Nephrol Dial Transplant (2001) 16: 1448± 1451
Original Article
A randomized, double-blind, placebo-controlled trial of
supplementary vitamins E, C and their combination for
treatment of haemodialysis cramps
Parviz Khajehdehi, Mohammad Mojerlou, Saeed Behzadi and Ghanbar Ali Rais-Jalali
Division of Nephrology, Department of Internal Medicine, Namazee Hospital, Shiraz University of Medical Sciences,
Shiraz, Iran
Abstract
Background. Muscle cramps that improve after carnitine or vitamin E therapies are common in haemodialysis (HD) patients. Because vitamin C participates
in carnitine biosynthesis, and its levels are reduced in
uraemia, subclinical vitamin C depletion may contribute to HD cramps. Our aim was to determine the
effects of vitamins C, E and their combination on the
frequency and intensity of HD cramps.
Methods. In this placebo-controlled, double-blind
study, 60 HD-patients were randomized into four
therapeutic groups. Each group (ns15) received six
identical capsules daily for 8 weeks, containing one of
the following: vitamin E (400 mg), vitamin C (250 mg),
their combination, or placebo.
Results. The frequency and intensity of HD cramps
decreased signi®cantly in all three vitamin groups
compared with the placebo group at the end of the
trial, and compared with the pre-treatment values. At
the end of the trial, vitamins E, C, their combination,
and placebo produced cramp reductions of 54, 61, 97
and 7%, respectively. The percentage cramp reduction
had no signi®cant correlation with age, sex, aetiology
of end-stage renal disease, serum electrolytes or HD
duration, but showed a positive correlation (rs0.33,
Ps0.01) with the type of therapy. No vitamin-related
adverse effects were encountered during the trial.
Conclusion. Short-term treatment with the combination of vitamins E and C is safe and effective in
reducing HD cramps; however, its safety for prolonged
therapy has yet to be evaluated in HD patients.
Keywords: haemodialysis; muscle cramps; placebo;
vitamin C; vitamin E
Correspondence and offprint requests to: Prof P. Khajehdehi,
House 53, Lane 10-Jangali, Mirza-Kouchak-Khan-Jangli Highway,
Shiraz 71959, Iran.
#
Introduction
In haemodialysis (HD) patients, painful involuntary
muscular contractions, called cramps and found
typically in the lower extremities, are common w1±3x.
Most commonly, HD patients complain of waking
in the night with severe pain due to cramps, which
interferes with functioning in normal life w3±6x. To
deal with this problem, many approaches have been
proposed, but none has been conclusively effective,
and some have been associated with serious side effects
w6±8x. Considering the potential toxicity of quinine,
vitamin E has been recommended as the initial
treatment of choice for HD cramps w7x. However,
given the fact that muscle cramps due to carnitine
de®ciency improve after carnitine therapy in HD
patients, and that vitamin C levels have been reported
to be low in uraemia, it is possible that subclinical
vitamin C depletion might contribute to HD cramps
w9±15x. This study was initiated to determine whether
ascorbic acid is effective against HD cramps, and
whether it is more effective when combined with
vitamin E.
Subjects and methods
Our patients underwent two to three HD sessions per week
on polysulfune membranes in the three main teaching
hospitals of the Shiraz University of Medical Sciences in
southern Iran. Patients with the following criteria were
selected:
(1) Those signing a written consent to participate in
a 8-week trial of vitamin E and C.
(2) Patients who had at least two muscle cramps (sudden
and recurrent tonic or clonic painful involuntary muscle
contractions, usually in lower extremities, occurring
most commonly at night and interfering with sleep and
normal life) per week.
2001 European Renal Association±European Dialysis and Transplant Association
Vitamins E and C for treatment of haemodialysis cramps
(3) Patients who were stable on HD without any episode of
hypotension at least for 3 months.
(4) Those being adequately dialysed with a total weekly
KtuV of P3.6.
(5) Patients without renal stones who had neither personal
nor family history of nephrolithiasis.
(6) Those who were not receiving any drugs with muscle
cramp-producing or -relieving properties.
(7) Patients who had not been scheduled for kidney
transplantation during the course of the trial.
Sixty out of 239 patients undergoing regular HD in our
three main teaching university hospitals ful®lled the abovementioned criteria. There were 31 men and 29 women, aged
50.8"15.2 years, with a duration on HD of 28.2"27.7
months (mean"SD). All 60 HD-patients were given one
tablet of multi-vitamins daily that was replaced by one tablet
of vitamin B complex. After 1 month on vitamin B complex
they were randomized into the four therapeutic groups, as
follows. Each group (ns15) received one tablet of vitamin B
complex plus one of the following treatments: vitamin E
(400 mg), vitamin C (250 mg), their combination or placebo,
daily for 8 weeks. Each patient received six capsules daily
that were identical in size, colour and weight, and were made
and supplied under secret codes by the Shiraz School of
Pharmacology. Both clinicians and patients were blind to the
type of therapy during the trial. Frequency of cramps was
recorded daily, for 1 week before the start of trial and up to
the end of the trial. The intensity of cramps was recorded
daily only during the week before the trial and on the ®nal
week of the trial. Cramp intensity was scored using following
scale: no pain, mild, discomforting, distressing, horrible and
excruciating, which were given scores ranging from one to
six, respectively. All patients were interviewed and examined
twice weekly during HD sessions to assess compliance
with the therapies and to detect vitamin-related side effects.
Each patient served as self-control, and heruhis pre- and
post-therapy values were compared. Ultrasonography of
genitourinary systems was performed just before and at
the end of the trial. In all patients, clinical manifestations
of scurvy including perifolicular hyperkeratotic papules with
fragmented and buried hairs, perifollicular haemorrhage,
purpura coalescing to become ecchymoses, haemorrhages in
muscle and joints, gingivitis, loosening of teeth, and splinter
haemorrhage in the nail beds, were examined at the time of
randomization.
Statistical analysis
Data are presented as means"SD. For comparisons among
the four therapeutic groups, standard analysis of variance
(ANOVA) with BonferroniuDunn post-hoc correction was
used. Student's t-tests and x2 tests were used for comparing
means and percentages when appropriate. Multiple regression analysis was used to correlate the percentage of cramp
reduction obtained at end of the trial with age, sex, HD
duration, aetiology of end-stage renal disease, serum
electrolytes, and the type of therapy that each group received.
Results
Table 1 compares patient characteristics among
the four therapeutic groups at randomization. No
statistically signi®cant differences were found and
there were no differences in pre- and post-dialysis
1449
serum creatinine, blood urea nitrogen and blood
pressure. Haemoglobin and haematocrit values
remained unchanged during the course of the study.
The frequency of HD cramps at the different time
points (1 week pre-trial and for 8 weeks during the
trial) is shown in Figure 1. HD cramp frequency
decreased progressively and signi®cantly in all three
groups receiving vitamins compared with the placebo
group and the pre-treatment values at all weekly time
points. The decline in frequency of cramps was
signi®cantly more prominent in the combination
group than in the two groups receiving vitamin C or
E alone at all weekly time points. At the end of trial,
the percentage cramp reduction was 54, 61, 97 and 7%
in vitamin E, vitamin C, combination and placebo
groups, respectively. The percentage cramp reduction
had no signi®cant correlation with the age, sex,
aetiology of end-stage renal disease, serum electrolytes
or HD duration, but showed a positive correlation
with the type of therapy (rs0.33, Ps0.01). Table 2
compares the intensity score of cramps among the four
therapeutic groups just before therapy and at the
end of the trial. The intensity score decreased
signi®cantly in all three vitamin groups compared
with the placebo group and with pre-treatment values,
with the strongest effect shown in the combination
group (receiving vitamin C and E). All patients except
for two had leg cramps characterized by sudden tonic
or colonic involuntary contractions of the gastrocnemius muscle; the remaining two had cramps in the
biceps and ®nger muscles. In addition to the gastrocnemius muscle, concomitant contractions in other
muscles, mainly in the upper extremities, were present
as follows: 11, nine, three and two patients had
concomitant cramps of ®nger, biceps, intercostal and
neck muscles, respectively. No vitamin-related adverse
effects or urinary stone formation were encountered
during the trial. No clinical features of scurvy were
found in any patient at randomization.
Discussion
Numerous advances have been made in the medical
management of the end-stage renal disease of HD
patients. However, painful nocturnal cramps interfering with normal life still remain a common complication of HD w1±6x. Many approaches for the treatment
of HD-related cramps have been proposed, but most
have been associated with serious side effects, and
none have been conclusively effective w6±8x. Considering the potential toxicity of quinine, vitamin E has
been recommended as the initial treatment of choice
for HD cramps w7x. Accordingly, in this study, shortterm vitamin E supplementation was safe and effective for HD cramps, but was less effective than the
combination of vitamins C and E.
It has been shown that vitamin C levels are lower
in HD patients than in healthy controls, and due to
its bene®cial effects against lipid metabolism abnormalities and oxidative stress, it has been recommended for
1450
P. Khajehdehi et al.
Table 1. Comparison of patient characteristics at randomization
Patient characteristics
Age, years (mean"SD)
Sex, femaleumale ratio
HD duration, months (mean"SD)
ESRD due to diabetes (n)
ESRD due to glomerulopathy (n)
ESRD due to tubular disease (n)
ESRD of unknown aetiology (n)
Sodium, mEqul (mean"SD)
Potassium, mEqul (mean"SD)
Calcium, mgudl (mean"SD)
Phosphorous, mgudl (mean"SD)
Haemoglobin, gudl (mean"SD)
Haematocrit, % (mean"SD)
Frequency of cramps (mean"SD)
Cramp intensity score (mean"SD)
Total weekly KtuV (mean"SD)
Sixty haemodialysis patients randomized into four therapeutic groups
Vitamin E
(ns15)
Vitamin
C (ns15)
Vitamins E and
C (ns15)
Placebo
(ns15)
49.7"18.4
8u7
20.7"12.7
6
5
2
2
141.4"2.6
4.6"0.44
9.3"0.33
4.4"0.85
10.6"0.99
32.2"3.1
4.0"1.9
3.5"1.6
4.0"0.26
56.1"16.5
6u9
32.6"31.5
4
6
4
1
141.8"3.0
4.5"0.45
9.4"0.44
4.5"0.54
11.1"1.0
34.0"3.1
4.8"2.1
2.8"1.4
3.9"0.34
47.5"12.1
8u7
31.7"21.1
5
5
2
3
140.6"2.9
4.8"0.26
9.3"0.44
4.7"0.32
10.9"1.0
33.2"3.4
4.4"1.1
3.5"1.6
4.0"0.24
49.4"12.9
7u8
27.6"39.0
3
7
4
1
140.8"4.8
4.7"0.38
9.4"0.50
4.5"0.81
11.0"0.97
33.1"2.9
4.4"1.7
3.1"1.6
3.9"0.27
Total
(ns60)
P value
50.8"15.2
29u31
28.2"27.7
18
23
12
7
141.1"3.4
4.6"0.39
9.3"0.42
4.5"0.66
10.9"0.99
33.1"3.1
4.4"1.7
3.2"1.6
3.9"0.28
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS, no signi®cant difference among the four groups; ESRD, end-stage renal disease.
Fig. 1. There was no signi®cant difference in the frequency of haemodialysis cramps among the four therapeutic groups at randomization.
However, cramp frequency decreased progressively and signi®cantly in all three vitamin groups compared with the placebo group and baseline
values at all weekly time points (PO0.001 and PO0.02, respectively). The decline in the frequency of cramps was more prominent in the
combination group (vitamins E and C), which was signi®cantly lower than in either of the groups receiving vitamin C or E alone, at all weekly
time points (PO0.01 and PO0.04, respectively).
HD patients w15±20x. However, muscle cramps due to
carnitine de®ciency have been shown to improve after
carnitine therapy in HD patients, and experimental
studies provide compelling evidence that vitamin C
participates in carnitine biosynthesis w9±14x. Since HD
patients are generally placed on vitamin C-restricted
diets, it is possible that a subclinical vitamin C de®cit
may contribute to carnitine de®ciency and the development of muscle cramps in HD-patients w9±20x. Yet,
to our knowledge, vitamin C has never been used for
the treatment of muscle cramps in HD patients.
Although none of our patients had clinical features
of scurvy, we found for the ®rst time that vitamin C
therapy signi®cantly decreased the frequency and
intensity of muscle cramps in HD patients. Although
the percentage cramp reduction by vitamin C was
higher than for vitamin E, and was sustained for
8 weeks, the difference never reached statistical
signi®cance.
The initial concerns of our study were to trust the
ef®cacy of vitamin C and combined vitamin E and C
supplementation against HD cramps. We showed for
the ®rst time that combined vitamin E and C
supplementation was conclusively effective against
them. Combination therapy was signi®cantly more
effective than treatment with either vitamin E or C
given alone. This synergistic effect of vitamin C and E,
the reduction in cramps after treatment with various
drugs, and the fact that a small percentage (3%) of
our patients did not improve after combination
Vitamins E and C for treatment of haemodialysis cramps
1451
Table 2. Comparison of cramp intensity scores among 60 haemodialysis patients randomized into the four therapeutic groups shown just
before therapy and at the end of the trial
Parameter
Intensity score of cramps
(mean"SD)
P value
Vitamin E (ns15)
Vitamin C (ns15)
Vitamins C and E (ns15)
Placebo (ns15)
Before
After
Before
After
Before
After
Before
After
3.5"1.6
2.1"1.2
2.8"1.4
2.0"0.76
3.5"1.6
1.1"0.35
3.1"1.6
3.1"1.9
0.00003a
0.03b, 0.02c
0.04a
0.01b, 0.04c
0.00003a
0.00003b
Intensity of cramps was scored using the following scale: no pain, mild, discomforting, distressing, horrible and excruciating, which were given
scores of 1±6, respectively.
a
Difference between pre- and post-treatment values in each therapeutic group; b and c, different from placebo and combination (vitamins E
and C) groups, respectively.
therapy, all suggest that HD cramps represent a
multifactorial derangement. Nonetheless, the improvement in HD cramps after vitamin C and E could
be due to their antioxidant properties. It also may be
secondary to the bene®cial effect of vitamin C on
carnitine biosynthesis, or may be due to unde®ned
mechanisms w14,18±20x. Since we were not able to
measure oxidant±antioxidant status or serum levels of
carnitine and vitamins, the extent of the contribution
of each of the aforementioned mechanisms to the
bene®cial effect of vitamin C and E in HD cramps
cannot be determined in this study.
Prolonged vitamin therapy may be associated with
serious adverse effects, and several authors have
indicated that vitamin C doses in HD patients should
not exceed 200 mguday. Vitamin C therapy is known to
produce hyperoxaluria, oxalate containing urinary
stones, and renal damage w21±23x. However, the shortterm vitamin supplementation in the present trial was
well tolerated in our patients and no vitamin-related
side effects, including urinary stone formation, were
seen during the trial. Our ®ndings indicate that
short-term therapy with a combination of vitamin E
and C is effective and safe in reducing HD cramps. The
safety of prolonged therapy has yet to be evaluated
in HD patients.
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Received for publication: 29.9.00
Accepted in revised form: 30.1.01