Alcohol & Alcoholism Vol. 33. No. 6. pp. 631-638. 1998
BENFOTIAMINE IN TREATMENT OF ALCOHOLIC POLYNEUROPATHY:
AN 8-WEEK RANDOMIZED CONTROLLED STUDY (BAP I STUDY)
H. WOELK*, S. LEHRL1, R. BITSCH 2 and W. KOPCKE 3
Psychiatrisches Krankenhaus, Licher Str. 106, 35394 Giessen, 'Kopfklinikum. Abteilung fur medizinische Psychologie und
Psychopathometrie, Schwabachanlage 6. 91054 Erlangen, "Friedrich Schiller Universitat, Institut fur Emahrung und Umwelt.
Domburger Str. 24-29. 07743 Jena and 3Westfalische Wilhelms-Universitat. Institut fur medizinische Informatik, Domagkstr. 9,
48149 Miinster, Germany
(Received 24 October 1997: accepted in revised form 27 April 1998)
INTRODUCTION
Alcoholic polyneuropathy is a disorder of the
peripheral nerves that interferes with sensory,
motor, and autonomic nerve function. Whereas
mild and moderate forms of the condition cause
mainly pain and dysaesthesia. severe forms may
involve paralysis. Progression of the disorder can
cause inability to walk.
About 20% of chronic alcoholics experience
axonal degeneration and demyelinization of peripheral nerves in the course of their addiction
(Heimann and Naumann, 1981); at the same time,
their levels of vitamin B, are significantly lowered
(Meyer, 1981). This is due to the nutritional
inadequacy of the chronic alcoholic's diet, which
is heavy in carbohydrates. In addition to the
deficient supply of thiamine, absorption by the gut
is impaired by chronic alcoholism. Furthermore,
ethanol reduces the storage capacity of the liver
*Author to whom correspondence and reprint requests should
be addressed.
for thiamine, which is low to start with, and
additionally the toxic effects of alcohol and its
metabolite acetaldehyde interfere with the utilization of vitamin B, (Bitsch and Bitsch, 1987).
Apart from the requirement of alcohol abstinence, a causal treatment for alcoholic polyneuropathy is long-term administration of vitamin B|.
Effective oral treatment with vitamin B) requires
high bioavailability of the active principle. However, intestinal absorption of water-soluble thiamine depends on active saturation transport, so
that, even in healthy persons, the rate of absorption of therapeutic doses (50-100 mg) is relatively
small (4-6%) (Heinrich, 1990). In alcoholics,
intestinal absorption is often impaired, and so an
even lower rate of absorption must be assumed
(Bitsch, 1989). It is therefore essential, particularly for alcoholics, to administer thiamine
compounds that are readily absorbed. In the
early 1950s, a Japanese team developed a new
group of thiamine derivatives (the allithiamines)
that met this requirement. Benfotiamine was first
synthesized in the early 1960s (Fujiwara, 1954).
The extremely high bioavailability of thiamine
following administration of the pro-drug benfoti631
© 1998 Medical Council on Alcoholism
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Abstract — A three-armed, randomized, multicentre, placebo-controlled double-blind study was used
to examine the efficacy of benfotiamine vs a combination containing benfotiamine and vitamins B 6 and
B,2 in out-patients with severe symptoms of alcoholic polyneuropathy (Benfotiamine in treatment of
Alcoholic Polyneuropathy. BAP I). The study period was 8 weeks and 84 patients fulfilled all the
prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of
alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly
improved in the course of the study, as did motor function, and the overall score reflecting the entire
range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain
and co-ordination, no therapy-specific adverse effects were seen.
632
H. WOELK et al.
In bioavailability studies on healthy human
subjects, it was shown that absorption of benfotiamine was several times better than that of
water-soluble vitamin B,, and that there was a
120-fold higher increase of metabolically active
thiamine diphosphate in erythrocytes (Heinrich,
1990). Within a short time, orally administered
benfotiamine results in levels of thiamine comparable to those after i.v. administration of watersoluble vitamin B) salts given at the same dosage.
Furthermore, benfotiamine was less toxic than
water-soluble vitamin B| in animal experiments
(Bitsch, 1989).
A bioequivalency investigation has produced
evidence demonstrating not only the higher
bioavailability of benfotiamine, but also the
activation of erythrocytic thiamine-dependent
transketolase activity, and its activation to thiamine pyrophosphate in vitro (Bitsch et al., 1991).
Two additional bioequivalency studies confirmed
the significantly better bioavailability of benfotiamine even when compared to the lipophilic
thiamine derivatives fursultiamine and thiamine
disulphide (Keller-Stanislawski, 1989; Bitsch,
1995).
Thus, benfotiamine fulfils the prerequisite for
effective oral treatment of alcoholic polyneuropathy. The present study was designed to examine
the therapeutic effectiveness of benfotiamine in
marked alcoholic polyneuropathy in comparison
with that of a neurotropic B vitamin combination
in a formulation that had already proved effective
in the treatment of diabetic polyneuropathy
(Ledermann and Wiedey, 1989; Stracke et al.,
1996).
PATIENTS AND METHODS
Study design and patients
The experimental design was a three-armed,
randomized,
multicentre,
placebo-controlled
double-blind study (benfotiamine in treatment of
alcoholic polyneuropathy study, BAP I). Treatment lasted for 8 weeks, with a total of five
examinations at 2-weekly intervals (El = baseline
workup, E5 = final examination).
The following medication was used in the
study: (1) benfotiamine (Benfogamma*, Worwag
Pharma GmbH, Stuttgart, Germany) at a dosage of
320 mg/day during weeks 1 to 4 (2 capsules q.i.d.)
and 120 mg benfotiamine/day during weeks 5 to
8 (1 capsule t.i.d.); (2) a combination of neurotropic B vitamins (Milgamma® N, Worwag
Pharma GmbH, Stuttgart, Germany), consisting
of 320 mg benfotiamine + 720 mg vitamin
Bg + 2 mg vitamin B12 for the first 4 weeks (2
capsules q.i.d.), and thereafter 120mg benfotiamine + 270 mg vitamin Bg + 0.75 mg vitamin
B 12 (1 capsule t.i.d.); (3) placebo: identical
capsules lacking the active components.
After the Ethics Committee of the Landesarztekammer Hessen in Frankfurt am Main, Germany,
granted its approval and the patients gave their
informed consent, the nine physicians who were
involved in the clinical studies assigned a total of
104 out-patients of both sexes, ranging from 30 to
70 years of age, to the three arms of the study: 34
patients to be given benfotiamine alone, 35
patients to be given the neurotropic B vitamin
formulation, and 35 patients to be given placebo.
The study was strictly monitored according to the
GCP international standards by the US Clinical
Research Organization (CRO: Institut fur Klinische Forschung Dr Wiedey GmbH, Zeppelinstr.
5, Konstanz, Germany).
The criteria for admission to the study were: (1)
alcoholism as defined by DSM-IH-R; at least three
of the criteria were required; and (2) alcoholic
polyneuropathy with vibration perception thresh-
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amine has been confirmed by many studies. Thus,
the superiority of the pharmacokinetic properties
of benfotiamine to those of thiamine hydrochloride was shown in animals and humans (Wada,
1961) and the mechanism of uptake and transport
of benfotiamine in red blood cells was documented by Shindo (1967). A number of other studies
(Fujiwara, 1954; Utsumi, 1962; Thomson, 1971;
Baker, 1974; Davis, 1983) showed that the
allithiamines are absorbed better, lead to higher
thiamine levels in erythrocytes and cerebrospinal
fluid, and are retained longer in the body than
other water-soluble vitamin B, derivatives. In
absorption experiments in mice and rats with
radioactively tagged benfotiamine, clearly higher
rates of incorporation into the heart, liver, brain,
and diaphragm were found than after oral
administration of water-soluble vitamin B)
(Mizuhira, 1968). These results were corroborated
by other autoradiographic studies on the
incorporation of benfotiamine in mouse organs
(Hilbig, 1995).
BENFOTIAMINE IN ALCOHOLIC POLYNEUROPATHY
Assessment of peripheral nerve function
At randomization (El), after 2 weeks (E2), 4
weeks (E3), 6 weeks (E4), and 8 weeks (E5), data
on the following parameters of peripheral nerve
function were recorded. Vibration perception
thresholds (biothesiometry) at the great toe (the
major objective criterion), inside ankle, metatarsal
bone, and mid-tibia were determined using a
graduated tuning fork according to the method of
Rydel and Seiffer (8/8 scale; Claus et al, 1988;
Thivolet et al., 1990). The endpoint was the time
elapsed until the patient no longer perceived the
vibration of the tuning fork. A vibration threshold
of 8 was defined as normal, and 0 corresponded to
severe impairment. The arithmetic mean was
determined from three individual measurements.
The intensity of pain, a major subjective
criterion, was assessed by McGill's pain questionnaire (ppi scale: 5 = no pain, 0 = devastating
pain; Melzack, 1984).
Scoring for motor function involved the degree
of paralysis (5 = normal, 0 = total inactivity),
sensory function (2 = no impairment, 0 =
impaired perception of touch distally and proximally to the ankle), co-ordination (2 = no impairment, 0 = evident ataxis) and reflexes (2 = no
impairment, 0 = absence or weakening of the
Achilles tendon reflex and other reflexes), and
was done according to frequently used assessment
scales.
An overall score describing the severity of
polyneuropathy symptoms was obtained by adding
the data for individual parameters (16 = free of
symptoms, 0 = maximum clinical expression).
Scores >10 are indicative of a less severe clinical
picture.
The 'clinical global impression' (CGI) was
based on a questionnaire from the Collegium
Internationale Psychiatriae Scalarum (1986).
Laboratory evaluation
At the beginning and end of the investigation,
the following laboratory studies were completed,
using standard methods: serum glutamate-oxaloacetate aminotransferase or aspartate aminotransferase
(SGOT), serum
glutamate-pyruvate
aminotransferase or alanine aminotransferase
(SGPT), y-glutamyltransferase (GGT), alkaline
phosphatase, triglycerides, cholesterol, creatinine,
blood alcohol, fasting blood sugar and sedimentation rate after 1 and 2 h.
Statistical analysis
The required number of patients was estimated
on the basis of a study on diabetic polyneuropathy
(Ledermann and Wiedey, 1989), in which the
endpoint variable, vibration perception threshold
at the tip of the great toe as measured with a tuning
fork by the method of Rydel and Seiffer, was
found to increase by an average of 1.38 units.
Assuming that the improvement of vibration
perception threshold in the alcoholic polyneuropathy under treatment would be of a similar
magnitude, a sample size of 22 patients in each
group was determined (a = 0.05, ft = 0.20). The
sample size was raised to 25 per group in order to
make up for loss of discrimination by the
transition from parametric to non-parametric
methods. On the assumption that the dropout rate
could be ~ 25%, the number of cases was further
raised to 35 patients in each group.
For biometric analysis, comparison of treatment
groups was undertaken using the >;2-test for
contingency tables for discrete variables and
using variate analysis for continuous variables.
The level of significance was defined as a
probability of error of P = 0.05. Means, SD and
95% confidence intervals were used for description.
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old at the great toe <2, pain score <3, and sensory
score <1. These inclusion criteria ensured that
only patients with marked symptoms of alcoholic
polyneuropathy were admitted to the study. All
patients (including those who received placebo)
were instructed not to change their drinking habits
during the study.
Patients with allergies to any of the constituents
of the drugs under study, diabetes mellitus,
alcoholic polyneuropathy of long duration (>8
years), Parkinson's disease, toxic neuropathy of
non-alcoholic origin, known neurologic conditions, endocrinological disorders, psychiatric disorders, collagenosis, skin eruptions in the regions
of assessment, poor overall condition, drug
dependency, pregnancy or lactation, or vitamin
replacement within the previous 4 weeks were
excluded, as were patients participating in other
studies.
633
H. WOELK et al.
634
Table 1. Homogeneity of the patient groups
Placebo
Male sex (%)
Daily alcohol consumption of >200g (%)
Alternating constipation and diarrhoea (%)
Pain intensity score (<3)* (%)
Motor function score (<3)** (%)
Coordination score (<1)** (%)
Sensory function score (=0)** (%)
Reflexes score (<1)** (%)
Age (years)
Body weight (kg)
Duration of polyneuropathy (years)
Vibration perception threshold (graduated tuning fork)
Tip of right great toe
Tip of left great toe
65.5
44.8
62.1
100
75.9
82.8
62.1
58.6
53.6
76.6
2.19
74.2
58.1
64.5
100
74.2
77,4
64.5
74.2
54.6
76.5
2.61
0.762
0.772
0.765
0.765
Benfotiamine
71.9
48.4
62.5
100
68.8
62.5
68.7
68.8
52.0
74.5
1.91
0.791
0.756
*Pain intensity according to McGill (5-0); **according to assessment scales.
RESULTS
Homogeneity of the patient groups
A review of the criteria for inclusion and
exclusion at biometric evaluation revealed that
12 of the patients did not fulfil all inclusion
criteria; these patients were therefore not evaluated. A further eight patients did not complete the
study; however, their withdrawal had no apparent
connection with the treatment regimen. Thus, the
following data are based on the 84 patients who
completed the entire study (benfotiamine group,
n = 30; neurotropic B vitamin formulation group,
n •=• 26; placebo group, n — 28).
For evaluation of the homogeneity of the patient
groups after randomization, a total of 28 discrete
and 24 continuous variables were assessed. Some
of the data are given in Table 1. None of the
variables was found to be significantly different
between the groups at baseline examination; this is
also true of the variables not listed in Table 1.
Changes in vibration perception
Tip of great toe. During the treatment period,
vibration perception improved in all three groups,
regardless of whether it was assessed on the left or
right side (Table 2). Figure 1 depicts the data for
the right great toe. The vibration perception
thresholds in the placebo and neurotropic B
vitamin groups were nearly identical. For this
reason, the data of these two groups were
combined in order to raise the number of cases,
and compared with those of the benfotiamine
group by means of variate analysis.
Benfotiamine proved to be significantly more
effective (P = 0.040) than the neurotropic B
vitamin formulation and placebo. At the end of
treatment, vibration perception was still noticeably
impaired in all treatment groups.
Medial ankle, metatarsal bone, and mid-tibia.
In all three therapy arms, there was a steady
improvement of vibration perception at the medial
ankle, the metatarsal bone, and mid-tibia (on both
the right and left sides) until the end of the study
period. At all measurement sites, the most marked
improvement was found at E5 in the group treated
with benfotiamine; Table 3 shows the data for the
right and left medial ankles as an example. Despite
the increased success with benfotiamine treatment,
the results did not reach statistical significance.
Similarly beneficial, but likewise not statistically
significant, effects were also found in the courses
of vibration perception threshold at the metatarsal
bones and mid-tibia (data not shown).
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Variable at initial randomization
Neurotropic
B vitamin
formulation
BENFOTIAMINE IN ALCOHOLIC POLYNEUROPATHY
635
Table 2. Improvement of vibration perception units at the tip of the great toe
Treatment
Placebo, right side (n = 28)
Placebo, left side (n = 28)
Neurotropic B vitamin
formulation, right side (n = 26)
Neurotropic B vitamin
formulation, left side (n = 26)
Benfotiamine, right side (n = 30)
Benfotiamine, left side (n = 30)
Initial
assessment
(El)
Final
assessment
(E5)
Improvement
(units)*
0.79 ± 0.29
0.80 ± 0.29
0.73 ± 0.26
2.25 ± 0.52
2.30 ± 0.53
2.30 ± 0.61
1.46
1.50
1.57
0.71 ± 0.26
2.04 ± 0.53
1.33
0.77 ± 0.26
0.75 ± 0.27
2.89 ± 0.61
2.91 ± 0.58
2.12
2.16
El was performed at randomization, whereas E5 was after 8 weeks of treatment. Values are means ± SD. *Mean of
units of the graduated tuning fork.
Effect on motor function (degree of paralysis)
The patients in the benfotiamine group had a
significantly lower degree of paralysis than those
on placebo (P = 0.038). In 64.3% of the patients
taking placebo, 73.1% of those taking the
neurotropic B vitamin formulation and 90% of
those taking benfotiamine, motor function was
impaired only slightly or not at all at final
assessment of the study (Fig. 3).
Effect on co-ordination, sensory function and
reflexes
At the end of the study, 60.7% of the patients in
the placebo group, 53.9% of those on the
neurotropic B vitamin formulation, and 80% of
those on benfotiamine had no impairment
(P = 0.093). Assessment of sensory function and
reflexes revealed no differences that could be
attributed to treatment.
- Benfotiamine
- Neurotropic B
\itamin
formulation
- Placeho
Effect on the overall neuropathy score
At the end of the study, 67.9% of the placebo
patients, 76.9% of the patients taking the neurotropic B vitamin formulation, and 93.3% of those
on benfotiamine had scores of 10 or more. The
superior outcome of treatment with benfotiamine
was statistically significant (P = 0.39; Fig. 4).
Time of assejsment (week of study)
Fig. 1. Improvement of vibration perception at the tip of the
right great toe due to treatment with benfotiamine,
neurotropic B vitamin combination or placebo.
Values are arithmetic means with upper and lower limits
of the 95% confidence interval as error bars. The numbers
of subjects in each of the above three groups was 30, 26.
and 28, respectively, in this and all subsequent figures.
*P = 0 040.
Clinical global impressions
When the severity of disease, therapeutic
effectiveness, and estimate of change of the
overall situation at the end of the study were
assessed, benfotiamine was judged clearly superior to the other two treatment groups. However,
the beneficial effect of benfotiamine treatment did
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Effect on pain intensity
Intensity of pain decreased in all treatment
groups during the 8-week therapy course. At the
conclusion of treatment, considerably more of the
patients taking benfotiamine (77%) were free of
pain or had only mild complaints than in the
comparison groups (54% in each; Fig. 2). However, the apparently better results under benfotiamine still did not reach statistical significance
(P = 0.3l).
636
H. WOELK et al.
Table 3. Improvement of vibration perception threshold at the medial ankle
Treatment
Placebo, right side
Placebo, left side
Neurotropic B vitamin formulation,
right side
Neurotropic B vitamin formulation,
left side
Benfotiamine, right side
Benfotiamine, left side
Initial
assessment
(El)
Final
assessment
(E5)
Improvement
(units)*
1.32 ± 0.49
1.28 ±0.52
1.32 ± 0.48
2.64 ± 0.58
2.94 ± 0.70
2.77 ± 0.63
1.32
1.66
1.45
1.23 ±0.53
2.68 ± 0.60
1.45
1.24 ± 0.48
1.31 ±0.47
3.08 ± 0.55
3.18 ±0.58
1.84
1.87
For definitions of El and E5, see Table 2. Values are means ± SD. * Mean units of the graduated tuning fork.
Compliance and side-effects
Three patients had to be reminded to improve
their compliance, but it was not necessary to
remove them from the study. Apart from this,
compliance was considered in line with the study
plan. No adverse events related to treatment
occurred.
Laboratory results
All parameters examined at the start and finish
of the study showed a statistically non-significant
trend toward diminished levels.
DISCUSSION
The literature shows that thiamine levels are
Benfotiamim-
UL
Placebo
R vitamin
Fig. 2. Percentage of patients without pain or with mild
pain at the end of the investigation.
frequently diminished in alcoholics and patients
with alcoholic polyneuropathy (Heimann and
Naumann, 1981; Meyer, 1981; Bachevalier,
1981; Waldenlind, 1981; Woelk, 1982; Posthuma,
1983); however, controlled, double-blind interventional studies in alcoholic polyneuropathy have
not been published until now.
In addition to correcting vitamin 1$! deficiency,
therapeutic administration of thiamine may also
produce some pharmacological effects. In animals
given dosages that exceeded basic requirements by
100- or 1000-fold thiamine has analgesic and
neuroprotective effects (Woelk and PeilerIchikawa, 1985; Jurna, 1988; Reeh, 1988, 1991;
Wild, 1988). However, if high levels are to be
achieved with oral vitamin Bi treatment, lipid
soluble thiamine derivatives or pro-drugs with
high bioavailability, such as benfotiamine, are
required. Benfotiamine fulfils the pharmacokinetic
Be nfoti urine
I
Neil rot rone
Placebo
B Mtamin
formulation
Fig. 3. Percentage of patients with unimpaired or only
slightly impaired motor function at the conclusion of the
study. *P = 0.038.
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not reach statistical significance.
BENFOTIAMINE IN ALCOHOLIC POLYNEUROPATHY
637
and mode of action. The results of the present
BAP I study, by demonstrating the effectiveness of
benfotiamine in polyneuropathy of alcoholism,
where intestinal mucosa is often damaged and
active transport of thiamine impaired, illustrates
that the use of the lipophilic pro-drug benfotiamine is imperative in alcoholism.
30
Beafotiajnine
Neurotronic
B vitamin
Placebo
REFERENCES
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Fig. 4. Percentage of patients with an overall score of
polyneuropathy symptoms of > 10 at the conclusion of the
study. *P = 0.039.
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requirements for effectiveness essential for successful oral vitamin B] therapy.
The results of the present investigation have
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with the pro-drug benfotiamine in alcoholic
polyneuropathy. Within the 8-week study period,
benfotiamine led to a significant improvement of
the threshold of vibration perception at the great
toe, motor function, and the overall symptom
score. Marked improvement occurred in both pain
and co-ordination.
In the present study, the combined formulation
produced no statistically significant effect. Since
the benfotiamine content of both active formulations was identical, the explanation is conjectural.
Perhaps in alcoholic polyneuropathy, the addition
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(Ledermann and Wiedey, 1989; Stracke et ai,
1996) and benfotiamine alone (Haupt, 1995)
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beneficial
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