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The Open Nutrition Journal, 2008, 2, 100-105
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,
tion significantly reduces pain and disability . Our own observations of some RA patients also suggest the positive A large body of epidemiological and experimental stud- effect of a complementary treatment with alkalines. We have ies has demonstrated that nutrition has an important impact therefore conducted a pilot study to investigate, in more de- on the occurrence and severity of various chronic diseases tail, the effects of an alkaline supplement on pain symptoms . The level of disease-associated pain may also be diet- in patients with RA. In addition to subjective indicators of related. For example, patients with rheumatoid arthritis (RA) pain, disability, and quality of life, the change of the concen- frequently experience a positive effect of a change in diet on tration of beta-endorphin (ir-EP) has been determined in the the activity of their disease. The hypothesis of our present plasma of patients as a more objective parameter of pain study was that patients with RA, consuming an ordinary problems. Significantly lower ir-EP levels have been re- Western diet as most of the population of the world's devel- ported in RA patients than in controls, and an inverse corre- oped countries, develop a diet-induced low-grade systemic lation has been found between the rheumatoid disease activ- metabolic acidosis . There is strong evidence that a diet ity score and plasma ir-EP concentration . rich in fruit and vegetables acts protectively against a wide variety of human diseases. However, such a diet usually also MATERIALS AND METHODS
supplies excess alkalinity, and part of its beneficial effects Patients and Study Design
might be associated with a reduction of the chronic acid load . The chronic inflammatory process in RA patients leads Prior to commencing the study, approval by the local to a local increase in acidity; the pH in synovial fluids from ethical committee (Scientific Committee of St John's Hospi- patients with RA is significantly lower than that in patients tal, Budapest) was obtained, and the ethical principles of the with osteoarthritis or controls . This change in local acid- Helsinki Declaration were followed. All patients were in- ity might aggravate pain symptoms, especially in connective formed orally and in writing about the study design and the tissues. Therefore, alkaline supplementation might lead to an underlying hypothesis and of the participant's right to with- improvement of the clinical outcome in RA patients. In pa- draw at any time. The study design was a single-center ran- tients with chronic low back pain, alkaline supplementa- domized parallel trial over a period of three months. *Address correspondence to this author at the Institute for Prevention and Out of 76 outpatient candidates who were screened for Nutrition, Adalperostr. 37, D-85737 Ismaning, Germany; Tel: +49 (0)89 the trial and were willing to participate, 37 patients fulfilled 55267989; Fax: +49 (0)89 55267990; E-mail: firstname.lastname@example.org 2008 Bentham Open
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
cals, Germany) for a 12-week period in addition to their were randomly selected into a supplemented group or an usual medication. The mineral composition was as follows unsupplemented control group. Baseline characteristics of (mg/daily dose): Ca (400), K (250), Na (250), Mg (100), Fe patients in both groups are shown in Table 2.
(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- After a 4-week wash-out period (other supplements), line mineral supplement was taken twice daily in the form of patients in the supplemented group started to take, on a twice a powder mixed in one of the following: soup, yoghurt, tea, daily basis, 30 g (2 x 15 g) of a lactose-based alkaline mul- or cereal. A suitable inert placebo in a similar daily dose was timineral supplement (Basica Vital®, Protina Pharmaceuti- not available, and the use of sugar as a placebo seemed not Inclusion and Exclusion 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. Baseline Characteristics of Patients who Completed the Trial. Data are Presented as Mean (Range) Unless Otherwise
SD Patients (n=19)
CG Patients (n=17)
Sex (men/women)* Body Mass Index (kg/m) 26.1 (22.3-31.9) 27.6 (17.6-49.5) Disease Duration (years) Rheumatoid Factor Positive* 5.2 (3.6-6.9)† 4.5 Corticosteroids/mg prednisolone Hypertension 2/2 * 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 intra-articular injection with triamcinolone hexacetonide was pilot trial. During the trial, patients were not allowed to take reported what expectedly influenced the disease acitivity, any dietary supplements except for the alkaline mineral sup- and this patient was excluded from the study. Hence, 19 sup- plementation in the supplemented group. The individual dose plemented and 17 control patients completed the trial. At the of non-steroidal anti-inflammatory drugs (NSAID) could be start of the experiment, the two groups were equal in all re- adjusted but had to be recorded. spects, except for disease activity score (DAS28). At base-line, the control patients showed a score of 4.5 (range: 2.8- Determinations and Measurements
6.0) versus the supplemented group with a score of 5.2 All patients were evaluated by the same investigator in (range: 3.6-6.9); this difference is statistically significant (t- accordance with a written protocol that included medical test). At the end of the observation period, the supplemented history, ACR criteria , complete evaluation, articular group, in which members had started with significantly evaluation, and extra articular evaluation of RA (history of higher disease activity score, showed significantly lower rheumatoid nodules, Reynard's phenomenon, or pulmonary, DAS28 compared with control patients (Fig. 1). DAS28 de-
cardiac, dermal, ocular, and nervous system involvement). creased in the supplemented group, whereas there was no Disease activity was assessed by determination of the num- significant change in disease activity score during the trial in ber of swollen joints, the score of tender and swollen joints, the control patients. There were also significant differences and the duration of morning stiffness (in minutes). A com- between supplemented and unsupplemented groups at 4, 8, posite disease activity score (DAS 28) , a physical func- and 12 weeks. The level of pain (according to the patient's tion index Health Assessment Questionnaire (HAQ) , C- visual analog scale (VAS)) decreased to a considerable ex- reactive protein (CRP), and rheumatoid factor were meas- tent in the supplemented group (Fig. 2). In the control pa-
ured at baseline and 4, 8, and 12 weeks after starting the tients, the pain increased between week 0 and week 4. Be- trial. DAS28 is a composite disease activity index and also a response index with good discriminatory validity. It includes disease associated symptom index (DAS28)
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 . In short, synthetic human EP (Sigma) was used both for the standard Fig. (1). DAS28 in supplemented (first column) and unsupple-
and 125I-labeled tracer, and a second antibody was used to mented (second column) RA patients at 0, 4, 8, and 12 weeks. Sig- separate the bound and free fractions. 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; 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- pain (VAS)
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- 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 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- A total of 37 patients were enrolled of whom 19 were sons with time 0 of the respective group; a: p = 0.045; b: p = 0.004, randomly allocated to the supplemented group and 18 to the c: p = 0.048. Significant differences between groups; A: p = 0.003; unsupplemented control group. In one control patient, an B: p = 0.001, C: p = 0.037; mean ± SEM. 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, tients no longer needed to take NSAIDs. In the control 8, and 12 weeks. HAQ results showed a significant im- group, one patient had to be put on medication because of provement in supplemented patients by the end of the trial, hypertension during the trial, and one patient's steroid dosage whereas no change was seen in the control patients (Fig. 3).
had to be increased, in the other patients medication was At the end of the trial, the difference between groups also unchanged. The reduction in medication in the supplemented became significant. compared with the control group was statistically significant according to the Fisher´s exact test (p=0.014). physical function index (HAQ)
The cause of RA is still unknown, but it is likely to in- volve both genetic susceptibility and environmental factors such as diet . 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 ? . Case-controlled studies indicate that the lifelong con-sumption of fish, olive oil, and cooked vegetables may have Fig. (3). Physical function index (HAQ) in supplemented (first
protective effects on the development or severity of RA [13, column) and unsupplemented (second column) RA patients at 0, 4, 14]. Patients with RA have been reported to consume too 8, and 12 weeks. Significant difference in comparisons with time 0 much total fat and too little polyunsaturated folic acid of the respective group; a: p = 0.009. Significant differences be- (PUFA) and fibre . The so-called Western diet (which is tween groups; A: p = 0.049; mean ± SEM. also ingested by most of the population in Hungary) is well known to lead to the development of latent metabolic acido- ESR, CRP, and the level of rheumatoid factor showed no sis . Compensation of this acidosis is possible by in- significant change during the trial in either of the groups (not creasing the intake of organic mineral salts either from the diet (increased intake of vegetables and fruits) or from sup- In healthy subjects, the plasma ir-EP levels were signifi- plements. The main alkaline substances in our diet are cit- cantly higher than in RA patients: (plasma ir-EP in fmol/ml, rates; a useful supplement therefore should contain a mixture mean ± SEM) healthy subjects, 12.6 ± 3.9 (n = 12); RA pa- of various citrate salts of sodium, potassium, calcium, and tients, 4.1 ± 0.5 (n = 37). Plasma ir-EP levels significantly magnesium. The used supplement contains all these salts, increased in the supplemented and control group; however, together with trace elements and lactose, which increases the the increase in the supplemented group occurred earlier and bioavailability of minerals. The used dose of the supplement was higher than in the control patients (Fig. 4); at the end of
provides a total of 45 mEq base per day. The usual daily the supplementation period, there was also a significant dif- surplus of acid in the Western diet is 60 mEq in an elderly ference between both groups. population , 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 Fig. (4). Plasma endorphin concentration in supplemented (first
smaller than the probable pH or buffer changes in the inter- 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. The reduced pain sensation can be explained by the sig- Significant differences between groups; A: p = 0.043; mean ± SEM. 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 At the end of the study, the medication of 6 out of 19 is that ir-EP binds predominantly to the mu opioid receptors supplemented patients was reduced: in 3 patients, the daily  that are present in several peripheral tissues including steroid dose was decreased by 2-4 mg, and three other pa- 104 The Open Nutrition Journal, 2008, Volume 2
Cseuz et al.
immune cells [20, 21] and the synovial membrane . Spo- We are grateful to Protina Pharm GmbH for their financial radic experimental data suggest that peripheral ir-EP and its support and for providing the mineral supplement. JV is a opioid receptor system play a role in the physio-pathology of research consultant to Protina Pharm GmbH in acid-base local inflammatory processes. The above experimental re- metabolism. The other authors declare no competing inter- sults and the reported negative correlation between RA activ- ity and plasma ir-EP levels , together with the general REFERENCES
opinion that relative ir-EP deficiency may play a part in the manifestation of autoimmune diseases [24, 25], all suggest a Neel JV. When some fine old genes meet a new environment? In: causality between the circulating ir-EP levels and the arthri- Simopoulus A Ed, Evolutionary aspects of nutrition and health, tis-induced pain. Karger: Basel 1999; 1-15. Vormann J, Remer T. Dietary, metabolic, physiologic, and disease- In addition to a pain-reducing direct effect of endorphins, related aspects of acid-base balance: foreword to the contributions an alternative explanation might be the more alkaline envi- of the second International Acid-Base Symposium. J Nutr 2008; 138: 413S-4S. ronment in the local surrounding of the joints, as pain recep- Vormann J, Goedecke T. Acid base homeostasis. Latent acidosis as tors are sensitive to small pH changes. Significant changes in a cause of chronic disease. Schweiz Zschr Ganzheits Medizin 2006; pH have been shown to occur in the interstitium without de- tectable changes in blood pH . Farr M, Garvey K, Bold AM, Kendall MJ, Bacon PA. Significance of the hydrogen ion concentration in synovial fluid in rheumatoid The finding that 6 out of 19 patients taking an alkaline arthritis. Clin Exp Rheumatol 1985; 3: 99-104. supplement could reduce their daily steroid or NSAID dos- Vormann J, Worlitschek M, Goedecke T, Silver B. Supplementa-tion with alkaline minerals reduces symptoms in patients with age also supports the view that a reduction in latent meta- chronic low back pain. J Trace Elem Med Biol 2001; 15: 179-83. bolic acidosis has a positive effect on pain sensation. As the Elbeialy A, Elbarbary M, Kamel M. Peripheral beta-endorphin in chronic need for pain medication is connected to potential rheumatoid Arthritis. A correlation with the disease activity. Scand side-effects, it is of great importance to find safe adjuvant J Rheumatol 1997; 26: 88-91. therapies for these patients, such as supplementation with Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheuma-tism Association 1987 revised criteria for the classification of alkaline minerals, even though the supplementation does not rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24. influence the severity of the disease itself. Van Riel PLCM, van Gestel AM. Clinical outcome measures in rheumatoid Arthritis. Ann Rheum Dis 2000; 59 (Suppl 1): 28-31. The limitations of this study include its small sample size Bruce B, Fries J. The Stanford Health Assesment Questionnaire and the lack of an active control group. However, the results (HAQ): A review of its history, issues, porgress and documenta- of this pilot trial should encourage further randomized pla- tion. J Rheumatol 2003; 30: 167-78. cebo-controlled studies to investigate the effects of alkali Barna I, Koenig JI. Effects of mediobasal hypothalamic lesion on immunoreactive ACTH/beta-endorphin levels in cerebrospinal fluid, in discrete brain regions, in plasma, and in pituitary of the rat. CONCLUSIONS
Brain Res 1992; 593: 69-76. Pattison DJ, Harrison RA, Symmons PMD. The role of diet in Studies of the effects of dietary habits and nutrient sup- susceptibility to rheumatoid arthritis: a systematic review. J Rheu-matol 2004; 31: 1310-9. plementation on RA are, to quote Ollier et al. , "ham- Rennie KL, Hughes J, Lang R, Jebb SA. Nutritional management pered by the inherent variability in the clinical course of the of rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet disease and the wide spectrum of clinical phenotypes." Pa- 2003; 16: 97-109. tients frequently self-prescribe complementary medicines Haugen M, Fraser D, Forre Ø. Diet therapy for the patient with including diet modifications. This leads to considerable dif- rheumatoid arthritis. Rheumatology 1999; 38: 1039-44. Linos A, Kaklamani VG, Kaklamani E, et al. Dietary factors in ficulties in selecting an appropriate group of patients for relation to rheumatoid arthritis: a role for olive oil and cooked study. Improvement in symptoms may be dependent on the vegetables? Am J Clin Nutr 2000; 71: 1010. severity of the disease and on the underlying inflammatory Calder PC, Zurier RB. Polyunsaturated fatty acids and rheumatoid status. An important finding of this study is the significant arthritis. Curr Opin Clin Nutr Metab Care 2001; 4: 115-21. Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of decrease in pain and DAS28 level and elevation in plasma ir- the Western diet: health implications for the 21st century. Am J EP levels following several weeks of alkaline supplementa- Clin Nutr 2005; 81: 341-54. tion. Our study is the first to demonstrate the effect of the Rylander R, Remer T, Berkemeyer S, Vormann J. Acid-base status metabolic acid-base balance on plasma ir-EP levels. The affects renal magnesium losses in healthy, elderly persons. J Nutr results of our study suggest that an alkaline supplement may 2006; 136: 2374-7. Street D, Nielsen J-J, Bangsbo J, Juel C. Metabolic alkalosis re- improve function and pain in rheumatoid arthritis and repre- duces exercise-induced acidosis and potassium accumulation in sents an easy and safe addition to the usual treatment of RA human skeletal muscle interstitium. J Physiol 2005; 566: 481-9. Mizoguchi H, Tseng LF, Suzuki T, Sora I, Narita M. Differential mechanism of G-protein activation induced by endogenous mu- opioid peptides, endomorphin and betaendorphin. Jpn J Pharmacol 2002; 89: 229-34. The authors wish to express their gratitude to all the pa- Chan TK, Killam Jr KF, Chuang LF, et al. Mu opioid receptor gene tients who so willingly participated in the study. For her un- expression in immune cells. Biochem Biophy Res Commun 1995; tiring help and painstaking administrative skills, Agnes Be- Rogers TJ, Peterson PK. Opioid G protein-coupled receptors: sig- senyei deserves extra special appreciation. We are also grate- nals at the crossroads of inflammation. Trends Immunol 2003; 24: ful to Professor George Kunos (U.S.National Institutes of Health) for his constructive remarks. Dr Beatrix Kocsis is Hayashi K, Sugisaiki M, Ota S, Tanabe H. mu-Opioid receptor warmly thanked for her constant and valuable support with mRNA expression and immunohistochemical localization in the rat the biochemistry. The authors also wish to express their temporomandibular joint. Peptides 2002; 23: 889-93. thanks to Istvan Ratkó for assistance with the bio-statistics. Alkaline Mineral Supplementation Decreases Pain in Rheumatoid Arthritis Patients
The Open Nutrition Journal, 2008, Volume 2 105
Martinez JH, Mondragon CE, Cespedes A. An evaluation of the Sacerdote P, Gaspani L, Panerai AE. Role of b-endorphin in the antiinflammatory effects of intraarticular synthetic beta-endorphin modulation of immune responses: perspectives in autoimmune dis- in the canine model. Anest Analg 1996; 82: 177-81. eases. Adv Exp Med Biol 2001; 63: 1037-41. Morch H, Pedersen BK. Beta-endorphin and the immune system – Ollier WE, Harrison B, Symmons D. What is the natural history of possible role in autoimmune diseases. Autoimmunity 1995; 21: rheumatoid arthritis? Best Pract Res Clin Rheumatol 2001; 15: 27- Received: July 10, 2008 Revised: September 12, 2008 Accepted: November 05, 2008 Cseuz et al.; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
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