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100 The Open Nutrition Journal, 2008, 2, 100-105
1874-2882/08 2008 Bentham Open
Open Access
Alkaline Mineral Supplementation Decreases Pain in Rheumatoid Arthri-
tis Patients: A Pilot Study
Regina Maria Cseuz1, Istvan Barna2, Tamas Bender3 and Jürgen Vormann*,4
1Revita Klinik, Budapest, Hungary; 2Institute of Experimental Medicine of the Hungarian Academy of Sciences,
Budapest, Hungary; 3Hospital Brothers of St. John of God, Budapest, Hungary, 4Institute for Prevention and Nutrition,
Ismaning, Germany
Abstract: The aim of this pilot study was to investigate the efficacy of an alkaline mineral supplement as a means of sup-
pressing disease activity in rheumatoid arthritis (RA) patients, and to check whether any change occurs in the circulating
beta-endorphin concentration. Thirty-seven patients with moderately active RA of at least two years duration, who were
receiving stable pharmacological treatment, participated in a 12-week study. All patients were randomly allocated to a
supplemented group (30g of an alkaline mineral supplement daily) or to an unsupplemented group. Their usual diet and
medication was maintained. Disease activity, pain, and health-associated status were recorded (DAS 28 - Disease Activity
Score 28, VAS - visual analogue scale for pain, HAQ - Health Assessment Questionnaire). Plasma immunoreactive en-
dorphin (ir-EP) was measured in the study groups and also in healthy subjects. DAS 28 and VAS decreased in the sup-
plemented group, whereas there was no change in these parameters during the trial in the control group. The functions
(HAQ) of the supplemented patients improved. The ir-EP levels increased in both groups but to a higher degree in the
supplemented group. During the trial, medication (NSAIDs and steroids) could be reduced in the supplemented group
only. Conclusion: This study suggests that an alkaline supplement may improve function and pain in rheumatoid arthritis
and may represent an easy and safe addition to the usual treatment of RA patients.
Keywords: Pain, rheumatoid arthritis, acid-base balance, beta-endorphin.
Conference Paper, presented at the 2nd International Acid-Base Symposium, Nutrition – Health – Disease in Munich,
September 2006.
INTRODUCTION
A large body of epidemiological and experimental stud-
ies has demonstrated that nutrition has an important impact
on the occurrence and severity of various chronic diseases
[1]. The level of disease-associated pain may also be diet-
related. For example, patients with rheumatoid arthritis (RA)
frequently experience a positive effect of a change in diet on
the activity of their disease. The hypothesis of our present
study was that patients with RA, consuming an ordinary
Western diet as most of the population of the world's devel-
oped countries, develop a diet-induced low-grade systemic
metabolic acidosis [2]. There is strong evidence that a diet
rich in fruit and vegetables acts protectively against a wide
variety of human diseases. However, such a diet usually also
supplies excess alkalinity, and part of its beneficial effects
might be associated with a reduction of the chronic acid load
[3]. The chronic inflammatory process in RA patients leads
to a local increase in acidity; the pH in synovial fluids from
patients with RA is significantly lower than that in patients
with osteoarthritis or controls [4]. This change in local acid-
ity might aggravate pain symptoms, especially in connective
tissues. Therefore, alkaline supplementation might lead to an
improvement of the clinical outcome in RA patients. In pa-
tients with chronic low back pain, alkaline supplementa-
*Address correspondence to this author at the Institute for Prevention and
Nutrition, Adalperostr. 37, D-85737 Ismaning, Germany; Tel: +49 (0)89
55267989; Fax: +49 (0)89 55267990; E-mail: vormann@ipev.de
tion significantly reduces pain and disability [5]. Our own
observations of some RA patients also suggest the positive
effect of a complementary treatment with alkalines. We have
therefore conducted a pilot study to investigate, in more de-
tail, the effects of an alkaline supplement on pain symptoms
in patients with RA. In addition to subjective indicators of
pain, disability, and quality of life, the change of the concen-
tration of beta-endorphin (ir-EP) has been determined in the
plasma of patients as a more objective parameter of pain
problems. Significantly lower ir-EP levels have been re-
ported in RA patients than in controls, and an inverse corre-
lation has been found between the rheumatoid disease activ-
ity score and plasma ir-EP concentration [6].
MATERIALS AND METHODS
Patients and Study Design
Prior to commencing the study, approval by the local
ethical committee (Scientific Committee of St John’s Hospi-
tal, Budapest) was obtained, and the ethical principles of the
Helsinki Declaration were followed. All patients were in-
formed orally and in writing about the study design and the
underlying hypothesis and of the participant’s right to with-
draw at any time. The study design was a single-center ran-
domized parallel trial over a period of three months.
Patients
Out of 76 outpatient candidates who were screened for
the trial and were willing to participate, 37 patients fulfilled
Alkaline Mineral Supplementation Decreases Pain in Rheumatoid Arthritis Patients The Open Nutrition Journal, 2008, Volume 2 101
all the inclusion criteria according to Table 1. These patients
were randomly selected into a supplemented group or an
unsupplemented control group. Baseline characteristics of
patients in both groups are shown in Table 2.
Supplementation
After a 4-week wash-out period (other supplements),
patients in the supplemented group started to take, on a twice
daily basis, 30 g (2 x 15 g) of a lactose-based alkaline mul-
timineral supplement (Basica Vital®, Protina Pharmaceuti-
cals, Germany) for a 12-week period in addition to their
usual medication. The mineral composition was as follows
(mg/daily dose): Ca (400), K (250), Na (250), Mg (100), Fe
(5), Cu (1) all as citrates, Zn (5) as gluconate, I (0.1) as po-
tassium iodide, Mo (0.08) as sodium molybdate, Cr (0.06) as
chromium chloride, Se (0.03) as sodium selenite. The alka-
line mineral supplement was taken twice daily in the form of
a powder mixed in one of the following: soup, yoghurt, tea,
or cereal. A suitable inert placebo in a similar daily dose was
not available, and the use of sugar as a placebo seemed not
Table 1. Inclusion and Exclusion Criteria
Inclusion Criteria:
• Rheumatoid arthritis based on the 1987 American College of Rheumatology (ACR) criteria
• Disease duration of at least two years
• Seropositive for rheumatoid factor
• Clinically, the disease must have been characterized as stable and under adequate control
• Current use of non-steroidal anti-inflammatory drugs (NSAID)
• Disease activity score from 28 joints (DAS28) >2.0 indicating active disease
• Unchanged corticosteroids for 4 weeks, maximum daily oral dose of prednisolone <12.5 mg.
• No change of daily doses of disease modifying anti-rheumatic drug (DMARD) for 3 months
Exclusion Criteria:
• Co-morbidity (such as diabetes, gastrointestinal diseases) - except hypertension and osteoporosis.
Table 2. Baseline Characteristics of Patients who Completed the Trial. Data are Presented as Mean (Range) Unless Otherwise
Stated
SD Patients (n=19) CG Patients (n=17)
Age (years) 61 (32-76) 57 (31-85)
Sex (men/women)* 2/19 2/17
Body Mass Index (kg/m) 26.1 (22.3-31.9) 27.6 (17.6-49.5)
Disease Duration (years) 11.8 (2-26) 12.8 (2-22)
Rheumatoid Factor Positive* 19 17
DAS28, Score 5.2 (3.6-6.9)† 4.5 (2.8-6.0)
ARA Class I* 0 0
Class II 5 5
Class III 14 11
Class IV 0 1
Current Drugs
NSAID 19 17
Corticosteroids/mg prednisolone 6/4.6 7/4.2
Co-morbidity
Hypertension 2/2 4/4
Osteoporosis 1/0 3/3
* Number of patients.
† Statistically significant difference between SD and CG, p<0.05.
Abbreviations used in Table 2. : SD - supplementary diet; CG - control group; DAS – disease activity score; ARA -American Rheumatology Association; NSAID - non-steroidal
anti-inflammatory drug, The use of other disease modifiing drugs was equally distributed over both groups.
102 The Open Nutrition Journal, 2008, Volume 2 Cseuz et al.
to be appropriate. Therefore, a placebo was omitted in this
pilot trial. During the trial, patients were not allowed to take
any dietary supplements except for the alkaline mineral sup-
plementation in the supplemented group. The individual dose
of non-steroidal anti-inflammatory drugs (NSAID) could be
adjusted but had to be recorded.
Determinations and Measurements
All patients were evaluated by the same investigator in
accordance with a written protocol that included medical
history, ACR criteria [7], complete evaluation, articular
evaluation, and extra articular evaluation of RA (history of
rheumatoid nodules, Reynard’s phenomenon, or pulmonary,
cardiac, dermal, ocular, and nervous system involvement).
Disease activity was assessed by determination of the num-
ber of swollen joints, the score of tender and swollen joints,
and the duration of morning stiffness (in minutes). A com-
posite disease activity score (DAS 28) [8], a physical func-
tion index Health Assessment Questionnaire (HAQ) [9], C-
reactive protein (CRP), and rheumatoid factor were meas-
ured at baseline and 4, 8, and 12 weeks after starting the
trial. DAS28 is a composite disease activity index and also a
response index with good discriminatory validity. It includes
28 joint counts for tenderness (tender joint count) and swel-
ling (swollen joint count), the erythrocyte sedimentation rate
(ESR), and the patient's global assessment of disease activity
on a horizontal visual analog scale (patient global VAS, 0-
100mm). As a parameter connected to pain, the level of ir-
EP was determined in blood samples of both patient groups
and from healthy subjects (6 females, 6 males; mean age: 45
years). Blood samples were collected into K2-EDTA-
containing plastic tubes and then centrifuged, after which
plasma aliquots were stored at –20 °C until assayed. Details
of the EP radioimmune assay (RIA) including the percental
cross-reaction data were as described earlier [10]. In short,
synthetic human EP (Sigma) was used both for the standard
and 125I-labeled tracer, and a second antibody was used to
separate the bound and free fractions.
Compliance
Compliance of supplemented patients was monitored by
the weekly determination and recording of the pH of the first
morning urine with pH paper strips by the patients them-
selves. Supplementation induced a significant increase in
urinary pH by at least one pH unit after one week in all sup-
plemented patients and remained high throughout the sup-
plementation period thus indicating adherence to the sup-
plement.
Statistical Methods
Determined parameters were normally distributed and
variations were compared between time 0 and 4, 8, and 12
weeks, respectively, and between the supplemented and un-
supplemented groups by using Student’s t-test. Frequencies
of reduction of medication were compared between groups
by means of the Fisher exact test. All reported P values are
2-sided.
RESULTS
A total of 37 patients were enrolled of whom 19 were
randomly allocated to the supplemented group and 18 to the
unsupplemented control group. In one control patient, an
intra-articular injection with triamcinolone hexacetonide was
reported what expectedly influenced the disease acitivity,
and this patient was excluded from the study. Hence, 19 sup-
plemented and 17 control patients completed the trial. At the
start of the experiment, the two groups were equal in all re-
spects, except for disease activity score (DAS28). At base-
line, the control patients showed a score of 4.5 (range: 2.8-
6.0) versus the supplemented group with a score of 5.2
(range: 3.6-6.9); this difference is statistically significant (t-
test). At the end of the observation period, the supplemented
group, in which members had started with significantly
higher disease activity score, showed significantly lower
DAS28 compared with control patients (Fig. 1). DAS28 de-
creased in the supplemented group, whereas there was no
significant change in disease activity score during the trial in
the control patients. There were also significant differences
between supplemented and unsupplemented groups at 4, 8,
and 12 weeks. The level of pain (according to the patient's
visual analog scale (VAS)) decreased to a considerable ex-
tent in the supplemented group (Fig. 2). In the control pa-
tients, the pain increased between week 0 and week 4. Be-
Fig. (1). DAS28 in supplemented (first column) and unsupple-
mented (second column) RA patients at 0, 4, 8, and 12 weeks. Sig-
nificant difference in comparisons with time 0 of the respective
group; a: p = 0.049; b: p = 0.011, c: p = 0.004. Significant differ-
ences between groups; A: p = 0.006; B: p = 0.016, C: p = 0.028;
mean ± SEM.
Fig. (2). Pain level according to a visual analog scale in supple-
mented (first column) and unsupplemented (second column) RA
patients at 0, 4, 8, and 12 weeks. Significant difference in compari-
sons with time 0 of the respective group; a: p = 0.045; b: p = 0.004,
c: p = 0.048. Significant differences between groups; A: p = 0.003;
B: p = 0.001, C: p = 0.037; mean ± SEM.
disease associated symptom index (DAS28)
0
20
40
60
80
100
120
0 4 8 12
weeks
%
b
a
c
A
B
C
pain (VAS)
0
20
40
60
80
100
120
140
160
0 4 8 12
weeks
%
a
c
A
B
C
b
Alkaline Mineral Supplementation Decreases Pain in Rheumatoid Arthritis Patients The Open Nutrition Journal, 2008, Volume 2 103
tween groups, significant differences were detected after 4,
8, and 12 weeks. HAQ results showed a significant im-
provement in supplemented patients by the end of the trial,
whereas no change was seen in the control patients (Fig. 3).
At the end of the trial, the difference between groups also
became significant.
Fig. (3). Physical function index (HAQ) in supplemented (first
column) and unsupplemented (second column) RA patients at 0, 4,
8, and 12 weeks. Significant difference in comparisons with time 0
of the respective group; a: p = 0.009. Significant differences be-
tween groups; A: p = 0.049; mean ± SEM.
ESR, CRP, and the level of rheumatoid factor showed no
significant change during the trial in either of the groups (not
shown).
In healthy subjects, the plasma ir-EP levels were signifi-
cantly higher than in RA patients: (plasma ir-EP in fmol/ml,
mean ± SEM) healthy subjects, 12.6 ± 3.9 (n = 12); RA pa-
tients, 4.1 ± 0.5 (n = 37). Plasma ir-EP levels significantly
increased in the supplemented and control group; however,
the increase in the supplemented group occurred earlier and
was higher than in the control patients (Fig. 4); at the end of
the supplementation period, there was also a significant dif-
ference between both groups.
Fig. (4). Plasma endorphin concentration in supplemented (first
column) and unsupplemented (second column) RA patients at 0, 4,
8, and 12 weeks. Significant difference in comparison with time 0
of the respective group; a: p = 0.016; b: p = 0.018, c: p = 0.045.
Significant differences between groups; A: p = 0.043; mean ± SEM.
At the end of the study, the medication of 6 out of 19
supplemented patients was reduced: in 3 patients, the daily
steroid dose was decreased by 2-4 mg, and three other pa-
tients no longer needed to take NSAIDs. In the control
group, one patient had to be put on medication because of
hypertension during the trial, and one patient's steroid dosage
had to be increased, in the other patients medication was
unchanged. The reduction in medication in the supplemented
compared with the control group was statistically significant
according to the Fisher´s exact test (p=0.014).
DISCUSSION
The cause of RA is still unknown, but it is likely to in-
volve both genetic susceptibility and environmental factors
such as diet [11]. The role of nutrition should be clarified
with respect to two fundamental aspects: 1) Does it have any
effect in the clinical expression of the disease or in suscepti-
bility to RA? 2) Could any diet or nutrient supplementation
play a role in the management of RA by alleviating symp-
toms such as pain, by decreasing the progression of the dis-
ease, or by reducing the reliance on or combating the side-
effects of NSAIDs ? [12].
Case-controlled studies indicate that the lifelong con-
sumption of fish, olive oil, and cooked vegetables may have
protective effects on the development or severity of RA [13,
14]. Patients with RA have been reported to consume too
much total fat and too little polyunsaturated folic acid
(PUFA) and fibre [15]. The so-called Western diet (which is
also ingested by most of the population in Hungary) is well
known to lead to the development of latent metabolic acido-
sis [16]. Compensation of this acidosis is possible by in-
creasing the intake of organic mineral salts either from the
diet (increased intake of vegetables and fruits) or from sup-
plements. The main alkaline substances in our diet are cit-
rates; a useful supplement therefore should contain a mixture
of various citrate salts of sodium, potassium, calcium, and
magnesium. The used supplement contains all these salts,
together with trace elements and lactose, which increases the
bioavailability of minerals. The used dose of the supplement
provides a total of 45 mEq base per day. The usual daily
surplus of acid in the Western diet is 60 mEq in an elderly
population [17], and so a significant reduction in acid load is
achieved with the supplementation. There is to date no indi-
cation that single constituents of the supplement alone work
in improving the symptoms in RA patients.
Supplementation of the usual diet with alkaline minerals
improved the DAS28 in this study. Of the contributory fac-
tors of DAS, the level of pain changed most remarkably in
the supplemented group; however, laboratory parameters
indicating the degree of inflammation (ESR, CRP) did not
change in either of the groups, indicating that the severity of
the disease by itself was not influenced by the supplementa-
tion. One might argue that plasma parameters of acid-base
status (pH and bicarbonate values) should have been deter-
mined in this study; however, these parameters are extremely
well buffered, and changes in these parameters are much
smaller than the probable pH or buffer changes in the inter-
stitium [18].
The reduced pain sensation can be explained by the sig-
nificant elevation of plasma ir-EP levels following alkaline
supplementation. The exact physiological role of circulating
ir-EP is still obscure. What is clear from biochemical studies
is that ir-EP binds predominantly to the mu opioid receptors
[19] that are present in several peripheral tissues including
physical function index (HAQ)
0
20
40
60
80
100
120
140
160
0 4 8 12
weeks
%
a
A
plasma endorphins
0
2
4
6
8
10
12
14
0 4 8 12
weeks
fmol/ml
a
b
c
A
104 The Open Nutrition Journal, 2008, Volume 2 Cseuz et al.
immune cells [20, 21] and the synovial membrane [22]. Spo-
radic experimental data suggest that peripheral ir-EP and its
opioid receptor system play a role in the physio-pathology of
local inflammatory processes. The above experimental re-
sults and the reported negative correlation between RA activ-
ity and plasma ir-EP levels [23], together with the general
opinion that relative ir-EP deficiency may play a part in the
manifestation of autoimmune diseases [24, 25], all suggest a
causality between the circulating ir-EP levels and the arthri-
tis-induced pain.
In addition to a pain-reducing direct effect of endorphins,
an alternative explanation might be the more alkaline envi-
ronment in the local surrounding of the joints, as pain recep-
tors are sensitive to small pH changes. Significant changes in
pH have been shown to occur in the interstitium without de-
tectable changes in blood pH [18].
The finding that 6 out of 19 patients taking an alkaline
supplement could reduce their daily steroid or NSAID dos-
age also supports the view that a reduction in latent meta-
bolic acidosis has a positive effect on pain sensation. As the
chronic need for pain medication is connected to potential
side-effects, it is of great importance to find safe adjuvant
therapies for these patients, such as supplementation with
alkaline minerals, even though the supplementation does not
influence the severity of the disease itself.
The limitations of this study include its small sample size
and the lack of an active control group. However, the results
of this pilot trial should encourage further randomized pla-
cebo-controlled studies to investigate the effects of alkali
therapy.
CONCLUSIONS
Studies of the effects of dietary habits and nutrient sup-
plementation on RA are, to quote Ollier et al. [26], "ham-
pered by the inherent variability in the clinical course of the
disease and the wide spectrum of clinical phenotypes." Pa-
tients frequently self-prescribe complementary medicines
including diet modifications. This leads to considerable dif-
ficulties in selecting an appropriate group of patients for
study. Improvement in symptoms may be dependent on the
severity of the disease and on the underlying inflammatory
status. An important finding of this study is the significant
decrease in pain and DAS28 level and elevation in plasma ir-
EP levels following several weeks of alkaline supplementa-
tion. Our study is the first to demonstrate the effect of the
metabolic acid-base balance on plasma ir-EP levels. The
results of our study suggest that an alkaline supplement may
improve function and pain in rheumatoid arthritis and repre-
sents an easy and safe addition to the usual treatment of RA
patients.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to all the pa-
tients who so willingly participated in the study. For her un-
tiring help and painstaking administrative skills, Agnes Be-
senyei deserves extra special appreciation. We are also grate-
ful to Professor George Kunos (U.S.National Institutes of
Health) for his constructive remarks. Dr Beatrix Kocsis is
warmly thanked for her constant and valuable support with
the biochemistry. The authors also wish to express their
thanks to Istvan Ratkó for assistance with the bio-statistics.
We are grateful to Protina Pharm GmbH for their financial
support and for providing the mineral supplement. JV is a
research consultant to Protina Pharm GmbH in acid-base
metabolism. The other authors declare no competing inter-
ests.
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Received: July 10, 2008 Revised: September 12, 2008 Accepted: November 05, 2008
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