{"paper_id":"37ba6f15-bfd7-4031-813d-4b9a5207d2ce","body_text":"Vitamin D for painful diabetic neuropathy: a systematic review and meta-analysis of randomised controlled trials | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return\"[object Function]\"==o.call(a)}function e(a){return\"string\"==typeof a}function f(){}function g(a){return!a||\"loaded\"==a||\"complete\"==a||\"uninitialized\"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){(\"c\"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){\"img\"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),\"object\"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height=\"0\",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),\"img\"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||\"j\",e(a)?i(\"c\"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName(\"script\")[0],o={}.toString,p=[],q=0,r=\"MozAppearance\"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&\"[object Opera]\"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?\"object\":l?\"script\":\"img\",v=l?\"script\":u,w=Array.isArray||function(a){return\"[object Array]\"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split(\"!\"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split(\"=\"),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(\".\").pop().split(\"?\").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split(\"/\").pop().split(\"?\")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&\"css\"==i.url.split(\".\").pop().split(\"?\").shift()?\"c\":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Vitamin D for painful diabetic neuropathy: a systematic review and meta-analysis of randomised controlled trials Abraham Gilbody , View ORCID Profile Joseph Gilbody doi: https://doi.org/10.1101/2025.03.10.25323653 Abraham Gilbody 1 Foundation Year Doctor, North Bristol NHS Trust : Bristol, England, UK BSc MBBS Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: joe.gilbody{at}bristol.ac.uk Joseph Gilbody 2 Senior Research Assistant in Epidemiology, MRC Integrative Epidemiology Unit, University of Bristol , Bristol, UK BSc MSc PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joseph Gilbody For correspondence: joe.gilbody{at}bristol.ac.uk Abstract Full Text Info/History Metrics Data/Code Preview PDF ABSTRACT Background Diabetes mellitus contributes increasingly to the Global Burden of Disease [GBD]; particularly in high and increasingly in low-and middle-income countries. Strategies to prevent and mitigate the impact are a public health priority. Painful diabetic neuropathy (PDN) is a syndrome of sensory disorders caused by both type 1 and type 2 diabetes mellitus. Available treatments include antidepressant medications and strong analgesics. These are often only partly effective and associated with significant side effect profiles. There is a need for effective treatments with low toxicity. Vitamin D has been proposed as potential therapeutic and biologically plausible agent. Non-randomised studies demonstrate benefit, but are subject to biases. There is a need for robust evidence derived from randomised data to inform patient care in this debilitating complication of diabetes. Review aim To synthesise randomised controlled trials (RCTs) of Vitamin D supplementation and its effects on painful diabetic neuropathy. Review methods A range of databases [Medline, EMBASE, Web of Science, Cochrane Library, CINHAL, EBSCO and Google Scholar] were searched from inception to March 2025, with backwards and forward citation searches to identify eligible studies. RCTs comparing Vitamin D with placebo in patients with diabetes [type 1 or 2] and PDN were sought. The primary outcome was pain as measured using a validated pain measure or measure of PDN. A fixed effects meta-analysis of continuous pain data was conducted, with standardisation between studies to calculate a standardised mean difference [SMD] between Vitamin D and placebo. Small study and publication bias was tested using an Egger plot, and study quality was assessed using the Cochrane Risk of Bias [RoB] tool. Results Four eligible studies were identified and three of these studies [comprising 260 participants] provided meta-analysable data. There was a statistically significant short-term benefit for vitamin D (pooled standardised mean difference =-0.70; 95%CI-0.95 to-0.45). There was moderate between study heterogeneity, and there was an intermediate level of heterogeneity (I = 54.9%). No studies reported medium-or long-term outcomes. The quality of studies was variable (either low or moderate risk of bias), with poor concealment of allocation as the most important design limitation. Two of the studies had been prospectively registered, making it difficult to check for bias in one study due to potential selective reporting of outcomes. Despite conducting an Egger Funnel Plot, it was not possible to exclude the influence of small study and selective publication bias. Discussion Based on a meta-analysis of non-registered small size studies there was evidence of short-term reduction in pain symptoms in painful diabetic neuropathy. This benefit needs to be confirmed in fully powered RCTs with a longer duration of follow up. Vitamin D remains a viable low-cost treatment option for PDN, but more research is needed before this can confidently be recommended for routine patient care. INTRODUCTION Painful diabetic neuropathy (PDN) is a syndrome of sensory disorders caused by both type 1 and type 2 diabetes mellitus. PDN is known to be not only one of the most common diabetic peripheral neuropathies, but is also detrimental to the overall health of people with diabetes [ 1 ]. PDN is characterised by distressing tingling, burning, sharp, shooting, and lancinating or even as electric shock sensations [ 2 ], with nocturnal exacerbation and impacts on sleep. PDN also contributes to diabetic foot disease by causing poorly-healing ulcers and eventual amputation [ 3 ]. This contributes to reduced physical activity, depression, and decline in quality of life (QOL) [ 4 ]. Epidemiological data demonstrates that the incidence of pain symptoms in diabetes is 10-20% and 40-50% with diabetic neuropathy [ 5 ]. PDN also contributes to higher rates of healthcare utilisation and costs [ 6 ]. Patients with PDN have increased costs due to more frequent and prolonged hospitalizations and increased rates of outpatients visits, coupled with reduced economic productivity and sickness absence [ 6 ]. Treatment of PDN comprises three approaches: (1) intensive glycaemic control and risk factor management, (2) treatments based on pathogenetic mechanisms, and (3) symptomatic pain management [ 7 ]. Intense glucose control is currently the only intervention that has been proven to reduce the risk of development of neuropathy [ 8 , 9 ]. Peripheral nerve injury is largely understood as the main source of pain, however recent literature supports the role the central nervous system in the disinhibition and amplification of pain [ 10 ]. Consequently, clinical guidelines recommend symptomatic relief of neuropathic pain through the ‘centrally acting’ analgesic effects of antidepressant drugs (tricyclic antidepressants or selective serotonin reuptake inhibitors), anticonvulsants, and opioids [ 11 ]. Treatment of PDN is far from satisfactory with many medications providing limited pain relief with a significant side effect profile [ 7 ]. Another treatment modality is emerging is the use of Vitamin D which will be the focus of this systematic review, and meta-analysis. Vitamin D deficiency been shown to be an independent risk factor for the development of PDN [ 12 ]. Vitamin D has also been shown in some studies to have a significant influence in PDN compared to painless DPN [ 13 ]. Furthermore, non-randomised evidence shows that high-dose intramuscular injections of vitamin D can reduce pain [ 14 ]. This all presents the biologically-plausible mechanism that the correction of low vitamin D might in turn have therapeutic benefit in PDN. However definitive evidence will only emerge from robust controlled clinical studies. Research intelligence is needed to establish whether vitamin D therapy treats or delays the onset of symptoms in painful diabetic neuropathy. REVIEW AIM The overarching aim of this systematic review was to synthesise data from randomised controlled trials of Vitamin D supplementation and its effects on painful diabetic neuropathy. By using systematic review methods, a supplementary aim was to map the strengths and limitations of existing available research, and to make recommendations for clinical practice and identify the need for further research. REVIEW METHODS The systematic review was undertaken in march 2025 in accordance with the Methods of the Cochrane Handbook for Systematic Reviews [ 15 ], and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRiSMA) guidelines [ 16 ]. Search strategy A search strategy was devised to identify relevant studies from the following electronic databases: Medline, EMBASE, Web of Science, Cochrane Library, CINHAL, EBSCO and Google Scholar. These databases were selected, as recommended by the Cochrane Handbook, as MEDLINE, Cochrane Central and Embase are effective in identifying randomized controlled trials [ 15 ]. The additional databases facilitates a wider and more extensive search of sources thus minimizing selection bias for the studies [ 15 ]. Search terms were devised from the PICO structure [described below] such as ((diabetic AND neuropathy AND painful AND (“25(OH) D” OR “25-Hydroxyvitamin D” OR “vitamin d”)). The search utilized optimal Cochrane strategies to identify randomized controlled studies [ 17 ], whilst excluding non-randomised data (a sensitive and specific search). Resources were only available for English language publication, therefore the search was restricted. In addition to the electronic bibliographic searches, reference lists from included papers were scrutinised to identify additional studies [‘backwards citation searching’]. Additional studies citing included studies were also sought using Google Scholar [‘forward citation searching’] [ 18 ]. Criteria for study selection Only randomised controlled trials (RCTs) were considered as they are considered the gold standard design for studying cause-effect relationships between an intervention and outcome. Randomization is the optimum design in eliminating much of the bias inherent with other study designs, and [most importantly] minimises the distortion of cause-effect from both known and unknown confounding factors [ 19 ]. Non-randomised controlled studies, reviews and case-series were excluded. Potentially eligible studies were assessed for inclusion against the PICO criteria for inclusion in the systematic review are summarised in table 1 . View this table: View inline View popup Download powerpoint Table 1: study inclusion criteria for systematic review Data collection and extraction Relevant data were first extracted into a spreadsheet. Relevant data were: the mean pain scores, % change in pain score, Dosage and type of Vitamin D supplementation used, standard deviations, sample sizes and patient gender in both intervention and control groups. Study authors were contacted to provide missing data. Quality assessment of trials As per the Cochrane Handbook (21), trials were assessed on quality based on 3 main parameters (greater detail in appendix 1): Randomisation (Allocation sequence generation and allocation sequence concealment present) Blinding (Double blinding, Effective blinding, Bias due to measurement of outcomes, Bias due to missing outcome data) Attrition bias (Loss to follow up, correct analysis preformed) Each parameter underwent a risk-of-bias judgement and was assigned to 3 groups: ‒ Low risk-of-bias ‒ Moderate risk-of-bias ‒ High risk-of-bias The overall judgement of bias was based on the collection of ratings. Quality assessed data were plotted into the risk of bias (RoB) tool found on Revman5 [see table 2 ]. This presented the overall judgement of risk of bias using an infographic. The GRADE tool was used to assess the quality of the data from each study using several domains. Study quality was marked down for: Risk of bias, Imprecision, Inconsistency, Indirectness and Publication bias. Marked up for: Magnitude of effect, Dose-dependent gradient and all residual confounding would decrease magnitude of effect The criteria for Cochrane for randomisation [Cochrane Handbook for Systematic Reviews of Interventions 4.2.5(21)] are reproduced in appendix 1. View this table: View inline View popup Download powerpoint Table 2: Overall risk-of-bias judgement criteria Small study, publication and outcome reporting bias A range of databases were searched to minimise study identification and selection biases. Publication bias arises through the inclusion of only published studies, and the potential omission of negative studies since these are often unpublished [ 15 ]. A funnel plot analysis was planned to detect if authors publish smaller studies with positive results [ 15 ]. This is commonly found among studies which are smaller in size which are typically performed with reduced methodological rigor producing an overestimation of the intervention effect [ 15 ]. An asymmetrical funnel plot indicates that smaller studies were subject to publication and small study bias. The greater the asymmetry the increased likelihood that the amount of bias will be substantial. To quantify the magnitude of funnel plot asymmetry, an Egger test was planned [ 22 ]. Selective reporting of outcome bias was addressed (where possible) by comparing the outcomes described in the study trial register or pre-study protocol with the range of outcomes reported in the final study publication [ 23 ]. Proposed meta-analysis In line with Cochrane guidance, where similar [non-heterogenous] data were available for three or more studies, then a fixed effects meta-analysis was undertaken using RevMan 5 software [ 24 ]. It was anticipated that the primary pain outcome would be presented as a continuous variable of change in pain scores in both control and intervention groups. Endpoint data in each group were combined to calculate between-group differences. Where trials used different instruments to measure the pain outcomes a standardized mean difference (SMD) with 95% confidence intervals was calculated. The standardised mean difference measures the size of the intervention effect of each study compared to the between-participant variability in outcome measurements recorded in each individual study. To allow for easier interpretation and analysis of the results, we planned to convert the SMD into the specific clinical measures used in the studies (such as the McGill Pain Questionnaire, or the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale). This can be done by multiplying the SMD by an estimate of the standard deviation (SD) associated with the outcome measure instrument, according to the Cochrane Handbook. Assessment of heterogeneity Heterogeneity was tested using Higgins’ test (I) to test for between-study variation in order to determine if studies can be pooled for meta-analysis [ 25 ]. If <75% use fixed effects If more than 75% use random effects If more than 90% just use systematic narrative review (no meta-analysis undertaken) Where significant heterogeneity was found, sources of heterogeneity were explored. Anticipated source of heterogeneity included: dose and route of Vitamin D; baseline Vitamin D status of participants, duration of follow up. RESULTS Study selection The selection process of summarised using the PRISMA flow diagram ( figure 1 ). The literature search identified a total of 73 potentially eligible studies. After removal of duplicates, 63 papers were included in the initial screening procedure. Electronic titles and abstracts of papers from the search were first screened for eligibility. Following the removal of 12 papers, the remaining papers were screened on their full text against PICO criteria detailed below. Where the full text was not available study corresponding author was contacted via email. In 4 papers were found the be eligible for use in the systematic review [ 26 – 29 ] and three provided sufficient data for the meta-analysis [ 26 ] [ 27 , 28 ]. Common reasons for exclusion included: inappropriate outcome measurements, lack of comparator groups and inappropriate study design (non-randomised). Download figure Open in new tab Figure 1: PRISMA flow diagram Three studies that were randomised and met the PICO inclusion criteria [ 26 ] [ 27 , 28 ] were eligible for inclusion into the meta-analysis. One study was a five-arm trial, and two arms provided data that allowed a comparison between Vitamin D and placebo. Study size ranged from 68 to 112 and 260 participants were eligible for meta-analytic pooling. The weighting of each paper in the meta-analysis was proportional to their respective participant totals (and inversely related to the variance). Each study reported a different pain scales, with the visual analogue scale [ 28 ], the NSS [ 26 ] and using the Neuropathic pain scale (NPS) [ 27 ]. Each study recruited patients who were Vitamin D deficient at baseline, with placebo arm levels ranging from 11.68 ng/mL (SD 3.8) to 24.6 ng/mL (SD 5.5) [ 27 ]. Vitamin D was administered orally in all cases, and dose regimens ranged from 4,000 IU per day to 50,000 IU over two weeks. Duration of follow up ranged from 8 weeks [ 28 ] [ 26 ] to 12 weeks [ 27 ]. For PICO and study details see table 3 . View this table: View inline View popup TABLE 3: DATA EXTRACTED FOR STUDIES MEETING PICO INCLUDING CRITERIA With respect to study quality, all studies were rated using the GRADE criteria to assess for overall risk-of-bias. One study [ 26 ] maintained an over-all low risk of bias by adhering to stringent experimental techniques to minimise bias. Two studies ([ 27 ] [ 28 ]) were moderate risk-of-bias due to omitting key techniques such as concealment of allocation and effective double blinding. It is not clear what the impact this limitation may have on the observed effect sizes, however sub-par allocation concealment is generally associated with the exaggerated inflation of an effect relative to the true effect [ 30 ]. For full summary of quality assessment criteria see table 4 and summary of Cochrane Risk of Bias see figure 2 [below]. Download figure Open in new tab Figure 2: Cochrane risk of bias assessment View this table: View inline View popup TABLE 4: Quality Assessment of studies using Cochrane Risk of Bias tool Meta-analysis A fixed effects meta-analysis was performed using RevMan 5. All studies were positive [favouring vitamin D] irrespective of choice of outcome measure (Neuropathic Pain Severity (NPS), Neuropathy Symptom Score (NSS), Visual Analogue Scale (VAS)). Standard effect sizes ranged from SMD =-1.03 (95%CI-1.50 to-0.57) [ 27 ] to SMD =-0.32 (95%CI-0.79 to 0.16) [ 28 ]. The overall pooled effect size was strongly in favour of Vitamin D supplementation (pooled standard effect size =-0.70; 95%CI - 0.95 to-0.45). There was low to moderate between study heterogeneity (Higgins I = 54.9%). See figure 3 . Download figure Open in new tab Figure 3: Forest plot of a fixed effect meta-analysis of the effect of Vitamin D on short term outcomes. The standard effect size of-0.70 was moderate in size, and equivalent to 9.6 (95%CI 13.0 to 6.2) points on the Neuropathic Pain Scale [assuming SD of 13.7, derived from the placebo arm baseline data]. Test for small study bias There were three eligible studies, with little variation in sample size, making the Egger forest plot difficult to interpret. The effect of publication and small study bias was therefore difficult to exclude. See figure 4 for Funnel plot. The Egger test was not performed. Download figure Open in new tab Figure 4: Funnel plot to test for small study bias among included studies Selective reporting bias Two studies were pre-registered and the reported pain outcomes in the final manuscript corresponded with the study protocol [ 27 , 28 ]. One study was unregistered and there was no available public domain protocol [ 26 ]. DISCUSSION Summary of main results Randomised trials were available to answer the main review question. Three small scale trials showed a reduction in the painful symptoms of peripheral diabetic neuropathy, regardless of the pain outcome used. When the data were pooled, the meta-analysis results demonstrated a significant statistical improvement in reported neuropathic pain by participants. This strongly favours Vitamin D supplementation for the reduction in painful symptoms of diabetic neuropathy compared to control treatment in all trials. Agreements and disagreements with other studies or reviews The review findings are consistent with previous non-experimental studies that have reported Vitamin D as an independent risk factor in peripheral neuropathy in patients with low vitamin D [ 12 ]. Non-randomised studies have established that correction of vitamin D deficiency leads to an improvement in symptoms [ 31 ], and this is the first time this has been demonstrated in the context of a meta-analysis of RCT data. It is however difficult to establish if the effects of vitamin D supplementation were due to an elevation in the pain threshold, due to improvement of affected nerves, or via improvement in diabetic markers (HbA1c) or a synergy of them all [ 31 – 33 ]. There are plausible biological mechanisms by which this reduction in pain can be explained. Vitamin D is a potent inducer of neurotrophins and neurotransmitters, nerve growth factor (NGF) is such an example [ 32 ]. Vitamin D supplementation has been shown to increase nerve growth factor (NGF), a protein required for nerve growth and maintenance in the peripheral nervous system [ 32 ]. Epidermal keratinocytes are the primary source of NGF in the skin, lower dermal levels of NGF in patients with diabetic polyneuropathy is associated with neuropathic signs of sensor and autonomic nerve function. This suggests that the diminished levels of NGF in epidermal keratinocytes contribute to the pathogenesis of peripheral neuropathy [ 32 ]. Furthermore there is a suggested mechanistic association between neuropathic pain and vitamin D through nociceptive calcitonin gene associated peptide (CGRP)-positive neurons which have been shown to have a distinct vitamin D phenotype alongside hormonally controlled receptor and ligand levels [ 28 , 34 ]. Applicability of evidence Correcting vitamin D levels in patients where there is deficiency is already clinically indicated. However, the observed effects in this preliminary meta-analysis demonstrate the potential added benefit of reduction in painful symptoms of PDN. On top of this, correction of Vitamin D levels is a comparatively low-risk intervention that has also been related to lowering HbA1c levels, reducing insulin resistance and improvement in insulin sensitivity [ 33 , 35 ]. Therefore, there is the potential for Vitamin D to not only relieve painful symptoms but also improve glycaemic regulation. Reduction in pain severity and pain disability has many benefits including an improvement in QOL of patients through better outcomes in sleep quality, general activity and mood symptoms [ 36 ]. Individuals with reduced pain severity are less likely to use incur healthcare costs through the use of polypharmacy and increased outpatient visits along with increased economic productivity [ 6 , 36 ]. The widespread use of vitamin D as a adjuvant medication in the control of the symptoms of PDN could therefore be useful in mitigating the high economic and healthcare burden associated with diabetic complications [ 37 ]. Of note is that all three of the studies recruited participants who reported a baseline vitamin D deficiency. This remains highly applicable to many patients with painful diabetic neuropathy since Vitamin D deficiency is commonly observed across diabetic populations with one study finding 89% of participants were found to be deficient in Vitamin D with just 9 in 300 participants having sufficient levels of vitamin D [ 38 ]. One potential limitation to the findings is the specificity of the results to those patients with an underlying vitamin D deficiency with the outcome effects being as a result of correcting this pre-existing deficiency. This provides limitations to the applicability of these results to non-vitamin D deficient patients with PDN. It is difficult to make firm conclusions for the applicability of this evidence. However, one important clinical implication is the need for patients with PDN to be routinely tested for vitamin D levels, and to have a low threshold for prescribing Vitamin D for patients at risk of deficiency. Furthermore, the indicated pharmaceutical benefits of vitamin D are significant due to its many perceived advantages over traditional pharmaceutical treatment for diabetic neuropathy. Vitamin D is a relatively low cost, meaning it could be a useful adjunct to existing treatments. With the potential to demonstrate likely cost effectiveness by offsetting the need for prescriptions of expensive analgesic drugs or fewer iatrogenic side effects of high dose analgesic medicines. According to the NICE treatment pathways for neuropathic pain in adults, vitamin D is not currently recommended due to its limited evidence base [ 39 ]. In light of this review, Vitamin D therapy demonstrated a significant effect that might be useful in the formulation of future guidelines. Quality of the evidence The risk of bias assessment indicated a variation in the overall assessment of each study included. There was moderate to high risk of bias for 2 of the studies for the category describing bias in the blinding process. This was typically because of suboptimal blinding process or only single blinding occurring. In the domain bias due to missing outcome data, most studies were found to have a low risk of bias. However, one study was found to have a moderate risk of bias, this was due to failure to perform intention to treat analysis. The impact of the missing data on the observed effects of this study was unclear. In the final domain, bias in the selection of the reported outcome, most papers papers were reported as having a low risk of bias however in one there was an absence of a pre-registered report of trial details thus making it moderate risk of bias. This makes it difficult to make sure that the reported analysis was consistent with the pre-planned analysis. One limitation of the studies included was the large variation in the prescribed vitamin supplementation ranging from a single weekly oral dose of 50000 IU vitamin D to a daily dose of 5000 IU. Furthermore, analysis was hampered by an overall small sample size (n = 260) over the 3 papers. There is a need to replicate the findings of this review, based on small scale studies, in a large scale randomised controlled trial, with sufficient statistical power. Tests for small study bias using Funnel plots were difficult to interpret, and there is a risk that these results might be overturned by a large-scale trial that is free from publication bias. Implications for research These preliminary results on a relatively small sample size confirm the need for a large fully powered study with a concurrent cost effectiveness analysis to explore whether vitamin D therapy represents good value for money. Mechanisms by which it might demonstrate cost effectiveness include decreased need for polypharmacy, particularly expensive and potentially toxic painkiller medications. This is because the cost of treating diabetic neuropathy is very high and is therefore very important to find the most effective and cost-effective medications [ 6 ]. Future research should centre around whether these results are applicable to patients suffering from PDN who do not have underlying vitamin D deficiency and ascertain whether clinical findings are due to the correction of underlying vitamin D deficiency. Furthermore, future research on the proper dosing in addition to the route and duration of treatment is essential to further explore the efficacy and clinical benefits of the use of Vitamin D supplementation for PDN and effectively help advice policy on the dispensation of the drug. Secondary objectives assessing the effect of vitamin D supplementation on glycaemic control should also be addressed. Declaration of interest & contribution The meta-analysis was carried out by the author Abraham Gilbody. Quality assessment and scrutiny of studies for inclusion was carried out by all authors. Statistical and epidemiological expertise was provided by Dr Joe Gilbody. The authors declare that they have no conflicts of interest, financial support, or grants. We are grateful to Dr Uazman Alam of the University of Liverpool who first interested Dr Abraham Gilbody in this topic as an undergraduate at the University of Liverpool. Data Availability All data produced are available online in this manuscript. View this table: View inline View popup Download powerpoint APPENDIX 1: Criteria for the quality assessment of trials using the Cochrane Risk of Bias tool REFERENCES 1. ↵ Walsh , J. , et al. , Association of diabetic foot ulcer and death in a population-based cohort from the United Kingdom . Diabetic Medicine , 2016 . 33 ( 11 ): p. 1493 – 1498 . 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