Neuropathy affects 66% of patients with diabetes mellitus, of which the most common presentation is a diffuse peripheral symmetrical polyneuropathy. Only 10–20% of patients with diabetic neuropathy are affected by pain, paresthesia, or dysesthesia that requires antinociceptive therapy.1–3 Symptomatic diabetic neuropathy is typically treated by control of diabetes and the utilization of agents typically employed for the treatment of paresthesia and dysesthesia associated with peripheral neuropathy. Treatment of symptomatic neuropathy may include opioid or opioid-like analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, or anticonvulsant medications, all of which are directed at management of symptomatology, but do not address the underlying pathophysiology. As a result, antinociceptive therapy for the symptomatic treatment of diabetic neuropathy typically results in only 30–50% resolution of symptoms. Management of the pathophysiology and a disorder associated with diabetic peripheral neuropathy includes management of the diabetes itself, and efforts at remittive therapy in order to restore nerve health. A variety of agents may be utilized as individual therapy or in combination with antinociceptive therapy to reduce symptomatic paresthesia, pain, or dysesthesia. These agents include methylcobalamin, pyridoxine, folate, biotin, taurine, L-arginine, alpha-lipoic acid, and others.5 Remittive therapy, in combination with analgesic therapy, offers the opportunity to restore nerve health while concurrently reducing symptomatology. Many of the most destructive changes associated with diabetic neuropathy are not associated with pain, paresthesia, or dysesthesia. Examples include neuropathic ulceration with osteomyelitis, Charcot’s joint disease, peripheral autonomic neuropathy with vasomotor and sudomotor dysfunction, and motor neuropathy with associated foot deformity. Additionally, anesthesia associated with diabetic neuropathy is frequently responsible for undetected injury such as penetration wounds, ulceration, or ulceration with infection, which as a result allows advancing disease frequently complicated by infection and vascular disease, to go undetected. Negative symptoms are not treated utilizing antinociceptive therapy, but are instead managed by good control of diabetes and the use of remittive agents in order to restore nerve health. Remittive Therapy Remittive therapy implies the restoration of nerve function. Remittive therapy suggests the possibility of relieving anesthesia present in some patients with advanced diabetic neuropathy, restoring or improving motor nerve function, or restoring or improving autonomic nerve function. Such therapy involves manipulation of underlying metabolic pathophysiology and relief of oxidative stress. The regeneration of peripheral nerves in diabetic laboratory specimens has been demonstrated by utilization of pharmacologic therapy, as well as surgical decompression.6–9 Methylcobalamin has been demonstrated to improve sensory and motor nerve conduction velocity. Methylcobalamin reduced symptomatology in 40% of patients; resolved neuropathic symptomatology in 20% of patients; reduced cramping; and restored diminished or absent reflexes in 60% of studied individuals. These outcomes suggest that “negative symptomatology,” such as that associated with motor neuropathy, can be reversed or improved with remittive therapy.10,11 The reversal of autonomic neuropathic signs and symptoms with normalization of autonomic nerve dysfunction has been demonstrated by the administration of methylcobalamin, which again attests to the possible effectiveness of remittive therapy in the management of negative symptoms associated with diabetic neuropathy.12–14 A reduced level of pyridoxine has been demonstrated in patients with diabetes as well as in elderly patients, and has been associated with neuropathy. Supplementation with pyridoxine has been demonstrated to reduce symptomatology.15–17 Utilizing pressure specified sensory device (PSSD) measurements, normalization and restoration of nerve function 6 months and 1 year following the administration of L-methylfolate, pyridoxal 5'phosphate, and methylcobalamin in patients with negative diabetic symptomatology has been demonstrated.18 One-point static touch and two-point static touch were evaluated in this study. Remittive Therapy for the Management of Positive Symptoms The findings of this study were consistent with previous reports suggesting statistical improvement in somatic and autonomic symptoms, and any regression of diabetic neuropathy while utilizing methylcobalamin.19 We examined the efficacy of L-methylfolate, methylcobalamin, and pyridoxal 5'phosphate for the management of symptomatic diabetic neuropathy. The randomized, controlled trial (RCT) utilized a proprietary combination of these agents (Metanx®, PamLab, LLC, Mandeville, Louisiana) given as a twice-daily dosage. Twice-daily acetaminophen dosage acted as the comparator drug. One hundred thirty patients were initially enrolled into this RCT. Study group participants received either 2.8-mg L-methylfolate, 2.0-mg methylcobalamin, or 25-mg pyridoxal 5'phosphate twice daily. The active control group participants received 500-mg acetaminophen twice daily for 20 weeks. A baseline visual analog scale (VAS) utilized as a neuropathy pain scale was obtained and evaluated at 0, 10, and 20 weeks. Patient characteristics are reviewed in Table 1. Patients were eliminated from the study if any change was made in the management of their diabetes, or any medication was added to the care of the patient that could have influenced diabetic neuropathy (e.g., analgesics, anti-inflammatories, statin drugs, antioxidant therapy). The active treatment group demonstrated an 11.6% reduction in VAS at 10 weeks. The study group averaged 32.9% reduction in VAS at 10 weeks (Table 2). At 20 weeks, the active treatment group demonstrated a reduction of 11.7% on the VAS, while the study group demonstrated a reduction of 35.3%. The odds of VAS reduction for male versus female, and as a function of duration of symptomatology and duration of diabetes, are summarized in Table 3. This RCT indicated that while effective at all ages, the maximum VAS reduction in the study group was achieved in patients less than 65 years old who had diabetes for less than 7 years. There was no significant difference in response between genders. The twice daily administration of 2.8-mg L-methylfolate, 2.0-mg methylcobalamin, and 25-mg pyridoxine 5'phosphate was effective in reducing burning paresthesia associated with diabetic peripheral neuropathy. The results also indicated that the combination of L-methylfolate, methylcobalamin, and pyridoxine 5'phosphate was most effective in reducing burning paresthesia when administered early following the diagnosis of diabetes, and when neuropathic symptoms were present for less than 5 years. Remitttive Plus Antinociceptive Therapy We examined the effects of twice daily L-methylfolate, methylcobalamin, and pyridoxine 5'phosphate on burning paresthesias in patients with diabetic peripheral neuropathic pain who had obtained partial symptom resolution with the use of pregabalin. The theory was that the addition of a remittive agent to an antinociceptive agent would result in further symptom relief than the use of an antinociceptive agent alone. Twenty-four consecutive patients, who had received pregabalin for more than 4 months with partial (Discussion The etiology of diabetic neuropathy remains unclear. Additionally, a variety of histologic abnormalities have been described in association with diabetic neuropathy including reduced nerve fiber branch density, reduced peripheral nerve branch length, epidermal axon swelling, dermal axon swelling, thinning of subepidermal nerve plexus, sprouting of nerve terminals, encapsulation of nerve endings, and the presence of a mural reactive basal cells.20–22 Elevated homocysteine levels have been demonstrated to be present in those patients with diabetes affected by neuropathy,23 and have been shown to be a risk factor for increased prevalence of neuropathy in a patient with diabetes.24 Elevated homocysteine levels have also been demonstrated as an independent risk factor for autonomic neuropathy.2 Homocysteine elevation may result in both direct and indirect neuropathic processes resulting in the evolution of both positive and negative symptoms. The direct effects of homocysteine results from the endothelial toxicity of homocysteine, which causes endothelial thrombosis and loss of vascular supply to the peripheral nerves.26 As a result, homocysteine contributes to peripheral ischemic neuropathy with resultant symptomatology. Homocysteine interferes with the synthesis of nitric oxide, a gaseous free-radical constitutively required for normal nerve and vascular function. Nitric oxide is a smooth muscle relaxant that increases neural blood flow, in part, due to relaxation of the tunica media. Nitric oxide is required for normal neural function. The effectiveness of L-methylfolate, methylcobalamin, and pyridoxine 5'phosphate in reducing both positive and negative diabetic neuropathic effects may be partly related to the ability of these agents to reduce homocysteine levels and stimulate elevated levels of nitric oxide. L-methylfolate is a cofactor for homocysteine metabolism. It is the active form of folic acid, is 7 times more bioavailable than folate, and is 3 times more effective in the reduction of homocysteine levels than folic acid.27,28 In addition, L-methylfolate directly stimulates increased vascular nitric oxide formation. Methylcobalamin levels may be reduced in elderly patients. Supplementation with methylcobalamin has been demonstrated to reverse symptomatic sensory and autonomic neuropathy, in addition to its neuroprotective effects.29–31 Reduced activity of cobalamin and holotranscobalamin had been demonstrated in patients taking metformin for more than 6 months,32,33 and may be a contributing factor in the evolution of homocysteine-driven diabetic neuropathy by reduction of those cofactors necessary to inhibit homocysteine concentration. Additionally, declining renal function, which is commonly encountered, in a patient with diabetes may result in an increased homocysteine level secondary to reduced elimination of homocysteine. Other factors that may predispose the patient with diabetes to elevated homocysteine levels include excessive alcohol consumption, inactivity, and the use of seizure medications such as gabapentin, which are commonly employed in the management of positive diabetic neuropathic symptoms. Furthermore, polymorphism in the metabolism of folic acid and its conversion to its bioactive form L-methylfolate, primarily due to a deficiency in methylene-tetrahydrofolate-reductase, may contribute to elevated homocysteine levels in the patient with diabetes mellitus, as may occur in a patient without diabetes. Serious consideration must be given to remittive therapy in patients with negative symptomatology for which no additional alternatives are available other than control of hyperglycemia. Motor neuropathy may be associated with significant extremity weakness,34 accelerated neurodegeneration, and diminished stability in gait.35 Motor neuropathy might also be an initiating factor in the development of Charcot’s joint disease36 and cause deformity resulting in neuropathic foot ulceration and infection.37 Improved motor conduction velocity and reversal of motor symptomatology with the use of methylcobalamin has been demonstrated.10,12,19 The presence of significant muscle atrophy in patients with diabetic neuropathy,38 and the existence and progression of such atrophy preceding the diagnosis of neuropathy,39 suggest that remittive therapy with agents such as L-methylfolate, methylcobalamin, and pyridoxine 5'phosphate should be considered to prevent or interdict motor neuropathy to reduce the incidence of serious sequela, such as deformity with ulceration and infection or Charcot’s joint disease. The manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypotension, neurogenic bladder dysfunction, gustatory sweating, and gastric motility abnormalities, vascular calcification, Charcot’s joint disease, erectile dysfunction, peripheral pseudomotor dysfunction, and neuropathic edema. Autonomic neuropathy is associated with significant morbidity and mortality. A 53% mortality in patients with diabetes mellitus and autonomic neuropathy versus a 15%, 5-year mortality in patients with diabetes without autonomic neuropathy, has been demonstrated.40 The incidence of autonomic neuropathy in patients with diabetes mellitus increases over time, correlates to poor glycemic control, and is associated with increased cardiovascular mortality.41 Remittive therapy has been demonstrated to reverse the signs and symptoms of autonomic neuropathy,12–14 and as is the case with motor neuropathy, remittive therapy may offer the opportunity to reduce the incidence or intensity of autonomic neuropathy. A discussion of the potential interdiction of negative symptomatology must include a discussion of anesthesia and profound numbness in the patient with diabetes mellitus. As noted earlier in this discussion, restoration of nerve function and increased return of protective sensation has been demonstrated with the use of remittive therapy, specifically with the use of L-methylfolate, methylcobalamin, pyridoxine 5'phosphate (Metanx).18,19 Conclusion The majority of patients with diabetes mellitus demonstrate manifestations of neuropathy. The symptoms experienced by such patients may include positive symptoms such as pain, paresthesia, or dysesthesia. Positive symptoms represent 10–20% of the manifestations of diabetic neuropathy. The overwhelming majority of patients with diabetic neuropathy have undetected negative symptomatology including anesthesia, motor neuropathy, and autonomic neuropathy. The positive symptomatology associated with diabetic neuropathy may be managed effectively with rigorous control of diabetes, antinociceptive therapy, and remittive therapy. The negative symptoms and signs of diabetic peripheral neuropathy are best managed with rigorous diabetic control and the utilization of remittive agents. Interestingly, it is the negative neuropathic process that results in the most significant morbidity and mortality. Remittive therapy, particularly if initiated early in the disease process, offers the potential to interdict or lessen the clinical manifestations of negative symptomatology. ___________________________ From American College of Foot and Ankle Surgeons and Dr. Jacobs is a Fellow of the American Professional Wound Care Association, St. Louis, Missouri. Disclosure: Dr. Jacobs has disclosed that he is a member of the speakers’ bureau for Pamlab, LLC. Correspondence: Allen Jacobs, DPM, 6400 Clayton Rd # 402, St Louis, MO 63117. E-mail: firstname.lastname@example.org.