A Closer Look At The ADA’s Recommendations For Distal Symmetric Polyneuropathy

Diabetic neuropathies are the most common complication of diabetes. Study results vary but reportedly 30 to 90 percent of patients with diabetes have peripheral neuropathy.1 Distal symmetric polyneuropathy is the most common form of diabetic neuropathy, accounting for approximately 75 percent of cases.2

Given the profound complications that can severely affect patients’ quality of life, the American Diabetes Association (ADA) recently released a new position statement on diabetic neuropathy aimed to aid in the prevention, early recognition and treatment of diabetic neuropathies.3 While primarily aimed toward primary care physicians, this report is important for podiatrists given their role in the treatment of distal symmetric polyneuropathy as well as its complications.

While researchers have not identified the exact cause of distal symmetric polyneuropathy, the hypothesis is that metabolic dysfunction causes oxidative stress and inflammation, which leads to nerve cell damage.4-6 Rates of distal symmetric polyneuropathy are as high as 15 percent in newly diagnosed patients with type 2 diabetes and 50 percent in patients with a disease duration of 10 years or more.7,8 When it comes to patients who have had type 1 diabetes for more than 20 years, 20 percent reportedly have distal symmetric polyneuropathy.7,8 Distal symmetric polyneuropathy reportedly occurs in 10 to 30 percent of patients with pre-diabetes.9

Distal symmetric polyneuropathy has variable symptoms depending on the nerve fibers that are damaged. Damage to small fiber nerves typically occurs earlier in the disease process and results in pain and paresthesias. Later involvement of large nerve fibers can result in numbness and loss of protective sensation, which researchers say causes several complications including foot ulceration, Charcot neuroarthropathy, gait unsteadiness and falls.10-12 The economic burden associated with neuropathic pain, foot ulcerations, Charcot neuroarthropathy and falls is staggering.

Diabetic peripheral neuropathy is largely a clinical diagnosis. Review of family history, medication use and possibly laboratory studies can help to exclude other potential (and possibly reversible) causes of neuropathy. The new ADA position statement recommends that screening for distal symmetric polyneuropathy begin at the diagnosis of type 2 diabetes and five years after diagnosis of type 1 diabetes.3 Recommended screening includes evaluation of temperature or pinprick sensation, evaluation of vibration sensation using 128-Hz tuning fork and annual testing with 10 g monofilament to assess loss of protective sensation and risk of foot ulceration. The ADA also recommends screening in patients with pre-diabetes with symptoms of distal symmetric polyneuropathy. Electrophysioloigic testing is rarely needed for the diagnosis of distal symmetric polyneuropathy unless atypical features such as motor involvement, rapid progression or asymmetric distribution are present.

The new ADA position statement highlights the prevention of peripheral neuropathy in patients with diabetes.3 For patients with type 1 diabetes, the ADA recommends strict blood glucose control with maintenance of near normal glycemic levels for prevention of distal symmetric polyneuropathy. Research has shown that strict blood glucose control in patients with type 1 diabetes provides a 78 percent reduction in the risk of distal symmetric polyneuropathy development.13-15 In patients with type 2 diabetes, especially in the presence of comorbidities, studies have shown strict blood glucose control to be moderately effective (5 to 9 percent risk reduction) in preventing distal symmetric polyneuropathy.1,16

As a result, in patients with pre-diabetes and type 2 diabetes, the ADA recommends lifestyle interventions for the prevention of distal symmetric polyneuropathy.3 Several large lifestyle intervention studies, including the Diabetes Prevention Program, Italian Diabetes and Exercise study and the University of Utah type 2 diabetes study, have shown that exercise and dietary changes can help to prevent distal symmetric polyneuropathy.17-19 These studies provide good models for evidence-based lifestyle interventions for patients with diabetes and pre-diabetes.

What The Guidelines Recommend On Medications

Currently, no treatment modalities exist that can reverse the nerve damage that occurs with distal symmetric polyneuropathy. While glycemic control and lifestyle modification can help to prevent distal symmetric polyneuropathy, no evidence supports these modalities as a treatment for diabetic neuropathic pain.20,21 The ADA guidelines recommend using either pregabalin (Lyrica, Pfizer) or duloxetine (Cymbalta, Lilly) as the initial pharmacologic treatment for neuropathic pain in patients with diabetes.3 The evidence in support of gabapentin for the treatment of neuropathic pain is not as strong as that of pregabalin but one may also consider this agent as an initial treatment modality when considering a patient’s economic status.

Tricyclic antidepressants may be an effective treatment modalities for neuropathic pain but they have a higher side effect profile. The ADA does not recommend the use of opioids including tramadol (Ultram, Janssen Pharmaceuticals) or tapentadol (Nucynta, Depomed) as first- or second-line agents for the treatment of neuropathic pain in diabetes.3 While opioids are effective treatment modalities for diabetic neuropathic pain (with tapentadol having FDA approval for this indication), the ADA does not recommend their use as either first- or second-line agents, given risks including addiction, abuse, sedation and respiratory depression.

In Conclusion

Given the numerous complications, effects on quality of life and costs associated with distal symmetric polyneuropathy due to diabetes, prevention of this pathology is extremely important. Additionally, recognition and treatment of distal symmetric polyneuropathy have the potential to improve symptoms, reduce complications and improve quality of life. Podiatrists play a key role in the identification and treatment of distal symmetric polyneuropathy as well as its complications. Additionally, podiatric physicians can play a role in the prevention of distal symmetric polyneuropathy by promoting lifestyle interventions in patients with type 1 and type 2 diabetes.

References

1. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521-534.
2. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgraduate Med J. 2006;82(964):95-100.
3. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
4. Kiasalari Z, Rahmani T, Mahmoudi N, Baluchnejadmojarad T, Roghani M. Diosgenin ameliorates development of neuropathic pain in diabetic rats: Involvement of oxidative stress and inflammation. Biomed Pharmacother. 2017;86:654-661.
5. Erbas O, Taskiran D, Oltulu F, et al. Oxytocin provides protection against diabetic polyneuropathy in rats. Neurol Res. 2017;39(1):45-53.
6. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7(10):573-583.
7. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993;36(2):150-154.
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9. Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 2014;126:3-22.
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11. Dingwell JB, Ulbrecht JS, Boch J, Becker MB, O’Gorman JT, Cavanagh PR. Neuropathic gait shows only trends towards increased variability of sagittal plane kinematics during treadmill locomotion. Gait Posture. 1999;10(1):21-29.
12. Mustapa A, Justine M, Mohd Mustafah N, Jamil N, Manaf H. Postural control and gait performance in the diabetic peripheral neuropathy: a systematic review. Biomed Res Int. 2016;2016:9305025.
13. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38(6):869-880.
14. Linn T, Ortac K, Laube H, Federlin K. Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism. 1996;45(12):1508-1513.
15. Diabetes C, Complications Trial Research G, Nathan DM, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.
16. Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376(9739):419-430.
17. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
18. Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications. 2006;20(4):216-223.
19. Singleton JR, Marcus RL, Jackson JE, M KL, Graham TE, Smith AG. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Transl Neurol. 2014;1(10):844-849.
20. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006;29(6):1294-1299.
21. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ. The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabet Med. 2002;19(10):870-873.

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