The presence of DPN is determined largely through clinical diagnosis based on the development of the symptoms and signs mentioned above (Table 1) in an individual with diabetes or prediabetes in whom other causes of neuropathy have been excluded (1,45). Jan. 21, 2022. Unsurprisingly, then, individuals with type 1 diabetes living in more socially deprived areas in Scotland were found to be 2.17 times more likely to have DPN (8). The sub-acute forms of DPN may be seen with acute weight loss or may be induced by diabetes treatment, developing within 24 weeks (occasionally up to 6 weeks) after the achievement of rapid and sustained glycemic control with insulin, oral antidiabetic agents, or dietary measures. Despite the prominent pain, sensory loss may be mild or absent, there is no weakness, and reflexes are generally preserved. A number of treatment options exist for symptomatic diabetic neuropathy. Accessed Nov. 11, 2021. Clinically, a formal exercise prescription can stress the therapeutic value of exercise, encourage increased activity, and regulate progression to allow tissue adaptation without causing injury. This explains why small fibers are the earliest fibers to undergo injury secondary to diabetes and why pain and dysesthesias are frequently the first symptoms of DPN. Thiamine (vitamin B1) is a water-soluble vitamin that constitutes an essential cofactor of several enzymes involved in carbohydrate metabolism. Topical capsaicin and a variety of nonpharmacological approaches are also available, and combination therapy may be needed. Benfotiamine, a lipid-soluble allithiamine homolog, is a synthetic S-acyl derivative (prodrug) of thiamine and has been shown to inhibit the formation of AGEs (106). It can also follow an episode of ketoacidosis, and in young people, particularly females, it may be associated with eating disorders (87). These trials found large effect sizes favoring pain reduction with SCS over a 6-month follow-up period. There are also warnings to use these agents with caution in the presence of ischemic heart disease or glaucoma. Despite its major clinical impact, the condition still remains underdiagnosed and undertreated (102). Up-titration should be based on pain relief. None have been shown to alter the natural history of DPN progression. SCS and high-frequency SCS provide long-lasting reduction in neuropathic pain in people with DPN pain refractory to medical therapy but must be balanced against serious potential complications in this population. Anatomical studies from sural nerve biopsies of patients with diabetic neuropathy align with their presenting symptoms (22). R.P.-B. Clinical and post-marketing surveillance studies have revealed a highly favorable safety profile (108). Figures 1 and 2 were created with BioRender.com. However, aerobic training has also been shown to improve mobility, balance, and gait outcomes in DPN. Nonetheless, these pharmacological therapies are being used for considerably longer periods in clinical practice if residual neuropathic symptoms or pain persist. Feldman EL, et al. Accessed Jan. 10, 2020. The adverse effects of gabapentin are similar to those of pregabalin and include dizziness, somnolence, and, on occasion, gait disturbances. The rationale for using nutraceuticals in DPN is primarily to favorably influence the underlying neuropathic process and its clinical consequences rather than only relieving symptomatic pain, which is usually the goal of analgesic therapy. Complications of exercise, including joint and muscle pain, hypoglycemia, orthostasis associated with autonomic dysfunction, and skin irritation, occur in more than one-third of mentored exercise participants with DPN and should be expected (137). Indeed, specialized electrophysiological testing is usually not cost-effective, and its high associated costs and typically long waiting times would place unnecessary additional burden on both people with DPN and the health care system. Diabetes Care. Duloxetine is a selective norepinephrine and serotonin reuptake inhibitor and can be given once daily at a dose of either 60 or 120 mg. Its efficacy has been proven in a number of randomized controlled trials (RCTs), and it has been shown in head-to-head trials to have similar efficacy to other agents, including pregabalin and gabapentin (45). In the NATHAN (Neurological Assessment of Thioctic Acid in Diabetic Neuropathy) 1 trial, which included 460 patients with diabetes and mild to moderate, largely asymptomatic DPN, after 4 years of ALA treatment using 600 mg daily, neuropathic deficits (i.e., signs) were improved, suggesting a potential to favorably influence the underlying neuropathy, and the drug was well tolerated throughout the trial (108). sexual dysfunction. If you are a Mayo Clinic patient, this could It is likely that interventions that address more upstream causes of health disparities at structural and societal levels will be more effective for a larger population of patients at risk for DPN. ALADIN, Alpha-Lipoic Acid in Diabetic Neuropathy; BEDIP, Benfotiamine in the Treatment of Diabetic Polyneuropathy: a Three-Week Randomized, Controlled Pilot Study; BENDIP, Benfotiamine in Diabetic Polyneuropathy; DPN, diabetic peripheral neuropathy; GI, gastrointestinal; IV, intravenous; NATHAN, Neurolog ical Assessment of Thioctic Acid in Diabetic Neurop athy; NSC, nerve conduction studies; ORPIL, Oral Pilot; PO, oral administration; PP, per protocol analysis; QoL, quality of life; SAEs, severe adverse events; SYDNEY, Symptomatic Diabetic Neuropathy; T1D, type 1 diabetes; T2D, type 2 diabetes; VENUS, Vitamin E in Neuroprotection Study; VPT, vibration perception threshold. It is also well recognized that eGFR falls with age (99); thus, although a patient who is 80 years of age and has an eGFR of 50 mL/min/1.73 m2 may be considered as having normal renal function, extra care must still be taken when setting dosages for the drugs discussed above. It found only nonsignificant trends toward improvement in both measures over the treatment period (152). Neuropathy (new-ROP-uh-thee) is a diabetes complication that causes nerve damage throughout your body. Several well-established, effective clinical tests exist to assess small- and large-fiber function as part of routine clinical care and require only simple tools that can be carried easily in a lab coat pocket. None of the contents may be reproduced without the written permission of the American Diabetes Association. Well-designed studies investigating the impact of reduced sedentary time on DPN outcomes are lacking, but epidemiological evidence linking inactivity to cardiovascular risk and poor health outcomes, independent of time spent in aerobic exercise, makes anti-sedentary behavioral modification an alluring future research direction (138). In such cases, neurological deficits may be discovered by chance during a routine clinical examination (1,46). Exercise participation, guided by exercise prescription and supervision by an exercise specialist, is safe and can improve exercise behaviors and reduce the risk for exercise-associated injury. However, it has a shorter half-life and therefore must be dosed three times daily. Those with sensation loss may choose the incorrect time or state that they did not feel the stimulus either time. Online ahead of print on 14 March 2021 (doi: New perspective in diabetic neuropathy: from the periphery to the brain, a call for early detection, and precision medicine, Treating pain in diabetic neuropathy: current and developmental drugs, Update on the management of diabetic neuropathy, Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms, Sleep impairment in patients with painful diabetic peripheral neuropathy, Painful diabetic peripheral neuropathy: results of a survey characterizing the perspectives and misperceptions of patients and healthcare practitioners, Clinical practice: neuropathic diabetic foot ulcers, Simple screening tests for peripheral neuropathy in the diabetes clinic, The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy, A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy, Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy, Peripheral and Autonomic Neuropathy in Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases, Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Imputed state-level prevalence of achieving goals to prevent complications of diabetes in adults with self-reported diabetes: United States, 20172018, Social determinants of health and diabetes: a scientific review, Health disparities in endocrine disorders: biological, clinical, and nonclinical factors. These authors also recommend starting with asymmetric dosing, with a larger dose being given in the evening. Biological factors such as alterations in glucose metabolism, insulin resistance, and obesity have been found to account for some of this increased risk (71). Interestingly, a recently published randomized, double-blind, crossover clinical trial (95) paradoxically suggested that the opioid receptor antagonist naltrexone 24 mg daily might be effective in the treatment of painful DPN. Confirmatory tests in ambiguous cases may include determining changes in nerve conduction studies to assess predominantly large-fiber dysfunction. These modalities have been extensively reviewed in practice guidelines, structured reviews (144), and detailed reports from the Agency for Healthcare Research and Quality (136). Diabetic neuropathy. We have provided here a targeted DPN management strategy that includes the currently available oral (e.g., anticonvulsants and tricyclic antidepressants) and topical pharmacological agents with evidence of clinically meaningful pain reduction, as well as HBIs specifically for painful DPN (Figure 8). Naltrexone showed comparable efficacy but greater safety and tolerability than amitriptyline in this trial. The available evidence for the second pillar is outlined here. Several nutraceuticals represent biofactors required by the body for its normal physiological functioning and may exert health-beneficial or disease-preventive biological activities. In this setting, nonpharmacological approaches that might alter the natural history of DPN or ameliorate neuropathic pain have received increasingly sophisticated evaluation. Its adverse effects are well recognized and include nausea, somnolence, and dizziness, among others (1,45,82). has served as a consultant to Allergan, Bayer, Berlin-Chemie, Biogen, Cannaxan, Clexio, Grnenthal, Mitsubishi Tanabe, Mundipharma, Nevro, Novaremed, Novartis, Pathways Public Health, Pfizer, Procter & Gamble, Stada, Takeda, Viatris, and Wrwag; he has been a speaker for Astellas, AstraZeneca, Berlin-Chemie, Mundipharma, Pfizer, Sanofi, Takeda, Viatris, and Wrwag; and he has received research support from Mitsubishi Tanabe, Novartis, and Wrwag. In humans, the metabolic pool of carnitine comprises nonesterified levo-carnitine (L-carnitine) and acyl carnitine esters, among which the amino acid acetyl-L-carnitine represents the greatest component. And if left untreated, has the potential to lead to infection and/or amputation of the affected area. Clinically Relevant Anatomy Accessed Jan. 11, 2020. Autonomic neuropathy causes symptoms related to dysfunction of an organ system, such as: urinary incontinence, diarrhea or constipation, or. *Document impairment/loss in symmetrical, distal-to-proximal pattern. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. Reduction of neuropathic pain is perhaps the most important outcome of interest to individuals with DPN. Up to one in three patients cannot tolerate even the lowest dose of amitriptyline because of these predictable side effects. Because there are no clearly effective, disease-modifying agents for DPN (1), targeting proximal diabetes outcomes such as glycemic control, blood pressure control, and adequate treatment of lipid pathways remains the mainstay of therapy for prevention of DPN. It is no surprise, then, that the most recent ADA position statement on the treatment of DPN (1) recommends lifestyle modifications that include supervised aerobic and/or resistance training, alone or in combination with dietary modifications based on those used in the DPP trial or based on a predominantly plant-based diet, for the treatment of DPN. Common symptoms of diabetic neuropathy include: Numbness and tingling of the hands or feet. However, the number of available RCTs is lower and their durations have been shorter than for ALA. Based on the results of the BENDIP study (102), the appropriate dose of benfotiamine over the first 6 weeks is 300 mg twice daily. These studies reported improvement in neuropathic pain measures, with large effect sizes in the surgical subject or limb. Restricted contraction of postural support muscles alters lipid metabolism and increases free fatty acid and adipokine release. In a large, community-based study in the United Kingdom, painful DPN was more common in individuals with type 2 diabetes, and there was a weak association with older age (79). *U.S. Food and Drug Administrationapproved for the treatment of painful diabetic peripheral neuropathy. Deprescribing through shared decision making. Obesity, prediabetes, and type 2 diabetes constitute important risk factors for vitamin D deficiency. We seek here to complement this report with a focus on the impact of SDOH specifically on DPN. and J.R.S. Disorders of mitochondrial dynamics in peripheral neuropathy: clues from hereditary neuropathy and diabetes. Importantly, none of these agents should be regarded as lifetime medications, and periodic review of pharmacological therapy is recommended, with gradual reduction of drug treatment in response to symptom abatement over time. No other potential conflicts of interest relevant to this work were reported. It is characterized by very severe neuropathic symptoms, as described earlier, that typically occur after a sudden change in glycemic control and has been described as occurring after normalization of blood glucose levels after simultaneous pancreas and kidney transplantation. The efficacy and safety of several nutraceuticals, including ALA, benfotiamine, vitamin B12, acetyl-L-carnitine, vitamin D, vitamin E, and the PUFA GLA have been studied in RCTs, some better designed than others. If your blood sugar levels are higher than your goal, you may need changes in your daily management, such as adding or adjusting your medications or changing your diet or physical activity. Finally, more genetic forms of polyneuropathy are being discovered, and novel treatments have become available for disorders such as familial transthyretin amyloidosis. There are four main types of diabetic neuropathy. Painful DPN is not uncommon in older people with diabetes, in whom caution must be taken with any prescribed medications. Treatments reviewed here fall broadly into three categories: health behavior interventions (HBIs), including exercise, dietary counseling, and their combination (Table 3); passive modalities, including massage and biofeedback; and nonpharmaco-logical energy or nerve stimulation treatments. To request permission to reuse or reproduce any portion of this publication, please contact permissions@diabetes.org. It advocates a personalized care approach to ultimately reduce sequelae and the related health care burden and optimize quality of life for people with diabetes and DPN. The pain progresses over days to weeks to constant burning dysesthesias and allodynia involving the legs in a stocking distribution. https://doi.org/10.2337/db2022-01. Examples include vitamins (A, B1, B6, B9, B12, C, D, E, and K), minerals (selenium, magnesium, and zinc), fatty acids (-lipoic acid [ALA], polyunsaturated fatty acids [PUFAs]), and amino acids (acetyl-L-carnitine) (106). There are some epidemiological differences between DPN in type 1 versus type 2 diabetes, despite there being no major structural differences in nerve pathology. Data specific to the effects of SDOH on DPN are limited but crucial to provide a comprehensive understanding of the contributors to this debilitating and common complication of diabetes. DPN assessment should be performed annually starting at diagnosis for type 2 diabetes and 5 years after the diagnosis for type 1 diabetes. Thus, the absence of a prior diagnosis of diabetes should not rule out the need for formal DPN screening, particularly in the presence of several of the risk factors mentioned above and with the typical clinical characteristics (Table 1) (1,46). Available evidence shows that up to 2530% of people with diabetes will experience DPN pain, and because it heralds early disease, neuropathic pain may be present even in the absence of any neurological deficits (1,45,48). Diminished sensation of the hands or feet. Oral magnesium supplementation is safe in adults when used in dosages below the upper intake level of 350 mg daily, but because of its renal secretion, magnesium should be used with caution in individuals with kidney disease (123). It has been extensively studied in painful DPN (1,82,91), and evidence suggests a dose-dependent response, with weaker effect at lower doses (92). General and abdominal obesity and incident distal sensorimotor polyneuropathy: insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort, Glucose control and diabetic neuropathy: lessons from recent large clinical trials, Falls in individuals with type 2 diabetes; a cross-sectional study on the impact of motor dysfunction, postural instability and diabetic polyneuropathy, The impact of diabetic neuropathy on activities of daily living, postural balance and risk of falls: a systematic review. 2019; doi:10.1007/s11940-019-0584-z. This variety of neuropathy was originally called insulin neuritis, but a more recent review by Gibbons and Freeman (88) suggested the term treatment-induced neuropathy of diabetes, as insulin is not the only cause. Framework for social determinants of health and their impact on diabetic peripheral neuropathy. Diabetic nephropathy is asymptomatic in early stages. The DCCT (124) showed in 1993 that tight glucose control reduces the risk of developing DPN in type 1 diabetes by >60%. Make your tax-deductible gift and be a part of the cutting-edge research and care that's changing medicine. It can also cause problems with the digestive system, urinary tract, blood vessels and heart. Historically, our treatment strategies for DPN have focused on improving symptoms such as pain in individuals but are limited in terms of their effectiveness, with only 50% of people with DPN responding to such interventions (1). Thus, DPN pain may be underreported. All of these sensory modalities should be tested initially by application of the sensory stimulus to a body site where normal responses are expected, such as the forehead. In small fibers, mitochondria are found along the length of the axons. Given that the mean age of the 15,000 patients in this study was 61 years, this finding suggests that the management of painful DPN in the elderly requires special attention. This test indicates your average blood sugar level for the past 2 to 3 months. As described above, people with lower SES, as determined by poverty and low education status, are more likely to have type 2 diabetes. With fewer functional mitochondria in the cell body and along the axons, energy-starved small and large nerve fibers lose their ability to function and undergo degeneration, with the axons farthest from the cell body (i.e., those in the feet) being most vulnerable. Importantly, when screening for DPN, one should keep in mind that each of the specific types of nerve fibers has a specific function and role; thus, targeted evaluations can be performed easily in the clinic. 2021. https://care.diabetesjournals.org/content/44/Supplement_1. In addition to HBIs and passive modalities, other nonpharmacological approaches to painful DPN that have received prospective evaluation include decompressive surgery and various forms of electrical modulation of nerve or other tissues, including transcutaneous electrical nerve stimulation (TENS), frequency-modulated electromagnetic stimulation, transcranial magnetic stimulation (TMS), and the previously mentioned SCS. About half of all people with diabetes have some form of nerve damage. (+) Indicates trend toward improvement compared to placebo. Activation of AGEs and RAGEs leads to downstream inflammation, ROS accumulation, and decreased blood flow to peripheral nerves. TMS using deep cortical stimulation has been reported in a 5-day, sham-controlled, crossover trial to provide significant short-term reduction in perceived neuropathic pain in people with DPN, with a return to baseline pain over 3 weeks (149). With an increased understanding of the importance of SDOH in diabetes prevalence, incidence, and outcomes, the upstream social and political contexts that contribute to and perpetuate health disparities have been receiving increased attention. The lack of myelin results in slow, continuous conduction of small fibers secondary to a uniform distribution of ion channels along the axon. Physical activity is defined as any movement that increases energy use. It is more common in those who have had diabetes for many years and . These dietary precepts are embodied in the low-fat and low-sugar eating pattern outlined in the DPP curriculum (125) and in predominantly plant-based diets such as the Mediterranean eating pattern (45% carbohydrate, 3540% fat, and <10% of saturated fat) (139). Later, with the advent of continuous glucose monitoring, a small study confirmed that people with painful DPN have greater fluctuations in glucose and poorer overall glycemic control than matched subjects with painless neuropathy (85). The following sections briefly describe the commonly used pharmacological agents, topical treatments, and physical therapies, as summarized in Figure 8. SCS and high-frequency SCS provide long-lasting reduction in neuropathic pain in people with DPN pain refractory to medical therapy and may be recommended in these situations. This type of neuropathy may also be called distal symmetric peripheral neuropathy. There is increasing evidence that psychological determinants such as emotional distress (75) and depression (76) significantly affect sleep and quality of life in painful DPN (77). Mayo Clinic; 2021. Ongoing monitoring of neuropathic symptoms, glucose, heart rate, and blood pressure, as well as musculoskeletal and integumentary status, is recommended. Sensation testing with pin and vibration is more sensitive. Mononeuropathy may lead to: Call your health care provider for an appointment if you have: The American Diabetes Association (ADA) recommends that screening for diabetic neuropathy begin immediately after someone is diagnosed with type 2 diabetes or five years after diagnosis with type 1 diabetes. R.P.-B. The RCT results described below are also summarized in Table 2. Incidence: 38% (ALA) versus 28% (placebo), including cardiovascular and cerebrovascular disorders, infections, inflicted injuries, and fractures; deaths: 1.3% (ALA) versus 2.7% (placebo). These include HBIs such as exercise, dietary modification, or their combination; passive modalities such as massage and biofeedback; and nonpharmacological energy or nerve stimulation treatments. Recognizing that social factors are the root cause for health disparities, particularly for type 2 diabetes, the American Diabetes Association (ADA) in 2021 published a scientific review on SDOH and diabetes (59). But you can prevent many of these problems by having a thorough foot exam at least once a year. Up to 30% of people with type 2 diabetes who are treated with metformin may develop B12 deficiency.