Friday, 13 January 2017

Why Do We Take Extra Vitamin B For Neuropathy?

Today's post from (see link below) is an important one for several reasons, not least of which is how it shows readers how complex medical studies are set up and planned. It also questions the role of Vitamin B (in all its forms) in neuropathy treatment. It is true, wherever you look on the internet, you will see articles blithely recommending vitamin B supplementation as an answer to neuropathy symptoms and this has resulted in patients rushing to health food shops and supermarkets to stock up on vitamin B supplements. The problem is that serious studies into vitamin B supplementation are conspicuous by their absence, although occasionally, you'll see a vague warning not to 'overdose'. The most important lesson from all this is that you should only ever supplement an existing deficiency and how will you know you're deficient in vitamin B unless your doctor tests you for it? 90% of the time, patients look at the disease and wrongly conclude that extra vitamin B is the answer, without finding out the levels in their own bodies. Apart from this; which sort of vitamin B are you going to choose...and why. You'll often see vitamin B12 being recommended; or Bi, B2 etc etc, or combinations of B compounds. You get the picture!
This article refers to a study begun in the middle of last year intended 'to assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.' It also examines the various sorts of vitamin B and explains their purpose. Pretty important don't you think and hopefully it's just the first of many serious studies into supplements and nerve damage. The problem is that when people exhaust all the standard chemical options and the symptoms continue, their next port of call is the supplement industry and its all too voracious marketing campaigns. There's nothing wrong with that, as long as you do your research first and consult your doctor and then stop the supplement if it's having no effect!! Otherwise you're sticking a pin in the ever-growing supplement list and hoping for the best...never the healthiest option...I'm sure you agree.

Vitamin B for treating diabetic peripheral neuropathy
Hanan Khalil, Helen Chambers, Vivian Khalil, Cynthia D Ang

First published: 8 June 2016
Editorial Group: Cochrane Neuromuscular Group
DOI: 10.1002/14651858.CD012237View/save citation
Cited by: 0 articles


This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.

Description of the condition

Peripheral neuropathy is the most common risk factor for foot ulcers in people with diabetes (Duby 2004). More than 80% of all non-traumatic amputations in diabetic patients are the result of foot ulcers (Singh 2005). In 2010, the estimated world prevalence of diabetes was 285 million, a figure expected to rise to 439 million by 2030 (Shaw 2010). Diabetic peripheral neuropathy (DPN) is then expected to affect around 236 million, constituting a major cause of mortality and morbidity, with a significant associated financial cost (Tesfaye 2012). The annual cost of DPN in the United States was estimated to be USD 10.9 billion in 2010 (Gordois 2003; Zhang 2010).

Diabetic neuropathy can be divided into four broad patterns, depending upon which nerves are affected: DPN, proximal neuropathy, autonomic neuropathy, and focal neuropathies (American Diabetes Association 2014; Boulton 2004). Diabetic neuropathy affects long fibres first, including the feet and distal legs. Proximal neuropathy is often asymmetric and may involve the thighs, hips, or buttocks. Autonomic neuropathy can cause dysfunction of the gastrointestinal system, blood vessels, and urinary system, and sexual dysfunction. Focal neuropathies often occur at common sites of nerve compression and affect nerves such as the ulnar and median nerves in the arm, the peroneal nerve in the leg, nerves of the thoracic and lumbar regions, and specific cranial nerves (Boulton 2004).

The American Diabetes Association has defined DPN as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (American Diabetes Association 2014). Symptoms of DPN include numbness or reduced ability to feel pain, muscle weakness, difficulty walking, and serious foot problems (Boulton 1998; Hughes 2002; Huskisson 1974).

No gold standard for diagnosing DPN exists; the history and physical examination are key, as the diagnosis remains clinical (American Diabetes Association 2014). Supportive semi-quantitative testing, such as monofilament testing (using von Frey hairs), nerve conduction studies, electromyography, and quantitative sensory testing, can also be used (Bril 2013). Exclusion of non-diabetic causes should also be undertaken, again through history, examination, and the judicious use of investigations such as serum vitamin B₁₂, thyroid function tests, blood urea nitrogen, and serum creatinine (Perkins 2001).

Early diagnosis and management of DPN are crucial for the prevention of amputations, foot ulcers, and other injuries. Successful diagnosis and management require early screening for high-risk individuals (American Diabetes Association 2014; Khalil 2013a).

Treatment of DPN is multifaceted: components include stable glucose control; regular physical check-ups including foot care; patient education; and specialist care when needed (Callaghan 2012). Pain management includes the use of medications such as, for example, pregabalin, sodium valproate, dextromethorphan, tramadol, opioids and, in some cases, topical capsaicin and lidocaine (Khalil 2013b).

Description of the intervention

The B vitamins comprise eight water-soluble compounds that have essential roles in cell metabolism: vitamin B₁ (thiamine), vitamin B₂ (riboflavin), vitamin B₃ (niacin, niacinamide, or nicotinic acid), vitamin B₅ (pantothenic acid), vitamin B₆ (pyridoxine, pyridoxal, pyridoxamine, or pyridoxine hydrochloride), vitamin B₇ (biotin), vitamin B₉ (folic acid) and vitamin B₁₂ (hydroxycobalamins, cobalamins). Each one of these components has a different physical and chemical structure and completes an essential function in the human body (Chaney 1992; Olson 1996).

Vitamins B₁, B₂, B₃, and biotin are involved in energy production; vitamin B₆ is required for amino acid metabolism. Thiamine is converted to thiamine pyrophosphate which has a role in carbohydrate metabolism. Thiamine pyrophosphate also plays a role in the transmission of nerve impulses. Riboflavin is converted into flavin mononucleotide and flavin adenine dinucleotide that serve as coenzymes for respiratory flavoproteins. The active forms of nicotinic acid are coenzymes for proteins that catalyse oxidation-reduction reactions in tissue respiration (Chaney 1992; van Boxtel 2001).

Vitamin B₆ is converted to pyridoxal phosphate and is involved in the metabolic transformations of amino acids and in the metabolism of sulphur-containing and hydroxyl-amino acids. Pyridoxal phosphate is required for the synthesis of sphingolipids for myelin formation. Vitamin B₁₂ has several congeners: cyanocobalamin, hydroxocobalamin, methylcobalamin, and 5’-deoxyadenosylcobalamin. Vitamin B₁₂ and folic acid facilitate essential steps in cell division (Chaney 1992; Hillman 1996).

Common vitamin B deficiency features include peripheral neuropathy, depression, mental confusion, lack of motor co-ordination, and malaise. Vitamin B deficiencies cause various diseases in humans such as beriberi (thiamine deficiency), pellagra (nicotinamide deficiency), megaloblastic anaemia (folic acid deficiency), and pernicious anaemia (cobalamin deficiency) (De-Regil 2010; Lassi 2013; Rodríguez-Martín 2001). The therapeutic doses for the various forms of vitamin B complex range widely, from 3 μg/day for vitamin B₁₂ to 18 mg/day for vitamin B₃ in adult males (Chaney 1992; Hillman 1996).

How the intervention might work

The mechanisms by which neuropathic pain develops in diabetes are unclear; mechanisms postulated include alteration in peripheral blood flow, increased vascularity, oxidative stress, and autonomic dysfunction (Edwards 2008; Tesfaye 2011). Overall, there is a paucity of evidence on the role of B vitamins in diabetes. Several studies found lower than normal levels of thiamine in people with diabetes, thought to be due to high renal clearance of thiamine and increased albuminuria in diabetes (Thornalley 2005). Moreover, vitamin B₁₂ deficiency has also been observed in patients with diabetes, partially explained by metformin-induced vitamin B₁₂ deficiency, particularly among people on high doses of metformin (Kibirige 2013). Mecobalamin is a derivative of vitamin B₁₂ involved in processes essential to myelin repair (Sun 2005).

Why it is important to do this review

Untreated DPN is not only associated with a significant cost to the health care system, but has a serious impact on a person's quality of life and general health. If left untreated, serious complications such as loss of function and amputations can occur. To date, evidence on the effectiveness and safety of vitamin B supplements for the treatment of DPN as an additional or alternative option to current treatments have not been fully evaluated. This review will address these issues (Rolim 2009).


To assess the effectiveness and safety of vitamin B supplements for the management of pain and nerve damage in people with diabetic peripheral neuropathy.
Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs) and quasi-RCTs (studies that allocate participants to groups by methods that are partially systematic, for example by allocation, case record number or date of birth). We will apply no language limitations. We will include studies completed but not fully reported to reduce the risk of publication bias.

Types of participants

We will include trials of adults, children, or both, with a diagnosis of DPN based on symptoms, abnormal physiological test results, or both. For the purpose of this review, we will use the definitions of diabetes and DPN set by the American Diabetes Association (American Diabetes Association 2014). We will exclude participants with other types of neuropathy. We will exclude people who are vitamin B depleted and taking supplements for replenishment. Participants should not have taken B vitamins in the six months before the start of treatment.

Types of interventions

We will consider trials for inclusion where the intervention is any dose and type of vitamin B supplement (thiamine (B₁), riboflavin (B₂), nicotinic acid (B₃), pyridoxine (B₆), and methylcobalamin, cyanocobalamin, hydroxycobalamin, methylcobalamin, or 5’-deoxyadenosylcobalamin (B₁₂), given by any route, singly or in combination as vitamin B complexes, in comparison to placebo, no treatment, or any comparators for a minimum period of 12 weeks. We will consider trials of vitamin B complexes so long as details of the components are provided.

We will exclude studies using supplements in combination with other vitamins or drugs unless the other vitamins or drugs are administered at the same dose in both intervention and control groups.
Types of outcome measures

Primary outcomes

For painful neuropathy: short-term (three months or less) change in pain intensity, measured as the number of participants with more than a 30% improvement in pain intensity.

For non-painful neuropathy: short-term change in impairment measured by a validated scale, e.g. neuropathy impairment score (NIS) (Dyck 2005).

Secondary outcomes

Long-term (after more than three months) change in pain intensity, measured as the number of participants with more than a 30% improvement in pain.

Long-term (after more than three months) change in impairment measured by a validated scale as for the primary outcome.

3. Change in quality of life measured by a validated scale (e.g. Short-Form 36 Health Survey (SF-36)).

4. Adverse events, reported as all adverse events, adverse events which led to cessation of treatment, and serious adverse events which were life-threatening, fatal, or required or prolonged hospitalisation.
Search methods for identification of studies

Electronic searches

We will identify trials from the Cochrane Neuromuscular Specialized Register, which is maintained by the Information Specialist for the Group. The Information Specialist will search the Cochrane Central Register of Controlled Trials (CENTRAL) (current issue in The Cochrane Library), MEDLINE (January 1966 to current), EMBASE (January 1980 to current), and CINAHL Plus (January 1937 to current). We will adapt the draft MEDLINE strategy in Appendix 1 to search the other databases.

We will also search the US National Institutes of Health Clinical Trials Registry ( and the World Health Organization International Clinical Trials Registry Platform (ICTRP) ( We will search all databases from inception to present.

Searching other resources

We will search reference lists of all primary studies and review articles to identify additional references. We will search relevant manufacturers' websites for trial information. We will search for errata or retractions of included trials.
Data collection and analysis

Selection of studies

Three review authors (HK, CA, and VK) will independently screen titles and abstracts of references from the literature searches and code them as either 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full-text study reports or publications and three review authors (HK, CA and VK) will independently screen the full text and identify studies for inclusion. The review authors will identify and record reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (HC). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table. The review authors will not assess trials in which they are investigators.

Data extraction and management

We will use a data extraction form, which has been piloted on at least one study in the review, for study characteristics and outcome data. Two review authors (VK and HK) will extract study characteristics from included studies.

 We will extract the following study characteristics.

Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.

Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline characteristics, inclusion criteria, and exclusion criteria.

intervention, comparison, concomitant medications, and excluded medications.

Outcomes: primary and secondary outcomes specified and collected, and time points reported.

Notes: funding for trial, and notable conflicts of interest of trial authors.

Two review authors (CA and HK) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if the trial report did not provide usable outcome data. We will resolve disagreements by consensus or by involving a third person (VK). One review author (HK) will transfer data into Review Manager (RevMan 2014). A second author will check the outcome data entries. A second review author (CA) will spot-check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies

Two review authors (HK and CA) will independently assess risk of bias in each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (VK). We will assess the risk of bias according to the following domains.

Random sequence generation.

Allocation concealment.

Blinding of participants and personnel.

Blinding of outcome assessment.

Incomplete outcome data.

Selective outcome reporting.

Other bias.

We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgments across the included studies for each of the domains listed. We will consider blinding separately for different key outcomes (e.g. for unblinded outcome assessment, risk of bias for all-cause mortality may be very different than for a patient-reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the Cochrane review.

Measures of treatment effect

We will analyse dichotomous data as risk ratios and continuous data as mean difference, or standardised mean difference for results across studies with outcomes that are conceptually the same but measured in different ways. We will enter data presented as a scale with a consistent direction of effect. We will combine all the data for the outcomes measures provided that the intervention lasted for 12 weeks or more irrespective of the differences in times at which outcomes are calculated between trials.

We will undertake meta-analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

The unit of analysis is based on the individual participant (unit to be randomised for interventions to be compared), that is the number of observations in the analysis should match the number of individuals randomised (Higgins 2003).

Where multiple trial arms are reported in a single trial, we will include only the arms relevant to this review. If two or more comparisons (e.g. drug A versus drug B versus placebo) are suitable for inclusion in the same meta-analysis we will combine the relevant intervention groups together or relevant control groups together, or both, as appropriate to create a single pair-wise comparison as recommended in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If this is not possible we will follow alternative methods described in the same chapter.

We will consider only first period data from eligible randomised cross-over studies.

Dealing with missing data

We will report drop-out rates in the 'Characteristics of included studies' table and we will use intention-to-treat analysis (Higgins 2011). We plan to contact trial authors for missing data.

Assessment of heterogeneity

We will consider clinical heterogeneity before making a decision whether to pool studies. We will only perform meta-analysis if participants, interventions and comparisons are sufficiently similar. We will use the I² statistic to measure statistical heterogeneity among the trials in each analysis. If we identify substantial unexplained heterogeneity we will report it and explore possible causes by prespecified subgroup analysis. We will use the following thresholds as a rough guide for interpretation of I², as described in Higgins 2011.

0% to 40%: might not be important.

30% to 60%: may represent moderate heterogeneity.

50% to 90%: may represent substantial heterogeneity.

75% to 100%: considerable heterogeneity.
Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases.

Data synthesis

We will use a fixed-effect model in meta-analysis and if heterogeneity is present, compare these results with a those of a random-effects analysis. If the review includes more than one comparison that cannot be included in a single analysis, we will report results for each comparison separately. If the studies have significant heterogeneity and cannot be combined, we will report findings in a narrative form.

We will consider studies of vitamin B complexes as one supplement for the purposes of meta-analysis, taking into account the potential heterogeneity and indirectness of evidence from such analyses when we assess the quality of the evidence.

'Summary of findings' tables

We will create 'Summary of findings' tables using the primary and secondary outcomes. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEproGDT software (GRADEpro 2014). We will justify decisions to downgrade or upgrade the quality of the evidence using footnotes and where necessary we will make comments to aid readers' understanding of the review.
Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.

Types of vitamin B supplement.

Children under 18 and adults.

We will use the primary outcome in subgroup analyses in Review Manager (RevMan 2014).
Sensitivity analysis

We plan to perform the following sensitivity analyses.

Repeat the analysis excluding studies at high risk of bias (from randomisation or blinding of participants).

If there is one or more very large study, repeat the analysis excluding them to determine how much they dominate the results.

Repeat the analysis using a random-effects model if heterogeneity is present.
Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies. Our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.

The authors would like to acknowledge the editorial support from Cochrane Neuromuscular and the Information Specialist (Angela Gunn) who developed the search strategy in collaboration with the review authors.

Some sections of the review are based on Ang 2008 and on a protocol template originally developed by Cochrane Airways and adapted by Cochrane Neuromuscular.

This project was supported by the National Institute for Health Research (NIHR) via Cochrane Infrastructure funding to Cochrane Neuromuscular. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service, or the Department of Health. Cochrane Neuromuscular is also supported by the MRC Centre for Neuromuscular Diseases.

Appendix 1. DRAFT MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 2014="" 4="" october="" to="" week="">
Search Strategy:
1 randomized controlled (397786)
2 controlled clinical (90503)
3 randomized.ab. (293092)
4 placebo.ab. (154196)
5 drug therapy.fs. (1777958)
6 randomly.ab. (205733)
7 trial.ab. (305213)
8 groups.ab. (1307610)
9 or/1-8 (3350308)
10 exp animals/ not (4082107)
11 9 not 10 (2854354)
12 exp Diabetes Mellitus/ (328635)
13 diabet$.mp. (462274)
14 12 or 13 (463642)
15 exp Peripheral Nervous System Diseases/ (119617)
16 15 or (neuropath$ or polyneuropath$).mp. (182081)
17 14 and 16 (20728)
18 Diabetic Neuropathies/ (12459)
19 17 or 18 (20728)
20 exp Vitamin B Complex/tu [Therapeutic Use] (23726)
21 (aminonicotinamide or cobamide$1 or cyanocobalamin or flavin mononucleutide or flavin adenine dinucleotide or fursultiamin or hydroxycobalamin or hydroxocobalamine).mp. (7678)
22 (methylcobalamin or nicorandil or nicotinic acid or nikethamide or pyridoxal or pyridoxamine or pyridoxine or riboflavin or thiamine or vitamin b complex).mp. (54422)
23 or/20-22 (74266)
24 11 and 19 and 23 (203)
25 remove duplicates from 24 (199)
Contributions of authors
HK drafted the protocol. All the other authors provided feedback on it.
Declarations of interest
None known.
Sources of support
Internal sources

None, Other.
External sources

No sources of support supplied

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