Peripheral neuropathy (PN) is a progressive disease with high prevalence worldwide. In the broadest sense, peripheral neuropathy refers to a range of clinical syndromes affecting a variety of peripheral nerves, including motor, sensory and autonomic fibres [1] . Diagnosis of peripheral neuropathy depends on the recognition of signs and symptoms which encompasses sensory and motor deficits. Often, in diabetes, the symptoms are symmetrical and involve hands and feet with “glove and stocking” distribution [2] . It is characterized by debilitating outcomes like pain, numbness, burning and tingling in the extremities; slowed nerve conduction; loss of balance, reduced vibration perception threshold & decreased tendon reflexes.

Nutritional deficiency has a great influence on nervous system because optimal functioning of the central and peripheral nervous system is dependent on a constant supply of appropriate nutrients [3] . The State of Food Insecurity in the World estimated that almost 870 million people were chronically undernourished in 2010-12 [4] . It is not uncommon that conditions like old age, eating disorders, diabetes, gastrointestinal diseases, alcohol abuse, etc. are characterized by multiple nutritional deficiencies and these conditions are linked to peripheral neuropathy as well [3] . Further, even the post harvesting processing has led to emergence of crops that are not very nutritionally appropriate. Hence, the presumed balanced diet may not suffice the nutritional requirement [5] .

The correlation between nutrition and peripheral neuropathy dates back to 19th century based on the epidemic of polyneuropathy and heart failure due to beriberi [6] . The strong evidence is bariatric surgeries leading to nutritional deficiencies and consequent neurologic problems [7] [8] . Also, it is well documented that neurologic symptoms are the earliest and often the only manifestation of cobalamin deficiency [9] .

Nutripathy, the science that deals with nutritional management of diseases, has proven significant benefits in treatment of peripheral neuropathy. Being a multifactorial complication, resolution of peripheral neuropathy demands a multinutrient treatment approach. It is well accepted that B-vitamins are required for optimum functioning of nervous system in combination with antioxidants [3] [10] - [16] . Methylcobalamin, the active form of vitamin B12, helps in the formation of methionine from neurotoxic homocysteine; methionine, in turn, is required for methylation reactions associated with myelin sheath & neurotransmitter formation. Folic acid participates in DNA synthesis and a range of metabolic and nervous system biochemical processes. Benfotiamine, a fat soluble analogue of thiamine, increases transketolase activity involved in glucose metabolism. As a result, it blocks the pathways leading to hyperglycemic damage to nerves. Unavailability of biotin & thiamine decreases the activity of various enzymes associated with pyruvate metabolism, thus resulting in neurotoxic pyruvate accumulation. Also, biotin has shown to inhibit hyperglycemia induced damage to peripheral nerves. Vitamin B6 metabolizes neurodamaging homocysteine via cystathione pathway and nerve conduction studies reveal severely reduced sensory nerve action potentials in vitamin B6 deficient patients. Also, nerve biopsy of subjects with pyridoxine deficiency confirms axonal degeneration of small and large myelinated fibers. Antioxidant like alpha lipoic acid (ALA) has shown its efficacy in neuroprotection by scavenging a wide range of reactive oxygen species.

The present study was a post-marketing surveillance (PMS) conducted to evaluate the safety and efficacy of once daily administration of fixed dose combination comprising of methylcobalamin, ALA, folic acid, biotin, benfotiamine and vitamin B6 for the treatment of peripheral neuropathy.

A total of 497 cases were evaluated in the study. The overall demographic profile of the patients is presented in Table 1. The physical examination parameters such as temperature, pulse rate, respiratory rate and blood pressure were within normal limits at baseline as shown in Table 2.

Peripheral neuropathy affects a substantial percentage of population and presents with significant morbidity. Pain in the fingers, toes, hands or feet is the most common symptom of neuropathy. The other frequently described symptoms of PN are numbness, tingling, burning, abnormal temperature perception, decreased muscle strength and compromised movement [17] . It can have extremely devastating consequences; patients experiencing PN report a reduced quality of life, chronic discomfort and disruption of physical abilities for general life activities.

Conventional neuropathy treatment includes tricyclic antidepressants, selective serotonin reuptake inhibitors, anticonvulsants, lidocaine patches, topical capsaicin, opioid and non-opioid analgesics. While these agents exhibit modest resolution of symptoms, low tolerability limits their long term use. Further, they merely mask the symptoms of neuropathy and do not address the underlying pathologies [18] . Aldose reductase inhibitors like epalrestat, is a promising class of drugs that tackles one of the pathogenic pathways of diabetic neuropathy [19] - [21] .

The physiology of nervous system is considerably interrupted by nutritional deficiency itself [22] . Particularly important for efficient functioning of the nervous system are the B-group vitamins (vitamin B12, thiamine, niacin, folic acid and pyridoxine) [23] . Chronic B-vitamin deficient state leads to demyelination of axons and subsequently destruction of underlying axons. Occurrence of vitamin B derangement is the shared pathogenic mechanism in the varied etiologies of peripheral neuropathy viz. diabetes, certain medications, alcoholism, eating disorders, bariatric or gastrointestinal surgeries, malabsorptive states, HIV infection, etc. Hyperhomocysteinemia is an independent risk factor for peripheral neuropathy and it is stated that deficiency of vitamin B12, folate and pyridoxine results in elevated homocysteine levels [24] . Oxidative stress, too, is an identified cause of physical damage to neurons by demyelination, mitochondrial dysfunction, depletion of antioxidant defenses, neuroinflammation and neuronal death through apoptosis [25] .

Unbalanced diet consumption, veganism, low economic status appears to be the most common reasons for dietary deficiency. Moreover, diabetes, malabsorption syndromes, depression, cancer, chronic infections and prolonged consumption of alcohol are among the other common predisposing factors. In addition, several drugs like metformin, isoniazid, PPIs, anticonvulsants, etc. have been found to interact with B-vitamin metabolism [26] - [29] and hence their long-term use may consequently result in nerve dysfunction. Thus, neuropathy develops as a late complication of nutritional deficiency in most of the patients.

Compromised peripheral nerve function may lead to impaired physical function and disability in patients with nutritional deficiency and hence, it is vital to combat the potentially modifiable risk factors. B-vitamin deficiency is a well-recognized risk factor for the disease of peripheral nervous system. Usually the deficiency is multifactorial; it is rare that deficiency of single B-vitamin is identified as the sole cause of neuropathy [23] . Thus, it trails that combination therapy aimed at correcting the pathogenic features of neuropathy such as disturbances in the synthesis of lipids needed for nerve tissue, oxidative stress, decreased neuronal blood supply, impaired neurotransmission, etc. has the potential to provide effective treatment for neuropathy.

B-vitamins and ALA are well researched treatment options for peripheral neuropathy [18] . Methylcobalamin has been extensively studied as a nerve regenerator leading to significant improvement in the symptoms of neuropathy [30] [31] . Analysis of controlled clinical trials of methylcobalamin by Yu Sun et al. revealed benefits in somatic symptoms such as pain and paresthesia as well as autonomic symptoms. In their previous work, M. Maladkar et al. reported faster and better resolution of symptoms with the combination of epalrestat and methylcobalamin compared to epalrestat alone in diabetic patients with PN [19] . In a double-blind, randomized, controlled clinical study, benfotiamine in combination with vitamin B12 and pyridoxine has demonstrated effectiveness against diabetic peripheral neuropathy. Neurotropic benfotiamine and other B vitamin combination has been suggested as first line treatment approach in management of diabetic PN [32] . Several clinical studies have confirmed the positive clinical effects of ALA on neuropathy symptoms [18] [33] [34] .

In subjects with impaired neurological functions, folate deficiency was one of the abnormal parameters identified, thus confirming its role in neuropathy progression [35] . The efficacy of biotin has been verified in hemodialysis and diabetic patients with PN [36] [37] . Considerable improvement was noted with biotin treatment in paresthesia and difficulty in walking.

The present post-marketing surveillance study was undertaken to evaluate efficacy and safety of fixed dose combination of methylcobalamin, ALA, folic acid, benfotiamine, biotin and vitamin B6 in the management of PN. The observation items included reduction in neuropathic pain, numbness, tingling, burning sensation and muscle weakness.

The clinical assessment showed statistically significant (p < 0.05) change in bothersome symptoms of neuropathy i.e. pain, numbness, tingling and burning sensation with combination therapy. Favorable effects were exhibited within 4 weeks of study commencement and continued till end of treatment period. Treatment efficacy was rated as very good by the majority of both physicians and patients, thus ratifying the usefulness of combination therapy. Pain intensity decreased by 78% and more than 90% improvement in numbness, tingling and burning sensation was achieved at study completion.

Noteworthy improvement was demonstrated by the patients in physical activity limiting parameter viz. muscle weakness at all the visits during the study duration. Muscle weakness score reduced by approximately one-third at the first follow-up and further decreased by 96.9% at the end of treatment phase. The differences in the score from baseline were statistically significant (p < 0.05) throughout the treatment follow-up.

The beneficial effects of combination therapy were possibly due to enhancement in motor and sensory function by promoting myelin formation, axonal phospholipid synthesis, improvement in neuroconduction facilitated by enhanced neurotransmitter synthesis and reduction in oxidative stress.

The combination was well tolerated with no major adverse effects being experienced by the patients. Commonly reported adverse effects were mainly gastrointestinal related; the intensity of these effects was described as mild and resolved during the course of treatment.

This clinical trial confirms the marked and clinically relevant effect of fixed dose combination of methylcobalamin, ALA, folic acid, biotin, benfotiamine and vitamin B6 on neuropathy symptoms in a real-life situation. Thus, it is a safe and effective option for the management of peripheral neuropathy.