Most practitioners are aware that controlling glucose levels through diet is one way to manage symptoms of peripheral neuropathy. What’s less widely known is that there is also evidence to support the use of nutritional supplements in the same patient population.
By David Shofler, DPM and Jonathan Labovitz, DPM, FACFAS
Peripheral neuropathy is the most common complication of diabetes mellitus. Diabetic peripheral neuropathy (DPN) has been estimated to affect roughly half of all patients with type 2 diabetes mellitus.1 Neuropathic pain can have a substantial effect on the patient’s quality of life, and also imposes a significant financial burden. In addition to the potential pain, which can greatly alter quality of life, peripheral neuropathy is an independent risk factor for ulcer formation in diabetic patients. The ulcers are often complicated by soft tissue infection or osteomyelitis, further impairing the patient’s functional status and adding to the financial burden. Peripheral neuropathy is also associated with motor and autonomic neuropathy, which can lead to various types of foot deformities, and Charcot arthropathy, a devastating condition that causes gross joint malalignment and foot and ankle instability.
The most intuitive and cost effective answer to DPN is controlling blood sugar levels. Blood sugar levels can be regulated through diet, exercise, and weight management, each of which affects the disease process and its subsequent complications. In a comparison study of patients with type 1 diabetes, intensive blood sugar control yielded a median group hemoglobin A1C (HbA1C) of 7.2%, compared to an HbA1C of 9.1% in a conventional therapy group. This was found to result in a 60% reduction in the occurrence of peripheral neuropathy.2
A study by Ohkubo of type 2 diabetic patients found that controlling blood sugar levels with insulin injections delayed the onset of peripheral neuropathy, diabetic retinopathy, and diabetic nephropathy. Specifically, the study concluded that maintaining a fasting blood glucose below 110 mg/dl prevented the onset and progression of these complications.3 A subsequent study of patients with type 2 diabetes found that a 1% reduction in HbA1C correlated with a 37% reduction in microvascular complications, and a 43% reduction in amputation or death from peripheral vascular disease. 4
The nutritional status of patients with diabetes is also a major factor, and may be estimated using serum albumin levels. In fact, serum albumin levels have been shown to predict the severity of neuropathy. In a study of 130 Japanese patients with type 2 diabetes,using multiple regression analysis, serum albumin was found to be independently related to the severity of peripheral neuropathy.5 Low serum albumin levels have also been found to correlate with the severity of other microvascular complications, including nephropathy and retinopathy.
Dietary correction for malnutrition includes improving oral protein and calorie intake.6 Among diabetic patients with normal renal function, protein should provide 15% to 20% of calories, according to recent guidelines from the American Diabetes Association for controlling diabetes.7 These guidelines also recommend two or more servings of fish weekly, fiber intake of at least 14 g/1,000 kcal, and that saturated fat be kept below 7% of total calories.7
The sensory loss associated with diabetic neuropathy typically affects the most distal aspects of the lower extremities first, and subsequently ascends proximally. The disease process soon can affect the hands, described as a “stocking and glove” pattern of sensory loss. Diabetic peripheral neuropathy can be associated with pain in 3% to 25% of patients.8 The diagnosis of painful DPN is clinical, and symptoms are typically distal, symmetrical, and worse in the evenings. The pain is often described as sharp, burning, or tingling, and may be preceded by poor glycemic control.
Several medications have Food and Drug Administration approval for treating neuropathic pain. These are gabapentin, pregabalin, duloxetine, carbamazepine, and a 5% lidocaine patch.9 However, when it comes to painful DPN specifically, the FDA has only approved duloxetine and pregabalin.10
Though they do not have FDA approval, tricyclic antidepressants and venlafaxine have also been suggested as first-line treatments for DPN pain. Second-line treatments for painful DPN have been suggested to include opioid analgesics, tramadol, and topical Capsaicin. 11,12 It should be noted that the two medications applied topically, Capsaicin and the 5% lidocaine patch, are more effective when the pain can be localized to a specific area. These options have all shown some level of efficacy in the literature.
Practitioners are usually familiar with the medications listed above: however, there are several other options that may be less familiar. The first of these is Metanx. Metanx is a prescription strength vitamin supplement, containing L-methylfolate, methylcobalamin, and pyridoxal 5’-phosphate. Each of these three ingredients function to control homocysteine levels.13-15
The amino acid homocysteine is a known inhibitor of nitric oxide, which mediates many pathways, including pathways related to elasticity of arteries, vascular supply, and wound healing. Both elevated levels of homocysteine and reduced bioactivity of nitric oxide induce endothelial dysfunction, endothelial injury, and may impair vasodilation.14,16 In a prospective study of 65 patients with type 2 diabetes, elevated levels of homocysteine were found to be independently associated with the prevalence of peripheral neuropathy.17 The authors suggested that this specific association could be explained either by direct cytotoxic effects on nerve function, or by small vessel occlusions caused by endothelial damage. This results in a loss of blood supply to nerve fibers, a pathogenetic mechanism of peripheral neuropathy.18 It should be noted that the oral anti-hyperglycemic medication metformin has also been associated with elevated homocysteine levels due to malabsorption of vitamin B12.19 It has, as a result, been suggested that vitamin B12 levels be monitored in long-term metformin patients with type 2 diabetes.
The ingredients of Metanx each help correct for nutritional deficiencies in folic acid, pyridoxal 5’-phosphate, and methylcobalamin, keeping homocysteine levels controlled. In particular, the active form of folic acid, L-methylfolate, has been shown to be more bioavailable and more effective in lowering homocysteine levels than naturally occurring folic acid.15
Methylcobalamin, or Vitamin B12, also has additional features. The vitamin is active in the spinal fluid, and is essential during peripheral nerve repair and regeneration.20 A double-blinded study by Yaqub found statistical improvement in symptoms and regression of signs of diabetic neuropathy with methylcobalamin, and no side effects were reported.21
Metanx has been labeled as a remittive form of therapy, based on the effects of restoring nerve health and reducing neuropathic symptoms. Providing remittive therapy would suggest protection against the complications of neuropathy, including neuropathic ulcerations, Charcot arthropathy, and motor neuropathy. Analgesic therapy can still be useful, though a restoration of nerve health through remittive therapy can improve even positive symptoms such as pain and dysesthesias present in painful DPN.22
Metanx was recently the focus of several studies. A collection of studies presented at the Diabetic Foot Global Conference in 2009 and at the New Cardiovascular Horizons Conference in 2008 investigated the use of Metanx for diabetic peripheral neuropathy.
The first study compared acetaminophen with Metanx as a remittive therapy to relieve burning pain associated with diabetic peripheral neuropathy.23 One hundred thirty patients were randomly assigned to receive Metanx or acetaminophen BID for 20 weeks. Ninety-seven patients completed the study, and no adverse reactions were reported. The Metanx group had a statistically significant reduction in pain, as measured using a visual analog scale (VAS), at both 10 weeks and 20 weeks. The medication was most effective in patients with symptoms less than three years in duration.
Another study evaluated Metanx for patients with painful DPN who partially responded to pregabalin.24 Twenty-four consecutive patients with a less than 50% reduction in pain at a pregabalin dosage of 100 mg TID were included in the study. Sixteen of these patients were given Metanx orally BID as a supplemental treatment. Eight patients who continued with pregabalin at the same dosage formed the control group. After 20 weeks of treatment, the study group reported a significant reduction of 87.5% on a neuropathic pain scale, compared to a 25% reduction in the control group. There was an average absolute pain reduction of 3.0 in the study group and 0.25 in the control group, and the difference between the groups was statistically significant.
A third study found Metanx to significantly improve two-point discrimination at six months and one year. Although this was only a pilot study of 16 patients, it is encouraging that there may be an opportunity to restore sensation.25 The findings also seem to be consistent with those of another study on epidermal nerve fiber density,26 which supported claims that the supplement is remittive. Skin punch biopsies demonstrated increased epidermal nerve fiber density in eight of 11 patients with DPN after six months of Metanx.
The use of anticonvulsant medication can also be lower in patients using Metanx for painful DPN management.27 This statistically significant finding in a study involving 267 patients was suggested to be due to a reduced need for pain medication. Costs related to DPN were also lower in the Metanx group, though the difference between groups was not statistically significant.
A summary in 2009 by Jacobs concluded that Metanx is effective for the negative symptoms and signs of DPN, including anesthesia, motor neuropathy, and autonomic neuropathy. The supplement was also concluded to be effective for the positive symptoms, which include pain, paresthesia, and dysesthesia.23
ALA and other alternatives
The second nutritional product practitioners are often unfamiliar with for DPN is alpha-lipoic acid (ALA), a potent anti-oxidant that can be effective for both nerve deficits and painful DPN. Reactive oxygen species (free radicals) may lead to neurovascular damage and can be associated with the pathogenesis of diabetic neuropathy.28 As an anti-oxidant, ALA is capable of scavenging reactive oxygen species. A study by Ziegler found that the medication can improve blood flow and reduce nerve conduction deficits, but did not find an improvement in nerve conduction after four years of treatment.29 Although not FDA approved for diabetic neuropathy, ALA has been licensed for symptomatic diabetic neuropathy in Germany for more than 40 years.13
A number of Level I, prospective, randomized studies have shown statistically significant improvement in both subjective and objective outcomes, such as reduced pain, paresthesias, and numbness, following treatment with ALA.29-31 In one such study, an oral dose of 600 mg daily was recommended as providing the highest risk-to-benefit ratio.31 ALA has also been shown to have a low toxicity profile, with infrequent adverse events.32
Practitioners are also often unfamiliar with the medication lacosamide, a functionalized amino acid with promise for painful DPN. Originally synthesized as an anticonvulsant, lacosamide selectively enhances slow sodium channel inactivation, a novel mechanism in normalizing activation thresholds and nerve function, thus reducing the symptoms of painful DPN.32 In a prospective, randomized, double-blinded study of 246 patients by Ziegler,33 lacosamide was compared to placebo for painful diabetic neuropathy. The study administered lacosamide at a dose of 400 mg/day or 600 mg/day over a six-week titration and a 12-week maintenance period, and found that lacosamide decreased neuropathic pain and was well tolerated. However, the reduction in pain was not significantly different from that seen in patients given placebo, perhaps secondary to the high placebo effect found in neuropathic studies.33 However, in a similar double-blinded, placebo-controlled 18-week study, the group of patients who took lacosamide (400 mg/day) did experience a significantly greater reduction in pain than the control group. Several adverse events, mostly mild or moderate in intensity, were reported, including nausea (15%), dizziness (22%), and headache (13%).34
Epalrestat, an aldose reductase inhibitor, is approved in Japan and India for subjective neuropathy symptoms, and has shown promise for painful DPN. Aldose reductase catalyzes the first step of the polyol pathway, which reduces unused glucose to sorbitol, and is believed to be responsible for many diabetic complications.35 Epalrestat is well tolerated, and it has been suggested that the medication may slow the progression of DPN.
A review of six clinical trials concluded that epalrestat 50 mg TID improved subjective neuropathic symptoms relative to baseline and was more effective than placebo.36 The review determined that epalrestat may improve motor and sensory nerve conduction velocity. A prospective, comparative study of 242 patients with diabetic neuropathy compared epalrestat with methylcobalamin over a 12-week period. Epalrestat was shown to have better efficacy (in terms of improved sensation, reduced burning pain, reduced numbness, and reduced spontaneous pain) and a better safety profile than methylcobalamin for diabetic neuropathy.37 Still, the overall benefits of epalrestat have so far been modest, and investigation of the medication in a U.S. clinical trial setting will be necessary before it can be applied clinically in this country.36
When a patient presents with painful diabetic neuropathy, both pharmacologic and nutritional options should be considered. It is important to note that, unlike pharmaceutical therapy for diabetic neuropathy, nutritional therapy has been shown to be remittive in preliminary studies. There has also been shown to be an improved adverse effect profile. This may make it a more viable choice than traditional pharmaceutical treatments.
First and second-line treatment options for DPN should be adjusted or changed if not they are appropriately controlling patient symptoms. Treatment options can also be combined or supplemented with other pharmacologic or nutritional agents. The literature is constantly evolving, and both traditional and newer agents should be considered when treating these patients.
David Shofler, DPM, is a faculty scholar and instructor and Jonathan Labovitz, DPM, FACFAS, is associate professor and chair in the Department of Podiatric Medicine, Surgery, and Biomechanics at the Western University of Health Sciences College of Podiatric Medicine in Pomona, CA.
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