Diabetic Neuropathy Treatment & Management
- Author: Dianna Quan, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
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.[64, 65, 66, 67]
Consider any patient with clinical evidence of diabetic peripheral neuropathy to be at risk for foot ulceration, and provide education on foot care. 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.
The primary care physician is responsible for educating patients about the acute and chronic complications of diabetes, 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.
Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy. 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.[23, 71] 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.
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.
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.
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.[75, 55] 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. 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. . 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.
Erythromycin, cisapride (not available in the United States), 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.
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.
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. 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.[79, 80] 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.[81, 82]
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. Other studies of this drug are ongoing.
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.
Spinal cord stimulators and other therapies
Pain medicine specialists have been experimenting with spinal cord stimulator implants in severely painful cases. 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. Further study is necessary. Alternative and complementary therapies for pain (eg, acupuncture) are under investigation.[85, 20]
Treatment of Autonomic 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.
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.
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.
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.[86, 87]
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; see Charcot-Marie-Tooth Disease) from frequent and multiple traumas. Charcot foot can be treated with bracing or special boots. In some cases, surgery is used to correct the deformity.[88, 89]
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 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.
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.
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. The 2011 AAN/AANEM/AAPMR guideline supports TENS as probably effective as a treatment for PDN.
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 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.
Involvement of a speech therapist rarely is indicated, but professionals from this discipline can help with patients affected by gastroparesis or dysphagia.
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.
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.
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.
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.
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|A-alpha (I)||13-20 micrometers||Limb proprioception||Yes|
|A-beta (II)||6-12 micrometers||Limb proprioception, vibration, pressure||Yes|
|A-delta (III)||1-5 micrometers||Mechanical sharp pain||Yes|
|C (IV)||0.2-1.5 micrometers||Thermal pain, mechanical burning pain||No|