Diabetic Neuropathy

Diabetes

Diabetic Neuropathy is a disorder associated with diabetes mellitus. These conditions are thought to result from diabetic micro vascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic Neuropathy include third nerve palsy; Mononeuropathy; Mononeuropathy multiplex; Diabetic Amyotrophy; a painful Polyneuropathy; Autonomic Neuropathy; and Thoracoabdominal Neuropathy. Diabetes is the leading known, cause of Neuropathy in developed countries, and Neuropathy is the most common complication and greatest source of morbidity and mortality in diabetes patients. It is estimated that the prevalence of Neuropathy in diabetes patients is approximately 20%. Diabetic Neuropathy is implicated in 50-75% of non-traumatic amputations.

Diabetic nerve pain, or painful diabetic peripheral neuropathy, is a separate    condition from diabetes. It is the result of damaged nerves caused by uncontrolled    blood sugar over time or fluctuations in blood sugar. This nerve damage is what    causes the pain in your feet and hands. You can’t undo the damage that has already    occurred. But there are 2 things you can do.

The following symptoms of diabetes are typical. However, some people with type 2 diabetes have symptoms so mild that they go unnoticed.

Common symptoms of diabetes:

  • Urinating often
  • Feeling very thirsty
  • Feeling very hungry – even though you are eating
  • Extreme fatigue
  • Blurry vision
  • Cuts/bruises that are slow to heal
  • Weight loss – even though you are eating more (type 1)
  • Tingling, pain, or numbness in the hands/feet (type 2)

Resources

Resources

  • Neurology April 11, 2011, doi:10.1212/WNL.0b013e3182166ebe 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 http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/200533s001lbl.pdf

  • Effective than antineuritics alone in painful diabetic neuropathy]”. Rev Med Chil 134 (12): 1507–15. PMID 17277866.

  • “Diabetic Neuropathy”. PubMed Health. 2010-04-19. Retrieved 2011-05-03.

  • Rader A, Barry T (Nov/Dec 2006). “A proposed mechanism for pain relief following NIR or MIRE therapy”. Diabetic Microvascular Complications Today: 27–8.

Treatments

Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.

Options for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). A systematic review concluded that “tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants.” A combination of these medication (gabapentin + nortriptyline) may also be superior to a single agent. The only three drugs approved by the FDA for diabetic peripheral neuropathy are the antidepressant duloxetine, the anticonvulsant pregabalin, and the long-acting opioid tapentadol ER. Before trying a systemic medication, some doctors recommend treating localized diabetic periperal neuropathy with lidocaine patches.

  • Tricyclic antidepressants

    TCAs include imipramine, amitriptyline, desipramine and nortriptyline. These drugs are effective at decreasing painful symptoms but suffer from multiple side effects that are dosage dependent. One notable side effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicity is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects.

  • Serotonin-norepinephrine reuptake inhibitors

    The SSNRI duloxetine (Cymbalta) is approved for diabetic neuropathy, while venlafaxine is also commonly used. By targeting both serotonin and norepinephrine, these drugs target the painful symptoms of diabetic neuropathy, and also treat depression if it exists. On the other hand, selective serotonin reuptake inhibitors are not useful.

  • Selective Serotonin reuptake inhibitor

    SSRIs include fluoxetine, paroxetine, sertraline and citalopram and are not recommended to treat painful neuropathy because they have been found to be no more efficacious than placebo in several controlled trials.

    Side effects are rarely serious, and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic’s glycemic control. They can be used at dosages that also relieve the symptoms of depression, a common comorbidity of diabetic neuropathy.

  • Antiepileptic drugs

    AEDs, especially gabapentin and the related pregabalin, are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amitriptyline in terms of efficacy, and is clearly safer. Its main side effect is sedation, which does not diminish over time and may in fact worsen. It needs to be taken three times a day, and it sometimes causes weight gain, which can worsen glycemic control in diabetics. Carbamazepine (Tegretol) is effective but not necessarily safe for diabetic neuropathy. Its first metabolite, oxcarbazepine, is both safe and effective in other neuropathic disorders, but has not been studied in diabetic neuropathy. Topiramate has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexia and weight loss, and is anecdotally beneficial. Clinical studies have differed regarding its effectiveness; improved diabetic control may improve this.

  • Classic analgesics

    The above three categories of drugs fall under the heading of “atypical, adjuvant and potentiators” and are often combined with opioids and/or NSAIDs, usually having effects greater than the sum of their parts.

    Duloxetine + extended release morphine ± naproxen ± hydroxyzine (esp. with oxycodone) ± morphine or hydromorphone immediate release for breakthrough pain is a common recipe in cases where diabetic neuropathy is a complicating factor in a debilitating chronic pain condition — amitryptiline may be more effective than Duloxetine in some. Opioids requiring Cytochrome P-450 activation (e.g. codeine, dihydrocodeine) should perhaps be used with an agent not chemically related to the SSRIs; conversely, they may impact parts of the Liberation, Absorption, Distribution, Metabolism & Elimination profile for morphine, hydromorphone, oxymorphone &c the other way.

  • Physical therapy

    Physical therapy can be an effective and alternative treatment option for patients with diabetes. This may help reduce dependency on pain relieving drug therapies. Certain physiotherapy techniques can help alleviate symptoms brought on from diabetic neuropathy such as deep pain in the feet and legs, tingling or burning sensation in extremities, muscle cramps, muscle weakness, sexual dysfunction, and diabetic foot. Transcutaneous electrical nerve stimulation (TENS) and interferential current (IFC) use a painless electric current and the physiological effects from low frequency electrical stimulation to relieve stiffness, improve mobility, relieve neuropathic pain, reduce oedema, and heal resistant foot ulcer.

    Gait training, posture training, and teaching these patients the basic principles of off-loading can help prevent and/or stabilize foot complications such as foot ulcers. Off-loading techniques can include the use of mobility aids (e.g. crutches) or foot splints. Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis.

    Exercise programs, along with manual therapy, will help to prevent muscle contractures, spasms and atrophy. These programs may include general muscle stretching to maintain muscle length and a person’s range of motion.  General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting.  Aerobic exercise such as swimming and using a stationary bicycle can help peripheral neuropathy, but activities that place excessive pressure on the feet (e.g. walking long distances, running) may be contraindicated.  Heat, therapeutic ultrasound,  hot wax  and short wave diathermy  are also useful for treating diabetic neuropathy.  Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.

 

Other treatments include:

  • α-lipoic acid, an anti-oxidant that is a non-prescription dietary supplement has shown benefit in a randomized controlled trial that compared once-daily oral doses of 600 mg to 1800 mg compared to placebo, although nausea occurred in the higher doses.

  • Methylcobalamin, a specific form of Vitamin B-12 found in spinal fluid, has been studied and shown to have significant effect, taken orally or injected, in treating and improving diabetic neuropathy.[16][17][18]

  • Though not yet commercially available, C-peptide has shown promising results in treatment of diabetic complications, including neuropathies. Once thought to be a useless by-product of insulin production, it helps to ameliorate and reverse the major symptoms of diabetes.

  • In more recent years, Photo Energy Therapy devices are becoming more widely used to treat neuropathic symptoms. Photo Energy Therapy devices emit near infrared light (NIR Therapy) typically at a wavelength of 880 nm. This wavelength is believed to stimulate the release of Nitric Oxide, an Endothelium-derived relaxing factor into the bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in various clinical studies to decrease pain in diabetic and non-diabetic patients.  Photo Energy Therapy devices seem to address the underlying problem of neuropathies, poor microcirculation, which leads to pain and numbness in the extremities,.
  • Sativex, a cannabis based medicine has not been found to be effective for diabetic neuropathy.
  • There has been experimental work testing the efficacy of sildenafil (Viagra) but this study described itself as an “isolated clinical report” and cited a need for further clinical investigation.

 

Tight glucose control

  • Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control.  Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes is recent in onset. Conversely, painful symptoms of neuropathy in uncontrolled diabetics tend to subside as the disease and numbness progress.

Data from the 2011 National Diabetes Fact Sheet (released Jan. 26, 2011)

Total prevalence of diabetes

Total: 25.8 million children and adults in the United States—8.3% of the population—have diabetes.

  • Diagnosed: 18.8 million people
  • Undiagnosed: 7.0 million people
  • Prediabetes: 79 million people*
  • New Cases: 1.9 million new cases of diabetes are diagnosed in people aged 20 years and older in 2010.
  • Under 20 years of age: 215,000, or 0.26% of all people in this age group have diabetes, About 1 in every 400 children and adolescents has diabetes
  • Age 20 years or older: 25.6 million, or 11.3% of all people in this age group have diabetes
  • Age 65 years or older: 10.9 million, or 26.9% of all people in this age group have diabetes
  • Men: 13.0 million, or 11.8% of all men aged 20 years or older have diabetes
  • Women: 12.6 million, or 10.8% of all women aged 20 years or older have diabetes

* In contrast to the 2007 National Diabetes Fact Sheet, which used fasting glucose data to estimate undiagnosed diabetes and prediabetes, the 2011 National Diabetes Fact Sheet uses both fasting glucose and A1C levels to derive estimates for undiagnosed diabetes and prediabetes. These tests were chosen because they are most frequently used in clinical practice.

Race and ethnic differences in prevalence of diagnosed diabetes

  • After adjusting for population age differences, 2007-2009 national survey data for people diagnosed with diabetes, aged 20 years or older include the following prevalence by race/ethnicity:
    • 7.1% of non-Hispanic whites
    • 8.4% of Asian Americans
    • 12.6% of non-Hispanic blacks
    • 11.8% of Hispanics

Among Hispanics rates were:

    • 7.6% for Cubans
    • 13.3% for Mexican Americans
    • 13.8% for Puerto Ricans

Morbidity and Mortality

  • In 2007, diabetes was listed as the underlying cause on 71,382 death certificates and was listed as a contributing factor on an additional 160,022 death certificates. This means that diabetes contributed to a total of 231,404 deaths.

Complications

  • Heart disease and stroke
    • In 2004, heart disease was noted on 68% of diabetes-related death certificates among people aged 65 years or older.
    • In 2004, stroke was noted on 16% of diabetes-related death certificates among people aged 65 years or older.
    • Adults with diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes.
    • The risk for stroke is 2 to 4 times higher among people with diabetes.
  • High blood pressure
    • In 2005-2008, of adults aged 20 years or older with self-reported diabetes, 67% had blood pressure greater than or equal to 140/90 mmHg or used prescription medications for hypertension.
  • Blindness
    • Diabetes is the leading cause of new cases of blindness among adults aged 20–74 years.
    • In 2005-2008, 4.2 million (28.5%) people with diabetes aged 40 years or older had diabetic retinopathy, and of these, almost 0.7 million (4.4% of those with diabetes) had advanced diabetic retinopathy that could lead to severe vision loss.
  • Kidney disease
    • Diabetes is the leading cause of kidney failure, accounting for 44% of new cases in 2008.
    • In 2008, 48,374 people with diabetes began treatment for end-stage kidney disease in the United States.
    • In 2008, a total of 202,290 people with end-stage kidney disease due to diabetes were living on chronic dialysis or with a kidney transplant in the United States.
  • Nervous system disease (Neuropathy)
    • About 60% to 70% of people with diabetes have mild to severe forms of nervous system damage.
  • Amputation
    • More than 60% of nontraumatic lower-limb amputations occur in people with diabetes.
    • In 2006, about 65,700 nontraumatic lower-limb amputations were performed in people with diabetes.

Cost of Diabetes

  • $174 billion: Total costs of diagnosed diabetes in the United States in 2007
  • $116 billion for direct medical costs
  • $58 billion for indirect costs (disability, work loss, premature mortality)
  • After adjusting for population age and sex differences, average medical expenditures among people with diagnosed diabetes were 2.3 times higher than what expenditures would be in the absence of diabetes.
  • The American Diabetes Association has created a Diabetes Cost Calculator that takes the national cost of diabetes data and provides estimates at the state and congressional district level.
  • Factoring in the additional costs of undiagnosed diabetes, prediabetes, and gestational diabetes brings the total cost of diabetes in the United States in 2007 to $218 billion.
    • $18 billion for people with undiagnosed diabetes
    • $25 billion for American adults with prediabetes
    • $623 million for gestational diabetes

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