Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Describe the various types of diabetes and their impact on chronic pain.
2. Explain how diabetes leads to pain-related comorbid conditions that negatively affect quality of life.
3. Interpret select genetic markers that have potential correlations to type 2 diabetes.
In 2018, 34.2 million Americans (10.5% of the nation's population) had diabetes, and up to 88 million American adults had prediabetes.1 Diabetes mellitus is a systemic condition that can cause micro- and macrovascular complications in multiple systems, including cardiovascular, neurologic, renal, and ophthalmologic problems.
Type 1 diabetes mellitus (T1DM) is caused by autoimmune damage to insulin-producing [beta] cells of the pancreas, is usually diagnosed in childhood, and is characterized by inability of the pancreas to produce insulin, or enough of it to sustain life.
In contrast, type 2 diabetes mellitus (T2DM) is largely preventable and is caused by high blood sugar, insulin resistance, and deficiency of insulin. T1DM is less common than T2DM, affecting between 5% and 10% of people diagnosed with diabetes.
Approximately 75% of individuals with diabetes have at least one comorbid condition and 44% have at least 2.2 In addition, up to 60% of individuals with diabetes report chronic pain, which can affect the ability to perform self-management behaviors that are important for minimizing diabetes-related complications.3 In 2017, the estimated cost of diabetes-related expenditures in the United States was $327 billion, including $237 billion in direct medical costs and $90 billion in reduced productivity.4 On an individual level, people with diagnosed diabetes incur average medical expenditures of $16,750 per year, of which $9600 is attributed to diabetes.4 On average, this average expenditure is 2.3 times higher than the average person without diabetes. Treatment and management of comorbid pain, in addition to the typical costs of managing diabetes, is estimated to contribute billions in related expenses and loss productivity each year.
Diabetic neuropathy, one of the most common conditions causing chronic pain among individuals with diabetes mellitus, has a higher incidence among individuals with T2DM compared with individuals with T1DM. Incidence among those with T2DM is 6100 per 100,000 person-years, compared with 2800 per 100,000 person-years among those with T1DM.5 However, the prevalence of neuropathy is similar between those with T1DM and T2DM, likely due to the differences in age of onset/disease duration, and underlying pathophysiology.6 Diabetic neuropathy includes peripheral (distal), proximal, autonomic (cardiovascular, gastrointestinal, genitourinary, and sudomotor dysfunction), and focal neuropathies (isolated mononeuropathies, radiculopathy, or polyradiculopathy).7
Of the diabetic neuropathies, the most common painful condition is distal symmetric polyneuropathy (Table 1), which affects up to 30% of people with prediabetes, 15% with newly diagnosed T2DM, and 20% of people with T1DM of greater than 20 years' duration.8
Other painful conditions associated with diabetes duration and disease control include carpal tunnel syndrome, Dupuytren's contracture, trigger finger, frozen shoulder, and tendinitis. Charcot joint (also known as neuropathy arthropathy) can cause joint pain, numbness, heat (calor), redness, and swelling. In addition, people with diabetes mellitus are twice as likely to develop arthritis; T1DM is associated with rheumatoid arthralgias, whereas T2DM is associated with a higher risk of osteoarthritis.
Among musculoskeletal conditions, chronic low back pain (cLBP) is the most frequently reported painful condition, affecting approximately 37% of patients with T2D and surpassing the prevalence of painful diabetic neuropathy.9-13 Shared risk factors of diabetes and cLBP have been identified and include older age, lower education, history of smoking, physical inactivity, inflammatory burden, and body mass index (BMI).14
Mechanisms of Diabetes-Related Chronic Pain
A chain of events triggered by metabolic imbalances from excess glucose, dyslipidemia, and insulin resistance is thought to cause symptoms of diabetic neuropathy.9 One of the most studied is disruption of the polyol pathway, in which excess glucose is converted to sorbitol. Osmotic stress due to build-up of sorbitol results in efflux of myoinositol, an essential component of sodium/potassium ATPase. The loss of myoinositol leads to impairment of normal nerve physiology.
In addition, due to accelerated activity of aldose reductase required to convert glucose to sorbitol, cellular stores of nicotinamide adenine dinucleotide phosphate are depleted, leading to reduced production of nitric oxide that is needed for antioxidant glutathione, resulting in reduced capability to inactivate reactive oxygen species (ROS) and, consequently, ROS-mediated intracellular injury.9
Increased protein kinase C activity as a result of elevated blood glucose can alter vascular permeability, basement membrane synthesis, and cellular proliferation, which can lead to the development of microvascular complications. Damage to sensory nerves can occur through these mechanisms and through hyperglycemic-activated generation of advanced glycation end products that accumulate and impair function of the peripheral nerves.15
AMPK, a cellular energy sensor that monitors energy expenditure to regulate demands of energy homeostasis, has been found to have a functional link with the transient receptor potential ankyrin 1 (TRPA1) channel that is sensitive to noxious cold and mechanical stimuli. High glucose exposure decreases activated AMPK levels and increases activity of TRPA1 channels.16
Although diabetes-related chronic pain traditionally has been associated with damage to peripheral nerves, more recent research is investigating the role of the central nervous system (brain and spinal cord) in the development of chronic pain conditions, including diabetic peripheral neuropathy.
Accounting for all people with diabetes, approximately 50% have diabetic peripheral neuropathy, and about 25% suffer with painful diabetic peripheral neuropathy. Risk factors of diabetic peripheral neuropathy include high blood glucose, high cholesterol, and obesity. Small blood vessel disease leading to reduced oxygen supply to the peripheral nerves contributes to its development-these changes can be seen using MRI and spectroscopy to identify changes in the width of the spinal cord, loss of volume in the primary sensory cortex, and changes in higher brain areas.17
Assessment of Diabetic-Related Chronic Pain
The American Diabetes Association encourages assessment of distal symmetric polyneuropathy in patients with prediabetes who have symptoms of peripheral neuropathy, at the time of diagnosis and yearly for those with T2DM and at least after 5 years postdiagnosis of T1DM.8 The annual 10-g monofilament test alone is used to detect neuropathy and screen for risk of ulceration or amputation.
A complete history and examination using temperature or pinprick sensation is used to assess small fiber function, and vibration sensation using a 128-Hz tuning fork, proprioception, and 10-g monofilament on the dorsal aspect of each great toe and ankle reflexes to assess large fiber function. Tests to evaluate gait and risk of fall should be administered, as well.
Other differential diagnoses to consider include alcohol abuse, which can lead to alcoholic neuropathy, medication-induced neuropathy from chemotherapeutic agents or HIV treatment, neoplasia, and amyloidosis.
Laboratory testing is helpful to exclude other conditions that could cause symptoms. Tests should be ordered for serum vitamin B levels (especially B12 and folic acid) to evaluate for vitamin deficiency, particularly for patients taking metformin; thyroid function tests; complete blood count; metabolic panel; and serum protein immunoelectrophoresis to evaluate for monoclonal gammopathy.6
Studies have shown that insulin treatment in T1DM significantly improves symptoms of diabetic neuropathy, whereas glycemic control in individuals with T2DM does not, which may be related to the characteristic state of systemic insulin resistance in T2DM.7
Risk factors associated with painful diabetic peripheral neuropathy include female sex, poor glycemic control, impaired renal function, elevated cholesterol, high BMI, and smoking, and genetic factors. Polymorphisms in several genes encoding interleukins [interleukin-4 (IL-4), IL-10, and interferon-[gamma]], sensory channels, circulatory enzymes (nitric oxide synthase), and vascular endothelial growth factor, and mitochondrial function, have been found to be associated with increased risk of painful diabetic neuropathy.18-22 In addition, a genome-wide association study identified an association between painful diabetic peripheral neuropathy and chromosomes 1p35.1 and 8p23.1,23,24 whereas a meta-analysis of polymorphisms in the ACE and MTHFR genes was associated with progression of diabetic peripheral neuropathy.25
With the use of mouse models of diabetic peripheral neuropathy, it has been reported that a comparison of gene expression patterns from peripheral nerves from mice and humans with T1DM and T2DM displays consistent transcriptomic pathways involving inflammation, adipogenesis, and lipid synthesis.26 With the goal of increasing understanding of the underlying mechanisms of painful diabetic neuropathy and other chronic pain conditions, these studies could eventually lead to improvements in identifying individual patients at risk, and development of novel preventative therapeutics. To provide an update on the screening, assessment, and treatment of painful diabetic neuropathy, a literature review was conducted on this topic with a summary of findings.
Literature Review
A nonexhaustive review of the literature was completed using the databases PubMed/Medline, CINAHL, PsycINFO, and Scopus with the key words: diabetes mellitus, chronic pain, mechanisms, pain mechanisms, glucose utilization, pain, and metabolism.
Articles were limited to primary research that focused on the evaluation of diabetic patients with chronic pain, published in the last 5 years (2015-2020) and written in the English language. Descriptions of these studies are listed in Table 2 with a brief summary of each study's findings.
Advancements in Screening for Painful Diabetic Neuropathy
Several studies have examined more efficient methods of screening for diabetic peripheral neuropathy. One study examined screening using self-report by comparing the DN4-interview questionnaire, the monofilament test, and the Michigan Neuropathy Screening Instrument (MNSI).27 The investigators concluded that use of the MNSI to identify patients at risk of diabetic neuropathy could be feasible to improve more timely assessment and treatment. Another study assessed intraepidermal electrical stimulation as a noninvasive way to measure pain threshold in patients with suspected peripheral neuropathy and demonstrated that it was more efficient, with less time to administer than nerve conduction studies.28,36
Finally, screening to identify people with Charcot arthropathy is important. Although this condition is rare, it is highly disabling, and a team of investigators found that people who developed Charcot's arthropathy had more severe peripheral neuropathy, higher BMI, and higher glucose levels.29 They also identified lack of pain as a significant factor and reported that an infrared thermometric temperature difference greater than 2[degrees]C in the affected foot was an important diagnostic method.
These advancements in screening could be useful for earlier identification of patients at risk for painful diabetic neuropathies and the detrimental effects on functioning.
Advancements in Treatment for Painful Diabetic Neuropathy
Several studies have shown that in addition to standard medical therapy, patients with diabetes and chronic pain can benefit from additional monitoring of health indicators such as blood pressure and BMI.31,32 Thus, in addition to providing support for self-management of medications, lifestyle changes including aerobic exercise, resistance training, and dietary intake can be useful for improving long-term health outcomes.
Additional studies have analyzed use of supplemental nanocurcumin in improvement of diabetic- and neuropathy-related outcomes,30 the use of intra-articular triamcinolone acetonide extended-release for knee osteoarthritis in patients with T2DM,34 and vitamin D supplementation on central obesity and pain-related indicators of quality of life.35,37,38 Although these studies have shown some positive results, replication in larger sample sizes will be required. Of interest, the rise in circulating 25-hydroxyvitamin D and benefit of vitamin D supplementation on central obesity was found only in individuals with the AA genotype of the vitamin D receptor Cdx-2 gene, suggesting that a genetic-targeted approach to treatment of complex multifactorial conditions could be effective.
Conclusion
Diabetes has been documented in humans for centuries and affects millions of people each year at a personal and economic level. With advancements in research and clinical care, there have been many breakthroughs, which have increased patients' quality of life. However, there is still a lack of clarity as to the specific mechanisms that cause the chronic painful conditions in T1DM and T2DM.
Emerging evidence suggests that development of diabetic-related chronic pain involves a chain of events with disordered metabolism and accumulation of metabolites that disrupt sensory neuron function, amplification of pain signaling in the spinal cord associated with neuroinflammation and spinal disinhibition, and enhanced thalamic activity in the brain. Recommendations for sensory screening, especially for distal symmetric polyneuropathy, should be routinely performed, especially for prediabetic patients who may receive preventive therapeutics. Genomic studies have identified many polymorphisms associated with the risk of developing painful diabetic neuropathy, which may be used in the future to identify patients with increased risk and to deliver targeted treatments.
References