Vitamin B for treating peripheral neuropathy (Review)

Transcription

Ang CD, Alviar MJM, Dans AL, Bautista-Velez GGP, Villaruz-Sulit MVC, Tan JJ, Co HU,
Bautista MRM, Roxas AA
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 4
http://www.thecochranelibrary.com
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . .
ABSTRACT . . . . . . . . .
PLAIN LANGUAGE SUMMARY .
BACKGROUND . . . . . . .
OBJECTIVES . . . . . . . .
METHODS . . . . . . . . .
RESULTS . . . . . . . . . .
DISCUSSION . . . . . . . .
AUTHORS’ CONCLUSIONS . .
ACKNOWLEDGEMENTS
. . .
REFERENCES . . . . . . . .
CHARACTERISTICS OF STUDIES
DATA AND ANALYSES . . . . .
ADDITIONAL TABLES . . . . .
APPENDICES . . . . . . . .
WHAT’S NEW . . . . . . . .
HISTORY . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS
DECLARATIONS OF INTEREST .
SOURCES OF SUPPORT . . . .
NOTES . . . . . . . . . . .
INDEX TERMS
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i
[Intervention Review]
Vitamin B for treating peripheral neuropathy
Cynthia D Ang1 , Maria Jenelyn M Alviar2 , Antonio L Dans3 , Gwyneth Giselle P Bautista-Velez4 , Maria Vanessa C Villaruz-Sulit5 ,
Jennifer J Tan6 , Homer U Co7 , Maria Rhida M Bautista8 , Artemio A Roxas9
1 Department of Rehabilitation Medicine, University of the Philippines - College of Medicine and Philippine General Hospital,
Manila, Philippines. 2 Department of Rehabilitation Medicine, Philippine General Hospital, Manila, Philippines. 3 Section of Adult
Medicine, College of Medicine, University of the Philippines, Ermita, Philippines. 4 Section of Allergy and Immunology, Department
of Medicine, University of the Philippines - College of Medicine and Philippine General Hospital, Quezon City, Philippines. 5 Section
of Adult Medicine, Department of Medicine, University of the Philippines - College of Medicine and Philippine General Hospital,
Ermita, Manila, Philippines. 6 Department of Internal Medicine, Harlem Medical Center, New York, New York, USA. 7 Department of
Medicine, University of the Philippines - College of Medicine and Philippine General Hospital, Ermita, Manila, Philippines. 8 Junior
Medical Staff Unit, Royal North Shore Hospital, St Leonards, Australia. 9 Department of Neurosciences, University of the Philippines
- College of Medicine and Philippine General Hospital, Pasig City, Philippines
Contact address: Cynthia D Ang, Department of Rehabilitation Medicine, University of the Philippines - College of Medicine and
Philippine General Hospital, Taft Avenue, Ermita, Manila, 1000, Philippines. [email protected].
Editorial group: Cochrane Neuromuscular Disease Group.
Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008.
Review content assessed as up-to-date: 31 August 2005.
Citation: Ang CD, Alviar MJM, Dans AL, Bautista-Velez GGP, Villaruz-Sulit MVC, Tan JJ, Co HU, Bautista MRM, Roxas AA.
Vitamin B for treating peripheral neuropathy. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD004573. DOI:
10.1002/14651858.CD004573.pub3.
ABSTRACT
Background
Vitamin B is frequently used for treating peripheral neuropathy but its efficacy is not clear.
Objectives
The objective of this review was to assess the effects of vitamin B for treating generalised peripheral neuropathy.
Search methods
We searched the Cochrane Neuromuscular Disease Group Trials Register (searched August 2005), MEDLINE (January 1966 to
September 2005), EMBASE (January 1980 to September 2005), Philippine databases (searched September 2005) and reference lists
of articles. We also contacted manufacturers and researchers in the field.
Selection criteria
Randomised and quasi-randomised trials where vitamin B was compared with placebo or another treatment in generalised peripheral
neuropathy.
Data collection and analysis
Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information.
1
Main results
Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included. In the comparison of vitamin B with
placebo, two small trials showed no significant short-term benefit in pain intensity while one of the trials showed a small significant
benefit in vibration detection from oral benfotiamine, a derivative of thiamine. In the larger of two trials comparing different doses of
vitamin B complex, there was some evidence that higher doses resulted in a significant short-term reduction in pain and improvement
in paraesthesiae, in a composite outcome combining pain, temperature and vibration, and in a composite outcome combining pain,
numbness and paraesthesiae. There was some evidence that vitamin B is less efficacious than alpha-lipoic acid, cilostazol or cytidine
triphosphate in the short-term improvement of clinical and nerve conduction study outcomes but the trials were small. There were few
minor adverse effects reported.
Authors’ conclusions
There are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is
insufficient to determine whether vitamin B is beneficial or harmful. One small trial in alcoholic peripheral neuropathy reported slightly
greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo. In another small study, a
higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs. Vitamin
B administered by various routes for two to eight weeks was less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate
in short-term improvement of clinical and nerve conduction study outcomes. Vitamin B is generally well-tolerated.
PLAIN LANGUAGE SUMMARY
Vitamin B for treating disorders of the peripheral nerves
Peripheral neuropathy is a disorder of the peripheral nerves resulting from different causes, such as diabetes mellitus and alcoholism,
leading to pain, numbness or weakness of the limbs and other problems. Vitamin B is commonly used to treat peripheral neuropathy
but it is not clear if it helps. This review of 13 trials on diabetic and alcoholic peripheral neuropathy with a total of 741 participants
showed only one study that suggested possible short-term benefit from eight-week treatment with benfotiamine (a derivative of vitamin
B1) with slightly greater improvement in vibration perception threshold compared to placebo. Vitamin B complex when given in a
higher dose administered for four weeks was more efficacious than a lower dose in reducing pain and other clinical problems based
on another study. Two to eight weeks of treatment with vitamin B was less efficacious than alpha-lipoic acid, cilostazol or cytidine
triphosphate in short-term improvement of clinical and nerve test findings. All these findings require confirmation in larger studies
before they can be accepted as definite. Vitamin B is generally well-tolerated with only a few reports of mild side effects.
BACKGROUND
The term ’peripheral neuropathy’ has been used to cover any disorder of the peripheral nervous system which may affect the sensory, motor or autonomic functions but this review focused on
generalised peripheral neuropathies. The prevalence is estimated
at 2400 per 100,000, increasing with age to 8000 per 100,000
(Hughes 2002). The common causes are diabetes, alcohol, human immunodeficiency virus infection, and, in some parts of the
world, leprosy.
The availability and affordability of vitamin B complex makes this
drug a frequent choice for treating peripheral neuropathy. Strong
evidence in the literature on the efficacy of vitamin B complex,
however, is lacking. The vitamin B complex is a group of water-
soluble compounds that differ in chemical structure and biological action. Traditionally, the vitamin B complex includes: thiamine (vitamin B1), riboflavin (vitamin B2), nicotinic acid (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6),
biotin (vitamin B7), folic acid (vitamin B9), cyanocobalamin (vitamin B12), para-aminobenzoic acid, inositol, and choline (Marcus
1996).
Some vitamin B compounds have derivatives. Benfotiamine is a
lipid-soluble derivative of vitamin B1 which is better absorbed after oral administration than the water-soluble thiamine salts resulting in higher levels of the active compound in blood and tissues
(Stracke 1996). Vitamin B12 has several congeners: cyanocobal-
2
amin, hydroxocobalamin, methylcobalamin, and 5’-deoxyadenosylcobalamin. The latter two are active co-enzymes. Vitamin B12
preparations for therapeutic use contain either cyanocobalamin or
hydroxocobalamin as these are the only derivatives that remain
active after storage (Kaushansky 2006). It is not clear whether vitamin B derivatives or congeners exert different therapeutic effects
from their parent compounds.
The vitamin B complex functions as coenzymes in several intermediary metabolic pathways for energy generation and blood cell
formation which cannot be explained simply. Thiamine is converted to thiamine pyrophosphate that functions in carbohydrate
metabolism as a coenzyme in the decarboxylation of alpha-keto
acids and alpha-ketoglutarate and in the utilisation of pentose in
the hexose monophosphate shunt. Thiamine pyrophosphate appears to play 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. Nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, the active forms of nicotinic acid,
are coenzymes for proteins that catalyse oxidation-reduction reactions in tissue respiration. Pyridoxine, pyridoxamine, and pyridoxal are converted to pyridoxal phosphate that is involved in the
metabolic transformations of amino acids and in the metabolism
of sulfur-containing and hydroxyl-amino acids. Pyridoxal phosphate is required for the synthesis of sphingolipids for myelin formation as well. Cobalamin is converted to methylcobalamin and
5-deoxyadenosylcobalamin which are vital in cell growth and replication. Folic acid is converted to several coenzymes essential in
cellular metabolism, including the synthesis of some deoxyribose
nucleic acid components and normal red blood cell formation.
Vitamin B plays a vital role in energy metabolism. Nerve tissue
may be affected in deficiency states due to its “high-energy demand
or specific effects of the vitamin” (Chaney 1992). Common deficiency features include peripheral neuropathy, depression, mental
confusion, lack of motor co-ordination, and malaise. Specific vitamin B deficiency diseases in humans include beriberi (thiamine),
pellagra (nicotinamide), megaloblastic anaemia (folic acid), and
pernicious anaemia (cobalamin). The required daily intakes of B
vitamins for a normal adult are as follows: thiamine 1.0 to 1.5 mg,
riboflavin 1.2 to 1.7 mg, pyridoxine 1.4 to 2.0 mg, niacin 13 to
19 niacin equivalents (Chaney 1992); cobalamin 3 to 5 mg and
folic acid 50 mg (Hillman 1996). Higher doses of vitamin B are
recommended for the treatment of certain deficiency states with
neuropathy such as: 40 mg oral thiamine per day for thiamine deficiency, 10 to 20 mg pyridoxine per day for peripheral neuropathy
induced by isoniazid (Olson 1996).
While the indications for some members of the vitamin B complex
for certain conditions such as thiamine for the treatment of Wernicke’s encephalopathy (RodriguezMartin 2002), and folic acid for
the treatment of folic acid deficiency anaemia (Mahomed 2002)
and the prevention of neural tube defects (Lumley 2001) are well
established, their role in the treatment of peripheral neuropathies
has not been well documented.
OBJECTIVES
Our objective was to review systematically the evidence from randomised controlled trials (RCTs) and quasi-randomised trials for
the efficacy of vitamin B for treating generalised peripheral neuropathy.
METHODS
Criteria for considering studies for this review
Types of studies
We included randomised and quasi-randomised studies in which
vitamin B was compared with placebo, another treatment, or no
treatment.
Types of participants
We included studies on all participants with generalised peripheral
neuropathy diagnosed on the basis of symptoms and impairments
or symptoms and abnormal neurophysiological results. Diagnosis
based on symptoms alone, impairments alone or abnormal neurophysiological results alone was not sufficient. Symptoms included
subjective complaints of pain, tingling, numbness, weakness, and
autonomic symptoms. Impairments were measured on neurological examination by testing sensory loss, weakness, decreased reflexes, decreased vibration perception, and abnormal autonomic
functions, or detected on nerve conduction studies.
Types of interventions
We included studies on vitamin B containing thiamine, riboflavin,
nicotinic acid, pyridoxine, or cobalamin (or their derivatives),
singly or in combination, given in any dose, by any route, for at
least two weeks. We included studies on folic acid only if it was a
part of a combined preparation containing other vitamin B compounds.
Types of outcome measures
Changes and number of events occurring over time were re-scaled
to ’change or number of events in a fixed period,’ eg three months,
to permit pooling of studies with differing follow up periods.
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Primary outcomes
Other search strategies
The primary outcome measure was short-term (three months or
less) change. For painful neuropathy, the primary outcome was
change in pain intensity measured with a validated scale such as the
visual analogue scale (Huskisson 1974). For non-painful neuropathy, the primary outcome was change in impairment measured by
a validated scale such as the neuropathy impairment score (Dyck
2005).
We reviewed the reference lists of articles identified. We contacted
the study authors, known experts in the field, and pharmaceutical
companies to identify additional published or unpublished data.
We handsearched Philippine journals and conference proceedings
for additional trials Appendix 4.
Data collection and analysis
Secondary outcomes
(1) Long-term (after more than three months) change in pain
intensity or impairment measured as for the primary outcome.
(2) Short-term and long-term (defined as above) change in neuropathic symptoms measured by a validated scale (Dyck 2005).
(3) Short-term and long-term (defined as above) change in nerve
conduction study (NCS) parameters:
(a) peak latency of sensory nerve action potential (SNAP) of the
median and sural nerves,
(b) SNAP amplitude of the median and sural nerves,
(c) sensory nerve conduction velocity (NCV) of the median and
sural nerves,
(d) distal latency of compound motor action potential (CMAP)
of the median and common peroneal nerves,
(e) CMAP amplitude of the median and common peroneal nerves,
(f ) motor NCV of the median and common peroneal nerves.
If the data on the common peroneal nerve were not available, the
data on another lower extremity motor nerve were used.
(4) Serious adverse events as a result of treatment within three
months and after three months. Serious adverse events are those
which are life threatening, prolong or require hospitalisations, or
lead to death.
Two authors independently reviewed the titles and abstracts of all
the articles identified by the search for relevance to the research
problem and eligibility based on specified inclusion criteria. We
retrieved the full text of relevant studies. All non-English language
articles were translated to English prior to detailed review. Two
authors independently reviewed the articles for eligibility using
predetermined inclusion criteria. We contacted the study authors
for missing information.
Quality review
Two authors independently appraised the methodological quality
of the studies using a four-item quality assessment instrument that
evaluated the following areas: secure method of randomisation,
concealment of allocation, blinding, and completeness of followup (Annane 2004). After independent evaluation, the authors convened and discussed individual ratings based on the assessment
criteria. We discussed and documented discrepancies on the quality evaluation. A third author arbitrated unsettled disagreements.
The consensus on the assessment of methodological quality of the
included studies is presented in Table 1.
Data extraction
Search methods for identification of studies
We searched the Cochrane Neuromuscular Disease Group Trials
Register for randomised trials using the following search terms:
’Vitamin B’ or ’Vitamin B complex’ and its different forms,
’aminobenzoic acid’, ’biotin’, ’folic acid’, ’tetrahydrofolate’, ’inositol’, ’nicotinic acid’, ’niacin’, ’niacinamide’, ’pantothenic acid’,
’riboflavin’, ’thiamine’, ’cobamide’, ’cobalamin’, ’pyridoxine’, and
’peripheral nervous system diseases’ and its synonyms, ’peripheral nervous system disorders’, ’neuropathies’, ’peripheral neuropathies’, ’neuritis’, ’neuralgia’, ’polyneuropathies’, ’generalized
peripheral neuropathies’. We also searched MEDLINE (from
January 1966 to September 2005) using the strategy given in
Appendix 1, and we adapted this strategy to search EMBASE (from
January 1980 to September 2005) Appendix 2. We also searched
Philippine databases using the search terms ’vitamin’, ’vitamin B’,
’neuropathy’, and ’peripheral neuropathy’ Appendix 3. We did not
impose any language restriction.
Two authors independently extracted the data from studies that
met the inclusion criteria and quality standard. The data extracted
included: study name, design, sample size, study duration (including follow up period), participant characteristics (age, sex),
inclusion and exclusion criteria, intervention including dosage,
route, and treatment duration, outcomes, number of drop-outs
and withdrawals, and number of participants analysed in the different treatment groups (Clarke 2001). We extracted data using
a specially-designed data extraction form. All disagreements were
settled by discussion.
Statistical methods
We performed quantitative analyses of outcomes based on intention-to-treat results. For dichotomous outcomes, we calculated the
relative rate (RR) with its 95% confidence intervals (CI) for the
individual studies. To combine the results of the studies if metaanalysis had been possible, we would have calculated the pooled
RR with its 95% CI. For continuous outcomes, we calculated the
4
mean difference (MD) with its 95% CI. For studies that did not
report outcomes in standard deviation (SD), we derived the SD
from the published variance or standard error. For change scores
or values, we compared the baseline means in the treatment and
control groups using two-sample t-test with equal variances. A P
value of 0.05 was used as the cut-off value to determine statistical
significance. If there was no sufficient evidence to conclude that
the baseline means in the treatment and control groups were different from each other (P > 0.05), we calculated the MD with its
95% CI using the endpoint means. If the P value was less than
0.05, we did not calculate the MD using the endpoint means, and
we did not estimate the treatment effect size. We provided qualitative summary of the treatment effect instead. For continuous
outcomes and outcomes in change scores, we would have summarised the measures across studies by calculating the weighted
mean difference (WMD) or standardised mean difference (SMD)
and 95% CI using Review Manager.
For studies with multiple reported outcomes on impairments and
neuropathic symptoms, we selected only one variable for each outcome for analysis. For neurophysiological outcomes, we analysed
predetermined nerves in the upper limb and lower limb for both
the sensory and motor nerve conduction studies.
If there had been sufficient trials, we would have calculated the
I2 statistic to assess heterogeneity using Review Manager. An I2
value greater than 50% is taken to mean that a significant amount
of heterogeneity existed among the studies. For analyses that are
found to be heterogeneous, the assumptions of the fixed-effect
model underlying the calculation of the WMD or SMD may not
be satisfied. Therefore, we would have based our analysis on the
random-effects model as this is more conservative and appropriate.
We did not perform the planned sensitivity analysis to further
explore heterogeneity or on studies with and without ’adequate’
rating for allocation concealment due to an insufficient number
of included studies.
We compared separately the different types of vitamin B and studies where vitamin B was compared with placebo, in different doses,
and with other active treatment (’other substance’). We did not
analyse separate subgroups of painful and painless neuropathy and
of diabetic, alcoholic, and other causes of neuropathy due to an
insufficient number of included studies. We also did not perform
separate analysis on participants with particular documented vitamin B deficiencies. We calculated the proportion of participants
who developed adverse events from treatment with vitamin B.
Excluded studies
We identified 49 studies as possibly eligible for inclusion from
1849 abstracts and titles identified from the search. A total of 36
out of 49 studies were excluded for various reasons. The diagnosis of peripheral neuropathy was based on symptoms alone in
five studies (Libarnes 1984; Devathasan 1986; Kretschmar 1996;
Haupt 2005; Wibowo 2005), and was part of a more complex
syndrome in two studies (Osuntokun 1970; Osuntokun 1974).
In one study, the diagnosis was based on impairments alone (Jorg
1988). The basis of diagnosis was unclear in four RCTs (Delcker
1989; Appiotti 1990; Zhu 2001; Wu 2002). The diagnosis was
based on symptoms alone, and both the intervention and comparison groups received vitamin B in two studies (Li G 1999;
Okada H 2000). In one study, the diagnosis was based on symptoms alone, and the type of vitamin B used was not specified
(Simeonov 1997). In four studies, the basis of diagnosis was unclear, and both the intervention and comparison groups received
vitamin B (Chen 2000; Li X 2001; Shi 2003; Yao 2004). In one
study, the type of vitamin B used was not stated (Reschke 1989).
Both the intervention and comparison groups received vitamin B
in one study (Montes De Oca 1979). Thirteen studies were not
considered as randomised studies on further evaluation (Zhong
1981; Malizia 1982; Yamada 1982; Cohen 1984; Gillioli 1984;
Okada S 1985; Ishihara 1992; Shindo 1994; MedinaSantillan
2004; Dueñas 2005; Moridera 2005; Kikkawa 2006; Tanigawa
2006). One study was reported only as abstract (Jorg 1989). Another study was reported only as ’letter to the editor’ (McCann
1983). Other studies that were excluded were duplicates, a congress
report, a feature article, case series, reviews, overviews or systematic reviews (’Characteristics of Excluded Studies’).
Included studies
We included 11 parallel group RCTs (Levin 1981; Yaqub 1992;
Ziegler 1993; Duque 1994; Stracke 1996; Abbas 1997; Woelk
1998; Strokov 1999; Kovrazhkina 2004; Li X 2005; Zhang 2005).
We also included two quasi-randomised trials (Winkler 1999; Hu
2004). Details of each included study in terms of participants, interventions, and outcomes are summarised in the ’Table of Characteristics of Included Studies’. All studies except for one trial were
published (Duque 1994). Six studies were non-English language
papers and all were translated to English prior to evaluation.
Participants
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
The 13 eligible studies included 741 participants with 488 patients
treated with vitamin B alone (including different doses) and 253
patients treated with either placebo or another substance (alphalipoic acid, berlition, cilostazol, cytidine triphosphate, epalrestat
or thioctic acid). Abbas 1997 was the largest study, accounting for
200 of the total 488 (41%) participants treated with vitamin B.
The age range of the participants was from 18 to 74 years. All participants were diagnosed to have generalised peripheral neuropathy
5
based on a priori selection criteria. Eleven studies were on diabetic
neuropathy and two were on alcoholic neuropathy (Woelk 1998;
Kovrazhkina 2004). None of the studies had documented vitamin
B deficiency. Two studies excluded participants with vitamin B1
deficiency (Li X 2005) and vitamin B12 deficiency (Stracke 1996).
Interventions
The 13 included studies were grouped into pair wise comparisons
according to: (1) the type of vitamin B compounds and (2) whether
vitamin B was compared with placebo, different doses, or other
substances. ’Vitamin B complex’ refers to combination of two or
more types of vitamin B compounds. Five studies compared vitamin B with placebo (Levin 1981; Yaqub 1992; Duque 1994;
Stracke 1996; Woelk 1998) and none compared vitamin B to no
treatment. ’Other substances’ are agents other than vitamin B used
as active treatments. Alpha-lipoic acid, berlition, and thioctic acid
are different names for the same substance which is an anti-oxidant. All of these are referred as ’alpha-lipoic acid’ throughout
this review. Cilostazol is a selective cAMP phosphodiesterase inhibitor. Cytidine triphosphate is a pyrimidine nucleotide. Epalrestat is an aldose reductase inhibitor. Seven studies compared vitamin B to active treatments of which two were different doses
of vitamin B (Abbas 1997; Winkler 1999). Six studies compared
vitamin B with other substances (Ziegler 1993; Strokov 1999; Hu
2004; Kovrazhkina 2004; Li X 2005; Zhang 2005). The 13 included studies used single or combined oral, intramuscular (IM)
or intravenous (IV) vitamin B preparations in varying doses that
were administered for at least two weeks.
Six studies reported concomitant use of drugs other than vitamin
B, eg oral hypoglycaemic agents, insulin, or both (Levin 1981;
Yaqub 1992; Ziegler 1993; Strokov 1999; Li X 2005; Zhang
2005). We assumed insulin was used in one study (Winkler 1999).
One study reported non-use of other agents in addition to vitamin
B but did not state if insulin was used (Duque 1994). In one
study, all except five participants continued to consume alcohol
during the trial (Kovrazhkina 2004). Data on the use of drugs
other than vitamin B were not published in four studies (Abbas
1997; Woelk 1998; Hu 2004; Kovrazhkina 2004). A total of six
studies excluded participants previously on vitamin B or other
medications for treating peripheral neuropathy (Ziegler 1993;
Duque 1994; Woelk 1998; Strokov 1999; Zhang 2005) and on
drugs for treating alcoholic polyneuropathy (Kovrazhkina 2004).
included studies reported clinical outcomes. Six studies reported
on short-term change in pain intensity and 10 studies on shortterm change in impairment. Three studies did not publish NCS
outcomes (Abbas 1997; Woelk 1998; Winkler 1999). The most
frequently reported NCS outcome was short-term change in motor NCV of the common peroneal nerve or other lower extremity motor nerves (eight studies). None of the studies published
data on serious adverse events. Six studies, however, reported nonserious adverse events from treatment with either vitamin B or
the comparison intervention (Duque 1994; Abbas 1997; Strokov
1999; Hu 2004; Kovrazhkina 2004; Li X 2005).
Risk of bias in included studies
Two authors independently assessed the methodological quality
of 49 possibly eligible studies. The following ratings were used:
(A) adequate, (B) unclear; (C) inadequate, and (D) not done.
Disagreements during the selection and assessment of studies were
settled by discussion. A third author arbitrated disagreements on
the methodological quality assessment in two studies (Yaqub 1992;
Winkler 1999).
Randomisation
Only one study had an adequate method of randomisation (Duque
1994). In this study, the method was not reported but additional
data from the author revealed the use of table of random numbers to generate the randomisation sequence. The majority of the
studies (10 out of 13) had unclear methods of randomisation since
the method was either not reported or was not described clearly.
There were two quasi-randomised trials with inadequate method
of randomisation (Winkler 1999; Hu 2004).
Allocation concealment
Allocation concealment was adequate in only four studies (Levin
1981; Yaqub 1992; Duque 1994; Abbas 1997). The allocation
concealment was considered unclear in eight studies since the
method was not described (Ziegler 1993; Stracke 1996; Woelk
1998; Strokov 1999; Hu 2004; Kovrazhkina 2004; Li X 2005;
Zhang 2005) and inadequate in one study (Winkler 1999).
Blinding
Outcomes
This review included four outcomes with two primary and two
secondary outcomes. Short-term (three months or less) change and
long-term (after more than three months) change for each outcome
were recorded. Most studies reported outcomes with short-term
change with only four studies reporting outcomes with long-term
change (Levin 1981; Yaqub 1992; Ziegler 1993; Zhang 2005). All
Six studies were double-blind RCTs (Levin 1981; Yaqub 1992;
Duque 1994; Stracke 1996; Abbas 1997; Woelk 1998) while
three were single-blind RCTs (Ziegler 1993; Strokov 1999; Zhang
2005). Patient blinding was considered adequate in eight studies (Levin 1981; Yaqub 1992; Duque 1994; Stracke 1996; Abbas
1997; Woelk 1998; Strokov 1999; Zhang 2005) and unclear in
two studies (Ziegler 1993; Kovrazhkina 2004). Patient blinding
was not performed in three studies (Winkler 1999; Hu 2004; Li
6
X 2005). The observer blinding was considered adequate in six
studies (Levin 1981; Yaqub 1992; Duque 1994; Stracke 1996;
Abbas 1997; Woelk 1998) and unclear in six studies (Ziegler 1993;
Strokov 1999; Hu 2004; Kovrazhkina 2004; Li X 2005; Zhang
2005). The observer blinding was not done in one study (Winkler
1999). All studies were assessed to have unclear outcome assessor
blinding except in two studies in which this procedure was not
performed (Duque 1994; Winkler 1999).
Completeness of follow-up
Patient follow-up was considered adequate in all included studies
except for four studies due to insufficient data on withdrawals,
dropouts, and losses to follow-up (Yaqub 1992; Ziegler 1993;
Stracke 1996; Winkler 1999).
Effects of interventions
The results are presented by outcomes for studies where vitamin
B was compared with placebo, compared in different doses, and
compared with other substances.
1. Vitamin B versus placebo
Primary outcomes
1.1 Short-term change in pain intensity
Two out of five studies published this outcome but the results
could not be combined. In one study, two out of 12 (16.67%)
participants treated with IM mecobalamin did not improve compared to four out of 18 (22.22%) participants on placebo after
four-week treatment (Duque 1994). The RR for reduction of pain
intensity was 0.75 (95% CI 0.16 to 3.47).
In another study, data in Group A (oral benfotiamine) and Group
B (oral vitamin B complex (benfotiamine, vitamin B6 and an unspecified congener of vitamin B12)) were combined and compared
with Group C (placebo). Seven out of 30 (23.33%) participants
in group A and 12 out of 26 (46.15%) participants in Group B
did not improve compared to 13 out of 28 (46.43%) participants
on placebo after eight weeks of treatment (Woelk 1998). When
Groups A and B were combined and compared with Group C,
there was no significant difference in the RR for reduction of pain
intensity which was 0.73 (95% CI 0.43 to 1.25).
1.2 Short-term change in impairment
Woelk 1998 reported on vibration perception threshold (VPT)
measured at both great toes and ankles, with increase in score indicating improvement. The baseline mean for VPT obtained at
the right great toe in the 30 participants treated with oral benfotiamine was 0.77 (SD 0.26) compared to 0.79 (SD 0.29) in the 28
participants on placebo, difference -0.02. There was insufficient
evidence to conclude that the baseline means were different from
each other (P = 0.78). After eight weeks of treatment, the means
were 2.89 (SD 0.61) and 2.25 (SD 0.52), respectively, with statistically significant difference favouring vitamin B (MD 0.64, 95%
CI 0.34 to 0.94).
Another study reported on “vibratory sensation” measured at the
upper and lower extremities, with decrease in score indicating improvement (Duque 1994). Only “vibratory sensation” measured
at the lower extremity was analysed among several impairments
reported. Eleven out of 14 (78.57%) participants treated with
mecobalamin did not improve compared to eight out of nine
(88.89%) participants on placebo after four weeks of treatment.
The RR of not having an improvement in “vibratory sensation”
was 0.88 (95% CI 0.62 to 1.26).
A third study published VPT measured at the metacarpal and
metatarsal bones with decrease in value indicating improvement (
Stracke 1996). This study published the means as geometric means
(upper and lower limits of the 95% CI) but the data were not
sufficient to transform the means to arithmetic means (SD) for
calculation of the MD. The baseline mean in VPT measured at
the lower limb was 17.00 micrometer (µm) (7.60 to 38.00) in the
11 participants treated with oral benfotiamine, pyridoxine, and
cyanocobalamin compared to 11.90 µm (4.70 to 30.30) in the 13
participants on placebo. The means after 12 weeks of treatment
were 12.00 µm (6.90 to 20.70) and 15.70 µm (6.90 to 35.80),
respectively.
Woelk 1998 also reported on an “overall neuropathy score” combining pain intensity, motor function, sensory function, co-ordination, and reflexes. Nine out of 28 (32.14%) participants in the
placebo group did not improve compared to two out of 30 (6.67%)
participants on oral benfotiamine and six out of 26 (23.08%) participants on oral vitamin B complex at the end of the trial. When
the two groups treated with vitamin B were combined and compared to the placebo group, the RR of not improving on this score
was 0.44 (95% CI 0.19 to 1.03).
Secondary Outcomes
1.3 Long-term change in pain intensity
No data were available for this outcome.
1.4 Long-term change in impairment
The only study that published this outcome reported on “signs”
(sensations, motor power, deep tendon reflex, and blood pressure changes) with a higher score indicating improvement (Yaqub
1992). The baseline mean in the 21 participants on oral methylcobalamin was 203.60 (SD 49.60) compared to 224.10 (SD
7
46.20) in the 22 participants on placebo, difference -20.5 (P =
0.17). After four months of treatment, the means were 229.60
(SD 43.00) in the vitamin B group and 221.80 (SD 50.90) in the
placebo group with no significant difference (MD 7.80, 95% CI
-20.32 to 35.92).
1.5 Short-term change in neuropathic symptom
This outcome was available from only one study (Duque 1994).
Only the symptom “numbness” among several neuropathic symptoms reported was analysed. There were more participants in the
placebo group (nine out of 20 or 45.00%) who did not improve
compared to the mecobalamin group (six out of 21 or 28.57%).
The RR for reduction of numbness was not statistically significant
0.63 (95% CI 0.28 to 1.46).
1.6 Long-term change in neuropathic symptom
Two studies reported this outcome but the results could not be
combined. In the study of Levin 1981 that published “neuropathic
symptoms,” two out of nine (22.22%) participants treated with
oral pyridoxine did not improve compared to one out of nine
(11.11%) participants on placebo after four months of treatment.
The RR for reduction of “neuropathic symptoms” was 2.00 (95%
CI 0.22 to 18.33). Data on “slight improvement” and “significant
improvement” were combined and compared with “no change”
for this analysis.
Another study reported this outcome as composite “somatic symptoms” (dull pain or tightness, numbness, cramps, fatigue, and
weakness) and “autonomic symptoms” with a higher score indicating improvement (Yaqub 1992). The baseline means for “somatic
symptoms” were 72.20 (SD 32.20) in the 21 participants on oral
methylcobalamin and 95.50 (SD 25.40) in the 22 participants
on placebo, difference -23.30. There was sufficient evidence to
conclude that the baseline means were different from each other
(P = 0.01) so it was not possible to calculate the MD using the
endpoint means. After four months of treatment, the means were
106.60 (SD 20.40) and 94.80 (SD 27.90), respectively.
1.7 Short-term change in NCS parameters
In the study of Duque 1994, the authors only reported means
and not standard deviations, so it was not possible to compare the
baseline means and to calculate the MD in all 12 outcomes on
short-term change in NCS parameters.
Stracke 1996 published the NCV values as arithmetic means (upper and lower limits of the 95% CI); the SD was derived from
the CI. Increase in NCV indicates improvement. There was no
significant difference in the motor NCV of the median nerve in
the group treated with benfotiamine, pyridoxine, and cyanocobalamin (verum) and in the placebo group after 12 weeks of treatment
(MD -0.90 m/s, 95% CI -4.03 to 2.28). The authors also reported
no significant difference in the motor NCV of the peroneal nerve
in the two groups at the end of the trial (MD 0.93 m/s, 95% CI
-3.76 to 5.62).
1.8 Long-term change in NCS parameters
No data were available for peak latency of the median SNAP and
the sural SNAP. The remaining 10 outcomes were reported in two
studies. Yaqub 1992 reported a composite “sensory score” for distal
latency, amplitude, area, and velocity of two sensory (median and
sural) nerves. After four months of treatment, there was no significant difference in the “sensory score” in the methylcobalamin
group and placebo group (MD -0.40, 95% CI -2.82 to 2.02).
Two studies reported on motor NCV of the peroneal nerve but the
results could not be pooled. Yaqub 1992 published a composite
“motor score” for distal latency, amplitude, area, and velocity of
two motor (median and common peroneal) nerves. There was no
significant difference in the “motor score” in the two groups at the
end of the trial (MD -0.81 m/s, 95% CI -3.02 to 1.40). In the
another study, this outcome was published as mean +/- SE; the
SD was derived from the SE (Levin 1981). After four months of
treatment, there was no significant difference in the group treated
with pyridoxine and the group on placebo (MD 1.70 m/s, 95%
CI -3.60 to 7.00).
1.9 Serious adverse events
Only one out of five studies reported adverse events. One participant had a mild stroke but the authors did not state the aetiology
and clinical course of the stroke, and to which group the participant was randomised (Duque 1994).
2. Vitamin B in different doses
Primary outcomes
Two out of two studies published this outcome but the results
could not be combined. In the largest study, we extracted data
indicating “change in worst symptom (pain) one month following
treatment.” One out of nine (11.11%) participants treated with
higher dose of oral vitamin B complex (thiamine and pyridoxine)
did not improve compared to eight out of nine (88.89%) participants on lower dose one month following treatment (Abbas 1997).
The RR of having reduced pain intensity in the higher dose group
was statistically significant (RR 0.13, 95% CI 0.02 to 0.08).
In the second study where only two of the three groups were compared, the means but not the standard deviations were published
so it was not possible to compare the means and to calculate the
MD (Winkler 1999). In this study, the baseline mean pain intensity in the 12 participants treated with higher dose of vitamin
8
B complex (benfotiamine, pyridoxine, and cyanocobalamin) was
13.60 compared to 13.00 in the 12 participants on lower dose. At
week 6 of treatment, the means were 6.50 and 6.80, respectively.
Both scores were reduced but the SDs were not provided so that
significance could not be formally tested.
This outcome was not available.
No data for any of the NCS outcomes were available.
Both studies published this outcome but the results could not be
pooled. In the study of Abbas 1997 that reported composite outcome measure (“pain, temperature, and vibration”), more participants in the lower dose vitamin B complex group did not improve
(70 out of 79 or 88.61%) compared to the higher dose group (45
out of 88 or 51.14%). The RR for reduction of composite impairments was 0.58 (95% CI 0.46 to 0.72) significantly favouring the
higher dose group.
In the second study, only “vibration sensation” among the reported
impairments was analysed but the SD was not published (Winkler
1999). In this study, the baseline mean in the vitamin B complex
higher dose group was 5.40 compared to 4.80 in the lower dose
group. At week 6 of treatment, the means were 6.10 and 5.50,
respectively.
No data for any of the NCS outcomes were available.
There were no serious adverse events reported in both studies
but one study reported a non-serious adverse event. Abbas 1997
reported one participant discontinued treatment because of gastroenteritis but the group to which the participant was randomised
and the details of the adverse event were not reported.
3. Vitamin B versus other substances
Secondary outcomes
Primary outcomes
Vitamin B versus alpha-lipoic acid
This outcome was available only from the largest study that reported both single and composite outcomes (Abbas 1997). Four
out of 39 (10.26%) participants in the vitamin B complex higher
dose group did not improve compared to 20 out of 33 (60.61%)
participants on lower dose. The RR for reduction of paraesthesiae
was 0.17 (95% CI 0.06 to 0.45) which was statistically significant. This study also reported a composite outcome measure of
pain, numbness and paraesthesiae. More participants (71 out of
79 or 89.87%) treated with lower dose of vitamin B complex did
not improve compared to participants (36 out of 88 or 40.91%)
on higher dose. The RR for reduction of composite neuropathic
symptoms was 0.46 (95% CI 0.35 to 0.59) significantly favouring
the higher dose group.
Two studies published this outcome but only one provided adequate numerical data. In the study of Kovrazhkina 2004, the baseline mean in the 27 participants treated with oral vitamin B1 with
“polivitamin” was 2.40 (SD 0.40) compared to 3.10 (SD 0.50)
in the 29 participants treated with another substance (oral alphalipoic acid), difference -0.70. There was sufficient evidence to conclude that the baseline means were different from each other (P =
0.00) so it was not possible to calculate the MD using the endpoint means. After six weeks of treatment, the means were 2.00
(SD 0.30) and 1.20 (SD 0.20), respectively.
In another study, the authors reported a significant reduction in
pain in the lower extremity in the group treated with IV and oral
alpha-lipoic acid compared to the group on IM and oral vitamin
B1 after three weeks of treatment (P < 0.05) but did not give any
more details (Ziegler 1993).
9
Two studies published single impairments but the results could not
be combined. Kovrazhkina 2004 reported on several impairments
with decrease in score indicating improvement but only “reflex”
impairment was analysed. The baseline mean in the 27 participants
on vitamin B1 with “polivitamin” was 1.20 (SD 0.40) compared
to 1.10 (SD 0.20) in the 29 participants treated with alpha-lipoic
acid, difference 0.10. There was insufficient evidence to conclude
that the baseline means were different from each other (P = 0.24).
After six weeks of treatment, the means were 1.20 (SD 0.40) in
the vitamin B group and 0.90 (SD 0.20) in the alpha-lipoic acid
group. There was significantly greater improvement in the alphalipoic acid group (MD 0.30, 95% CI 0.13 to 0.47). Another study
reported on “speed of mydriasis” with no clear basis for indicating
improvement of outcome measures (Ziegler 1993). In this study,
the baseline mean for “speed of mydriasis” in the 12 participants
treated with vitamin B1 was 0.83 (SD 0.08) compared to 0.61
(SD 0.06) in the 11 participants treated with alpha-lipoic acid,
difference 0.22 (P = 0.00). The means following three weeks of
treatment were 0.90 (SD 0.08) and 0.66 (SD 0.07), respectively.
Two studies published composite outcomes on impairments which
compared vitamin B with alpha-lipoic acid but the results could
not be combined. In the study of Strokov 1999, six out of 10
(60.00%) participants treated with IV riboflavin and oral placebo
for three weeks did not improve in “subjective symptoms” and
“objective symptoms” compared to one out of 40 (2.50%) participants treated with IV and oral alpha-lipoic acid. The RR of
not having an improvement in composite impairments was 24.00
(95% CI 3.25 to 177.40) which was statistically significant. In
another study, the baseline mean for the “sum score” was 8.40
(SD 1.40) in the 27 participants on vitamin B1 with “polivitamin”
compared to 8.90 (SD 1.50) in the 29 participants treated with
alpha-lipoic acid, difference -0.50 (P = 0.20) (Kovrazhkina 2004).
Decrease in score indicated improvement. Following six weeks of
treatment, the means were 7.70 (SD 1.30) and 4.60 (SD 1.10),
respectively. There was significantly greater improvement in the
alpha-lipoic acid group (MD 2.55, 95% CI 1.83 to 3.26).
In another study, 10 out of 25 (40.00%) participants on IM vitamin B1 and B12 for two weeks did not improve in symptoms,
signs, and NCV compared to three out of 25 (12.00%) participants treated with IV cytidine triphosphate (Li X 2005). The RR
of not having an improvement in composite impairments was 3.33
(95% CI 1.04 to 10.69) which was statistically significant in favour
of cytidine triphosphate. Li X 2005 also published a composite
outcome on “neurological signs” (pain, touch, tendon reflex) but
did not provide the baseline means and SD. After two weeks of
treatment, the means were 4.00 (SD 0.30) in the 25 participants
on vitamin B complex and 3.00 (SD 0.50) in the 25 participants
treated with cytidine triphosphate. The authors reported greater
improvement in the cytidine triphosphate group (P < 0.01).
Secondary outcomes
This outcome was available from only one study. Ziegler 1993
reported significant reduction in pain in the lower extremity in the
alpha-lipoic acid group compared to vitamin B1 group after 15
weeks of treatment (P < 0.05) but did not give any more details.
In one study of “speed of mydriasis,” there was sufficient evidence
to conclude that the baseline means in the two treatment groups
were different from each other (P = 0.00) (Ziegler 1993). The
means after 15 weeks of treatment were 0.91 (SD 0.08) in the
vitamin B1 group and 0.73 (SD 0.09) in the alpha-lipoic acid
group.
Vitamin B versus other substances
One study reported composite outcome on impairments (“physical sign score”) with decreasing score indicating improvement (Hu
2004). In this study, the baseline mean was 7.10 (SD 0.40) in the
25 participants on IM vitamin B1 and B12 compared to 7.00 (SD
0.20) in the 25 participants on oral cilostazol, difference 0.1 (P
= 0.27). After four weeks of treatment, the means were 6.90 (SD
0.30) and 6.40 (SD 0.30), respectively, with statistically significant
difference favouring cilostazol (MD 1.64, 95% CI 0.99 to 2.29).
Zhang 2005 reported on “signs” (tendon reflex and vibration)
with decrease in score indicating improvement. In this study, the
baseline mean in the 20 participants on oral mecobalamin was
4.95 (SD 2.78) compared to 6.00 (SD 2.47) in the 20 participants
treated with epalrestat (no details given), difference -1.05 (P =
0.21). At week 16 of treatment, the means were 3.00 (SD 3.36)
and 3.79 (SD 3.22), respectively, with no significant difference
(MD -0.79, 95% CI -2.83 to 1.25).
10
Zhang 2005 reported on composite “symptoms” (pain, sensory
abnormality, weakness of limbs, and injury of autonomic nerve)
with decrease in score indicating improvement. The baseline mean
in the 20 participants on mecobalamin was 17.29 (SD 9.83) compared to 16.26 (SD 10.90) in the 20 participants on epalrestat,
difference 1.03 (P = 0.76). At week 16 of treatment, the means
were 7.05 (SD 4.86) and 7.16 (SD 8.04), respectively, with no
significant difference (MD -0.11, 95% CI -4.23 to 4.01).
Two studies reported on single impairments but only one provided
adequate numerical data. In one study that reported on paraesthesiae with decrease in score indicating improvement, the baseline
means were 2.00 (SD 0.30) in the 27 participants on vitamin B1
with “polivitamin” compared to 1.80 (SD 0.20) in the 29 participants treated with alpha-lipoic acid, difference 0.20 (P < 0.01)
(Kovrazhkina 2004). The means after six weeks of treatment were
2.00 (SD 0.40) and 0.70 (SD 0.10), respectively.
In another study, the authors reported a significant reduction in
paraesthesiae in the lower extremity in the alpha-lipoic acid group
compared to the vitamin B1 group after three-week treatment (P
< 0.05) but did not give further details (Ziegler 1993).
Data were not available for the peak latency of the median SNAP
and sural SNAP, amplitude of the median SNAP, and distal latency of the median CMAP and common peroneal CMAP. The
remaining NCS outcomes were available from four studies.
Amplitude of the sural SNAP
Two studies published composite outcomes. In one study that reported on “neurological syndrome score” with decrease in score
indicating improvement, the baseline means were 5.50 (SD 0.30)
in the 25 participants on vitamin B1 and B12 and 5.60 (SD 0.20)
in the 25 participants treated with cilostazol, difference -0.10 (P =
0.17) (Hu 2004). Following eight weeks of treatment, the means
were 4.20 (SD 0.30) and 2.80 (SD 0.30), respectively, with significantly greater improvement in the cilostazol group (MD 1.40,
95% CI 1.23 to 1.57).
Li X et al. published “neurological symptoms” (“pain, numb, and
so on”) with decrease in score indicating improvement but did not
provide baseline means and SD (Li X 2005). The post-treatment
(week 2) means were 2.60 (SD 0.30) in the 25 participants on
vitamin B1 and B12 and 1.40 (SD 0.50) in the 25 participants on
cytidine triphosphate. The authors reported greater improvement
in the cytidine triphosphate group (P < 0.05).
Strokov 1999 published the means and SD of the alpha-lipoic acid
group but not for the vitamin B group. The authors reported a
significant increase in this parameter in the alpha-lipoic acid group
(P < 0.01) and no significant change in the vitamin B group.
Sensory NCV of the median nerve
Two studies published this outcome but the results could not be
combined. In the study of Kovrazhkina 2004, there was statistically significant difference favouring alpha-lipoic acid after six
weeks of treatment (MD -6.52 m/s, 95% CI -7.12 to -5.92). In
another study, there was sufficient evidence to conclude that the
baseline means in the vitamin B1 and alpha-lipoic acid groups
were different from each other (P < 0.01) (Ziegler 1993). The
means at week 3 were 42.90 m/s (SD 3.10) in the vitamin B1
group and 46.90 m/s (SD 2.70) in the alpha-lipoic acid group.
Ziegler 1993 reported a significant reduction in paraesthesiae in
the lower extremity in the group treated with alpha-lipoic acid
compared to the group on vitamin B1 after 15 weeks of treatment
(P < 0.05) but did not give any more details.
Hu et al. reported statistically significant difference favouring
cilostazol after eight-week treatment (MD -2.40 m/s, 95%CI 4.20 to -0.60) (Hu 2004).
11
Sensory NCV of the sural nerve and peroneal nerve
Three studies reported on the sensory NCV of the sural nerve
but only two provided adequate numerical data. In both of these
studies, there was sufficient evidence to conclude that the baseline
means in the two treatment groups were different from each other
(P < 0.01 (Ziegler 1993); P = 0.00 (Kovrazhkina 2004)). The
means following three weeks of treatment were 37.50 m/s (SD
1.30) in the vitamin B1 group and 34.80 m/s (SD 2.40) in the
alpha-lipoic acid group in the study of Ziegler 1993. In the study
of Kovrazhkina 2004, the means after six weeks of treatment were
33.61 m/s (SD 0.80) in the vitamin B complex group and 38.24 m/
s (SD 0.50) in the alpha-lipoic acid group. Strokov 1999 published
the means and SD for the alpha-lipoic acid group but not for the
vitamin B group. The authors reported a significant increase in
this parameter in the alpha-lipoic acid group (P < 0.01) and no
significant change in the riboflavin group.
In the study of Hu 2004 that reported on the sensory NCV of
the peroneal nerve, there was a statistically significant difference
favouring cilostazol after eight weeks of treatment (MD -6.10 m/
s, 95%CI -7.65 to -4.55).
evidence to conclude that the baseline means in the two treatment
groups were different from each other (P < 0.01 (Ziegler 1993); P
= 0.00 (Kovrazhkina 2004)). In the study Ziegler 1993, the means
following three weeks of treatment were 45.30 m/s (SD 1.70) in
the vitamin B1 group and 46.40 m/s (SD 1.00) in the alphalipoic acid group. In the other study, the means after six weeks of
treatment were 44.95 m/s (SD 1.10) in the vitamin B complex
group and 51.60 m/s (SD 1.10) in the alpha-lipoic acid group
(Kovrazhkina 2004). Strokov 1999 published the means and SD
of the alpha-lipoic acid group but not for the vitamin B group.
The authors reported significant increase in the alpha-lipoic acid
group (P < 0.05) and no significant change in the riboflavin group.
This outcome was available from two studies but only one provided
adequate numerical data. Hu 2004 reported statistically significant
difference favouring cilostazol after eight weeks of treatment (MD
-3.40 m/s, 95%CI -5.09 to -1.71). In the study Li X 2005, the
baseline means of the two treatment groups were not provided.
The means at week 2 of treatment were 46.41 m/s (SD 4.86) in
the 25 participants on vitamin B complex and 51.12 m/s (SD
5.36) in the 25 participants on cytidine triphosphate. The authors
reported greater improvement in the cytidine triphosphate group
(P < 0.01).
Motor NCV of the peroneal nerve and other lower extremity
nerves
Amplitude of the median CMAP and peroneal CMAP
Strokov 1999 reported no significant change in the amplitude of
the median CMAP in the vitamin B and alpha-lipoic acid groups
after three weeks of treatment but did not give any more details.
The authors also reported no significant change in the amplitude
of the peroneal CMAP in the two treatment groups at the end of
the trial but provided only the numerical data for the alpha-lipoic
acid group and not for the vitamin B group.
Motor NCV of the median nerve
Ziegler 1993 reported a statistically significant difference favouring
the alpha-lipoic acid group after three weeks of treatment (MD
2.00 m/s, 95% CI 0.69 to 3.31).
In the only study that reported motor NCV of the “tibialis” nerve,
there was sufficient evidence to conclude that the baseline means
in the two treatment groups were different from each other (P <
0.01) (Kovrazhkina 2004). Following six weeks of treatment, the
means were 37.79 m/s (SD 0.80) in the vitamin B complex group
and 42.22 m/s (SD 0.80) in the alpha-lipoic acid group. Strokov
1999 reported no significant change in the motor NCV of the
“fibular” nerve in the riboflavin and alpha-lipoic acid groups but
did not give any further details.
Three studies published this outcome but only two provided adequate numerical data. In both of these studies, there was sufficient
In the study Hu 2004, there was a statistically significant difference
favouring cilostazol after eight weeks of treatment (MD -4.00 m/
s, 95%CI -5.70 to -2.30).
12
Li X et al. reported this outcome but did not publish the baseline
means of the two treatment groups (Li X 2005). The authors
reported greater improvement in the cytidine triphosphate group
compared to the vitamin B complex group at week 2 of treatment
(P < 0.01).
Data were not available for the peak latency of the median SNAP
and sural SNAP, amplitude of the median SNAP and sural SNAP,
and distal latency of the median CMAP and common peroneal
CMAP, and amplitude of the median CMAP and common peroneal CMAP. The rest of the outcomes were available from two
studies.
Motor NCV of the median nerve
In the only study that published this outcome, there was sufficient
evidence to conclude that the baseline means in the two treatment
groups were different from each other (P < 0.01) (Ziegler 1993).
The means after 15-week treatment were 43.90 m/s (SD 1.40) in
the vitamin B1 group and 45.90 m/s (SD 0.90) in the alpha-lipoic
acid group.
Motor NCV of the peroneal nerve
In the study Ziegler 1993, there was no significant difference in
the vitamin B1 group and alpha-lipoic acid group after 15 weeks
of treatment (MD -0.20 m/s, 95% CI -1.44 to 1.04).
Sensory NCV of the median nerve
In the study Ziegler 1993, there was sufficient evidence to conclude
that the baseline means in the two treatment groups were different
from each other (P < 0.01). The means after 15 weeks of treatment
were 41.30 m/s (SD 3.10) in the group on vitamin B1 and 47.70
m/s (SD 2.10) in the alpha-lipoic acid group.
Zhang et al. reported no significant difference in the mecobalamin
group and epalrestat group at week 16 of treatment (MD -0.35
m/s, 95% CI -4.48 to 3.78) (Zhang 2005).
Sensory NCV of the sural nerve and “fibular” nerve
In the study Ziegler 1993, there was sufficient evidence to conclude
that the baseline means for the sensory NCV of the sural nerve
in the two treatment groups were different from each other (P <
0.01). After 15 weeks of treatment, the mean for the vitamin B1
group was 37.00 m/s (SD 1.70) in the vitamin B1 group compared
to 33.10 m/s (SD 2.20) in the alpha-lipoic acid group.
In the study Zhang 2005, there was no significant difference in
the sensory NCV of the “fibular” nerve in the mecobalamin group
and epalrestat group at week 16 of treatment (MD -1.95 m/s, 95%
CI -6.22 to 2.32).
There were no serious adverse events published but four out of
six studies reported non-serious adverse events. There were two
participants with headache and “lipothimic” condition in the one
study (Kovrazhkina 2004). In another study, three participants experienced mild nausea while 10 participants had a “strong smell of
urine” (Strokov 1999). The group assignment of participants who
developed side effects and details of the adverse events were not
available in either study. In the study Hu 2004, the participants
treated with cilostazol developed dizziness, headache, and rapid
heart rate which were unremarkable, but the number of participants who experienced the side effects was not stated. Li X 2005
reported that one out of 25 (4%) participants in the group treated
with cytidine triphosphate developed “low fever” that resolved
with cessation of treatment. In addition, three participants had
“heart throb,” three participants had dysuria, and 10 participants
experienced “temporary dry mouth” but it was not stated if these
participants were randomised to the group treated with vitamin
B or cytidine triphosphate or if the reported adverse events were
mutually exclusive.
Sensitivity analysis
Sensitivity analysis with and without trials lacking “adequate” rating for allocation concealment was not performed in this review
due to an insufficient number of included studies.
DISCUSSION
The trials of vitamin B for peripheral neuropathy in this review
varied in terms of type of vitamin B compound, dose, route, and
duration of treatment. Three studies published varying doses at
different time points with decreased dose schedule after three days
13
to four weeks of initiation of treatment (Stracke 1996; Abbas
1997; Woelk 1998). Treatment duration ranged from two weeks
(Li X 2005) to four months (Levin 1981; Yaqub 1992; Zhang
2005). The dose of vitamin B was within the recommended daily
allowance (RDA) in all included studies except for two studies.
The low dose regimen in the study of Abbas 1997 is within the
RDA for thiamine (1 mg/day) but not for pyridoxine (1 mg/day)
in which the dose was lower than the RDA. In the study of Strokov
1999, the dose of riboflavin at 1% solution in 200 ml of normal
saline solution is lower than the RDA. Theoretically, lower doses
of vitamin B would be expected to exert less therapeutic effect
or placebo-like effect. It is not known whether the adequate dose
for treatment approximates or is higher than the RDA for specific
types of vitamin B. The ideal route and duration of treatment and
the effects of combining different types of vitamin B for treating
peripheral neuropathy are also not known.
Interpretation of the treatment effects
vitamin B was less efficacious than cilostazol or cytidine triphosphate in short-term reduction of composite impairments after two
to eight weeks of treatment (Hu 2004, Li X 2005). There was also
evidence to suggest vitamin B administered for eight weeks was
less efficacious than cilostazol in short-term reduction of composite neuropathic symptoms (Hu 2004). There was no evidence to
suggest significant benefit or harm from 16-week vitamin B treatment in long-term reduction of composite impairments (Zhang
2005) and composite neuropathic symptoms (Zhang 2005).
For NCS outcomes, two out of three studies showed evidence to
suggest that three to six weeks of vitamin B treatment produced
significantly less short-term improvement of NCS parameters than
alpha-lipoic acid (Ziegler 1993, Kovrazhkina 2004). There was
also evidence to suggest vitamin B treatment administered for eight
weeks was less efficacious than cilostazol in short-term improvement of NCS parameters (Hu 2004). There was no evidence to
suggest significant benefit or harm from vitamin B treatment for
16 weeks in long-term improvement of NCS parameters (Zhang
2005).
1. Vitamin B versus placebo
Adverse effects of treatment
Only one out of five studies showed any evidence to suggest shortterm benefit from vitamin B. In this study, treatment for eight
weeks improved VPT compared to placebo (Woelk 1998). The
other trials did not suggest vitamin B produced significant shortterm reduction of pain intensity (Duque 1994, Woelk 1998), composite impairments (Woelk 1998), and numbness (Duque 1994),
and improvement of “vibratory sensation” (Duque 1994). There
was also no evidence to suggest significant benefit or harm from
vitamin B treatment in long-term reduction of composite impairments (Yaqub 1992) and neuropathic symptoms (Levin 1981).
There was no evidence to suggest that vitamin B treatment produced significant short-term (Stracke 1996) or long-term (Yaqub
1992, Levin 1981) changes in NCS parameters.
There were no studies that reported serious adverse events but six
out of 13 (46.15%) studies reported non-serious adverse events
from treatment with either vitamin B or other substances within
three months or less. The available data in all studies, however,
was insufficient to determine the proportion of participants with
adverse events in the specific treatment group except for one study
(Li X 2005). Only the overall proportion of participants with
adverse events was reported: 13 out of 50 (26%) (Strokov 1999),
two out of 56 (3.6%) (Kovrazhkina 2004), one out of 47 (2.1%)
(Duque 1994), one out of 50 (2%) (Li X 2005), and one out of
200 (0.5%) (Abbas 1997). Hu 2004 reported non-serious adverse
events in the treatment group but did not indicate the number of
participants involved. Overall, the reported non-serious adverse
events are mild side effects from treatment except for “mild stroke”
in one participant reported in the study of Duque 1994 but the
authors did not elaborate on the condition. There were no reported
side effects from vitamin B treatment in five studies (Yaqub 1992;
Ziegler 1993; Stracke 1996; Woelk 1998; Winkler 1999). No
data on adverse effects were available for two studies (Levin 1981;
Zhang 2005).
Vitamins of the B family are water-soluble compounds. Excessive intake of these vitamins is generally innocuous as they are
eliminated in the urine. There are few known side effects from
vitamin B when given in doses based on the recommended daily
requirement. There is no known toxicity even in large doses for
thiamine, riboflavin, folic acid, cobalamin, and pantothenic acid.
Overdose of pyridoxine can cause neurotoxicity presenting as peripheral sensory neuropathy and ataxia (Schaumburg 1983). Sensory neuropathy has been described in patients taking even lowdose pyridoxine for a protracted period (Parry 1985). None of
2. Vitamin B in different doses
There was some evidence to suggest a higher dose of vitamin
B complex (thiamine and pyridoxine) given for four weeks was
more efficacious than the lower dose in short-term reduction of
pain, composite impairments, paraesthesiae, and composite neuropathic symptoms (Abbas 1997).
3. Vitamin B versus other substances
Two out of three studies that compared vitamin B with alpha-lipoic
acid showed evidence to suggest three to four weeks of vitamin
B treatment was less efficacious than alpha-lipoic acid in producing short-term improvement of “reflex” impairment (Kovrazhkina
2004) and reduction of composite impairments (Strokov 1999,
Kovrazhkina 2004). Furthermore, there was evidence to suggest
14
the side effects pertaining to neurotoxicity from pyridoxine treatment was reported in the reviewed studies. However, pyridoxine
is indicated for vitamin B deficiency, some pyridoxine-responsive
anaemia, and isoniazid-induced neuropathy (van Boxtel 2001).
Large doses of niacin can lead to transient flushing of the skin and
tingling sensation, dizziness, nausea, gastrointestinal upset, peptic
ulcer disease, liver toxicity, and chemical abnormalities (McCarter
1992) but niacin was not included as one of the interventions for
any of the trials in this systematic review.
below the ’therapeutic’ dose, (2) the type of vitamin B compound
used was not appropriate, (2) the duration of treatment and the
period of observation were too short to detect therapeutic changes,
and (3) the assessment tools were not sensitive enough. High quality randomised trials are needed to establish whether vitamin B is
efficacious for peripheral neuropathy. Such trials need to specify
the type and dose of vitamin B and the type of peripheral neuropathy.
ACKNOWLEDGEMENTS
AUTHORS’ CONCLUSIONS
Implications for practice
There are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is insufficient to determine whether vitamin B is beneficial
or harmful. One trial suggested that oral benfotiamine given for
eight weeks was beneficial in short-term improvement of vibration
detection threshold compared to placebo. Another trial suggested
that four-week treatment with high doses of oral vitamin B complex (thiamine and pyridoxine) had a greater short-term beneficial
effect on neuropathic symptoms and signs than low doses. These
findings require confirmation. Small trials suggested that treatment with vitamin B for two to eight weeks was less efficacious
than alpha-lipoic acid, cilostazol or cytidine triphosphate in shortterm improvement of clinical and NCS outcomes. These also require confirmation.
Implications for research
The lack of evidence of short- or long-term benefit or harm from
vitamin B compared to placebo or other substances may be due
to genuine lack of therapeutic effect. However, several factors may
have contributed to these findings, namely: (1) the doses used were
We would like to acknowledge the assistance of:
Prof R Hughes, Ms K Jewitt, Ms J Fernandes, and the Cochrane
Neuromuscular Disease Group for providing logistical support
and training.
Thriplow Charitable Trust for providing research grant for protocol development and research implementation.
Research Implementation and Development Office, College of
Medicine, University of the Philippines Manila for providing research grant for research implementation.
Dr L Renales, Dr GG Bautista-Velez, and Hi-Eisai Pharmaceutical,
Inc. for providing unpublished data.
Dr J Chua for participating in the design and pilot test of the data
collection forms.
Prof ML Amarillo, Dr G Dalmacion, Dr JB Mantaring (Department of Clinical Epidemiology, College of Medicine, University
of the Philippines Manila) for providing technical and statistical
guidance.
Philippine General Hospital - Merck Sharp & Dohme Communication, Information and Networking Center for assisting in obtaining abstracts and full-text articles.
REFERENCES
References to studies included in this review
University of the Philippines-Philippine General Hospital,
Manila, Philippines. 1994.
Abbas 1997 {published data only}
Abbas ZG, Swai ABM. Evaluation of the efficacy of
thiamine and pyridoxine in the treatment of symptomatic
diabetic peripheral neuropathy. East African Medical Journal
1997;74(12):803–8.
Hu 2004 {published data only}
Hu JF, Su Q, Xing HL. Effect of cilostazol on peripheral
conductive velocity and syndrome of limb pain and
numbness in patients with diabetes. Zhongguo Linchuang
Kangfu [Chinese Journal of Clinical Rehabilitation] 2004;8
(18):3523–5.
Duque 1994 {unpublished data only}
Duque RRG, Renales-Chen L. A double-blind clinical
trial on the efficacy of parenteral mecobalamin (B12) in
sensorimotor and autonomic neuropathy among Filipino
diabetics. Section of Neurology, Department of Medicine,
Kovrazhkina 2004 {published data only}
Kovrazhkina EA, Ayriyan NY, Serkin GV, Glushkov KS,
Pavlov NA, Gekht AB, et al.Possibilities and perspective of
berlition usage in the treatment of alcohol polyneuropathy.
Journal of Neurology and Psychiatry 2004;104(2):33–7.
15
Levin 1981 {published data only}
Levin ER, Hanscom TA, Fischer M, Lauvstad WA, Lui
A, Ryan A, et al.The influence of pyridoxine in diabetic
peripheral neuropathy. Diabetes Care 1981;4(6):606–9.
Anonymous 1994 {published data only}
∗
Anonymous. Current topics on pathogenesis and therapy
of diabetic neuropathy [Diabetiker rosten schneller]. Praxis
Magazin Med 1994;6:84.
Li X 2005 {published data only}
Li X-M, Li Y, Zhao K-Y, Sun H-H. Effect of cytidine
triphosphate on nerve conduction velocity in paitents with
diabetic peripheral neuropathy. Zhongguo Linchuang Kangfu
2005;9(7):152–3.
Anonymous 1996 {published data only}
∗
Anonymous. Therapy of polyneuropathy-new study
results. Fortschritte der Medizin 1996;114(23-24):V–VIII.
Stracke 1996 {published data only}
∗
Stracke H, Lindemann A, Federlin K. A benfotiaminevitamin B combination in treatment of diabetic
polyneuropathy. Experimental and Clinical Endocrinology
and Diabetes 1996;104(4):311–6.
Strokov 1999 {published data only}
Strokov IA, Kozlova NA, Mozolevsky YV, Myasoedov SP,
Yakhno NN. Efficacy of intravenous administration of
trometamol salt of thiotic (alpha-lipoic) acid in diabetic
neuropathy. Zhurnal Nevrologii i Psikhiatrii Imeni S.S.
Korsakova 1999;99(6):18–22.
Winkler 1999 {published data only}
Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M,
Kempler P. Effectiveness of different benfotiamine dosage
regimens in the treatment of painful diabetic neuropathy.
Arzneimittelforschung 1999;49(3):220–4.
Anonymous 2004a {published data only}
Anonymous. [Oral benfotiamine therapy. Thus you protect
the nerves of diabetic patients]. MMW Fortschritte der
Medizin 2004;146(5):52–3.
Anonymous 2004b {published data only}
∗
Anonymous. Oral benfotiamine therapy in the prevention
of diabetic polyneuropathy [Orale benfotiamin–therapie.
So schutzen sie die nerven von diabetikern]. MMW
Fortschrite der Medizin 2004;146(5):52–3.
Appiotti 1990 {published data only}
∗
Appiotti A, Scarzella G. Clinical and electromyographic
study of the therapeutic effectiveness and general tolerability
of a new mixture of internal ester gangliosides in patients
with peripheral neuropathy caused by alcoholism [Studio
clinico ed elettromiografico dell’efficacia terapeutica e della
tollerabilita generale di una nuova miscela di gangliosidi
esteri interni in pazienti affeti da neuropatia periferica su
base alcolica]. Minerva Medica 1990;81(11):807–13.
Woelk 1998 {published data only}
∗
Woelk H, Lehrl S, Bitsch R, Kopcke W. Benfotiamine
in treatment of alcoholic polyneuropathy: an 8-week
randomized controlled study (BAP I Study). Alcohol and
Alcoholism 1998;33(6):631–8.
Biesenbach 1997 {published data only}
∗
Biesenbach G, Grafinger P, Eichbauer-Sturm G,
Zazgornik J. Treatment of painful diabetic neuropathy
with cerebrolysin [Cerebrolysin in der behandlung
der schmerzhaften diabetischen neuropathie]. Weiner
Medizinische Wochenschrift 1997;147(3):63–6.
Yaqub 1992 {published data only}
Yaqub BA, Siddique A, Sulimani R. Effects of
methylcobalamin on diabetic neuropathy. Clinical
Neurology and Neurosurgery 1992;94(2):105–11.
Bloomgarden 2004 {published data only}
∗
Bloomgarden ZT. Diabetes complications. Diabetes Care
2004;27(6):1506–14.
Zhang 2005 {published data only}
Zhang W-W, Yang X-P, Zhu G-M. Effects of epalrestat
made in China on sensory nerve conduction velocity in
patients with diabetic peripheral nervous disease. Chinese
Journal of Clinical Rehabilitation 2005;9(3):38–40.
Ziegler 1993 {published data only}
Ziegler D, Mayer P, Muhlen H, Gries FA. Effects of
alpha-lipoic acid and vitamin B1 treatment on diabetic
neuropathy [Effekte einer therapie mit alpha–liponsaure
gegenuber vitamin B1 bei der diabetischen neuropathie].
Diabetologie und Stoffwechsel 1993;2:443–8.
References to studies excluded from this review
Aaron 2005 {published data only}
∗
Aaron S, Kumar S, Vijayan J, Jacob J, Alexander M,
Gnanamuthu C. Clinical and laboratory features and
response to treatment in patients presenting with vitamin
B12 deficiency-related neurological syndromes. Neurology
India 2005;53(1):55–9.
Boulton 2004 {published data only}
∗
Boulton AJM, Malik RA, Arezzo JC, Sosenko JM.
Diabetic sensory neuropathies. Diabetes Care 2004;27(6):
1458–86.
Brecht 1999 {published data only}
∗
Brecht JG, Schadlich PK. Considerations on cost
effectiveness of a benfotiamine-vitamin B combination
in diabetic polyneuropathy: synthetic cost-effectiveness
analysis [Kostenwirksamkeit einer benfotiamin/
vitamin–B–kombination bei diabetischer polyneuropathie].
Gesundheitsokonomie und Qualitatsmanagement 1999;4(4):
99–105.
Buck 1995a {published data only}
∗
Buck G. New aspects in the therapy of polyneuropathy
[Neue ergebnisse zur therapie der polyneuropathie].
Zeitschrift fur Allgemeinmedizin 1995;71(5):355–8.
Buck 1995b {published data only}
∗
Buck G. Neurotropic vitamins B: proved effective in
polyneuropathy. Zeitschrift fur Allgemeinmedizin 1995;71
(4):263.
16
Buck 1996 {published data only}
∗
Buck G. Therapy safety and pharmaeconomics of diabetic
polyneuropathy/Diabetic polyneuropathy: therapy safety
and pharmaeconomy [Diabetische polyneuropathie.
Therapiesicherheit und pharmaokonomie]. Zeitschrift fur
Allgemeinmedizin 1996;72(21-22):1323–4.
Burns 2003 {published data only}
∗
Burns TM, Ryan MM, Darras B, Royden Jones H. Current
therapeutic strategies for patients with polyneuropathies
secondary to inherited metabolic disorders. Mayo Clinic
Proceedings 2003;78(7):858–68.
Calissi 1995 {published data only}
∗
Calissi PT, Jaber LA. Peripheral diabetic neuropathy:
current concepts in treatment. The Annals of Pharmacology
1995;29(7-8):769–77.
Chavez Olvera 1986 {published data only}
∗
Chavez Olvera JL, Anorve Borquez CR, Paz Morelos
GP. Controlled therapeutical evaluation of a mixture
of dexamethasone and complex B vitamins, and
dexamethasone alone. Compendium de Investigaciones
Clinicas Latinoamericanas 1986;6(2):101–5.
Chen 2000 {published data only}
∗
Chen D, Zhang J, Wang K. Curative effects of PGE1 and
mecobalamin on diabetic neuropathies. Journal of Henan
Practical Nervous Diseases 2000;3(5):1–2.
Cohen 1984 {published data only}
∗
Cohen KL, Gorecki GA, Silverstein SS, Ebersole JS,
Solomon LR. Effect of pyridoxine (vitamin B6) on diabetic
patients with peripheral neuropathy. Journal of the American
Podiatry Association 1984;74(8):394–7.
Delcker 1989 {published data only}
∗
Delcker A, Fischer P-A, Ulrich H. Randomised study
of thioctic acid compared with a preparation of vitamin
B in patients with diabetic polyneuropathy, taking
particular account of the peripheral nervous system
[Randomisierte studie thioctsaure gegenuber vitamin–
B–kombinationspraparat bei patienten mit diabetischer
polyneuropathie unter besonderer berucksichtigung des
peripheren nervensystems]. Thioctsaure: Neue biochemische,
pharmakologische and klinische Erkenntnisse 1989:335–44.
Dettori 1973 {published data only}
∗
Dettori AG, Ponari O. Antalgic effect of cobamamide
in the course of peripheral neuropathies of different
etiopathogenesis [Effetto antalgico della cobamamide in
corso di neuropatie periferiche di diversa etiopatogenesi].
Minerva Medica 1973;64(21):1077–82.
European Archives of Psychiatry and Neurological Sciences
1990;239(4):218–20.
Dueñas 2005 {unpublished data only}
∗
Dueñas. Clinical experience with mecobalamin at
N.O.H.-R.M.C. Data on file Year obtained 2005.
Eckert 1992a {published data only}
∗
Eckert VM, Schejbal P. Therapy of neuropathies with
a vitamin B combination. Symptomatic treatment of
painful diseases of the peripheral nervous system with a
combination preparation of thiamine, pyridoxine and
cyanocobalamin [Therapie von neuropathien mit einer
vitamin–B–kombination]. Fortschritte der Medizin 1992;
110(29):544–8.
Eckert 1992b {published data only}
Eckert VM, Schejbal P. Treatment of neuropathies with a
vitamin B combination. Symptomatic treatment of painful
diseases of the peripheral nervous system. Fortschritte der
Medizin 1992;110(29):60–4.
Faldini 1970 {published data only}
∗
Faldini A, Marchetti N. Clinical trial of a new synthetic
product: o-ethoxybenzylhydrazone of diethanolamine
pyruvate associated with vitamins B1, B6 and B12
and dichloroethanoate of disopropylammonium in the
treatment of rheumatic and neuritic pain syndromes
[Sperimentazione clinica di un nuovo prodotto di sintesi:
l’o–etossibenzoil–idrazone del piruvato di dietanolamina
associato alle vitamine B1, B6 e B12 ed al dicloroetanoato
di diisopropilammonio nel trattamento delle sindromi
dolorose reumatiche e nevritiche]. Minerva Ortopedica
1970;21(1):51–6.
Ferrante 2003 {published data only}
∗
Ferrante FM. The pharmacologic management of
neuropathic pain. Seminars in Anesthesia, Perioperative
Medicine and Pain 2003;22(3):168–74.
Fliege 1966 {published data only}
∗
Fliege VK, Mistler O. Treatment of chronic painful
conditions with a diazethylthiamine (fat-soluble vitamin
B1) combination preparation [Behandlung chronischer
schmerzzustande mit einem diazetylthiamin– (fettlosclichem
vitamin B1)– kombinationspraparat]. Medizinische Klinik
1966;61(52):2080–2.
FrancoisGermain 1980 {published data only}
∗
Francois-Germain LJ. Clinical trial on the combination
dexamethasone and vitamins B1, B6 and B12. Investigacion
Medica Internacional 1980;7(1):71–5.
Giannoukakis 2005 {published data only}
∗
Giannoukakis N. Pyridoxamine Biostratum. Current
Opinion in Investigational Drugs 2005;6(4):410–8.
Devathasan 1986 {published data only}
∗
Devathasan G, Teo WL, Mylvaganam A, Thai AC,
Chin JH. Methylcobalamin (CH3-B12; methycobal) in
chronic diabetic neuropathy: a double-blind clinical and
electrophysiological study. Clinical Trials Journal 1986;23
(2):130–40.
Gillioli 1984 {published data only}
∗
Gillioli R, Cotroneo L, Sanarico M. Controlled clinical
trial of brain gangliosides in the treatment of peripheral
neuropathies due to industrial chemicals. Clinical Trials
Journal 1984;21(6):459–74.
Djoenaidi 1990 {published data only}
∗
Djoenaidi W, Notermans SLH. Thiamine
tetraphydrofurfuryl disulfide in nutritional polyneuropathy.
Gregersen 1983 {published data only}
∗
Gregersen G, Bertelsen B, Harbo H, Larsen E, Andersen
JR, Helles A, et al.Oral supplementation of myoinositol:
17
effects on peripheral nerve function in human duabetics
and on the concentration in plasma, erythrocytes, urine
and muscle tissue in human diabetics and normals. Acta
Neurologica Scandinavica 1983;67(3):164–72.
Halat 2003 {published data only}
∗
Halat KM, Denneby CE. Botanicals and dietary
supplements in diabetic peripheral neuropathy. Journal of
the Americal Board of Family Practice 2003;16(1):47–57.
Haupt 2005 {published data only}
∗
Haupt E, Ledermann H, Kopcke W. Benfotiamine
in the treatment of diabetic polyneuropathy - a threeweek randomized, controlled pilot study (BEDIP Study).
International Journal of Clinical Pharmacology and
Therapeutics 2005;43(2):71–7.
Hughes 1995 {published data only}
∗
Hughes RAC, Heywood P, Sharrack B. Drug trials in
neuropathy. Baillieres Clinical Neurology 1995;4(3):607–27.
Ide 1987 {published data only}
∗
Ide H, Fujiya S, Asanuma Y, Tsuji M, Sakai H,
Agishi Y. Clinical usefulness of intrathecal injection of
methylcobalamin in patients with diabetic neuropathy.
Clinical Therapeutics 1987;9(2):183–92.
Ishihara 1992 {published data only}
∗
Ishihara H, Yoneda M, Yamamoto W, Ito T, Osawa H,
Okuno M, et al.Efficacy of intravenous administration of
methylcobalamin for diabetic peripheral neuropathy: a
quantitative study based on the measurement of peripheral
nerve conduction velocity. Medical Consultation and New
Remedies 1992;29(7):1–5.
Jorg 1988 {published data only}
∗
Jorg J, Metz F, Scharafinski H. Treatment of
diabetic polyneuropathy with alpha-lipoic acid or
vitamin B preparations: a controlled clinical trial
[Zur medikamentosen behandlung der diabetischen
polyneuropathie mit der alpha–liponsuare oder vitamin
B–praparaten]. Nervenarzt 1988;59(1):36–44.
Jorg 1989 {published data only}
∗
Jorg J. Treatment of diabetic polyneuropathy with thioctic
acid or with a vitamin B preparation. A controlled clinical
study. [Behandlung der diabetischen polyneuropathie
mit thioctsaure oder einem vitamin–B–praparat; eine
kontrollierte klinische studie]. Thioctsaure: Neue
biochemische, pharmakologische und klinische Erkenntnisse
zur Thioctsaure. Frankfurt: pmi Verlag, 1989:317.
Kastrup 1986 {published data only}
∗
Kastrup J, Peterson P. Treatment of painful diabetic
neuropathy [Behandling af smertefuld diabetisk neuropati].
Ugeskrift for Laeger 1986;148(38):2387–90.
Kikkawa 2006 {published data only}
∗
Kikkawa R, Hatanaka Y, Shigeta Y, Ohji K, Ohmori S,
Hoshi M, et al.Therapeutic effects of methylcobalamin and
a multi-vitamin preparation containing B1, B6 and B12 on
diabetic neuropathy. Data on file Year obtained 2006:2–12.
Kikuchi 1982 {published data only}
∗
Kikuchi T. Clinical studies of MCS 31 (mecobalamin) on
diabetic peripheral neuropathy. Japanese Pharmacology and
Therapeutics 1982;10(4):403–8.
Koltringer 1992 {published data only}
∗
Koltringer P, Langsteger W, Lind P, Klima G, Florian W,
Schubert B, et al.Ginkgo biloba extract EGb 761 and folic
acid in the treatment of diabetic polyneuropathy [Gingko
biloba–spezialextrakt EGb 761 und folsaure bei diabetischer
polyneuropathie. Eine ransomisierte placebokontrollierte
doppelblind–studie]. Zeitschrift fur Allgemeinmedizin 1992;
68(4):96–102.
Koyama 1997 {published data only}
∗
Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami
T, Tanaka N. Abnormal cyanide metabolism in uraemic
patients. Nephrology Dialysis Transplantation 1997;12(8):
1622–8.
Kretschmar 1996 {published data only}
∗
Kretschmar C, Kaumeier S, Haase W. Medicamentous
therapy of alcoholic polyneuropathy. Randomized doubleblind study comparing 2 vitamin B preparations and a
nucleotide preparation [Die medikamentose therapie
der alkoholischen polyneuropathie. Randomisierte
doppelblindstudie zum vergleich zweier vitamin–B–
praparate und eines nukleotid–praparates]. Fortschritte Der
Medizin 1996;114(32):439–43.
Leiner 2003 {published data only}
Leiner S. Painful sensory neuropathy. New England Journal
of Medicine 2003; Vol. 349, issue 3:306–7.
Li G 1999 {published data only}
∗
Li G (Beijing Methycobal Clinical Trial Collaborative
Group). Effect of mecobalamin on diabetic neuropathies.
Chinese Journal of Internal Medicine (Zhonghua Nei Ke Za
Zhi) 1999;38(1):14–7.
Li X 2001 {published data only}
∗
Li XF, Hu Q, Zhu D. Clinical trial of mecobalamin in
diabetic peripheral neuropathies. Chinese Journal of Primary
Medicine and Pharmacy 2001;8(5):452–3.
Libarnes 1984 {unpublished data only}
∗
Libarnes RL, Diy MLL, Renales LD, Perez MC. Clinical
study of methylcobalamin on diabetic neuropathies.
Department of Medicine, Section of Neurology, University
of the Philippines-Philippine General Hospital. 1984.
Lonsdale 2004 {published data only}
∗
Lonsdale D. Thiamine tetrahydrofurfuryl disulfide: a little
known therapeutic agent. Medical Science Monitor 2004;10
(9):RA199–203.
Malizia 1982 {published data only}
∗
Malizia E, Borgo S, Carapella C, Chiavarelli V, Russo A,
Gagliardi V, et al.Organic glue neuropathies: epidemiology,
clinical investigation and therapy of 100 cases. Archives of
Toxicology 1982;49(Suppl 5):103–4.
McCann 1983 {published data only}
∗
McCann VJ, Davis RE. Pyridoxine and diabetic
neuropathy: a double-blind controlled study. Diabetes Care
1983;6(1):102–3.
18
MedinaSantillan 2004 {published data only}
∗
Medina-Santillan R, Morales-Franco G, Espinoza-Raya J,
Granados-Soto V, Reyes-Garcia G. Treatment of diabetic
neuropathic pain with gabapentin alone or combined with
vitamin B complex. Preliminary results. Proceedings of the
Western Pharmacology Society 2004;47:109–12.
Meyer 2003 {published data only}
∗
Meyer FP. Polyneuropathy-therapy [Polyneuropathie–
therapie]. Deutsche Medizinische Wochenschrift 2003;128
(11):572.
Mocchi 1967 {published data only}
∗
Mocchi N, Pollini F. Clinical trials of the combination:
orthoxyquinoline sulfonate of aminophenazone-vitamin B6vitamin B12 (Liocausyth) in rheumatological and neuritic
diseases. Minerva Medica 1967;58(18:Suppl):766–9.
Montenero 1983 {published data only}
∗
Montenero P, Marozzi G, Chiaramonte F. Possibilities of
using brain gangliosides in treatment of peripheral diabetic
neuropathy [Possibilita di impiego dei gangliosidi cerebrali
nel trattamento della neuropatia diabetica periferica].
Clinica Terapeutica 1983;106(3):169–74.
Montes De Oca 1979 {published data only}
∗
Montes De Oca CL. A comparative study of high doses
of cobamamide and hydoxocobalamine in the treatment of
diabetic neuropathies [Estudio comparativo a altas dosis
entre cobamamida e hidroxocobalamina en el tratamiento de
neuropatias diabeticas]. Investigacion Medica Internacional
1979;6(4):310–5.
Mooradian 1994 {published data only}
Mooradian AD, Failla M, Hoogwerf B, Maryniuk M,
Wylie-Rosett J. Selected vitamins and minerals in diabetes.
Diabetes Care 1994;17(5):464–79.
Moridera 2005 {published data only}
∗
Moridera K, Yoshikawa N, Igarashi T. Clinical evaluation
of methyl-B12 in the treatment of diabetic autonomic and
peripheral neuropathy. Data on file. Year obtained 2005:
443–6.
Nakamura 2003 {published data only}
∗
Nakamura K, Roberson ED. Polyneuropathy following
gastric bypass surgery. The American Journal of Medicine
2003;115(8):679–80.
Nikolov 1997 {published data only}
∗
Nikolov N, Valcheva V, Manchev I. Therapeutic efficacy
research into the Milgamma-Dragees preparation used at
people suffering from diabetic polyneuropathy. Bulgarian
Medicine 1997;5(3-4):16–7.
Okada H 2000 {published data only}
∗
Okada H, Moriwaki K, Kanno Y, Sugahara S, Nakamoto
H, Yoshizawa M, et al.Vitamin B6 supplementation
can improve peripheral polyneuropathy in patients with
chronic renal failure on high-flux haemodialysis and
human recombinant erythropoietin. Nephrology Dialysis
Transplantation 2000;15(9):1410–3.
Okada S 1985 {published data only}
∗
Okada S, Miyai Y, Sato K, Masaki Y, Higuchi T, Ogino Y,
et al.Effect of methylcobalamin on diminished motor nerve
conduction velocity in the tibial nerve of poorly controlled
diabetics. Clinical Trials Journal 1985;22(6):534–6.
Osuntokun 1970 {published data only}
∗
Osuntokun BO, Langman MJS, Wilson J, Aladetoyinbo
A. Controlled trial of hydroxocobalamin and riboflavine
in Nigerian ataxic neuropathy. Journal of Neurology,
Neurosurgery and Psychiatry 1970;33(5):663–6.
Osuntokun 1974 {published data only}
∗
Osuntokun BO, Langman MJS, WIlson J, Adeuja
AOG, Aldetoyinbo MA. Controlled trial of combinations
of hydroxocobalamin-cystine and riboflavine-cystine,
in Nigerian ataxic neuropathy. Journal of Neurology,
Neurolsurgery and Psychiatry 1974;37(1):102–4.
Paggao 2006 {unpublished data only}
∗
Paggao J. Clinical experience on mecobalamin injection at
Dr. Efren C. Montemayor Memorial Medical Center. Year
obtained 2006.
Parry 1985 {published data only}
∗
Parry GJ, Bredesen DE. Sensory neuropathy with lowdose pyridoxine. Neurology 1985;35(10):1466–8.
Pfeifer 1995 {published data only}
∗
Pfeifer MA, Schumer MP. Clinical trials of diabetic
neuropathy: past, present, and future. Diabetes 1995;44
(12):1355–61.
Podell 1985 {published data only}
Podell RN. Nutritional supplementation with megadoses
of vitamin B6. Effective therapy, placebo, or potentiator of
neuropathy?. Postgraduate Medicine 1985;77(3):113–6.
Reschke 1989 {published data only}
∗
Reschke B, Zeuzem S, Rosak C, Petzoldt R, Althoff PH, Ulrich H, et al.High dose long term treatment with
thioctic acid in diabetic polyneuropathy: results of a
controlled randomised study with particular attention on
autonomic neuropathy [Hochdosierte langzeitbehandlung
mit thioctsaure bei der diabetischen polyneuropathie –
ergebnisse einer kontrollierten, randomisierten studie unter
besonderer berucksichtigung der autonomen neuropathie].
Thioctsaure: Neue biochemische, pharmakologische und
klinische Erkenntnisse zur Thioctsaure 1989:318–34.
Reyes 1980 {published data only}
∗
Reyes HE. An open study of the vitamin combination
B1-B6-B12 in diabetic neuropathies. Investigacion Medica
Internacional 1980;7(3):201–8.
Richter 2000 {published data only}
∗
Richter H-J. Benfotiamine protects diabetic patients
for neuropathy [Benfotiamin schutzt diabetiker vor
neuropathien]. Nervenheilkunde 2000;19(7):111.
Roimicher 1970 {published data only}
∗
Roimicher S, de Azevedo MN, Pereira O, Barros SM.
Comparative study of the effects of hydroxycobalamin and
cyanocobalamin on rheumatic pains (double blind test)
[Estudo comparativo da acao da hidroxocobalamina e da
cianocobalamina nas algias reumaticas (ensaio duplo–cego)].
Hospital 1970;78(2):373–81.
19
Sachse 1980 {published data only}
∗
Sachse G, Willms B. Efficacy of thioctic acid in the
therapy of peripheral diabetic neuropathy. Hormone and
Metabolic Research 1980;9 Suppl:105–7.
Tong 1980 {published data only}
∗
Tong HI. Influence of neurotropic vitamins on the nerve
conduction velocity in diabetic neuropathy. Annals Academy
of Medicine, Singapore 1980;9(1):65–70.
Saurugg 1977 {published data only}
∗
Saurugg VD, Hodkewitsch E. Clinical experiences
with an analgesic-acting infusion solution in neurological
painful conditions [Klinische erfahrungen mit einer
analgetisch wirkenden infusionslosung bei neurologischen
schmerzzustanden]. Wien Med Wochenschr 1977;127(15):
490–2.
Torri 1992 {published data only}
∗
Torri G, Arosio B. Open, comparative trial in the
evaluation of the efficacy and tolerability of a ganglioside
versus a combination of B vitamins in patients with
peripheral neuropathy [Studio aperto comparativo per
valutare l’efficacia e la tollerabilita’ di un preparato a base di
gangliosidi nei confronti di un polivitaminico del gruppo
B in pazienti affeti da neuropatie periferiche]. Ortopedia e
Traumatologia Oggi 1992;12(2-3):85–91.
Shi 2003 {published data only}
∗
Shi XW. The treatment for diabetic peripheral neuropathy
by combined puerarin with methylcobalamin. Zhejiang
Practical Medicine 2003;8(1):17–8.
Shindo 1994 {published data only}
∗
Shindo H, Tawata M, Inoue M, Yokomori N, Hosaka
Y, Ohtaka M, et al.The effect of prostaglandin E1-alpha
CD on vibratory threshold determined with the SMV-5
vibrometer in patients with diabetic neuropathy. Diabetes
Research and Clinical Practice 1994;24(3):173–80.
Simeonov 1997 {published data only}
∗
Simeonov S, Pavlova M, Mitkov M, Mincheva L, Troev
D. Therapeutic efficacy of “Milgamma” in patients with
painful diabetic neuropathy. Folia Medica (Plovdiv) 1997;
39(4):5–10.
Simonin 1981 {published data only}
∗
Simonin C, Hovette P, Rey M. Value of treatment with
arginine oxoglurate plus B-group vitamins in polyneuritis of
chronic alcoholism. Medecine Interne 1981;16(2):85–90.
Skelton 1991 {published data only}
∗
Skelton WP, Skelton NK. Neuroleptics in painful thiamine
deficiency neuropathy. Southern Medical Journal 1991;84
(11):1362–3.
Stein-Hammer 1996 {published data only}
∗
Stein-Hammer C. Benfothiamine-vitamin B complex in
polyneuropathy. Therapiewoche 1996;46(11):598–9.
Sun 2005 {published data only}
Sun Y, Lai M-S, Lu C-J. Effectiveness of vitamin B12 on
diabetic neuropathy: systematic review of clinical controlled
trials. Acta Neurologica Taiwanica 2005;14(2):48–54.
Suzuki 1985 {published data only}
∗
Suzuki K. Clinical effects of E-0723 (mecobalamin,
d-alpha-tocopherol acetate preparation) on peripheral
neuropathy in the field of orthopedics. Comparison with
a mecobalamin preparation. Japanese Pharmacology and
Therapeutics 1985;13(5):531–54.
Tanigawa 2006 {unpublished data only}
∗
Tanigawa K, Ikeda M. Effect of methylcobalamin on
diabetic neuropathy with special reference to its effectiveness
by intramuscular injection. Second Department of Internal
Medicine, Kyoto University School of Medicine, Japan.
Year obtained 2006.
Utsunomiya 1987 {published data only}
∗
Utsunomiya K. Clinical effect of vitamin B6 on diabetic
neuropathy - open multicenter trial. Therapeutic Research
1987;7(3):287–94.
Wibowo 2005 {unpublished data only}
∗
Wibowo BS, Sastradiwirjo S, Sukaton U, Nurhayatie T.
New aspects in the treatment of diabetic neuropathy with
methylcobalamin: electrophysiologic quantification of
diabetic neuropathy. Department of Neurology, University
of Indonesia, RSCM Hospital, Indonesia. Year obtained
2005.
Wu 2002 {published data only}
∗
Wu J, Zhong HJ, Sun ZX, Yi H, Lei MX. Efficacy of
erigeron on diabetic peripheral neuropathy. Bulletin of
Hunan Medical University 2002;27(4):337–40.
Yamada 1982 {published data only}
∗
Yamada K, Goto Y, Takebe K. Treatment of diabetic
peripheral neuropathy with methylcobalamin. Proceedings
of the International Symposium on Diabetic Neuropathy
and its Treatment, Tokyo. 1982.
Yao 2004 {published data only}
∗
Yao G, Qu SY, Wang XR, Li L, Li HJ, Chen XH. Effect
of medication on diabetic peripheral neuropathy by clinical
intervention. Chinese Journal of Clinical Rehabiliation 2004;
8(16):3032–3.
Yoshioka 1995 {published data only}
∗
Yoshioka K, Tanaka K. Effect of methylcobalamin on
diabetic autonomic neuropathy as assessed by power spectral
analysis of heart rate variations. Hormone and Metabolic
Research 1995;27(1):43–4.
Zhong 1981 {published data only}
∗
Zhong X, Zheng B, Hu G, Zhu X, Hu Z. Early treatment
of diabetic neuropathy. Chinese Medical Journal 1981;94
(8):503–8.
Zhu 2001 {published data only}
∗
Zhu XP, Zhou ZG. Clinical observation of combined
therapeutic effect of prostaglandin E1 and mecobalamin on
diabetic peripheral neuropathy. Bulletin of Hunan Medical
University 2001;26(4):343–4.
Additional references
20
Annane 2004
Annane D, Gunn A, Hughes R, Jewitt K, Miller R,
Moore D, O’Connor D, Rose M, Swan A. Neuromuscular
Disease Group. Neuromuscular Disease Group. About the
Cochrane Collaboration (Collaborative Review Groups
(CRGs)). The Cochrane Library 2004, issue 4.
Chaney 1992
Chaney S. Principles of nutrition II: micronutrients. In:
Delvin TM editor(s). Textbook of Biochemistry with Clinical
Correlations. New York: Wiley-Liss, 1992:1115–47.
Clarke 2001
Clarke M, Oxman A, editors. Collecting Data. Cochrane
Reviewers Handbook 4.1.4 [upated October 2001]; Section
7. In: The Cochrane Library [database on CDROM]. The
Cochrane Collaboration. Oxford: Update Software; 2001,
Issue 4.
Dyck 2005
Dyck P, Hughes R, O’Brien P. Quantitating overall
neuropathic symptoms, impairments and outcomes. In:
Dyck P, Thomas P editor(s). Peripheral Neuropathy. 4th
Edition. Philadelphia: Elsevier Saunders, 2005:1031–53.
Hillman 1996
Hillman R. Hematopoietic agents: growth factors, minerals
and vitamins. In: Gilman A, Goodman L, Gilman A editor
(s). Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. 9th Edition. McGraw-Hill, 1996:1311–40.
Hughes 2002
Hughes RAC. Peripheral neuropathy. BMJ 2002;324
(7335):466–9.
Huskisson 1974
Huskisson EC. Measurement of pain. Lancet 1974;2(7889):
1127–31.
Kaushansky 2006
Kaushansky K, Kipps TJ. Hematopoeitic agents: growth
factors, minerals and vitamins. In: Brunton LL, Lazo
JS, Parker KL editor(s). Goodman and Gilman’s The
Pharmacological Basis of Therapeutics. 11th Edition.
McGraw-Hill, 2006:1433–64.
Lumley 2001
Lumley J, Watson L, Watson M, Bower C. Periconceptional
supplementation with folate and/or multivitamins for
preventing neural tube defects. Cochrane Database
of Systematic Reviews 2001, Issue 3. [MEDLINE:
CD001056][Art. No.: CD001056. DOI: 10.1002/
14651858.CD001056]
Mahomed 2002
Mahomed K. Folate supplementation in pregnancy.
Cochrane Database of Systematic Reviews 2002,
Issue 1.[Art. No.: CD000183. DOI: 10.1002/
14651858.CD000183.pub2]
Marcus 1996
Marcus R, Coulston A. Water-soluble vitamins: the vitamin
B complex and ascorbic acid. Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 9th Edition.
McGraw-Hill, 1996:1555–72.
McCarter 1992
McCarter DN, Holbrook J. Vitamins and minerals. In:
Herfindal ET, Gourley DR, Hart LL editor(s). Clinical
Pharmacy and Therapeutics. 5th Edition. Baltimore:
WIlliams & Williams, 1992:133–49.
Olson 1996
Olson R. Water-soluble vitamins. Principles of Pharmacology
Basic Concepts and Clinical Application. Kentucky:
Chapman and Hall, 1996:949–79.
RodriguezMartin 2002
Rodriguez-Martin J, Qizilbash N, Lopez-Arrieta J.
Thiamine for Alzheimer’s disease. Cochrane Database of
Systematic Reviews 2002, Issue 1.[Art. No.: CD001498.
DOI: 10.1002/14651858.CD001498]
Schaumburg 1983
Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus
S, Pleasure D, et al.Sensory neuropathy from pyridoxine
abuse. The New England Journal of Medicine 1983;309(8):
445–8.
van Boxtel 2001
van Boxtel CJ. Vitamins. In: van Boxtel CJ, Santoso
B, Ralph Edwards I editor(s). Drug Benefits and Risks.
International Textbook of Clinical Pharmacology. Chichester:
John Wiley & Sons, Ltd., 2001:415–20.
∗
Indicates the major publication for the study
21
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Abbas 1997
Methods
Randomised, double blind, parallel group trial.
Participants
200 patients with diabetic peripheral neuropathy based on two or more of the following: symptoms, loss of
light touch, impairment of pain perception, absent ankle jerks, impairment of temperature and vibration
sense
Interventions
Treatment capsule containing 25 mg thiamine and 50 mg pyridoxine, 2 capsules once a day for 3 days
followed by 1 capsule daily for next 25 days; or placebo capsule containing 1 mg thiamine and 1 mg
pyridoxine taken in same regimen as treatment capsule
Outcomes
Change (improved or same) in best symptom, symptom severity, and sign severity one month after
treatment. Change in the worst symptom (pain, numbness, paraesthesiae) one month following treatment
Notes
Single center. Conducted in Tanzania.
Risk of bias
Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Duque 1994
Methods
Randomised, placebo- controlled, double blind, parallel group trial
Participants
40 adult patients with diabetes and peripheral neuropathy based on neurological signs and symptoms and
nerve conduction velocity studies, with or without clinical evidence of autonomic dysfunction
Interventions
500 mcg intramuscular mecobalamin 3 x a week for 4 weeks; or placebo
Outcomes
Change in neurologic findings (subjective - sensorimotor, autonomic; objective - sensorimotor) and motor
and sensory latencies, amplitudes, and nerve conduction velocities after 4 weeks of treatment
Notes
Single center. Conducted in the Philippines. Study sponsored by pharmaceutical company
Risk of bias
Item
Description
Yes
A - Adequate
22
Hu 2004
Methods
Quasirandomised, parallel group trial.
Participants
50 adult patients with diabetic peripheral neuropathy based on symptoms, signs, and nerve conduction
studies
Interventions
Oral cilostazol 500 mg 2 x a day for 8 weeks; or intramuscular vitamin B12 500 mcg and vitamin B1 100
mg 4 x a day for 8 weeks
Outcomes
Change in “neurological syndrome score” and “physical sign score” and nerve conduction velocities after
8 weeks of treatment
Notes
Single center. Conducted in China. Translated paper (Chinese)
Risk of bias
Item
Description
Unclear
B - Unclear
Kovrazhkina 2004
Methods
Randomised, parallel group trial.
Participants
56 adult patients with alcoholic polyneuropathy based on symptoms and signs
Interventions
Oral berlition 300 mlg (12 ml) 2 x a day for 2 weeks followed by 300 mlg tablets 2 x a day for 4 weeks;
or vitamin B1 2 ml 2 x a day for 2 weeks followed by “polivitamin” in tablets with unspecified dose 2x a
week for 4 weeks
Outcomes
Change in paraesthesiae, pain, superficial sensation, deep sensation, tone, trophics, reflexes, and sensory
nerve conduction velocities after 7 days, 14 days, and 42 days of treatment
Notes
Trial location not reported.
Conducted in Russia (?). Single center (?). Translated paper (Russian)
Risk of bias
Item
Description
Unclear
B - Unclear
23
Levin 1981
Methods
Participants
18 adult patients with symptomatic peripheral neuropathy. All patients had moderate to severe neuropathic
symptoms and signs of peripheral neuropathy
Interventions
Pyridoxine hydrochloride 50 mg tablet every 8 hours for 4 months; or placebo
Outcomes
Change in neuropathic symptoms, and motor nerve conduction velocity after 4 months of treatment
Notes
Single center. Conducted in USA.
Risk of bias
Item
Description
Yes
A - Adequate
Li X 2005
Methods
Randomised, parallel group trial.
Participants
50 adult patients with diabetic peripheral neuropathy based on symptoms, signs, and nerve conduction
velocity studies
Interventions
Intravenous cytidine triphosphate 60 mg in 100 ml normal saline 4 x a day for 14 days; or intramuscular
vitamin B1 100 mg and vitamin B12 500 mcg 4 x a day for 14 days
Outcomes
Change in curative effect of symptoms (pain, numbness), neurologic signs, and sensory and motor conduction velocities after 2 weeks of treatment
Notes
Risk of bias
Item
Description
Unclear
B - Unclear
Stracke 1996
Methods
Participants
24 adult patients with diabetes and polyneuropathy of at least 4 months but not more than 3 years
duration, with at least one subjective symptom and at least two of the three objective criteria of neuropathy
24
Stracke 1996
(Continued)
Interventions
1 capsule of verum contained 40 mg benfotiamine, 90 mg pyridoxine hydrochloride and 0.25 mg
cyanocobalamin.
2 capsules verum 4 x a day for weeks 1 to 2 (in-hospital) followed by 1 capsule 3 x a day for weeks 3 to
12 (out-patient); or placebo
Outcomes
Change in perception threshold and nerve conduction velocity at randomisation and after 2 weeks and
12 weeks of treatment
Notes
Single center. Trial location not mentioned. Conducted in Germany (?)
Risk of bias
Item
Description
Unclear
B - Unclear
Strokov 1999
Methods
Randomised, “placebo” controlled, single blind, parallel group trial
Participants
50 adult patients with diabetic neuropathy based on symptoms and electroneuro- graphy
Interventions
Intravenous alpha-lipoic acid 600 mg every 2 hours for 5 days followed by alpha-lipoic acid 600 mg daily
for 2 days; or 1% solution of riboflavin mononucleate (vit B2) and tablets of placebo “during holidays.”
Outcomes
Change in symptoms and nerve conduction studies at day 21 of treatment
Notes
Trial location not reported. Conducted in Russia (?). Single center (?). Translated paper (Russian)
Risk of bias
Item
Description
Unclear
B - Unclear
Winkler 1999
Methods
Quasi- randomised, three-arm, parallel group trial.
Participants
36 adult patients with diabetic symptoms lasting > 1 year and painful peripheral neuropathy based on
symptom and impairment
Interventions
1 capsule of complex B- vitamin contained 40 mg benfotiamine, 90 mg pyridoxine, 250 mcg cyanocobalamin.
Group A:
4 x 2 capsules/ day of complex B-vitamin (total of 320 mg/day benfotiamine) for 6 weeks;
Group B:
25
Winkler 1999
(Continued)
3 x 1 capsules/ day of complex B-vitamin (total of 120 mg/day benfotiamine) for 6 weeks;
Group C:
3 x 1 tablets/day benfotiamine (total of 150 mg/day) for 6 weeks
Outcomes
Change in pain sensation; vibration sensation; current perception threshold at the beginning of the study,
at the end of the week 3 and week 6 of treatment
Notes
Single center. Conducted in Hungary.
Risk of bias
Item
Description
No
C - Inadequate
Woelk 1998
Methods
Randomised, placebo- controlled, three-arm, double blind, parallel group trial
Participants
84 adult patients with alcoholism based on DSM-III-R and with alcoholic polyneuropathy based on
symptom and impairment.
Only patients with marked symptoms of alcoholic polyneuropathy were admitted to the study
Interventions
Group A:
Benfotiamine 320 mg/day (2 capsules 4 x a day) during weeks 1 to 4 followed by 120 mg/day (1 capsule
3 x a day) during weeks 5 to 8;
Group B:
Oral neurotropic B vitamins - benfotiamine 320 mg + vitamin B6 720 mg + vitamin B12 2 mg (2 capsules
4 x a day) for the first 4 weeks followed by benfotiamine 120 mg + vitamin B6 270 mg + vitamin B12
0.75 mg (1 capsule 3 x a day) during weeks 5 to 8;
Group C:
Placebo.
Outcomes
Change in vibration perception, pain intensity, motor function, co-ordination, sensory function and
reflexes; overall neuropathy score; and global impressions after 2 weeks, 4 weeks, 6 weeks, and 8 weeks of
treatment
Notes
Multicenter. Conducted in Germany.
Risk of bias
Item
Description
Unclear
B - Unclear
26
Yaqub 1992
Methods
Randomised, placebo- controlled, double blind, parallel group
trial.
Participants
50 adult patients with diabetic neuropathy based on clinical symptoms, signs and/or neurophysiologi cal
abnormalities
Interventions
Methylcobalamin 250 mg 2 capsules 3 x a day for 4 months; or placebo
Outcomes
Change in symptoms (somatic and autonomic), signs (sensa tions, motor power, deep tendon reflexes,
autonomic), and neurophysiological results (motor, sensory) after 4 months of treatment
Notes
Trial location not mentioned. Single center (?) Conducted in Saudi Arabia (?) Study sponsored by pharmaceutical company
Risk of bias
Item
Description
Yes
A - Adequate
Zhang 2005
Methods
Randomised, single blind, parallel group trial.
Participants
40 adult patients with diabetic peripheral neuropathy based on symptoms, signs, and abnormal sensory
nerve conduction velocity and amplitude
Interventions
Epalrestat (no details reported) or mecobalamin tablet 500 mg 3 x a day for 16 weeks
Outcomes
Change in symptoms, signs, and nerve conduction velocities at 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12
weeks, and 16 weeks of treatment
Notes
Risk of bias
Item
Description
Unclear
B - Unclear
Ziegler 1993
Methods
Randomised, single blind, parallel group trial.
Participants
23 adult patients with diabetes mellitus based on the National Diabetes Data Group and with peripheral
neuropathy based on symptoms and pathological delay of “speed of neural transmission.”
27
Ziegler 1993
(Continued)
Interventions
Parenteral phase (ward):
2 intravenous injections of alpha-lipoic acid 300 mg in 0.9% NaCl solution daily; or 2 intra venous
injections of vitamin B1 200 mg daily for 3 weeks followed by Preoral phase (out-patient):
Same dose of medicine for another 12 weeks for both groups.
Outcomes
Change in autonomic function (variation coefficient and speed of mydriasis) and “speed of neural transmission” (motor and sensory) after 3 weeks and 15 weeks
Notes
Trial location not mentioned.
Single center (?). Conducted in Germany (?). Translated paper (German). Study sponsored by pharmaceutical company (?)
Risk of bias
Item
Description
Unclear
B - Unclear
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Aaron 2005
Not described as randomised (observational, retrospective and prospective study)
Anonymous 1994
Overview of 2 studies; no reference.
Anonymous 1996
Overview of 2 studies; not eligible.
Anonymous 2004a
Duplicate of Anonymous 2004b.
Anonymous 2004b
Overview.
Appiotti 1990
RCT but unclear basis of diagnosis of participants.
Biesenbach 1997
Not described as randomised (longitudinal study).
Bloomgarden 2004
Review.
Boulton 2004
Review.
Brecht 1999
Systematic review.
Buck 1995a
Overview; symposium with 4 studies; no reference.
28
(Continued)
Buck 1995b
Congress report.
Buck 1996
Overview.
Burns 2003
Review.
Calissi 1995
Review.
Chavez Olvera 1986
Not described as randomised (observational study).
Chen 2000
RCT but unclear basis of diagnosis of participants; intervention and comparison groups received same type
and dose of vitamin B
Cohen 1984
Delcker 1989
Dettori 1973
Not described as randomised (longitudinal study); no comparator
Devathasan 1986
RCT but diagnosis of participants based on symptoms alone.
Djoenaidi 1990
Dueñas 2005
Eckert 1992a
Not described as randomised (observational study); no comparator
Eckert 1992b
Duplicate of Eckert 1992a.
Faldini 1970
Ferrante 2003
Review.
Fliege 1966
Overview.
FrancoisGermain 1980
Not described as randomised (before and after study).
Giannoukakis 2005
Review.
Gillioli 1984
Gregersen 1983
Halat 2003
Review.
Haupt 2005
29
(Continued)
Hughes 1995
Review.
Ide 1987
Ishihara 1992
Jorg 1988
RCT but diagnosis of participants based on impairments alone
Jorg 1989
Abstract only.
Kastrup 1986
Review.
Kikkawa 2006
Kikuchi 1982
Koltringer 1992
RCT but intervention did not include specified types of vitamin B (folic acid alone)
Koyama 1997
Kretschmar 1996
Leiner 2003
Letter to the editor.
Li G 1999
RCT but diagnosis of participants based on smptoms alone; intervention and comparison groups received
same type and dose of vitamin B
Li X 2001
RCT but unclear diagnosis of participants; intervention and comparison groups received vitamin B12
(adenosyl coenzyme B12 and mecobalamin)
Libarnes 1984
Lonsdale 2004
Review.
Malizia 1982
McCann 1983
MedinaSantillan 2004
Meyer 2003
Mocchi 1967
Case series.
Montenero 1983
30
(Continued)
Montes De Oca 1979
RCT but unclear basis of diagnosis of participants; unclear treatment duration; intervention and comparison
groups received vitamin B12 (coenzyme B12 and hydroxocobalamine)
Mooradian 1994
Review.
Moridera 2005
Nakamura 2003
Nikolov 1997
Not described as randomised (longitudinal study); no comparator
Okada H 2000
RCT but diagnosis of participants based on symptoms alone; intervention and comparison groups received
vitamin B
Okada S 1985
Osuntokun 1970
RCT but diagnosis of participants not eligible (neuropathy part of a syndrome); intervention and comparison groups received vitamin B
Osuntokun 1974
RCT but diagnosis of participants not eligible (neuropathy part of a syndrome); intervention and comparison groups received vitamin B
Paggao 2006
RCT but participants did not have generalised peripheral neuropathy
Parry 1985
Case series.
Pfeifer 1995
Review.
Podell 1985
Feature article.
Reschke 1989
RCT but unspecified components of vitamin B combination.
Reyes 1980
Richter 2000
Overview.
Roimicher 1970
Quasi-randomised study but participants did not have generalised peripheral neuropathy
Sachse 1980
Saurugg 1977
Shi 2003
Shindo 1994
31
(Continued)
Simeonov 1997
RCT but diagnosis of participants based on symptoms alone; unspecified components of vitamin B combination
Simonin 1981
RCT but intervention and comparison groups received same type and dose of vitamin B
Skelton 1991
RCT but intervention did not include vitamin B.
Stein-Hammer 1996
Sun 2005
Systematic review.
Suzuki 1985
Tanigawa 2006
Tong 1980
Torri 1992
RCT but participants did not have generalised peripheral neuropathy
Utsunomiya 1987
Wibowo 2005
Wu 2002
Yamada 1982
Yao 2004
Yoshioka 1995
Zhong 1981
Zhu 2001
32
DATA AND ANALYSES
This review has no analyses.
ADDITIONAL TABLES
Table 1. Assessment of Methodological Quality of Included Studies
Study ID
Randomisation
Alloc. Conceal- Subject Blind- Observer Blind- Assessor Blind- Completeness
ment
ing
ing
ing
of F-up
Levin 1981
B
A
A
A
B
A
Yaqub 1992
B
A
A
A
B
B
Ziegler 1993
B
B
B
B
B
B
Duque 1994
A
A
A
A
D
A
Stracke 1996
B
B
A
A
B
B
Abbas 1997
B
A
A
A
B
A
Woelk 1998
B
B
A
A
B
A
Strokov 1999
B
B
A
B
B
A
WInkler 1999
C
C
D
D
D
B
Hu 2004
C
B
D
B
B
B
Kovrazhkina
2004
B
B
B
B
B
A
Li X 2005
B
B
D
B
B
A
Zhang 2005
B
B
A
B
B
A
33
APPENDICES
Appendix 1. OVID MEDLINE search strategy
’mp’ denotes keyword search in title,abstract,subject heading
’ $’ denotes truncation
’/’ denotes a mesh subject heading
’Exp’ denotes explosion of mesh subject heading
1. randomized controlled trial.pt.
2. randomized controlled trials/
3. controlled clinical trial.pt.
4. controlled clinical trials/
5. random allocation/
6. double-blind method/
7. single-blind method/
8. clinical trial.pt.
9. exp clinical trials/
10. (clin$ adj25 trial$).tw.
11. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$ or dummy)).tw.
12. placebos/
13. placebo$.tw.
14. random$.tw.
15. research design/
16. (clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
17. multicenter study.pt.
18. meta analysis.pt.
19. Prospective Studies/
20. Intervention Studies/
21. Cross-Over Studies/
22. Meta-Analysis/
23. (meta?analys$ or systematic review$).tw.
24. control.tw.
25. or/1-24
26. Animal/
27. Human/
28. 26 and 27
29. 26 not 28
30. 25 not 29
31. exp Vitamin B Complex/
32. Vitamin B.mp.
33. Aminobenzoic$.mp.
34. Biotin$.mp.
35. Folic$.mp.
36. Inosit$.mp.
37. Nicotinic$.mp.
38. Niacin$.mp.
39. Pantothenic$.mp.
40. Riboflavin$.mp.
41. Thiamin$.mp.
42. Cobamide$.mp.
43. Cobalamin$.mp.
44. Pyridox$.mp.
34
45. or/31-44
46. exp Peripheral Nervous System Diseases/
47. neuropath$.mp.
48. 46 or 47
49. Pain.mp. or exp PAIN/
50. 48 and 49
51. exp Demyelinating Diseases/
52. demyelin$.mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
53. 51 or 52
54. (Guillain and Barre).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
55. (Miller and Fisher).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
56. exp LEPROSY/
57. (Leprosy or Leper$).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
58. (Hansen$ and Disease).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
59. or/54-58
60. Diabetic Neuropathies/
61. (motor and Sensory and Neuropath$ and Heredity).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
62. (Charcot and Marie).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
63. (Dejerine and Sottas).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
64. (Refsum and Syndrome$).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
65. (Spastic and Parapleg$).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
66. exp “Hereditary Sensory and Autonomic Neuropathies”/
67. (Sensory and autonomic and neuropath$ and heredity).mp. [mp=title, abstract, cas registry/ec number word, mesh subject heading]
68. or/60-67
69. 48 or 50 or 53 or 59 or 68
70. 45 and 69
71. 30 and 70
Appendix 2. OVID EMBASE search strategy
1. Randomized Controlled Trial/
2. Clinical Trial/
3. Multicenter Study/
4. Controlled Study/
5. Crossover Procedure/
6. Double Blind Procedure/
7. Single Blind Procedure/
8. exp RANDOMIZATION/
9. Major Clinical Study/
10. PLACEBO/
11. Meta Analysis/
12. phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/
13. (clin$ adj25 trial$).tw.
14. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.
15. placebo$.tw.
16. random$.tw.
17. control$.tw.
18. (meta?analys$ or systematic review$).tw.
19. (cross?over or factorial or sham? or dummy).tw.
20. ABAB design$.tw.
21. or/1-20
22. human/
35
23. nonhuman/
24. 22 or 23
25. 21 not 24
26. 21 and 22
27. 25 or 26
28. exp Vitamin B group/
29. Vitamin B.mp.
30. Aminobenzoic$.mp.
31. Biotin$.mp.
32. Folic$.mp.
33. Inosit$.mp.
34. Nicotinic$.mp.
35. Niacin$.mp.
36. Pantothenic$.mp.
37. Riboflavin$.mp.
38. Thiamin$.mp.
39. Cobamide$.mp.
40. Cobalamin$.mp.
41. Pyridox$.mp.
42. or/28-41
43. exp Neuropathy/
44. (neuropath$ or peripheral neuropath$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
45. 43 or 44
46. exp Pain/ or pain.mp.
47. 45 and 46
48. exp Demyelinating Disease/
49. demyelin$.mp.
50. 48 or 49
51. (Guillain and Barre).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
52. (Miller and Fisher).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer
name]
53. exp Leprosy/
54. (leprosy or leper$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer
name]
55. (Hansen$ and Disease).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug
manufacturer name]
56. or/51-55
57. Diabetic Neuropathy/
58. (motor and sensory and neuropath$ and heredity).mp.
59. (Charcot and Marie).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
60. (Dejerine and Sottas).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]
61. (Refsum and Syndrome$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug
manufacturer name]
62. (Spastic and Parapleg$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug
manufacturer name]
63. (hereditary sensory and autonomic neuropathy).mp. [mp=title, abstract, subject headings, drug trade name, original title, device
manufacturer, drug manufacturer name]
64. (Hereditary Sensory and Autonomic Neuropathy).mp. [mp=title, abstract, subject headings, drug trade name, original title, device
manufacturer, drug manufacturer name]
36
65. (sensory and autonomic and neuropath$ and heredity).mp. [mp=title, abstract, subject headings, drug trade name, original title,
device manufacturer, drug manufacturer name]
66. or/57-65
67. 45 or 47 or 50 or 56 or 66
68. 42 and 67
69. 27 and 68
Appendix 3. Philippine Databases searched
http://lib.upm.edu.ph
http://pimedicus.upm.edu.ph
Herdin (Copyright 1997)
Philippine Index Medicus (1987 to September 2005)
Union List of Periodicals
Faculty papers
Theses / dissertations
Index to Philippine Periodical Articles (Aralin)
South East Asian Medical Information Center reprints
Resource centers of local pharmaceutical companies, medical centers and training institutions
Appendix 4. List of Philippine Journals and Conference Proceedings handsearched
Journals
The Philippine Journal of Neurology 1994;2(2)
Conference Proceedings
24th Annual Philippine Neurological Association
5th Biennial ASEAN Neurological Association
23rd Asian and Oceanian Congress of Neurology (Part I, Part II)
37
WHAT’S NEW
Last assessed as up-to-date: 31 August 2005.
Date
Event
Description
12 August 2008
Amended
Correction of heading formatting by editorial base.
HISTORY
Protocol first published: Issue 1, 2004
Review first published: Issue 3, 2008
Date
Event
Description
14 May 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
J Alviar and C Ang prepared the first and updated protocols. C Ang designed and co-ordinated the review. M Alviar developed the
search strategy. M Alviar and C Ang undertook searches. J Alviar, C.Ang, and V Villaruz-Sulit screened search results. C Ang organised
retrieval of papers. C Ang, R Bautista and G Bautista-Velez screened retrieved papers against inclusion criteria. G Bautista-Velez checked
retrieved papers against inclusion criteria. J Alviar, C Ang, and J Tan appraised quality of papers and extracted data from papers. A
Roxas arbitrated on quality assessment of papers. C Ang wrote to authors for additional data. C Ang obtained data and screened data
on unpublished studies. G Bautista-Velez screened and checked data on unpublished studies. V Villaruz-Sulit helped organise data for
analysis. C Ang and H Co entered data into Review Manager. C Ang analysed and interpreted data. C Ang wrote the review. J Alviar, R
Bautista, G Bautista-Velez, H Co, A Dans, A Roxas, and V Villaruz-Sulit checked and agreed on the review. A Dans provided general
advice on the review. C Ang secured funding.
DECLARATIONS OF INTEREST
None
SOURCES OF SUPPORT
38
Internal sources
• Thriplow Charitable Trust, UK.
External sources
• Research Implementation and Development Office, College of Medicine, University of the Philippines Manila, Philippines.
NOTES
New searches will be undertaken in the next 12 months to update the review.
INDEX TERMS
Medical Subject Headings (MeSH)
Peripheral Nervous System Diseases [∗ drug therapy]; Randomized Controlled Trials as Topic; Vitamin B Complex [∗ therapeutic use]
MeSH check words
Humans
39

Vitamin B for treating peripheral neuropathy (Review)

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