Insulin Resistance May Play a Role in Fibromyalgia
Although insulin resistance (IR) is most often linked to diabetes, it is also associated with chronic pain. In a recent observational study, researchers detected a relationship between IR and fibromyalgia that may have pain management implications in the future.¹ Meanwhile, studies in rats have established a mechanistic link between metformin and pain perception.²
Fibromyalgia (FM) is a common cause of generalized chronic pain affecting approximately 2% of the population, according to the CDC. Management of fibromyalgia remains a challenge because the condition is not well understood, and while treatments can relieve some symptoms, no effective long term pain relief is currently available.“The pathophysiology of fibromyalgia is not fully known, but several theories exist,” said Shiloh Plaut, MD, of the University of Nicosia, Cyprus, who authored a recent review of myofascial pain/fibromyalgia syndrome in the journal PLoS One.³
“Studying the link between insulin resistance and fibromyalgia may provide a better understanding of both conditions and inform better treatments in the future,” Dr. Plaut said. “Some studies suggest that the effect of insulin resistance on pain and the nervous system could have a role in the underlying cause of conditions such as fibromyalgia. Moreover, it is possible fibromyalgia can contribute to – or lead to – insulin resistance,” he noted.Insulin Resistance and Chronic Pain
Similar brain vasculature occurs in both IR and FM, leading to focal cerebral hypoperfusion, according to Miguel A. Pappolla, MD, of the University of Texas Medical Branch at Galveston. Dr. Pappolla and colleagues published a study in Pain Physician exploring the hypothesis that IR may be associated with the pathophysiologic basis of FM.¹
The researchers reviewed data from 33 adults with FM, including 17 Hispanic patients, 10 white patients, and 6 African American patients. They compared HbA1c values between the patients with FM and 2 different control groups of nondiabetic individuals with normal glucose tolerance.Fibromyalgia
CRPS
Insulin Resistance May Play a Role in Fibromyalgia
Current research offers potential implications for management
Heidi Splete
A professional woman with Fibromyalgia sits at her desk with her eyes closed as she winces in pain while touching her neck with one hand and her lower back with her other hand.
Although insulin resistance (IR) is most often linked to diabetes, it is also associated with chronic pain. In a recent observational study, researchers detected a relationship between IR and fibromyalgia that may have pain management implications in the future.¹ Meanwhile, studies in rats have established a mechanistic link between metformin and pain perception.²
Fibromyalgia (FM) is a common cause of generalized chronic pain affecting approximately 2% of the population, according to the CDC. Management of fibromyalgia remains a challenge because the condition is not well understood, and while treatments can relieve some symptoms, no effective long term pain relief is currently available.
“The pathophysiology of fibromyalgia is not fully known, but several theories exist,” said Shiloh Plaut, MD, of the University of Nicosia, Cyprus, who authored a recent review of myofascial pain/fibromyalgia syndrome in the journal PLoS One.³
“Studying the link between insulin resistance and fibromyalgia may provide a better understanding of both conditions and inform better treatments in the future,” Dr. Plaut said. “Some studies suggest that the effect of insulin resistance on pain and the nervous system could have a role in the underlying cause of conditions such as fibromyalgia. Moreover, it is possible fibromyalgia can contribute to – or lead to – insulin resistance,” he noted.
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Insulin Resistance and Chronic Pain
Similar brain vasculature occurs in both IR and FM, leading to focal cerebral hypoperfusion, according to Miguel A. Pappolla, MD, of the University of Texas Medical Branch at Galveston. Dr. Pappolla and colleagues published a study in Pain Physician exploring the hypothesis that IR may be associated with the pathophysiologic basis of FM.¹
The researchers reviewed data from 33 adults with FM, including 17 Hispanic patients, 10 white patients, and 6 African American patients. They compared HbA1c values between the patients with FM and 2 different control groups of nondiabetic individuals with normal glucose tolerance.
Overall, HbA1c values, serving as an indicator of IR, were significantly higher in patients with FM compared to controls, and all patients with FM met laboratory criteria for IR. This difference remained significant after controlling for the association between age and HbA1c, the researchers noted. The age factor is important because “a large proportion of patients with FM showed HbA1c values considered to be ‘normal’ under current American Diabetes Association (ADA) guidelines (equal or less than 5.6%),” they wrote. Previous studies may have overlooked the association between FM and IR because of this distinction, they pointed out.
Because it was an observational study, the findings cannot prove causality, though they suggest an association, the researchers said.
The researchers also highlighted other studies suggesting an association between FM and IR, with findings that FM occurred significantly more often in individuals with type 2 diabetes than in controls without diabetes.⁴ Findings from another study suggested IR as a risk factor for cognitive impairment in FM patients, which may indicate a connection between IR and FM that goes beyond increased body mass index, the researchers added.⁵
Looking ahead, “randomized clinical trials of agents that enhance insulin sensitivity in FM should be pursued,” to further explore the IR and FM connection and whether IR treatment correlates to improved FM pain scores, the researchers concluded. However, future studies must consider that FM is a spectrum disorder, and not all chronic pain patients meet criteria for FM, the study authors said.Metformin (biguanide) is disease-modifying drug for type 2 diabetes, and recent studies suggest that these properties may reduce pain and pain comorbidities. Studies in rodent models have shown an association between metformin and reduction of nociceptive pain.
In the review, the authors went over the mechanism of action of metformin. Research published in 2001 showed that the activation of AMP-activated protein kinase (AMPK) may drive the anti-diabetic effects of metformin.⁶ Once activated, AMPK “diminished the expression of lipogenic genes, promoted glucose uptake, and suppressed SREBP-1 (insulin-stimulated transcription factor implicated in the pathogenesis of insulin resistance and type 2 diabetes),” the authors explained. Activated AMPK inhibits the mTORC1 pathways, and reduces pain.⁷
Studies in rodent models showed that treatment with metformin reduced tactile allodynia, the fibromyalgia symptom in which a simple touch causes pain.⁸ As for human studies, data on the effect of metformin on pain in humans are limited, but one study of 46 patients with diabetes showed decreased levels of radiculopathy pain associated with metformin treatment.⁹
No studies have shown the effect of metformin on anxiety and depression caused by nerve injury, but the review highlights several rodent studies showing that inducing IR increased anxiety, despair, and anhedonia, which may exacerbate chronic pain, and that metformin treatment reduced chronic stress-induced behaviors. Given the high comorbidity of anxiety and depression in chronic pain patients, “the possible therapeutic use of metformin could open a new avenue for the treatment of these comorbidities,” the authors wrote. However, they added that “whether metformin reduces comorbidities by reducing pain or other mechanisms is currently unknown.”Treatment with metformin may induce gastrointestinal side effects such as diarrhea, dyspepsia, and flatulence, which is important to consider in future studies, the authors added. Placebo-controlled trials are needed to support the effects on metformin on pain shown in preclinical studies “particularly in neuropathic pain and its comorbidities,” they concluded.
While metformin may be able to help manage chronic pain, as well as anxiety and depression, Dr. Plaut said, “it is important to understand that fibromyalgia is, as it seems, a multifactorial disease that is significantly influenced by factors including comorbidities, genetics, psychology, and unhealthy lifestyle.” Managing both fibromyalgia and diabetes necessitates a multidisciplinary approach and requires patience and good communication between clinician and patient, and managing diabetes holistically can help manage chronic pain, he added.
“Medical literature suggests a link between diabetes mellitus and fibromyalgia, the nature of which may be bidirectional and clearly needs more research,” Dr. Plaut emphasized. “The prevalence of fibromyalgia among diabetes mellitus patients is significantly higher compared to the general population, according to several studies. There may be many explanations for the relationship between diabetes and fibromyalgia, such as metabolic changes, obesity, lifestyle, psychological factors
Breaking Through Treatment Barriers
“In my experience, the first barrier for both patient and clinician in managing chronic fibromyalgia-like pain in any setting is knowledge,” said Dr. Plaut. “Patient education and an understanding of the condition are the most important factors in managing chronic diseases, and it is especially so in fibromyalgia.”
In diabetes and fibromyalgia-like pain, patients need a personalized plan, which is especially challenging for clinicians faced with a patient who has both conditions, he said. “Notably, one of the cornerstone treatments of diabetes mellitus type 2 and prediabetes is lifestyle change,” said Dr. Plaut. Although patients with diabetes or prediabetes often prefer drug treatment, “we know it is difficult, and perhaps even impossible, to effectively treat such conditions, including fibromyalgia, without lifestyle changes,” he said.
Polypharmacy can be a barrier to effective management of chronic pain in patients with diabetes or prediabetes, since many patients are deterred from taking multiple drugs daily, something often necessary for those who have both diabetes and chronic pain, Dr. Plaut said. “Overmedication with drugs such as opioids and sleeping pills can add problems instead of fixing them,” he noted, Other potential barriers to managing fibromyalgia in the context of diabetes include obesity, which can be a barrier to exercise, low motivation, or low hope, which can prevent patients from exploring lifestyle changes and non-drug treatments, he said. Social media, which is rife with false information and non-evidence-based advertising about fibromyalgia, also contributes to the problem, Dr. Plaut said.
“Some patients find themselves relying on unreliable sources of information such as social media posts in attempts to self-manage fibromyalgia because their doctors are unwilling to treat the pain seriously,” he said. “Clinicians should be careful not to assume a patient presenting with persistent unexplained chronic pain is malingering or factitious; this is a major barrier in many current clinical settings.”
