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Integrative Medicine in the Treatment of Diabetic Peripheral Neuropathy

MPH

Diabetic peripheral neuropathy (DPN) is a painful complication of diabetes that reduces quality of life and can impair a person's motivation to exercise. In addition, neuropathies frequently disrupt sleep, which may impact energy levels and blood glucose control. In my practice, I see neuropathies as a leading barrier to adopting better lifestyle choices, especially more exercise.

What Causes Neuropathy?

Neuropathy is caused by the oxidation and glycosylation (binding of sugar) of both nerve fibers and the small blood vessels that supply oxygen to nerve fibers. Eventually, the nerve fibers become physically squeezed by a thickening coating of glycosylation (imagine a lollipop stick getting coated with caramel!) and the blood vessels ultimately narrow to the point of no longer being able to supply blood. When nerve fibers become squeezed and lose their blood supply, pain and strange sensations - crawling sensations, pins and needles, and limbs falling “asleep” - may occur.

How Can I Tell if I Have Neuropathy?

In general your symptoms guide the diagnosis of neuropathy, although simple tests using a small piece of monofilament and a tuning fork can be performed in your doctor’s office to screen for neuropathy. Using a small piece of monofilament, your doctor will check your sensation on your feet to determine whether neuropathy is present. A tuning fork is used to check to see if you can detect vibration in your toes and feet as well. If either of these tests suggest neuropathy, additional testing can be done by a neurologist, however typically this is only done if the results of your physical exam are inconclusive. Additional testing is done if neuropathy is suspected in your autonomic nervous system (your autonomic nerves provide innervation to your organs and control things like bowel function, heart rate and breathing).

Treatments for Neuropathy

Drug Therapy

Unfortunately, many drugs used to treat neuropathy have side effects that, in some cases, are worse then the neuropathy symptoms themselves. Also, to my knowledge, none of the available prescription medications actually address the causative process, but rather trick the brain and body into not feeling pain. Prescription pharmacologic therapies for neuropathies include antidepressants like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), dopamine-agonists (e.g., levodopa), analgesics (e.g., tramadol) anticonvulsants and antiarrhythmics. Cymbalta® (duloxetine) and Lyrica® (pregabalin) are FDA-approved for neuropathy.

Common side effects for Lyrica® include: dizziness, somnolence, impaired concentration, blurred vision, weight gain and edema in >5% of patients (Source: Lyrica® prescribing information).

Common side effects for Cymbalta® include: major depressive episode, generalized anxiety, fibromyalgia symptoms including fatigue, nausea, dry mouth, constipation, somnolence, hyperhidrosis, and decreased appetite in >5% of patients (Source: Cymbalta® prescribing information).

Improve Glucose Control

Since neuropathies are caused by the glycosylation of basement membrane proteins in both nervous tissue and vascular tissue, neuropathy symptoms will continue to progress unless blood sugar control is optimized. A reduction in neuropathic symptoms typically occurs if blood sugar is optimized, however if neuropathy has been present for a very long time, or if blood sugar has been poorly controlled for a very long time, blood sugar lowering alone may not be enough to reduce or resolve neuropathy.

Consider Anti-inflammatory Dietary Changes

Increased consumption of glycosylation products in food triggers endothelial dysfunction in the microvasculature, which may have an impact on the progression of neuropathy. Glycosylation of food occurs from cooking and is especially common in meats, as well as fried, broiled and roasted foods, including vegetables. The microvascular effects of advanced glycosylation endproduct consumption have been most definitively researched in diabetic nephropathy, though because nephropathy and neuropathy share mechanistic pathways (increased oxidative stress), reducing glycosylation endproduct consumption may lead to improvements. See Complementary Corner July 2008 for more dietary advice on following an anti-inflammatory diet.

Other Treatments

As most people with diabetes are on many medications, non-prescription treatment options are preferred whenever possible. Fortunately, for neuropathy, there are several safe options, many of which have an evidence-base grounded in human clinical trials.

Topical Capsaicin Cream (Zostrix®)

Zostrix® is a 0.075% capsaicin cream can be applied topically for pain relief in both arthritis and diabetic peripheral neuropathy. Capsaicin depletes Substance P, the chemical messenger that facilitates the sensory perception of pain at the nerve ending. It is important to note that capsaicin does not change the course of neuropathy, but only masks the pain. Because it takes up to a week or more to deplete Substance P, and because capsaicin does stimulate local burning, you have to stick with it for several weeks (and tolerate some discomfort) before it is effective.

Vitamin B12

Vitamin B12 is a nutrient necessary for normal nerve conduction. The clinical use of B12 supplementation has recently undergone systematic review for the treatment of diabetic neuropathy with positive conclusions (1). Seven controlled, clinical trials of varying quality suggest benefit in autonomic or peripheral neuropathic symptoms. The impact of graded reductions in B12 status on nerve function have not been thoroughly explored, however clinically significant B12 deficiency is reported to occur in 7-8% of diabetic patients on metformin, suggesting reductions of B12 status may be common in those with diabetes. In addition, older adults are more at risk for B12 deficiency especially if they have a history of atrophic gastritis, proton pump inhibitor, or H2-receptor blocker medications.

A common clinical protocol involves evaluating clinical response to an intramuscular injection of B12; when effective, positive responses are rapid with most patients reporting improvement within 48 hours. Duration of response is variable ranging between days to weeks. Some patients prefer periodic repeat injections while others maintain on sublingual (drops taken under the tongue) B12 supplementation. If your doctor is not willing to provide you with a B12 injection, sublingual B12 can also work, but it may take longer to be effective.

Alpha-lipoic Acid (ALA)

Recently, a large, dose-finding clinical trial in 181 patients with diabetes demonstrated reductions in stabbing and burning pain scores, reductions in neuropathy symptom and change (NSC) score and improvements in global assessment of efficacy measures (2). Three doses were tested (600mg/1200mg/1800mg/day vs. placebo), and all three demonstrated positive results, without differences between groups. Nausea, vomiting and vertigo occurred at higher doses. Based on this study, 600mg per day of ALA orally appears to be an effective and tolerable dose. Debate remains over the best molecular form of ALA for clinical use. Chemically ALA is a racemic mixture- meaning it has several structural forms; the “R” isomer may prove superior, and is available as a supplement, however most trials have been performed on the mixture.

Acetyl-l-carnitine

Acetyl-l-carnitine (AC) is a form of the amino acid L-carnitine (required for the metabolism of fatty acids) with greater absorption in nerve tissue. AC has demonstrated the ability to improve nerve conduction velocities in both sensory and motor nerves, including improved pain scores and vibratory sense. The dose supported by clinical trials is between 1000-2000mg/day (3). Unfortunately AC may be cost prohibitive at the recommended dosage, however combination products that include ALA are available and may reduce the cost when both treatments are used together ($1-2/day). Clinical trials using both nutrients combined have not yet been conducted.

Benfotiamine

Benfotiamine is a synthetic, lipid-soluble form of the B vitamin thiamine (See Complementary Corner October 2007 for more information). Benfotiamine has superior absorption to thiamine, allowing for much lower doses to be used clinically. The mechanism of benfotiamine in neuropathy is not definitively established, although it appears to block advanced glycosylation endproduct formation on nerve tissue, which may improve nerve function. To date, two clinical trials have demonstrated improvements in nerve conduction velocity and/or improvement in neuropathic pain scores. Standard doses used in clinical trials have been 320-400mg per day. Reductions in neuropathic symptoms can occur within three weeks of initiation of therapy. No adverse effects of benfotiamine have been reported in clinical trials to date.

Summary

Diabetic peripheral neuropathy can be a significant barrier to lifestyle change in people with diabetes, especially exercise initiation and tolerance. Effective pharmacologic therapy is available, though side effects are reported and in some cases can negatively impact common co-morbidities in diabetes (i.e., depression and fatigue). Several natural and naturally-derived therapies, including vitamin B12, alpha-lipoic acid, acetyl-l-carnitine and benfotiamine, have clinical trial support for efficacy, are generally well-tolerated by patients and may correct common nutritional deficiencies in diabetes (e.g., B12). Achieving and/or maintaining good blood sugar control is fundamentally the only approach to prevent neuropathy from beginning or progressing.

In health-Ryan Bradley, ND, MPH



Dr. Ryan Bradley, ND, Doctor of Naturopathy

 

Ryan Bradley, ND, MPH is a naturopathic doctor, clinical researcher and epidemiologist in San Diego, CA. In addition to his research, he is a practicing clinician specializing in natural and integrative approaches to treating type 2 diabetes, chronic kidney disease and heart disease at Pacific Pearl La Jolla.

Complementary Corner More Articles

References

  1. Sun Y, Lai MS, Lu CJ. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurol Taiwan. 2005 Jun;14(2):48-54.
  2. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006 Nov;29(11):2365-70.
  3. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3(4):223-31.

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