Introduction
The global burden of diabetes is substantial and on the rise, particularly in developing nations such as India, largely driven by escalating rates of overweight/obesity and unhealthy behaviours. Estimations from 2019 indicated that India possessed 77 million cases of diabetes, a figure projected to surpass 134 million by 2045. Notably, approximately 57% of these cases remain undiagnosed.1 Based on the prevailing circumstances within the Indian population, the incidence of diabetic neuropathy stands at 29.2%. 2 Among patients with diabetic neuropathy, majority of them were having vitamin B12 deficiency.3
Cobalamin, a water-soluble vitamin, functions as a cofactor in numerous methylation processes. Its deficiency disrupts DNA synthesis, cell metabolism and red blood cell function. Adenosylcobalamin and methylcobalamin are the biologically active cofactor forms of vitamin B12. Cobalamin plays a vital role in the myelination of both central and peripheral nervous systems and its deficiency leads to demyelination in dorsal and lateral columns, as well as peripheral and optic nerves. Absorption occurs with intrinsic factor, synthesized by parietal cells in the stomach, primarily in the terminal ileum, and is eventually stored in the liver. 4 The primary cause for vitamin B12 deficiency prevalent today is food-bound cobalamin malabsorption, there is a hindered release of vitamin B12 from consumed food. For instance, achlorhydria, gastritis, gastrectomy and the usage of proton pump inhibitors (PPIs) or antacids all result in reduced secretion of hydrochloric acid, consequently diminishing the liberation of vitamin B12 from dietary proteins. A recent trial exhibited a dose- and time-dependent correlation between the use of PPIs or histamine H2-receptor antagonists and the eventual development of vitamin B12 insufficiency. Pervasive utilization of acid-suppressing agents may thus induce vitamin B12 deficiency, which could go unnoticed due to insufficient awareness. Similarly, the use of metformin also influences vitamin B12 levels. The alteration in cobalamin was concomitant with an elevation in serum homocysteine, noted to potentially amplify the risk of cardiovascular disease development in patients with type 2 diabetes mellitus. 5 Furthermore, there has been an increase in the utilization of RO water, a factor that may contribute to a further reduction in the vitamin B12 levels within the population. 6
Methylcobalamin (MeCbl) represents one bioactive form of vitamin B12 capable of directly engaging in homocysteine metabolism. Increasing research demonstrates the advantageous impact of MeCbl on both clinical and experimental peripheral neuropathy. IM injection of vitamin B12 is preferred as it has well defined pharmacokinetics and infrequent maintenance dosing. Nevertheless, the intramuscular route may induce pain and irritation at the injection site leading to patient non-adherence to long-term therapy. 7 The SC administration of methylcobalamin is currently preferred due to its equivalent bioavailability compared to the IM route. SC administration offers faster absorption and the added benefit of self-administration, which surpasses the IM route. 8
Materials and Methods
The methodology involved a comprehensive literature search across PubMed and Google Scholar databases using keywords related to vitamin B12, diabetes, neuropathic pain and administration routes. We incorporated a questionnaire-based survey targeting physicians, diabetologists, orthopaedics and neurophysicians. Within our study design, we incorporated inquiries pertaining to the utilization of vitamin B12 injections in patients afflicted with diabetic neuropathic pain, with a specific focus on eliciting feedback regarding their usage. Articles published were screened based on inclusion and exclusion criteria, focusing on comparative studies for SC and IM administration. Methodological quality assessment was performed using appropriate tools and data synthesis involved a narrative approach, summarizing key findings regarding bioequivalence, pharmacokinetics, clinical outcomes and practitioner preferences for SC versus IM administration of vitamin B12 in neuropathic pain management.
Questionnaire based survey analysis among patients with diabetic neuropathic pain
To explore the therapeutic potential of subcutaneous methylcobalamin for diabetic neuropathic pain management, we conducted a survey using a questionnaire to assess awareness levels among physicians, diabetologists, orthopaedics and neurophysicians. The conventional IM administration method is often avoided due to patient-reported injection site discomfort, irritation, the need for frequent clinic visits for administration and patients' time constraints. Conversely, the SC route may offer greater convenience for this patient demographic. The practitioners reached a consensus to prescribe the SC route under the stipulation that its pharmacokinetic profile matches to that of the IM route in all respects. Approximately 50% of healthcare professionals elect to recommend the administration of subcutaneous injections containing vitamin B12 to individuals diagnosed with diabetic neuropathic pain. After thoroughly assessing patients' serum vitamin B12 levels, this targeted approach aims to address deficiencies and improve overall health outcomes, particularly in diabetic neuropathic pain management. Long- term metformin therapy can contribute in development of vitamin B12 deficiency, primarily attributed to its influence on absorption mechanisms. Specifically, metformin is believed to hinder the binding of the calcium-dependent intrinsic factor-vitamin B12 complex to the ileal cubilin receptor by antagonizing the calcium cation. Generally, healthcare providers opted to administer a regimen of five vitamin B12 injections to patients, alternately every other day, aiming to enhance therapeutic outcomes. Patients who received vitamin B12 injections demonstrated an average compliance rate. Numerous factors contribute to suboptimal adherence to vitamin B12 injections, including the necessity for frequent clinic visits, discomfort associated with intramuscular injection, constraints on time for multiple appointments and administrations. 2/3rd of practitioners were aware that vitamin B12 injection can be given via subcutaneous route. A minority of practitioner’s demonstrated awareness regarding trials pertaining to the bioequivalence of vitamin B12 injections administered IM versus SC. The consensus among practitioners indicated that patient compliance rates can be enhanced through the self-administration of vitamin B12 injections using PFS via subcutaneous route.
Discussion
The article presented findings from a questionnaire-based study investigating healthcare practitioners' awareness of the bioequivalence between subcutaneous and intramuscular administration of vitamin B12 for neuropathic pain management. By assessing practitioners' understanding of this equivalence in pharmacokinetic profiles and clinical outcomes, the study aimed to shed light on the prevailing knowledge among healthcare professionals regarding optimal treatment approaches for managing vitamin B12 deficiency.
A study on treatment of vitamin B12 deficiency anemia suggested that cobalamin serves as a crucial cofactor for synthase and mutase enzymes, which play integral roles in maintaining methylation reactions within the brain. Insufficiency of cobalamin can lead to the impairment of myelin synthesis and enhancement of various neurotoxic processes. The classic manifestation of cobalamin deficiency is characterized by macrocytic megaloblastic anemia. 9, 10, 11
A research investigation into the prevalence of vitamin B12 deficiency among the population of North India determined that 47.0% of individuals in this demographic exhibit insufficient levels of vitamin B12 12. Furthermore, a study on vitamin B12 deficiency in metformin-treated type-2 diabetes patients, suggested that out of 121 patients, the prevalence of vitamin B12 deficiency was 29.1% among patients with diabetic neuropathy. 3 Ankar et al. presented that pernicious anemia (vitamin b12 deficiency) arises from an autoimmune response where antibodies target intrinsic factor, inhibiting its function in facilitating vitamin B12 absorption in the terminal ileum. Gastric bypass surgery poses a risk for B12 deficiency due to the altered route bypassing intrinsic factor production by parietal cells. Damage to the terminal ileum, as seen in Crohn's disease surgical resections, can also impair B12 absorption. Additionally, conditions like celiac disease, Diphyllobothrium latum infection and prolonged vegan diets can lead to B12 deficiency despite adequate liver stores. 13 Green et al. conducted a study investigating the implications of vitamin B12 deficiency, highlighting its potential impact across all age groups. Their findings suggest that individuals, particularly infants, children, adolescents and women of reproductive age have higher susceptibility to vitamin B12 deficiency, especially in regions where dietary access to B12-rich animal-derived foods is limited. 14
A systematic review and meta-analysis on association between neuropathy and B- vitamins by Stein et al revealed that patients diagnosed with peripheral neuropathy demonstrated higher susceptibility for vitamin B12 deficiency. 15 In a study investigating vitamin B12 deficiency among individuals with type 2 diabetes mellitus (T2DM) receiving metformin treatment, it was observed that nearly one-third of patients with a prior diagnosis of T2DM and peripheral neuropathy exhibited signs of vitamin B12 deficiency. 3 Neuropathies frequently stem from evident vitamin B12 deficiency, characterized by low serum B12 levels concurrent with elevated concentrations of B12-dependent metabolites, namely methylmalonic acid (MMA) and/or homocysteine (HCys). 16
Roy et al. suggested that metformin, the primary medication for managing Type 2 diabetes, is effective in controlling glucose levels. However, it can lead to deficiencies in vitamin B12 and folic acid, raising homocysteine levels and potentially causing peripheral neuropathy. Supplementing with vitamin B12 is advisable and monitoring B12 levels annually for long-term users is recommended. 17 A comprehensive study evaluating the respective therapeutic outcomes of vitamin B12 and nortriptyline in the context of alleviating symptomatic painful diabetic neuropathy underscored the superior efficacy of vitamin B12 as compared to nortriptyline. This finding suggests that vitamin B12 may represent a more favourable treatment option for individuals afflicted with painful diabetic neuropathy, highlighting its potential significance in clinical management strategies for this condition. 18
Methylcobalamin, whether utilized independently or in conjunction with other agents, demonstrates notable analgesic potential in various patient cohorts and animal models, including those afflicted with nonspecific low back pain, neck pain, diabetic neuropathic pain, subacute herpetic neuralgia, glossopharyngeal neuralgia and trigeminal neuralgia. Recent investigations suggest several plausible mechanisms: firstly, MeCbl enhances nerve conduction velocity; secondly, it promotes the regeneration of injured nerves, thereby restoring neuromuscular function and mitigating peripheral hyperalgesia (increased pain from a stimulus that usually provokes pain) and allodynia (pain due to a stimulus that does not usually provoke pain); and thirdly, it suppresses ectopic spontaneous discharges originating from peripheral primary sensory neurons during states of neuropathic pain. Given its classification as a vitamin, MeCbl holds promise as a potentially safe therapeutic option for peripheral neuropathy management. 19
A research investigation assessing the efficacy of various routes of vitamin B12 supplementation in treating individuals with vitamin B12 deficiency indicated preference for administration routes. IM delivery emerged as the most favoured and conventional route, followed by sublingual (SL) administration and oral ingestion. Although conventional IM route can be associated with injection site pain. These findings underscore the comparative effectiveness and acceptability of IM, SL and oral routes for vitamin B12 supplementation in the management of vitamin B12 deficiency within clinical practice. 20
A study on sciatic nerve injection injury suggested that nerve injury frequently arises as a consequence of intramuscular injection, with the sciatic nerve emerging as the most frequently affected, notably prevalent among paediatric, geriatric and underweight patients. The spectrum of neurological manifestations encompasses a broad range, extending from minor transient pain to severe sensory disturbances and motor loss, characterized by poor recovery. 21
SC injections offer immediate advantages over both intravenous (IV) and IM injections. They necessitate the use of a smaller needle and injections of volumes up to 1 mL are generally not painful. For patients necessitating multiple doses, SC injections provide a wider array of alternative sites. Furthermore, drug absorption following SC administration is slower compared to IV injections, potentially avoiding the risks associated with bolus administration, such as infusion reactions. SC injections generally exhibit a superior safety profile when compared to IV or IM injections. If an infectious agent is introduced subcutaneously, its effects are usually confined to a local rather than systemic infection. Additionally, unlike the skilled healthcare personnel required for IV and IM injections, SC injections can be self-administered by the patient or a caregiver, thereby facilitating potential at-home administration in certain cases. 22
A study published in the 2023 edition of the IP Indian Journal of Neurosciences compared the bioavailability of methylcobalamin administered via SC injection at a dose of 1500 mcg against IM injection. The research determined that commercially available oral vitamin B12 tablets suffer from restricted bioavailability. The SC injection method exhibited non-inferiority to the IM injection regarding bioavailability, displaying analogous pharmacokinetic characteristics. Safety assessments affirmed the well-tolerated and safe nature of both treatment modalities. 8
Conclusion
The conventional IM administration route of methylcobalamin may pose challenges, as patients often exhibit non-compliance due to pain related discomfort at the injection site. Furthermore, intramuscular injections frequently damage the sciatic nerve. However, this issue can be mitigated by employing subcutaneous PFS of methylcobalamin. Prefilled syringes of methylcobalamin offer a viable option across various patient demographics, including those undergoing prolonged metformin therapy for diabetes, individuals with poor adherence to vitamin B12 supplementation and those recently diagnosed with diabetic neuropathic pain. The convenience of administering PFS at home eliminates the need for frequent clinic visits.
Author Contributions
Dr. Yatri Dave conceptualized, designed, conducted data research and drafted the article. Dr. Keshini Dhande and Dimpal Maurya participated in the review and revision process of the draft article for the journal.
Data Availability
The authors declare that data supporting the findings of this study are available within the article.
Article DOI
