caused by the standard American diet (SAD) i.e. vegetable oils, processed carbs and excessive sugar. He talks about how junk food companies manipulate the fructose concentration higher than regular fructose corn syrup in order to increase the addiction factor.

What he is doing in the community is astounding. They have over 65,000 active patients in their online program which is totally free and he even contributes more than a million dollars of his own money every year to the program.
You can find out more about this program at

https://reversingdiabetesmd.com/

Patients with chronic pain have a signaling mechanism, whether induced by medications or their endogenous pain, that causes them to seek out dopaminergic stimulation, to relieve their pain.

Some of these dopaminergic stimulation can be substituted by dietary intake.

Excessive nonnutritive dietary intake leads to obesity and visceral adipose tissue accumulation, which is inflammatory.

Excessive inflammatory mediators aggravate pain, and the cycle repeats.

Could sugar self-substitution for opioids in our patient’s be leading to insulin resistance, obesity, T2DM?

In an experiment done on mini-pigs, they found that sugar can affect the brain’s reward system in a similar “manner similar to that of drugs of abuse”

Sugar’s impact on the brain’s reward system boils down to how it affects two types of receptors in the brain.

The first set is dopamine receptors — dopamine is a central player in the brain’s reward system, released during pleasurable activities.

The second set is opioid receptors, which are also found all over the brain but are particularly found in areas involved in eating-related rewards.

The sensitivity of both receptors was dampened when pigs were allowed unrestricted access to sugar water for one hour each day for twelve days. The pigs were also fed a normal diet, so sugar consumption was unrelated to their caloric needs.

After the first day, the sugar intake lowered the “availability” of opioid and dopamine receptors, essentially dampening the ability of these receptors to bind to their natural ligands. Both Opiate and Dopamine receptor binding was attenuated 14% in the anterior cingulate cortex and the nucleus accumbent, both are areas of the hedonic reward.

At the end of the 12 days, the scientists found that the pattern held — the availability of both types of receptors continued to decrease significantly.

Could sugar self-substitution for opioids in our patient’s be leading to insulin resistance, obesity, T2DM?

Winterdahl, M., Noer, O., Orlowski, D. et al. Sucrose intake lowers μ-opioid and dopamine D2/3 receptor availability in porcine brain. Sci Rep 9, 16918 (2019) DOI:10.1038/s41598-019-53430-9.

Padda Institute

Dr Gurpreet Padda is an interventional pain physician who treats with patients with profound, chronic, severe pain that is unrelenting. Over time he worked out that there was more to these people’s pain than just the physical source of it and that it was also a systemic or metabolic inflammatory issue and that hyperinsulinemia was at the root of it. He found that the majority of his patients were obese and either pre-diabetic or diabetic. He found that the majority of them also had leaky gut as well.

This was all caused by the standard American diet (SAD) i.e. vegetable oils, processed carbs and excessive sugar. He talks about how the junk food companies manipulate the fructose concentration higher than regular fructose corn syrup in order increase the addiction factor.

You can find out more about this program at:

https://reversingdiabetesmd.com/

It is estimated that by 2020, two-thirds of the global burden of disease will be due to chronic non-communicable diseases, most of which are associated with diet. While hunger is a tremendous global health concern that cannot be minimized, overnutrition should similarly be given concentrated attention. Malnutrition affects up-to 1 billion people. Even though undernutrition is the main cause of malnutrition, people who are overweight could also be malnourished.

The “dual burden of malnutrition” is a term coined by the World Health Organization (WHO) to describe a situation which is characterized by “the coexistence of undernutrition along with overweight and obesity, or diet-related non-communicable diseases, within individuals, households and populations, and across the life course. Globally, the problem is not the availability of food resources, but the allocation and consumption of food.

An explanation why motivation is reduced with metainflammation and a possible explanation why many patients with diabetes develop chronic pain pathologies with anhedonia, reflections on the addiction model of obesity.

The brain’s dopamine system, which drives motivation, is directly affected by chronic, low-grade inflammation. If your brain perceives that it is fighting off an infection or healing a wound, your brain recalibrates your motivation to do other things, so you don’t use up too much of your energy. This immune system mechanism regulates the use of energy resources during times of acute stress was likely adaptive in our ancestral environments, but the same mechanism to conserve energy for the immune system could become maladaptive when many people are less physically active and may have low-grade inflammation due to factors such as chronic stress, obesity, metabolic syndrome, or chronic pain.

Inflammatory cytokines have been shown to have a direct effect on mesolimbic dopamine (DA) that is associated with a reduced willingness to expend effort for reward. “the metabolic demands of chronic low-grade inflammation induce a reduction of striatal DA that in turn leads to a steeper effort-discounting curve because of reduced perceived ability (can’t) versus preference (won’t) for reward” ultimately contributing to motivational impairments

Michael T. Treadway, Jessica A. Cooper, Andrew H. Miller. Can’t or Won’t? Immunometabolic Constraints on Dopaminergic Drive. Trends in Cognitive Sciences, 2019; 23 (5): 435 DOI: 10.1016/j.tics.2019.03.003

Your pain physician should be addressing obesity and insulin resistance if they hope to ever reverse your pain. Metabolic inflammation (metainflammation) of obesity and hyperinsulinemia is an under-recognized cause of pain in the United States.

Musculoskeletal pain has been estimated to affect 13.5%–47% of the general population, and 75 percent of those affected have two or more areas of pain. Multi-joint pain and progression, including non-weight bearing joints, are linked independently to the inflammatory cascade triggered by obesity, not just simply the biomechanical forces.

Arthritis Care Res (Hoboken). 2017 Apr;69(4):509-516. DOI: 10.1002/acr.22963. Epub 2017 Feb 28.

Fibromyalgia pain is closely associated with insulin resistance, and elevated HgBA1C and fibromyalgia symptoms are improved with metformin therapy to reverse insulin resistance.

Pappolla MA, Manchikanti L, Andersen CR, Greig NH, Ahmed F, Fang X, et al. (2019) Is insulin resistance the cause of fibromyalgia? A preliminary report. PLoS ONE 14(5): e0216079.

I would suggest that most chronic pain pathologies are maintained by metainflammation, derived primarily from lifestyle choices leading to insulin resistance. In our chronic interventional pain clinic, we spend more than half of our time reversing the course of diabetes.