Sections

Treatment

Approach Considerations

Management of diabetic neuropathy should begin at the initial diagnosis of diabetes. The primary care physician needs to be alert for the development of neuropathy—or even its presence at the time of initial diabetes diagnosis—because failure to diagnose diabetic polyneuropathy can lead to serious consequences, including disability and amputation.^{[77, 78, 79, 80]}

Consider any patient with clinical evidence of diabetic peripheral neuropathy to be at risk for foot ulceration, and provide education on foot care.^[81]If necessary, refer the patient to a podiatrist. Admit patients for an infected diabetic foot ulcer or gangrene.

For more information, see Diabetic Foot.

For more information, see Diabetic Foot Infections.

Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. The provision of regular foot examinations and reinforcement of the educational message on foot care have been shown in several studies to significantly reduce rates of ulceration and even amputation.^[82]

The primary care physician is responsible for educating patients about the acute and chronic complications of diabetes,^[55]including the psychological impact of sexual dysfunction in both men and women. The importance of involving a neurologist (preferably with expertise in peripheral neuropathy) in the treatment of patients with diabetic neuropathy cannot be overemphasized.

Glycemic Control

Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy.^[4]Because rapid swings from hypoglycemia to hyperglycemia have been suggested to induce and aggravate neuropathic pain, the stability of glycemic control may be as important as the actual level of control in relieving neuropathic pain. The Diabetes Control and Complications Trial (DCCT) demonstrated that tight blood sugar control in patients with type 1 diabetes decreased the risk of neuropathy by 60% in 5 years.^{[29, 83]}The effect of tight glycemic control on polyneuropathy in patients with type 2 diabetes or those with impaired glucose tolerance/impaired fasting glucose is not as clear and requires further prospective study.^[84]

A 2012 Cochrane review indicates that tight glycemic control prevents the development of clinical neuropathy and reduces nerve conduction and vibration threshold abnormalities in patients with either type 1 or type 2 diabetes. However, tight glucose control also increases the risk of severe hypoglycemic episodes, and this should be considered when assessing its risk/benefit ratio.^[85]

Diabetic Neuropathic Pain Management

Many medications are available for the treatment of diabetic neuropathic pain. Oral agents include antidepressants and anticonvulsant drugs. According to the 2011 guideline issued by the American Academy of Neurology (AAN), American Academy of Physical Medicine and Rehabilitation (AANEM) and the American Academy of Physical Medicine and Rehabilitation (AAPMR) guideline for the treatment of painful diabetic neuropathy (PDN), pregabalin is recommended for treatment of diabetic neuropathic pain. The drug has been proven effective and can improve quality of life. However, physicians should determine if the drug is clinically appropriate for their patients on a case-by-case basis. Gabapentin and sodium valproate should also be considered for diabetic neuropathy pain management.

According to a Cochrane review evaluating gabapentin for chronic neuropathic pain and fibromyalgia, gabapentin leads to significant pain relief in patients with chronic neuropathic pain when compared with a placebo. Although patients frequently experience adverse side effects, these are usually tolerable, and serious side effects were not increased when compared with side effects associated with the placebo.^[86]

According to the 2011 AAN/AANEM/AAPMR guideline, dextromethorphan, morphine sulfate, tramadol, and oxycodone should be considered for PDN treatment. No one opioid is recommended over another.

Topical therapy with capsaicin or transdermal lidocaine may be useful in some patients, especially those with more localized pain or those in whom interactions with existing oral medications is a concern. The 2011 AAN/AANEM/AAPMR guideline recommends that both of these agents be considered in for treatment of PDN. In clinical trials, capsaicin has been effective in reducing pain in PDN, but many patients cannot tolerate the side effects, such as burning pain on contact with warm/hot water or in hot weather. Any of these medications may be associated with adverse effects, and patients should be counseled about possible problems before initiating treatment.^{[87, 67]}Patients should be assessed every 6 weeks so that adverse effects can be monitored if possible. Decrease or increase drug dose if indicated.

For many of these medications, use for neuropathic pain is off-label; they were approved by the Food and Drug Administration for other indications. Many are in the news for questionable side effects (eg, increased blood pressure and edema from salt retention with fludrocortisones). Nevertheless, multiple clinical studies show benefit for the use of these medications in the treatment of neuropathic pain. Use of these medications is well within the standard of care in most medical communities. A number of medications are currently undergoing evaluation in clinical trials. Some are licensed for use in other countries.

In a review of 6 trials (2220 patients) on duloxetine's effects on painful diabetic peripheral neuropathy (3 trials) and fibromyalgia (3 trials), Lunn et al concluded that 60 mg of duloxetine daily can relieve the pain of peripheral neuropathy in the short-term, calculating a 1.65 risk ratio for a 50% pain reduction at 12 weeks.^[88]Adverse events were common and dose dependent, according to the authors, but serious ones were rare. The 2011 AAN/AANEM/AAPMR guideline recommends considering the antidepressants amitriptyline, venlafaxine, and duloxetine for the treatment of PDN, although data are insufficient to recommend one of these agents over the others.

There was no difference identified between gabapentin and tricyclic antidepressants in the achievement of pain relief of diabetic neuropathy or postherpetic neuralgia in a study by Chou et al. The authors performed a meta-analysis of head-to-head trials comparing the results of gabapentin and tricyclic antidepressants for pain relief in diabetic neuropathy.^[89]. Pregabalin has similar efficacy as gabapentin for most part.

Pain Control in Pregnancy

During pregnancy, prescribing medicine for pain control is difficult. The best hope for pain control in rare cases of young women with severe neuropathy is to control their blood glucose diligently and try to control pain with acetaminophen. At the end of the third trimester, the physician can prescribe amitriptyline, gabapentin, and other medications as indicated if the benefit clearly outweighs the risk to the fetus. Physical therapy may be effective in pregnant patients by increasing their circulation.

To see complete information on Diabetes Mellitus and Pregnancy, please visit our main article.

Diabetic Gastroparesis

Erythromycin and metoclopramide are used to treat diabetic gastroparesis. Additionally, MiraLax (polyethylene glycol 3350) is gaining increasing popularity as the first-line agent for severe constipation and lower motor unit bowel.^[52]

A newer agent, tegaserod (Zelnorm), may be helpful in patients with chronic ileus. In early 2010, however, tegaserod marketing was suspended because of a meta-analysis showing an excess number of serious cardiovascular adverse events, including angina, myocardial infarction, and stroke, in those taking tegaserod compared with placebo. Tegaserod is currently available only on an emergency basis. For more information, see the FDA Postmarket Drug Safety Information for Patients and Providers.

Dietary Supplements

Vitamin supplementation is being studied to see if that can have an impact. One study of zinc sulfide showed improvement in glycemic control in 60 patients.^[90]Certain B vitamins are often prescribed in an attempt to reduce paresthesias.

Aldose reductase inhibitors

Aldose reductase inhibitors block the rate-limiting enzyme in the polyol pathway that is activated in hyperglycemic states. Numerous studies of aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat, epralrestat) have been published in the past 30 years, but many of the earlier trials had problems related to poor study design (eg, enrolling patients with advanced neuropathy who were unlikely to benefit from treatment).

These medications are not currently available in the United States.^{[91, 92]}Epralrestat is currently marketed only in Japan. Epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms, including pain, numbness, hyperesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting, were also improved.^{[93, 94]}

Alpha-lipoic acid

In a multicenter placebo-controlled trial of the antioxidant alpha-lipoic acid, Ziegler and colleagues reported short-term symptomatic relief of neuropathy symptoms in patients with type 2 diabetes and symptomatic neuropathy.^[21]Other studies of this drug are ongoing.

Actovegin

A deproteinized derivative of calf blood, actovegin contains inorganic substances (eg, electrolytes, trace elements) and organic components (eg, amino acids, oligopeptides, nucleosides, glycosphingolipids). Actovegin also contains inositol phospho-oligosaccharides (IPOs), which are thought to elicit central and peripheral insulin effects. Ziegler et al found that treatment with actovegin improved neuropathic symptoms, vibration perception threshold, sensory function, and quality of life in 567 patients with type 2 diabetes mellitus and diabetic polyneuropathy. In this multicenter, randomized, double-blind trial, sequential intravenous (2000 mg/d) and oral (1800 mg/d) actovegin treatment was given over 160 days.^[87]

Spinal cord stimulators and other therapies

Pain medicine specialists have been experimenting with spinal cord stimulator implants in severely painful cases.^[95]One such study of 10 patients showed that median background and peak pain scores at the end of the study were, respectively, 77 and 81 with the stimulator off and 23 and 20 with the stimulator on. Exercise tolerance significantly improved at 3 months (n = 7, median increase 85%) and at 6 months.

A study by Petersen et al indicated that high-frequency (10-kHz) spinal cord stimulation (SCS) is a safe and effective means of treating painful diabetic neuropathy that does not adequately respond to medication. In the report’s patients, pain from diabetic neuropathy was refractory to therapy with gabapentin or pregabalin, along with treatment using at least one other class of analgesic. Individuals received either conventional medical management (CMM) or CMM plus 10-kHz SCS. While 5% of those who underwent CMM achieved at least 50% pain relief, as measured on the visual analog scale, without observed neurologic deterioration, the same was true for 79% of patients who received CMM plus SCS.^[96]

Further study is necessary.^[97]Alternative and complementary therapies for pain (eg, acupuncture) are under investigation.^{[98, 24]}

Erectile dysfunction

Although several modalities are available, erectile dysfunction from diabetic neuropathy is a very difficult condition to treat. All other causes of impotence must be excluded. Once the diagnosis has been confirmed, the oral agent sildenafil Viagra) and related phosphodiesterase type 5 (PDE5) inhibitors can be used (if not contraindicated in the patient). Older methods such as vacuum devices or intracavernosal papaverine injections may be tried. Referral to a urologist is suggested.

Orthostatic hypotension

Symptomatic orthostatic hypotension can be troubling in patients with diabetic neuropathy. Increasing the dietary fluid and salt intake, along with use of compression stockings, may help. If these modalities do not improve symptoms, then medication may help.^[59]

Gustatory sweating

Glycopyrrolate is an antimuscarinic compound that can be used for the treatment for diabetic gustatory sweating. When applied topically to the affected area, it results in a marked reduction in sweating while eating a meal.

Surgical Treatment

Surgery is indicated in patients with infected foot ulcers when the infection cannot be controlled medically. Aggressive debridement or amputation may be necessary if signs of necrosis or infection do not improve with IV antibiotics.^{[99, 100]}

Jejunostomy may be performed in patients with intractable gastroparesis (ie, severe nausea and vomiting, severe weight loss). This will allow patients to be fed enterally, bypassing the paralytic stomach.

When impotence is a continual problem, the patient may pursue the option of a penile prosthesis.

The feet of patients with DM often become insensate and are highly susceptible not only to ulcers but also to the Charcot foot (ie, a foot that loses its structure secondary to trauma and acute arthropathy) from frequent and multiple traumas. Charcot foot, which occurs not only in diabetic peripheral neuropathy but in other types of severe neuropathy as well, can be treated with bracing or special boots. In some cases, surgery is used to correct the deformity.^{[101, 102]}

For more information, see Perioperative Management of the Diabetic Patient.

For more information, see Diabetic Foot.

For more information, see Diabetic Foot Infections.

Pancreatic Transplantation

Pancreatic transplantation in patients with diabetes and end-stage renal disease can stabilize neuropathy and in some instances improve motor, sensory, and autonomic function for as long as 48 months after uremia plateaus.^[82]

Physical therapy

Physical therapy may be a useful adjunct to other therapy, especially when muscular pain and weakness are a manifestation of the patient's neuropathy. The physical therapist can instruct the patient in a general exercise program to maintain his or her mobility and strength. An aquatic therapist can also be helpful.

Although the American Diabetes Association recommends moderate to vigorous exercise for patients with diabetes to help manage the disease, a literature review by Johnson and Takemoto indicated that in patients who have been inactive or cannot achieve such intensity levels, low-intensity aerobic therapy can improve sensation in the feet and reduce pain and tingling in the lower limbs.^{[103, 104]}

In addition to exercise, the patient also should be educated on independent pain management and relaxation strategies to assist with pain control. Transcutaneous electrical nerve stimulation (TENS) may be a recommended modality for patients with neuropathic pain, and the physical therapist can be helpful in teaching and monitoring the patient in its use. In a 1999 case report, Somers and Somers found that application of TENS to the skin of the lumbar region was an effective treatment for the pain of diabetic neuropathy, but no controlled studies have confirmed this finding.^[105]The 2011 AAN/AANEM/AAPMR guideline supports TENS as probably effective as a treatment for PDN.^[106]

In cases of foot ulcers, physical therapy may be indicated for wound care. Treatments may consist of whirlpool, Unna boots (if necessary, although not commonly used), and debridement. For patients with autonomic neuropathy, balance training and fall prevention education is paramount.

Brace assessment and orthotic or prosthetic training are useful when appropriate, and walking-aid assessment and implementation may be necessary.

Occupational therapy

Occupational therapy may be necessary in cases where there is severe loss of functional status. When only the lower limbs are involved, patients may need home modifications and equipment. When the upper limbs are involved, patients may need more extensive functional restoration and adaptive equipment. When secondary complications require amputation of a limb, even more intensive functional retraining is required.

Speech therapy

Involvement of a speech therapist rarely is indicated, but professionals from this discipline can help with patients affected by gastroparesis or dysphagia.

Recreational therapy

A recreational therapist may help the patient with performance of community activities. Many patients with chronic disease, especially elderly patients, become isolated and are at risk for comorbid conditions such as depression.

Complications of Disease

Peripheral neuropathy can lead to foot ulcers and leg amputations. When a foot ulcer shows signs of infection (eg, thick yellow drainage, erythema around the wound, fever, necrotic tissue), the patient often fares much better by being admitted to a hospital, having the extent of infection assessed (eg, with MRI), and receiving IV antibiotics and foot debridement (if necessary).

Autonomic neuropathy is associated with dizziness and falling with resultant injuries, nausea and vomiting, severe diarrhea, and dehydration, all of which can lead to hyperosmolar nonketotic diabetic coma or diabetic ketoacidosis and death. Cardiovascular autonomic neuropathy can cause death.

Consultations

Most diabetic patients benefit from consultation with an endocrinologist at periodic intervals, and those with more brittle diabetes may benefit from regular endocrinology consultations to assist in diabetes management.

Patients with diabetes who develop neuropathy should see a neurologist early in the course of neuropathy. Patients with neuropathy symptoms or signs that seem out of proportion to the severity of diabetes should be evaluated by a neurologist to help exclude other underlying causes of neuropathy.

Physical medicine and rehabilitation physicians provide a functional-based comprehensive evaluation and treatment program for patients with diabetic neuropathy. Ulcer management may warrant consultation with a specialist at a wound clinic or perhaps a vascular surgeon. A cardiologist should monitor patients who have electrocardiographic abnormalities and/or suggestion of cardiac autonomic neuropathy. A gastroenterologist can monitor patients with intractable GI problems, such as gastroparesis and diarrhea.

Consultation with the appropriate specialist is also advisable if there are questions about the diagnosis of a particular form of neuropathy, or if the patient does not tolerate first-line medications.

Long-Term Monitoring

Patients with diabetic neuropathy should have regular monitoring by a primary care physician. Patients should be monitored every 4 weeks to 3 months to try to assess whether therapy is working to decrease pain or nausea or vomiting and also to taper off medications for painful peripheral neuropathy. Objective measures of function and improvement should be taken at every visit. Examine the patient's feet and assess with monofilament and tuning fork on every visit when the patient comes in for DM care. Monitoring patients closely for glycemic control is essential.^[75]

Confocal microscopy of the cornea lends itself to longitudinally assessing progression of neuropathy. Furthermore, improvements in risk factors such as glycated hemoglobin (HbA1c) levels may be associated with morphological repair of nerve fibers.^[107]

Medication

Zeng L, Alongkronrusmee D, van Rijn RM. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US. J Pain Res. 2017 Jan 20. 10:219-228. [QxMD MEDLINE Link]. [Full Text].
Bodman MA, Varacallo M. Peripheral Diabetic Neuropathy. StatPearls. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Carmichael J, Fadavi H, Ishibashi F, Shore AC, Tavakoli M. Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy. Front Endocrinol (Lausanne). 2021. 12:671257. [QxMD MEDLINE Link]. [Full Text].
Skyler JS. Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am. 1996 Jun. 25(2):243-54. [QxMD MEDLINE Link].
Boulton AJ, Malik RA. Diabetic neuropathy. Med Clin North Am. 1998 Jul. 82(4):909-29. [QxMD MEDLINE Link].
Juster-Switlyk K, Smith AG. Updates in diabetic peripheral neuropathy. F1000Res. 2016. 5:[QxMD MEDLINE Link]. [Full Text].
Bromberg MB. Peripheral neurotoxic disorders. Neurol Clin. 2000 Aug. 18(3):681-94. [QxMD MEDLINE Link].
Goetz CG, Pappert EJ. Textbook of Clinical Neurology. Philadelphia: WB Saunders Co; 1999.
Pourmand R. Diabetic neuropathy. Neurol Clin. 1997 Aug. 15(3):569-76. [QxMD MEDLINE Link].
Sugimoto K, Murakawa Y, Sima AA. Diabetic neuropathy--a continuing enigma. Diabetes Metab Res Rev. 2000 Nov-Dec. 16(6):408-33. [QxMD MEDLINE Link].
Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000 Aug. 43(8):957-73. [QxMD MEDLINE Link].
Wilson JD. Williams Textbook of Endocrinology. 9th ed. Philadelphia: WB Saunders Co; 1998.
Zochodne DW. Diabetic polyneuropathy: an update. Curr Opin Neurol. 2008 Oct. 21(5):527-33. [QxMD MEDLINE Link].
Calcutt NA, Dunn JS. Pain: Nociceptive and Neuropathic Mechanisms. Anesthesiology Clinics of North America.; 1997.
Malik RA. Pathology and pathogenesis of diabetic neuropathy. Diabetes Reviews. 1999. 7:253-60.
Shigeta H, Yamaguchi M, Nakano K, Obayashi H, Takemura R, Fukui M. Serum autoantibodies against sulfatide and phospholipid in NIDDM patients with diabetic neuropathy. Diabetes Care. 1997 Dec. 20(12):1896-9. [QxMD MEDLINE Link].
Tavakkoly-Bazzaz J, Amoli MM, Pravica V, Chandrasecaran R, Boulton AJ, Larijani B. VEGF gene polymorphism association with diabetic neuropathy. Mol Biol Rep. 2010 Mar 30. [QxMD MEDLINE Link].
Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy: a critical review for the end of the 20th century. Diabetes Reviews. 1999. 7:275-99.
Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. 1999 Aug 11. 53(3):580-91. [QxMD MEDLINE Link].
Ryle C, Donaghy M. Non-enzymatic glycation of peripheral nerve proteins in human diabetics. J Neurol Sci. 1995 Mar. 129(1):62-8. [QxMD MEDLINE Link].
Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006 Nov. 29(11):2365-70. [QxMD MEDLINE Link].
Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: The oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. 2008 Dec. 9(4):301-14. [QxMD MEDLINE Link].
Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999. 107(7):421-30. [QxMD MEDLINE Link].
Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group. Neurology. 1998 Sep. 51(3):695-702. [QxMD MEDLINE Link].
Krendel DA, Zacharias A, Younger DS. Autoimmune diabetic neuropathy. Neurol Clin. 1997 Nov. 15(4):959-71. [QxMD MEDLINE Link].
Gastol J, Kapusta P, Polus A, et al. Epigenetic mechanism in search for the pathomechanism of diabetic neuropathy development in diabetes mellitus type 1 (T1DM). Endocrine. 2020 Jan 4. [QxMD MEDLINE Link].
Groener JB, Jende JME, Kurz FT, et al. Understanding Diabetic Neuropathy: From Subclinical Nerve Lesions to Severe Nerve Fiber Deficits. A Cross-Sectional Study in Patients with Type 2 Diabetes and Healthy Controls. Diabetes. 2019 Dec 11. [QxMD MEDLINE Link].
Dorsey RR, Eberhardt MS, Gregg EW, Geiss LS. Control of risk factors among people with diagnosed diabetes, by lower extremity disease status. Prev Chronic Dis. 2009 Oct. 6(4):A114. [QxMD MEDLINE Link]. [Full Text].
Diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30. 329(14):977-86. [QxMD MEDLINE Link].
Harati Y. Diabetes and the nervous system. Endocrinol Metab Clin North Am. 1996 Jun. 25(2):325-59. [QxMD MEDLINE Link].
Rutkove SB. A 52-year-old woman with disabling peripheral neuropathy: review of diabetic polyneuropathy. JAMA. 2009 Oct 7. 302(13):1451-8. [QxMD MEDLINE Link].
Finucane TE. Diabetic polyneuropathy and glucose control. JAMA. 2010 Feb 3. 303(5):420; author reply 420-1. [QxMD MEDLINE Link].
Boulton AJ, Malik RA. Neuropathy of impaired glucose tolerance and its measurement. Diabetes Care. 2010 Jan. 33(1):207-9. [QxMD MEDLINE Link]. [Full Text].
Jende JME, Groener JB, Oikonomou D, et al. Diabetic neuropathy differs between type 1 and type 2 diabetes Insights from magnetic resonance neurography. Ann Neurol. 2018 Feb 14. [QxMD MEDLINE Link].
Pai YW, Lin CH, Lee IT, Chang MH. Variability of fasting plasma glucose and the risk of painful diabetic peripheral neuropathy in patients with type 2 diabetes. Diabetes Metab. 2018 Feb 4. [QxMD MEDLINE Link].
Altaf QA, Ali A, Piya MK, Raymond NT, Tahrani AA. The relationship between obstructive sleep apnea and intra-epidermal nerve fiber density, PARP activation and foot ulceration in patients with type 2 diabetes. J Diabetes Complications. 2016 Jun 2. [QxMD MEDLINE Link].
Dabelea D, Stafford JM, Mayer-Davis EJ, et al. Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood. JAMA. 2017 Feb 28. 317 (8):825-35. [QxMD MEDLINE Link].
Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993 Apr. 43(4):817-24. [QxMD MEDLINE Link].
Perkins BA, Olaleye D, Bril V. Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care. 2002 Mar. 25(3):565-9. [QxMD MEDLINE Link].
Shaw JE, Zimmet PZ. The epidemiology of diabetic neuropathy. Diabetes Reviews. 1999. 7:245-52.
Singh R, Gamble G, Cundy T. Lifetime risk of symptomatic carpal tunnel syndrome in Type 1 diabetes. Diabet Med. 2005 May. 22(5):625-30. [QxMD MEDLINE Link].
Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000 Feb. 47(2):123-8. [QxMD MEDLINE Link].
Dyck PJ, O'Brien PC. Quantitative sensation testing in epidemiological and therapeutic studies of peripheral neuropathy. Muscle Nerve. 1999 Jun. 22(6):659-62. [QxMD MEDLINE Link].
Pirart J. Diabetes mellitus and its degenerative complication: a prospective study of 4,400 patient observed between 1947 and 1973. Diabetes Care. 1978. 1:168-188.
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 Feb. 36(2):150-4. [QxMD MEDLINE Link].
Pan Q, Li Q, Deng W, et al. Prevalence of and Risk Factors for Peripheral Neuropathy in Chinese Patients With Diabetes: A Multicenter Cross-Sectional Study. Front Endocrinol (Lausanne). 2018. 9:617. [QxMD MEDLINE Link]. [Full Text].
Moon SS, Kim CH, Kang SM, et al. Status of Diabetic Neuropathy in Korea: A National Health Insurance Service-National Sample Cohort Analysis (2006 to 2015). Diabetes Metab J. 2021 Jan. 45 (1):115-9. [QxMD MEDLINE Link]. [Full Text].
Aaberg ML, Burch DM, Hud ZR, Zacharias MP. Gender differences in the onset of diabetic neuropathy. J Diabetes Complications. 2008 Mar-Apr. 22(2):83-7. [QxMD MEDLINE Link].
Mai LM, Clark AJ, Gordon AS, et al. Long-Term Outcomes in the Management of Painful Diabetic Neuropathy. Can J Neurol Sci. 2017 Jan 9. 1-6. [QxMD MEDLINE Link].
D'Amato C, Morganti R, Greco C, et al. Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities. Diab Vasc Dis Res. 2016 Jun 22. [QxMD MEDLINE Link].
Tesfaye S, Watt J, Benbow SJ, Pang KA, Miles J, MacFarlane IA. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet. 1996 Dec 21-28. 348(9043):1698-701. [QxMD MEDLINE Link].
Johnson DA, Vinik AI. Gastrointestinal Disturbances. Therapy for Diabetes Mellitus. American Diabetes Association; 1998.
Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Reviews. 1999. 7:342-57.
Meijer JW, van Sonderen E, Blaauwwiekel EE, et al. Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care. 2000 Jun. 23(6):750-3. [QxMD MEDLINE Link].
Hokkam EN. Assessment of risk factors in diabetic foot ulceration and their impact on the outcome of the disease. Prim Care Diabetes. 2009 Nov. 3(4):219-24. [QxMD MEDLINE Link].
Coppini DV, Wellmer A, Weng C, Young PJ, Anand P, Sönksen PH. The natural history of diabetic peripheral neuropathy determined by a 12 year prospective study using vibration perception thresholds. J Clin Neurosci. 2001 Nov. 8(6):520-4. [QxMD MEDLINE Link].
Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care. 2001 Feb. 24(2):250-6. [QxMD MEDLINE Link].
Dyck PJ, Turner DW, Davies JL, O'Brien PC, Dyck PJ, Rask CA. Electronic case-report forms of symptoms and impairments of peripheral neuropathy. Can J Neurol Sci. 2002 Aug. 29(3):258-66. [QxMD MEDLINE Link].
Biaggioni I. Postural hypotension. Therapy for Diabetes Mellitus. American Diabetes Association; 1998. 423-30.
Ayad H. Diabetic neuropathy: classification, clinical manifestations, diagnosis and management. Baba S et al, eds. Diabetes Mellitus in Asia. Amsterdam: Excerpta Medica; 1977. 222-4.
Thomas PK. Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes. 1997 Sep. 46 Suppl 2:S54-7. [QxMD MEDLINE Link].
All About Diabetes. Date Accessed: October 30, 2008. American Diabetes Association. [Full Text].
Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: A report of the World Health Organization and International Diabetes Federation. Geneva, Switzerland: WHO Press; 2006.
Abbott CA, Vileikyte L, Williamson S, et al. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care. 1998 Jul. 21(7):1071-5. [QxMD MEDLINE Link].
Llewelyn JG, Tomlinson DR, Thomas PK. Dyck PJ and Thomas PK. Diabetic Neuropathies in Peripheral Neuropathy. Philadelphia: Elsevier Saunders; 2005. 1951-91.
Lozeron P, Nahum L, Lacroix C, Ropert A, Guglielmi JM, Said G. Symptomatic diabetic and non-diabetic neuropathies in a series of 100 diabetic patients. J Neurol. 2002 May. 249(5):569-75. [QxMD MEDLINE Link].
Waldman SD. Diabetic neuropathy: diagnosis and treatment for the pain management specialist. Curr Rev Pain. 2000. 4(5):383-7. [QxMD MEDLINE Link].
Davidson MB. Diabetes Mellitus: Diagnosis and Treatment. 4th Ed. 1998. 297-307.
Vinik AI. New Methods to Assess Diabetic Neuropathy for Clinical Research.60th Scientific Sessions of the American Diabetes Association. American Diabetes Association; 2000.
Busko M. Common Tests May Miss Pediatric Diabetic Neuropathy. Medscape Medical News. Apr 11 2014. [Full Text].
Hirschfeld G, von Glischinski M, Blankenburg M, et al. Screening for peripheral neuropathies in children with diabetes: a systematic review. Pediatrics. 2014 Apr 7. [QxMD MEDLINE Link].
Walter-Holiner I, Barbarini DS, Lutschg J, et al. High Prevalence and Incidence of Diabetic Peripheral Neuropathy in Children and Adolescents With Type 1 Diabetes Mellitus: Results From a Five-Year Prospective Cohort Study. Pediatr Neurol. 2017 Dec 13. [QxMD MEDLINE Link].
Tkac I, Bril V. Glycemic control is related to the electrophysiologic severity of diabetic peripheral sensorimotor polyneuropathy. Diabetes Care. 1998 Oct. 21(10):1749-52. [QxMD MEDLINE Link].
Bril V. Electrophysiologic testing. Gries FA, Cameron NE, Low PA, Ziegler D. Textbook of Diabetic Neuropathy. Stuttgart, Germany: Thieme Medical Publishers; 2003. 177-84.
Huang CC, Chen TW, Weng MC, Lee CL, Tseng HC, Huang MH. Effect of glycemic control on electrophysiologic changes of diabetic neuropathy in type 2 diabetic patients. Kaohsiung J Med Sci. 2005 Jan. 21(1):15-21. [QxMD MEDLINE Link].
Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006 Jun. 29(6):1294-9. [QxMD MEDLINE Link].
Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med. 1999 Aug 30. 107(2B):34S-42S. [QxMD MEDLINE Link].
Apfel SC. Diabetic Polyneuropathy. Diabetes and Endocrinology Clinical Management. 1999.
Argoff CE, Backonja MM, Belgrade MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006 Apr. 81(4 Suppl):S12-25. [QxMD MEDLINE Link].
Boulton A. Current and Emerging Treatments for Diabetic Neuropathies. Diabetes Reviews. 7:379-86.
Slovenkai MP. Foot problems in diabetes. Med Clin North Am. 1998 Jul. 82(4):949-71. [QxMD MEDLINE Link].
O'Brien SP, Schwedler M, Kerstein MD. Peripheral neuropathies in diabetes. Surg Clin North Am. 1998 Jun. 78(3):393-408. [QxMD MEDLINE Link].
Martin CL, Albers J, Herman WH, et al. Neuropathy among the diabetes control and complications trial cohort 8 years after trial completion. Diabetes Care. 2006 Feb. 29(2):340-4. [QxMD MEDLINE Link].
Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003 Jan 14. 60(1):108-11. [QxMD MEDLINE Link].
Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012 Jun 13. 6:CD007543. [QxMD MEDLINE Link].
Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011 Mar 16. CD007938. [QxMD MEDLINE Link].
Ziegler D. Treatment of diabetic neuropathy and neuropathic pain: how far have we come?. Diabetes Care. 2008 Feb. 31 Suppl 2:S255-61. [QxMD MEDLINE Link].
Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev. 2009. (4):CD007115. [QxMD MEDLINE Link].
Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009 Feb. 24(2):178-88. [QxMD MEDLINE Link].
Hayee MA, Mohammad QD, Haque A. Diabetic neuropathy and zinc therapy. Bangladesh Med Res Counc Bull. 2005 Aug. 31(2):62-7. [QxMD MEDLINE Link].
Kawai T, Takei I, Tokui M, Funae O, Miyamoto K, Tabata M, et al. Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of N(varepsilon)-carboxymethyl lysine. J Diabetes Complications. 2009 Aug 26. [QxMD MEDLINE Link].
Schemmel KE, Padiyara RS, D'Souza JJ. Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review. J Diabetes Complications. 2009 Sep 10. [QxMD MEDLINE Link].
Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care. 2006 Jul. 29(7):1538-44. [QxMD MEDLINE Link].
Ando H, Takamura T, Nagai Y, Kaneko S,. Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy. J Diabetes Complications. 2006 Nov-Dec. 20(6):367-70. [QxMD MEDLINE Link].
Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005 Jan 27. 352(4):341-50. [QxMD MEDLINE Link].
Petersen EA, Stauss TG, Scowcroft JA, et al. Effect of High-frequency (10-kHz) Spinal Cord Stimulation in Patients With Painful Diabetic Neuropathy: A Randomized Clinical Trial. JAMA Neurol. 2021 Jun 1. 78 (6):687-98. [QxMD MEDLINE Link]. [Full Text].
Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med. 2005 Apr. 22(4):393-8. [QxMD MEDLINE Link].
Ahn AC, Bennani T, Freeman R, Hamdy O, Kaptchuk TJ. Two styles of acupuncture for treating painful diabetic neuropathy--a pilot randomised control trial. Acupunct Med. 2007 Jun. 25(1-2):11-7. [QxMD MEDLINE Link].
Miller RD. Anesthesia. 5th ed. New York: Churchill Livingstone; 2000.
Ferreira MC, Carvalho VF, Kamamoto F, Tuma P Jr, Paggiaro AO. Negative pressure therapy (vacuum) for wound bed preparation among diabetic patients: case series. Sao Paulo Med J. 2009. 127(3):166-70. [QxMD MEDLINE Link].
Crouch J. Charcot's joint and bilateral foot neuropathy. Adv Nurse Pract. 2005 Mar. 13(3):18. [QxMD MEDLINE Link].
Pfeiffer MA, Schumer M. Painful or insensitive lower extremity. Therapy for Diabetes Mellitus. American Diabetes Association; 1998.
Johnson CE, Takemoto JK. A Review of Beneficial Low-Intensity Exercises in Diabetic Peripheral Neuropathy Patients. J Pharm Pharm Sci. 2019. 22 (1):22-7. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Colberg SR, Sigal RJ, Yardley JE, et al. Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care. 2016 Nov. 39 (11):2065-79. [QxMD MEDLINE Link]. [Full Text].
Somers DL, Somers MF. Treatment of neuropathic pain in a patient with diabetic neuropathy using transcutaneous electrical nerve stimulation applied to the skin of the lumbar region. Phys Ther. 1999 Aug. 79(8):767-75. [QxMD MEDLINE Link].
[Guideline] Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. Prepublished online April 11, 2011. [Full Text].
Tavakoli M, Kallinikos P, Iqbal A, et al. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med. 2011 Oct. 28(10):1261-7. [QxMD MEDLINE Link]. [Full Text].
Possidente CJ, Tandan R. A survey of treatment practices in diabetic peripheral neuropathy. Prim Care Diabetes. 2009 Nov. 3(4):253-7. [QxMD MEDLINE Link].
Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998 Dec 2. 280(21):1831-6. [QxMD MEDLINE Link].
Bennett GJ, Dworkin RH, Nicholson B. Anticonvulsant Therapy in the Treatment of Neuropathic Pain. Neurology Treatment Update. 2000.
Bomholt SF, Mikkelsen JD, Blackburn-Munro G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology. 2005 Feb. 48(2):252-63. [QxMD MEDLINE Link].
Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I. Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients. Diabetes Care. 2009 Aug. 32(8):1479-84. [QxMD MEDLINE Link]. [Full Text].
Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004 Dec 14. 63(11):2104-10. [QxMD MEDLINE Link].
Huffman CL, Goldenberg JN, Weintraub J, et al. Efficacy and Safety of Once-Daily Controlled-Release Pregabalin for the Treatment of Patients With Postherpetic Neuralgia: A Double-Blind, Enriched Enrollment Randomized Withdrawal, Placebo-Controlled Trial. Clin J Pain. 2017 Jul. 33 (7):569-78. [QxMD MEDLINE Link].
Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011 Apr 11. [QxMD MEDLINE Link].
Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev. 2011 Jan 19. CD005451. [QxMD MEDLINE Link].
FDA Requires Boxed Warning and Risk Mitigation Strategy for Metoclopramide-Containing Drugs. U.S. Food and Drug Administration. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Accessed: May 16, 2000.

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Author

Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine

Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Association of Neuromuscular and Electrodiagnostic Medicine<br/>Received research grant from: Alnylam; Pfizer; Ionis; Cytokinetics; Momenta; Viela Bio; .

Coauthor(s)

Helen C Lin, MD Assistant Professor of Neurology, Medical College of Wisconsin

Helen C Lin, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Milind J Kothari, DO Professor and Vice-Chair, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center

Milind J Kothari, DO is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association