Why You Should Consider The Use Of Supplements In The Management Of Diabetic Neuropathy

Supplements have proven useful for improved management of diabetes and diabetes-related complications such as neuropathy, wounds, cardiovascular complications, renal complications and ophthalmic complications. In looking at practical and rational therapies for the management of neuropathy, Singleton and Smith noted that medication and lifestyle changes should aim at improving hyperglycemia and insulin resistance, and reducing obesity and dyslipidemia.¹ With reference to specific pharmacologic therapy, the authors noted that one should direct therapy at rational targets for known pathophysiology. Furthermore, these authors noted that treatment should aim at prevention of complications such as ulceration. In the patient with diabetes, there are well-documented, specific deficiencies. However, most podiatric physicians are not trained in the use of supplements for the treatment or prevention of diabetes-related pathology. Most podiatric physicians are not familiar with nutritional or supplement therapy, and the literature relevant to the treatment of neuropathy. The majority of podiatric physicians tend to relegate supplement therapy to complementary alternative therapies rather than looking at the potential for disease prevention or resolution. Examples of identified deficiencies include deficiencies of magnesium, calcium, zinc, riboflavin, folate and vitamin A for the healing of diabetic foot wounds. In the case of neuropathy, long axons with smaller cell bodies are most vulnerable to the effects of malnutrition, environmental insults and reduced vascular supply with impaired autoregulation. The result is decreased blood flow to the nerves, relative ischemia, hypoxia and oxidative stress.² Chromium, for example, is a trace element required for glucose metabolism and lipid metabolism. The administration of chromium is effective for reducing glucose levels and improving glucose metabolism as well as decreasing insulin requirements. Chromium deficiency has been associated with increased serum glucose levels, cholesterol and triglyceride levels, and decreased HDL levels.³ Chromium deficiency has been associated with both peripheral neuropathy as well as central nervous system disorders. Researchers have shown that the administration of chromium picolinate decreases hemoglobin A1c.³ Chromium increases insulin binding, insulin receptor site numbers and receptor fossa correlation. Alpha lipoic acid is an antioxidant that increases insulin sensitivity and improves glucose metabolism diabetic neuropathy and vascular perfusion of tissues. Polyphenols are antioxidants found in tea and dark chocolate. Researchers have found them to be associated with protective cardiovascular effects as well as increased glucose control and insulin activity.⁴ A common source of such polyphenols is green tea. Cinnamon has an insulin-like activity. In a meta-analysis of 435 patients receiving cinnamon at a dose of 6 g per day, cinnamon had a beneficial effect on glycemic control with lowering of hemoglobin A1c as well as fasting blood glucose levels.⁵ We have long known zinc supplementation to be helpful in diabetic wound healing. Zinc improves the function of the immune system, providing antioxidant activity and glucose homeostasis. With reference to wound healing, zinc stabilizes cell membranes, is an enzyme cofactor and is required for cell mitosis and cell proliferation.⁶ Zinc is required for cell growth and proliferation, for protein, DNA and RNA synthesis. The administration of 50 or 20 mg of zinc per day improved wound healing within 24 hours. The role of supplements in diabetic management can be summarized by the conclusions of Boulton and colleagues.⁷ They noted "emerging evidence of positive findings with some natural products... has been reported in glycemic parameters, markers of cardiovascular risk, and quality of life in individuals with type 2 diabetes. However, further investigation in well designed, adequately powered studies is needed.”

A Closer Look At Diabetic Neuropathy

Diabetic neuropathy may manifest as sensory, motor or autonomic dysfunction. The most significant complications of diabetic neuropathy are associated with loss of sensation. Although many patients with diabetic neuropathy develop paresthesia and dysesthesia, the majority of patients affected by diabetic neuropathy suffer from loss of sensation, with associated ulceration, Charcot joint disease, infection and not infrequently, amputation. Additionally, motor neuropathy may manifest itself as aching pain, or a loss of intrinsic foot musculature and the development of bunions, hammertoes or metatarsal head prolapse. In addition, motor neuropathy may be associated with decreased knee and ankle reflexes, and weakness of the extrinsic foot musculature. Diabetic autonomic neuropathy may be associated with decreased ability to sense the position of the toes and feet, vasomotor instability, neuropathic edema, or cold paresthesia.⁷ As the majority of patients with diabetic neuropathy suffer from decreased or loss sensation rather than paresthesia or dysesthesia, clinical examination by the podiatric physician is critical to determine the presence of neuropathy as the patient may not be aware of sensory loss. Examination with a 128 Hz tuning fork, pinprick, 10 g filament and ankle reflexes can determine the presence of diabetic neuropathy without the need of advanced diagnostic testing, with an 87 percent sensitivity.⁷ Therefore, the podiatric physician may generally diagnose diabetic neuropathy in its most common presentation without the need of sophisticated or advanced diagnostic modalities.

What You Should Know About The Treatment Of Diabetic Neuropathy

Remember that diabetic neuropathy is a metabolic disorder. Therefore, the treatment of diabetic neuropathy must include not only management of diabetes but reversal of those metabolic abnormalities that cause diabetic neuropathy. A variety of metabolic disorders have been associated with diabetic neuropathy. They include increased sorbitol accumulation, increased fructose, decreased myoinositol, glycosylated end products, reactive oxygen species, decreased nitric oxide, activated protein kinase C and decreased nerve growth factors, to name but some of the metabolic etiologies proposed for diabetic neuropathy.⁷ The treatment of diabetic neuropathy therefore must include interdiction of symptomatology such as paresthesia or dysesthesia, prevention of nerve degeneration and advancement of the neuropathic process, and the enhancement of nerve regeneration.⁸

Why You Should Consider Vitamin D Supplementation For Diabetic Neuropathy

We generally consider vitamin D in discussions of bone metabolism and health. The effects of vitamin D deficiency include decreased calcium absorption, increased risk of osteoporotic fractures, delayed fracture healing, decreased neuromuscular coordination and muscle function. In addition, vitamin D plays a significant role in wound healing, participating in cell growth and differentiation, reversal of corticosteroid-induced epidermal atrophy, and the inhibition of hyperplastic epidermal tissue formation. This results in increased rates of wound healing and increased wound tensile strength. Recently, researchers have defined the role of vitamin D in diabetic neuropathy. Soderstrom and coworkers noted that a significant number of patients with diabetic neuropathy suffered from vitamin D deficiency.⁹ This deficiency was most common in Hispanic Americans and non-Hispanic African-Americans. Therefore, it is possible that some patients with diabetic neuropathy may benefit from the simple administration of vitamin D.

Can Vitamin B12 (Methylcobalamin) Supplementation Have An Impact For Diabetic Neuropathy?

Increasingly, we have identified the role of vitamin B12 in diabetic neuropathy and the need to supplement B12 in the patient with diabetes. Metformin, the most commonly utilized drug for the treatment of diabetes, is associated with worsening of diabetic neuropathy due to the inhibition of folic acid and B12 absorption as a result of the effects of metformin.¹⁰ Authors have demonstrated that the malabsorption of B12 and decreased folate levels associated with metformin result in an increased homocysteine level and increased risk of neuropathy.^11,12 The administration of B12 may be associated with a reversal of these effects. Homocysteine, when elevated, results in endothelial damage and decreased blood flow to peripheral nerve tissue by thrombus formation within the vascular supply to the nerve. In addition, homocysteine impairs the coupling of arginine and oxygen for the formation of nitric oxide, which is necessary to maintain vascular supply and normal nerve function.¹³ Cobalamin deficiency, which is exacerbated by the utilization of metformin, increases risk of neuropathy. B12 supplementation can be helpful in the reversal of this deficiency and neuropathy. In addition to those patients utilizing metformin, researchers have demonstrated that vitamin B12 deficiency and folate deficiency are associated with increased levels of homocysteine, increased oxidative stress secondary to low levels of glutathione, and decreased total antioxidant activity.¹⁴ Bailey and colleagues noted that cobalamin deficiency is common and the majority of cases are subclinical.¹⁵ In addition, they have suggested that cobalamin serum testing is unreliable. Solomon demonstrated that functional B12 deficiency is common in the elderly and common in 62 percent of patients with diabetic neuropathy.¹⁶ In these patients, normal serum cobalamin levels were associated with markers for B12 deficiency such as elevated levels of methylmalonic acid and the presence of neuropathy. Solomon showed that the administration of cobalamin reversed the effects of functional B12 deficiency in many patients. Wyckoff and Ganji demonstrated that vitamin B12 deficiency may exist even in the presence of patients who presumably have a "large intake" of B12.¹⁷ They further demonstrated that classic markers of B12 deficiency such as macrocytic anemia are not reliable markers for B12 deficiency. The administration of methylcobalamin at 1,500 mcg per day has been associated with normalization of hemoglobin A1c and improved motor conduction velocity, thereby suggesting that vitamin B12 therapy may be helpful in the reversal of diabetic motor neuropathy, or symptoms such as cramping.¹⁸ Others have demonstrated that the administration of methylcobalamin at 1,500 mcg daily was associated over three months with relieved muscle cramping, improvement in motor conduction velocity, reduction in neuropathic pain and improvement in two point discrimination, suggesting nerve regrowth.¹⁹ Yaqub and co-workers have demonstrated that methylcobalamin improves not only sensory but autonomic nerve dysfunction symptoms as well.²⁰ With reference to autonomic neuropathy, multiple studies have demonstrated the reversal of autonomic signs, autonomic symptoms and the normalization of autonomic nerve dysfunction with the administration of methylcobalamin.^21,22 Authors have also described a potential neuroprotective effect together with reversal of symptomatic sensory and autonomic neuropathy.^23-26

Key Insights On Alpha-Lipoic Acid

Alpha lipoic acid is an antioxidant. Researchers have shown that the use of alpha lipoic acid in insulin-resistant patients is associated with reduced body mass index, waist circumference and total cholesterol as well as improved insulin sensitivity, and suggested it as an adjunctive therapy for the treatment of patients with type 2 diabetes.²⁷ In the four-year NATHAN study, alpha lipoic acid demonstrated meaningful symptom improvement and delay in the progression of neurologic deficits.²⁸ Alpha lipoic acid is a lipophilic free radical scavenger that patients tolerate well. One generally administers it at a dosage of 600 mg-1,800 mg daily for effective clinical use in the treatment of neuropathy. It is important to remember that an adequate dose of alpha lipoic acid with a minimum of 600 mg daily is typically required for the treatment of symptomatic diabetic neuropathy. The effectiveness of alpha lipoic acid does not depend on the degree of metabolic control of diabetes. Multiple authors utilizing alpha lipoic acid have shown a reduction in diabetic neuropathic symptoms as well as oxidative stress.^29-34

What You Should Know About Acetyl-L-Carnitine

Acetyl-l-carnitine is an amino acid that is in frequent use for the treatment of Alzheimer’s disease, depression, painful diabetic neuropathy, drug-related neuropathy, HIV neuropathy and chemotherapy-related neuropathy. Neuropathy may be associated with a relative deficiency of acetyl-l-carnitine when the demand exceeds synthesis. In the patient with diabetes, this may occur secondary to coexisting renal disorders, hepatic disorders or the effects of certain drugs such as anticonvulsants for the treatment of neuropathy. Authors have described both the anti-nociceptive and neuroprotective effects of acetyl-l-carnitine as well as the ability of acetyl-l-carnitine to contribute to glucose and lipid metabolism.^35,36 Several large studies have demonstrated that at a dosage of 500-1,000 mg tid, acetyl-l-carnitine results in significant pain reduction, improved vibratory perception, improved nerve conduction velocity, improved nerve amplitude and nerve regeneration in the neuropathic patient.^37,38 The ability to decrease pain and improve electrodiagnostic studies as well as nerve regeneration has resulted in a recommendation that acety-l-carnitine therapy start early following the diagnosis of diabetes.³⁹ In addition, a dosage of 2 g per day has been associated with the reversal of cardiac autonomic neuropathic symptoms and signs, the reversal of symptoms and signs of diabetic sensory neuropathy, and time current improvement in both EKG and nerve conduction velocity studies.⁴⁰

Using L-Methylfolate For Diabetic Neuropathy

L-methylfolate is the active form of folic acid. The administration of l-methylfolate has been associated with increased levels of nitric oxide, thereby increasing blood flow to the peripheral nerve tissue.¹³ Furthermore, l-methylfolate possesses antioxidant activity in addition to stimulating the production of nitric oxide synthase. It is a critical factor in the reduction of serum homocysteine levels, which studies have noted to be elevated in patients with diabetic neuropathy in comparison with patients with diabetes without neuropathy.⁴¹

How Benfotiamine May Benefit Patients With Neuropathy

Benfotiamine is a lipid soluble analog of vitamin B1. Oral benfotiamine increases levels of intracellular thiamine diphosphate activating transketolase, which reduces advanced glycosylated end products. In the presence of hyperglycemia, non-enzymatic glycosylation of nerve protein alters nerve protein structure and function, resulting in or contributing to diabetic neuropathy. Studies have demonstrated a reduction in subjective symptoms of pain as well as improved sensory conduction and compounded nerve conduction with the use of benfotiamine.^29,42 Multiple studies have shown the clinical efficacy of benfotiamine at a dosage of 300-600 mg daily.^43-46

How Effective Is Combination Therapy?

Combinations of vitamin B have been effective in the treatment of diabetic neuropathy. Authors have shown improvement in two-point discrimination, epidermal nerve fiber density count, neuropathy total symptom score and quality of life measures, reduction in hospitalization and associated hospitalization costs with the use of combination vitamin B therapy with l-methylfolate, methylcobalamin, and pyridoxal-5-phosphate.^47-51 Researchers have also demonstrated synergistic effects with the use of benfotiamine with B6, B12, gabapentin and carbamazepine.^42,52-53

What You Should Know About Inositol

Inositol plays a role in electrolyte flux across neural membranes. It may be deficient in patients with diabetic neuropathy. Supplementation with 500 mg tid-qid has been helpful in the treatment of neuropathy.⁵⁴

In Summary

A large body of scientific literature supports the use of supplements in the management of diabetes and diabetes-associated complications such as peripheral neuropathy. Physicians frequently underutilize these modalities primarily because the majority of healthcare providers are not familiar with the adjunctive use of supplements for the management of diabetes and its complications, and are not familiar with the supportive literature regarding the use of supplements for the treatment of diabetic neuropathy. It is important to remember that diabetes is a metabolic disorder and diabetic neuropathy is the result of these metabolic disorders. Although a variety of agents are useful for the treatment of symptoms, supplements are helpful in assisting the reversal of the metabolic disorders responsible for diabetic neuropathy. Not uncommonly, I will combine traditional anti-nociceptive agents such as gabapentin (Neurontin, Pfizer), pregabalin (Lyrica, Pfizer) or amitriptyline (Elavil, Pfizer) with supplements so I can concurrently treat the etiology of the pathology together with symptomatic treatment. A variety of metabolic supplements are currently available for use in treatment of diabetic neuropathy. It is important to consider whether the dosage of these supplements is adequate to accomplish the intended goal and consistent with published literature regarding the effective use of supplements at particular stated dosages. References 1. Singleton JR, Smith AG. The diabetic neuropathies: practical and rational therapies. Semin Neurol. 2012; 32(3):196-203. 2. Yagihashi S, Mizukami H, Sugimoto K. Mechanism of diabetic neuropathy: Where are we now and where to go? J Diabetes Investig. 2011; 2(1):18-32. 3. Cefalu WT, Hu F. Role of chromium in human health and in diabetes. Diabetes Care. 2004; 27(11):2741-51. 4. McKeown P, Noad R, McCall D, McKinley M, Woodside J. Effect of a Polyphenol-rich Diet on Vascular Function and other Markers of Cardiovascular Risk. Heart. 2014 Jun;100(Suppl 3):A62. 5. Akilen R, Tsiami A, Devendra D, Robinson N. Cinnamon in glycaemic control: Systematic review and meta analysis. Clinical Nutrition. 2012; 31(5):609-15. 6. Heyland DK, Jones N, Cvijanovich NZ, Wong H. Zinc supplementation in critically ill patients: a key pharmaconutrient? JPEN J Parenter Enteral Nutr. 2008; 32(5):509-19. 7. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005; 28(4):956-62. 8. Yasuda H, Terada M, Maeda K, et al. Diabetic neuropathy and nerve regeneration. Prog Neurobiol. 2003; 69(4):229-85. 9. Soderstrom LH, Johnson SP, Diaz VA, Mainous AG 3rd. Association between vitamin D and neuropathy in a nationally representative sample: results from 2001-2004 NHANES. Diabet Med. 2012; 29(1):50-55. 10. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2009; 33(1):156-61. 11. De Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. 12. Palomba S, Falbo A, Giallauria F, et al. Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. Diabetes Care. 2010; 33(2):246-51. 13. De Luis D, Izaola O, Aller R, et al. Utility of a omega 3 fatty acids oral enhanced formula in biochemical parameters of head and neck cancer patients. Medical Clinics (Barc). 2004; 122(1):499-500. 14. Al-Maskari MV, Waly MI, Ali A, et al. Folate and vitamin B12 deficiency and hyperhomocysteinemia promote oxidative stress in adult type 2 diabetes. Nutrition. 2012; 28(7):23-26. 15. Bailey RL, Carmel R, Green R, et al. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. Am J Clin Nutrit. 2011; 94(2):552-61. 16. Solomon LR. Diabetes as a cause of clinically significant functional cobalamin deficiency. Diabetes Care. 2011; 34(5):1077-80. 17. Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post folic acid fortification period than in the pre folic acid fortification period. Am J Clin Nutrit. 2007; 86(4):1187-92. 18. Okada S, Miyai Y, Sato K, et al. Vitamin B for treating peripheral neuropathy. Clin Trials J. 1985;22:534–536. 19. Devathasan G, Teo WL, Mylvaganam A. Methylcobalamin in chronic diabetic neuropathy. Clin Trials J. 1986;23:130–140. 20. Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clinics Neurol Neurosurg. 1992; 94(2):105-111. 21. Ejiri K, Taniguchi H, Baba S. Treatment of autonomic nerve dysfunction in uremia with special reference to its normalisation by methylcobalamin. Nihon Jinzo Gakkai Shi. 1987 Jun;29(6):695-9. 22. Li J-B, Wang C-Y, Chen JW, et al. Expression of liver insulin-like growth factor 1 gene and its serum level in patients with diabetes. China J Clin Rehab. 2005; 10(2):255-9. 23. Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Aging. 2006; 35(4):416-22. 24. Morani AS, Bodhanker SL. Neuroprotective effect of early treatment with pioglitasone and methylcobalamin in alloxan induced diabetes in rats. Pharmacol Online. 2007;3:282–293. 25. Chen RJ, Zheng YL, Xu LS. Clinical trials on effects of methylcobalamin in the treatment of diabetic neuropathy. Chinese J Clin Rehab. 2002;6:1280–1281. 26. Sun Y, Lai MS, Lu CJ. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurolog Taiwanica. 2005; 14(2):48-54. 27. Udupa AS, Nahar PS, Shah SH, et al. Study of comparative effects of antioxidants on insulin sensitivity in type 2 diabetes mellitus. J Clin Diagn Res. 2012; 6(9):1469-73. 28. Papanas N, Trypsianis G, Tiaka EK, et al. Increased cardiovascular and renal disease but not reduced life expectancy among diabetic participants in the general Northern Greek population. Angiology. 2010; 63(3):443-7. 29. Winler G, Kempler P. Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy. Orvosi Hetilap. 2010; 151(24):971-81. 30. Forst TL, Weber MM, Hohberg C, Pfutzner A. Pharmkologische aspeke in der therapie der diabetischen neuropathie. Diabetes Stoffwechsel Und Herz. 2010;19(4);261-295. 31. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003; 26(3):770-6. 32. Ziegler D, Hanefeld N, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999; 22(8):1296-1301. 33. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004; 21(2):114-121. 34. Ziegler D, Schatz H, Conrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care. 1997; 20(3):369-73. 35. Chiecho S, Copani A, Nicoletti F, et al. L-acetylcarnitine: a proposed therapeutic agent for painful peripheral neuropathies. Curr Neuropharmacol. 2006; 4(3):233-7. 36. Tamler R, Mechanick J. Dietary supplements and nutraceuticals in the management of endocrine disorders. Curr Opin Endocrinol Diabetes Obesity. 2006; 13(5):425-30. 37. Sima AA, Calvani M, Mehra M, et al. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005; 28(1):89-94. 38. 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. 39. Evans JD, Jacobs TF, Evans EW. Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacol. 2008; 42(11):1686-91. 40. Ulvi H, Aygul R et al. Effect of l carnitine on diabetic neuropathy and ventricular dispersion in patients with diabetes mellitus. Turkish Journal of Medical Science, 2010; 40(2):169-175. 41. Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diab Med. 2001; 18(3):185-92. 42. Nikolic A, Kacar A, Lavrnic D, Basta A, Apostolski S. The effect of benfothiamine in the therapy of diabetic polyneuropathy. Srp Arh Celok Lek. 2009 Nov-Dec;137(11-12):594-600. 43. Anisimova EL, Danilov AB. Bendotiamine efficacy in alcoholic polyneuropathy therapy. Zh Nevrol Psikhiatr Im S S Korsakova. 2001;101(12):32–6. 44. Haupt E, Ledermann H, Kopcke W, et al. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther. 2005; 43(2):71-77. 45. Winkler G, Pál B, Nagybéganyi E, et al. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999; 49(3):220-4. 46. Stracke H, Gaus W, Achenbach U, et al. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Clin Endocrinol Diabetes. 2008; 116(10):600-605. 47. Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013; 126(2):141-9. 48. Wade RL, Cai Q. Impact of L-Methylfolate Combination Therapy Among Diabetic Peripheral Neuropathy Patients. Am J Pharm Benefits. 2012;4(5):218-225. 49. Jacobs AM, Cheng D. Management of diabetic small fiber neuropathy with combination l-methyl folate, methylcobalamine and pyridoxal 5’-phosphate. Rev Neurol Dis. 2011;8(1-2):39–47. 50. Walker M. Diabetic Peripheral Neuropathy: Symptomatic Treatment and Beyond. Presented at Diabetic Global Foot Conference, Los Angeles, 2008. 51. Jacobs AM, Cheng D, Thethi R. Addition of Metanx in pregabalin partial responders for painful diabetic neuropathy. J Diabetes Medicine. 2013; 3 (3). 52. Montiel-Ruiz RM, Granados-Sotos V, Garcia-Jiminez S, et al. Synergistic interaction of diclofenac, benfotiamine, and resveratrol in experimental acute pain. Drug Development Research. 2011; 72(5):397-404. 53. Mixcoatl-Zecuatit T, Quinonez-Bastidas GN, Caram-Salas N, et al. Synergistic antiallodynic interaction between gabapentin or carbamazepine and either benfotiamine or cyanocobalamin in neuropathic rats. Methods Find Exp Clin Pharmacol. 2008 Jul-Aug;30(6):431-41. 54. Agostini R, Rossi F, Pajalich R. Myoinositol/folic acid combination for the treatment of erectile dysfunction in type 2 diabetes men: a double-blind, randomized, placebo-controlled study. Eur Rev Med Pharmacol Sci. 2006 Sep-Oct;10(5):247-50.