Medical Hypotheses 1
Medical HypoUlser OLODpUlGarpuKW19V2
I (1992) 39,342-348
Ginger (Zingiber officinale) in Rheumatism and Musculoskeletal Disorders K. C. SRIVASTAVA’ and T. MUSTAFAt ‘Department of Environmental Medicine, Institute of Community Health, Odense University, Winsbwpatien 17, DK-5000 Odense M, Denmark Institute of Biology, Odense University, Campusvej 55, DK-5230 Odense iU, Denmark (Reprint requests to KCS)
Abstract-One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways-the cyclooxygenase (CO) and the 5-lipoxygenase (!I-LO)-leading to the production of prostaglandins and leukotrienes respectively. Amongst the CO products, PGE2 and amongst the 5LO products, LTB4 are considered important mediators of inflammation. More than 200 potential drugs ranging from non-steroidal anti-inflammatory drugs, corticosteroids, gold salts, disease modifying anti-rheumatic drugs, methotrexate, cyclosporine are being tested. None of the drugs has been found safe; all are known to produce from mild to serious side-effects. Ginger is described in Ayurvedic and Tibb systems of medicine to be useful in inflammation and rheumatism. In all 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort) used powdered ginger against their afflictions. Amongst the arthritis patients more than three-quarters experienced, to varying degrees, relief in pain and swelling. All the patients with muscular discomfort experienced relief in pain. None of the patients reported adverse effects during the period of ginger consumption which ranged from 3 months to 2.5 years. It is suggested that at least one of the mechanisms by which ginger shows its ameliorative effects could be related to inhibition of prostaglandin and leukotriene biosynthesis, i.e. it works as a dual inhibitor of eicosanoid biosynthesis.
Introduction
The average life span of people living in the industrialized world has increased. Incidence of chronic and degenerative afflictions such as cardiovascular disease, cancer and arthritis is also on the upswing in such populations. Arthritis in the USA is called ‘the nation’s primary crippler’, and with grim reason. As estimates have put it, arthritis affects more than 37 Date received 3 June 1992 Date accepted 10 July 1992
million Americans-one in every seven suffer from arthritis, and one in every three families is touched by the disease. Arthritis actually encompasses more than 100 afflictions which range from the ravaging disease like rheumatoid arthritis (RA) to osteoarthritis (which usually affects and cripples the elderly), to tendinitis affecting mostly athletes. Together, these afflictions in USA alone account for 27 million lost work-days a year which in terms of economy is estimated to be US
342
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IN RIiEUMATlSM
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dollars 8.6 billion a year. It is known that 94% of the arthritis patients during the course of the disaease try one or the other of the dozen or so known unconventional remedies to treat their affliction (1, 2). Most of these remedies have no sound scientific basis. Ginger is not included in the list of unconventional remedies for the treatment of arthritis though the use of ginger has been known to several civilizations. Ginger is used in folk medicine, and is popular as a food spice. Its therapeutic uses are many; it is useful in flatulence, flatulent colic, and spasmodic affections of the bowels. It helps in some forms of headache and various affections of the throat. It is mentioned in British and other Pharmacopoeas as a carminative. It finds an important place both in the Ayurvedic and Tibb systems of medicine where amongst other things it is recommended against rheumatic disorders (3). Also in the Chinese folk medicine it is mentioned to ameliorate or even cure several diseases. Even today at the end of the 20th century a majority of the world’s population receives its health care from traditional systems of medicine. This has prompted the present WHO’s Director General Dr Hiroshi Nakajima to stale that ‘a medical knowledge that works-no matter how scientific its origins-is a treasure that cannot be ignored’. In this paper, we report on the effect of ginger in arthritis and muscular discomfort, and suggest a possible mechanism of action. Rationale of the study It would not be inappropriate to mention here the situation under which this study with ginger began. One of us happened to mention during an interview, by a journalist of a leading Danish newspaper, about the usefulness of ginger in some diseases including rheumatic disorders he had known in his native country in the Indian sub-continent (4). That there might be some scientific basis in such claims was obviously based on the author’s experience with ginger in his laboratory experiments. It was found that ginger contained components with strong antiplatelet and prostanoid synthesis inhibiting activity (5-8). Initially, after the interview some arthritis patients in Denmark began consuming powdered ginger in different doses on their own, and apparently those who experienced relief contacted us. A short report involving 7 rheumatic patients in which ginger was found to have helped was published 3 years ago (9). Since then the number of arthritis patients who found benefit with ginger has increased several fold. We then prepared a questionnaire and sent them out to those who were interested to fill them out and return. This report is, therefore, a questionnaire-based open-trial on the effects of ginger in arthritis and muscular discomfort
together with some other cases with related symptoms where ginger was found to ameliorate mainly pain and inflammation. Case histories
Below are given case histories, selected one from each of RA and osteoarthritis, and two from muscular discomfort. We did not have access to the clinical reports of the patients. We had to depend, therefore, on the information submitted to us on the questionnaires by patients. Rheumatoid arthritis The patient is a male of Asian origin and settled in
Canada. At the age of 50 he was afflicted with RA which was diagnosed in Canada. The patient took ginger in an amount of ca 50 gram raw/fresh daily in the first month after the diagnosis. Ginger was taken through lightly cooked vegetable and meat dishes. Relief in pain and swelling was evident after 1 month of ginger intake. The patient was completely free of pain and swelling after 3 months of ginger consumption. He is active in his job as an automechanic, and 13-14 years have passed without relapse of symptoms. Since last year nodules have appeared on some of the joints of the fingers of both hands without any deformity and loss of function or pain. Osteoarthritis
A woman of 69 years suffered from back pain since she was 17 years of age due apparently to a bad sitting posture while she worked in an office. She later developed osteoarthritis involving 4-5, 5-6 and 67 vertebrae which was diagnosed in 1974. About a decade later the upper joint in right thumb was also afflicted. In 1990 both the knees and elbows were affected. The patient was given antiarthritis drugs of various types. The drugs produced side-effects, especially stomach irritation on prolonged use. She started taking powdered ginger since mid April 199 1. A sample provided by the patient to us weighed 7.6 gram, a dose she took daily. After four months on ginger she noticed relief in symptoms. Swelling in the right knee disappeared after 2 months. However, swelling persists in the thumb and the first finger. After 6 months on ginger she stopped taking antiarthritis drugs. Nevertheless, the patient was prescribed 2 tablets a day of a drug containing codein phosphate (9.6mg), phenobarbital (SOmg) and quininsulphate (50mg). This made her drowsy. She reduced the dose to 1 tablet a day which did not help. Now she takes half tablet of
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the drug without having this discomfort (drowsiness). The patient was not able to turn her head to left and look upwards due to osteoarthritic condition of the neck vertebrae, which she can do now with a little care after about 10 years. The patient has been advised to reduce the dose to about l/4 (ca &am/day). She continues to take this dose. Muscular disorder
The patient, a man of 49 years, developed muscular pain and pain in some joints about 5 years ago. The nature of his job was such that he had to cycle for several hours a day which he found hard to carry on. His condition was diagnosed to be muscular ‘arthritis’. He was prescribed analgesics which produced gastro-intestinal irritation. The patient’s condition became worse; the pain was more intense with the result he had to give up an extra job 3 years later. At times he could not leave bed and abstained from work. On advice of some of his friends he took one teaspoonful powdered ginger a day. He noticed marked reduction in pain after 14 days which disappeared completely in a month. He continued to take ginger in half dose for several months. He no longer takes it. Another patient, having myositis, is a woman now in her late forties. She developed stiffness in the neck some 25 years ago which she still suffers from. Stiffness is worst in the morning on getting out of bed. Analgesics do help, but she avoids them due to gastrointestinal irritation. She administered ginger on her own taking ca 3-4g powdered ginger a day. Within
HYPOTHESES
a few days relief was observed with the muscles of the neck relaxed. She consumes ginger in this dose whenever the stiffness becomes unbearable. Our observation on the efficacy of ginger-as reported by patients voluntarily-in arthritis and muscular discomfort involved 28 patients with RA, 18 patients with osteoarthritis and 10 with muscular discomfort. Besides, 7 other patients having one of the afflictions such as, stomach catarrh, sciatica, fibromyositis, gout (2 patients) and tendinitis also felt relief. Effect of ginger-intake on the usual symptoms-pain and swelling-in arthritis is shown in the Table. Marked reduction in pain was observed by all the patients with muscular discomfort after consumption of ginger. None of the patients, with the exception of two who were of Asian origin, were familiar with ginger and have used it in their diet as a condiment. The majority of patients included in this survey have had their afflictions for more than 3 years before taking ginger. Discussion The 19th century British physician Sir William Osler said ‘When a patient with arthritis walks in the front door, I feel like leaving out the back door’. The physicians of the present day may not feel this extreme way, but they do know that science has no cure for most forms of arthritis. However, the arsenal of medications is growing. The drugs range from non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, gold salts, disease-
Table Effect of ginger consumption in the relief of pain and swelling among rheumatoid arthritis and osteoathritis patients Relief (%) No.of patients
Marked
Moderate
Minimal
None
28 22
14 59
11 18
4
11 23
Rheumatoid arthritis*
Pain Swelling Osteoarthritis P&l
18
55
22
swelling
10
50
20
11 10
12 20
arthritis and osteoarthritis patients Pain
46
61
swelling
32
56
15 19
I 3
11 22
Total of rheumatoid
Total no. of patients (Age: Mean rLSD) Male 20 (58 f 13), Female 36 (59 f 15). Amount of ginger powder consumed was not uniform, and the degree of relief was evaluated by the patients themselves. ‘Includes 3 patients with non-specific arthritis (Bechterew’s syndrom&pondylitis)
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modifying anti-rheumatic drugs (DMARDs), antimalarial agents (hydroxychloroquine), methotrexate, cyclosporine---cmrently more than 200 potential drugs are being tested. None of the drugs has been found to be safe; all are known to produce from mild to serious side-efects. NSAIDs relieve pain and can reduce inflammation, but to achieve this the use of large doses over a long period of time is required. Gastro-intestinal irritation and intestinal blood loss are the usual side-effects. Hydroxychloroquine can cause eye damage. Methotrexate affects the liver and blood. Immune modulating drugs can affect the body’s ability to ward off infections. Corticosteroids, initially a drug of great promise, can produce devastating side-effects which include asceptic bone necrosis (brittle bones), thin skin and raised blood pressure. Thus, a race is on to design and/or find anti-inflammatory drug(s) which will suppress the manifestations without toxic effects.
Monohydroxy lipoxygenase products, 12-HETE and 5-HETE, show weak chemokinetic and chemotactic properties both in vitro and in vivo in human and rabbit polymorphonuclear leuccxzytes (PMNL) (14). The dihydroxy product, LTB4, on the contrary shows powerful effects on the PMNL. Its chemokinetic and chemotactic properties were demonstrated both in vitro and in vivo; it produced degranulation of PMNL of several species in vitro and accumulation of these cells in vivo (15, 16). That LTB4 had a similar effect in humans was tirst demonstrated by Klickstein et al (17), who showed that synovial fluids of patients with RA and spondyloarthritis contained higher levels of LTB4 and also of the pivotal product of 5lipoxygenase, 5-HETE from which leukotrienes are derived. From the above mentioned studies it is obvious that synovial tissue can produce 5-LO as well as cyclooxygenase products. Other cellular systems (polymorphonuclear and monomorphonuclear leucocytes, platelets, lymphocytes) which have important functions in controlling inflammation, produce much varied moeities of eicosanoids compared to those produced by synovial tissue. As one would expect, there are clear differences in the types and quantities of both cyclooxygenase and LO products produced by the inflammatory cells. Cellular co-operativity in the production of LO products has also been observed. For instance, 12-HPETE from blood platelets stimualte the production of 5, 12-diHETEs in lcucocytes (18), and stimulation of the 5-LO enzyme by 15-HETE (19) are examples of the co-operativity.
Eicosanoids in arthritis
Mechanical, chemical or immunological challenge stimulates phospholipase activity and living tissue responds to irritation and injury by producing inflammation. While enhanced production of arachidonic acid (AA)-oxygenated products is a characteristic feature in the inflamed tissues, it is becoming apparent that there may be qualitative as well as quantitative differences in the AA-metabolites produced in the inflamed tissues in different arthritic conditions. Of the eicosanoids, prostaglandin E2 (PGE2) is the prominent product although prostaglandin Fza (PGFz.J, prostaglandin D2 (PGDz), thromboxane B2 (TXB2) and 6-keto-PGFl, have also been detected. Prostaglandin E2 plays a crucial role in two ways: firstly, by causing resorption of bone by synoviocytes through increased number of bone osteoclasts, and secondly, by stimulating the secretion of collagenase by macrophages coupled with inhibition of the formation of proteoglycans by articular chondrocytes and synoviocytes (10, 11). Besides producing cyclooxygenase products (prostanoids), it has been found that human rheumatoid and osteoarthritic synovium can generate 5lipoxygenase (5-LO)-products: leukotrienes (LT) CJ, D4 and E4 which were identified in the synovial membranes from rheumatoid and osteoarthritic patients (12). The level of LTB4 in the thuds of RA patients is slightly in excess of that in the fluids horn osteoarthritis patients (13). Interestingly, the levels of LTB4 have been found to be increased six-fold in the synovial fluids from patients with gout compared to the LTB4 levels in corresponding fluids obtained from patients with RA and osteoarthritis (13).
Possible role of ginger in arthritis The chemical composition of dried ginger is as fol-
lows: ca 4060% starch, 10% proteins, 10% fats, 5% fibres, 6% inorganic material, 10% residual moisture and l-4% essential oil (oleoresin) (20). During the last 45 years many chemical investigations have been carried out on the constituents of the essential oil (20, 21). All together more than 200 different volatiles have been identified in essential oil wherein the pharmacological activity is confined. The essential oil contains mixture of various terpenes as well as some other non-terpenoid compounds. Due to the large battery of compounds belonging to various chemical classes, it is likely that crude ginger powder intake brings about amelioration of symptoms by interfering with the production and release of products of lipid membranes (eicosanoids, reactive oxygen), peptides and proteins (lysosomal enzymes, growth factors, lymphokines, bradykinin), amino acids (histamin, serotonin) etc. Although this is mostly speculative, the experimental data in our hands and observa-
346 tions of others suggest that ginger inhibits both the cyclooxygenase (7, 22) and lypoxygenase products (23, 24), i.e. it can be a dual inhibitor of eicosanoid synthesis. Ginger is reported to contain antihistaminic and antioxidant factors as well (25). Non-steroidal anti-inflammatory drugs have three major actions, all of which are related to inhibition of cycle-oxygenase resulting in decreased formation of prostanoids. Firstly, an anti-inflammatory action achieved by reduced production of vasodilator prostaglandins (PGE2, PGIi) which means less vasodilation and, indirectly less oedema. Secondly, an analgesic effect achieved by reduced prostaglandin production (less sensitisation of nociceptic nerve endings to the inflammatory mediators bradykinin and 5hydroxytryptamine). Thirdly, an antipyretic effect which is probably due to a decrease in the mediator PGE;! generated in response lo inflammatory pyrogens, such as interleukin-I. Since ginger inhibits prostanoid synthesis and also products of 5lipoxygenase, its ameliorative effects in arthritis and muscular discomforts could be related to reduced formation of prostanoids and leukotrienes. Because of such a possibility a decrease in the cararegeenan-induced cedema formation in the rat’s paw after 3h of ginger extract administration has been demonstrated and the potency of the extract in the acute inflammation test appears to be comparable to that exhibited by acetyl salicylic acid reported in the same study (26). Regimen and the safety ofginger Most of the spices from Allium to Zingiber are on the Food and Drug Administration’s (FDA’s) Generally Recognized as Safe (GRAS) list (Duke J A, personal communication). Accordingly, one should not have worries if ginger is consumed in amounts normally available through food for any length of time. Some of the patients with arthritic disorders who mistakenly took 34 times, or even more, the dose (OS-l.0 gram powdered ginger/day) suggested by us, reported quicker and better relief than those on the recommended dose. This might suggest that effective components in ginger are present in very small amounts, and to achieve an effective dose of the desired component(s) one would require large doses of powdered ginger. Most of the patients for reasons of convenience took one-half to a teaspoonful powdered ginger for which the corresponding weight would be ca 1 and 2 gram respectively. No adverse reactions were observed by any of the patients who had taken ginger from periods ranging from 3 months to 2.5 years. Most of the patients observed relief of symptoms
MEDICAL HY1’0’17l1iS12’
within l-3 months. Compelled by the nature of the disease most of them are coninuing with ginger. On our advice some of the patients who stopped taking their daily doses suffered a return of symptoms within weeks to 2 months. Relief was again achieved with the resumption of ginger intake. However, one incidental observation by Dr Dorso (the donor of blood) that only one-time consumption the previous evening of a large quantity of an excellent marmalade (Ginger with Grapefruit, Crabtree and Evelyn, London) whose major ingredient (15%) was ginger produced inhibition of AA-induced platelet aggregation which returned to normal after 1 week, might indicate that ginger components appear to remain in the body for several days (27). From this observation it could be inferred that like the NSAIDs, bioactive components of ginger remain effective while their blood levels are sustained, with symptoms of inflammation recurring after the withdrawal of ginger consumption which was observed in every case where ginger consumption was withheld. In acute toxicity test mice tolerated ginger extract as gavage of up to 2.5 g/kg with no mortality or side effects during a 7-day trial period. However, increase in doses to 3.0-3.5 g/kg the extract resulted in lO-30% mortality. Under similar experimental conditions, acetyl salicylic acid (600 mg/kg) produced mortality in 25% of animals, stomach ulcers in 40% of animals and discomfort and/or hypothermia in 60% of animals (26). Nevertheless, in SOS Chromotest on the toxicity and embryotoxicity test ginger was found to be non-toxic (Backon J, personal communication). There is no mention of adverse effects of ginger in the literature (28). However, as only one-time consumption of ginger resulted in producing a persistent effect on the function of blood platelets (27), the patients were advised to withhold consumption of ginger and to reduce the daily dose to half a gram powdered ginger. It would be worthwhile to mention a case of ginger consumption in a female osteoarthritis patient of 80 years of age whose one kidney was removed; she has consumed ginger for the last 3 years, in the first 6 months about 6g powdered ginger daily which was reduced later to ca 2g daily-dose. She has been able to tolerate this dose without any side-effects. As she has felt relief in symptoms, she is regularly taking it. Continued use and tolerance of ginger consumption by this patient may provide some insight towards the effect of ginger on renal function. It is known that in people with impaired renal function and advanced age NSAIDs reduce the creatinine clearance and increase serum creatinine concentrations probably by suppressing the vasodilatory function of re-
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341
nal prostaglandins. A number of NSAIDs cause acute nephritis though most patients recover with drug discontinuation (29). The fact that this patient of such an advanced age with one kidney has tolerated consumption of ginger for 3 years indicates that ginger unlike the NSAIDs does not impair renal perfusion or function especially in the elderly who may be predisposed with interstitial nephritis and/or decreased circulating blood volume. Like any other natural product if raw or powdered ginger is not stored properly danger of atlatoxin contamination is greater (30). Therefore, use of qualitycontrolled powdered ginger preferably from a drug store was suggested.
planned. A more specific study could also address to a possible interaction of ginger with other drugs. This information would be useful in evaluating the use of ginger-intake in juvenile and elderly arthritic patients.
GINGER IN RHJXJMATtSM
AND
Other benefits of ginger-intake Ginger has been used in Ayurvedic and Tibb systems of medicine for headache, nervous diseases, nausea and vomiting for centuries. Some of these age old observations have proven true when subjected to scientific scrutiny. Not long ago it was demonstrated that gastrointestinal symptoms of kinetosis were alleviated better by ginger than antihistamine agent in a controlled trial (31). In a double-blind randomized trial ginger was shown to reduce symptoms of nausea and vertigo (28). Rexently we have reported on the abortive and prophylactic effects of ginger in migraine headache (32). Possible use of ginger in several psychiatric problems where inhibition of thromboxane A2 is required has been suggested (33). Some of our patients have observed added benefits on taking ginger, and they include relief in cold sores and throat touchiness (‘squeamish throat’), fewer colds, amelioration of stomach irritation and constipation. Quite a few observed reduced tendency of motion-related nausea--an observation which has been confirmed in a controlled study (28). The patients slept better and suffered less pruritus and edema. Conclusion In the present study an observation describing the ameliorative effect of ginger consumption in arthritis and musculoskeletal disorders is described. It is suggested that bioactive components of ginger may act as dual inhibitors of cyclooxygenase and lipoxygenase pathways, and may act by inhibiting PGE2 and leukotriene B4 synthesis. It may be emphasized that this study presents only a hypothesis and must be verified in a double-blind placebo study. To evaluate the issue of life-long ginger consumption in prevention and/or amelioration of arthritic diseases, more detailed, larger and epidemiological studies should be
References 1. Brown J H, Spitz P W, Fries J F. Unorthodox treatments in rheumatoid arthritis (Abstract). Arthritis and Rheumatism (Suppl) 23: 657-658, 1980. 2. Wasner C K, Cassady J, Kronefeld J. ‘Ihe use of unproven remedies (Abstract). Arthritis and Rheumatism (Suppl) 23: 759-760, 1980. 3. Atal C K, Suri K A, Suri 0 P, Singh G B. Synthesis of anti-inflammatory compounds based on dehydrozingerone as model. Symposium-Recent Advances in Mediators of Inflammation and Anti-inflammatory Agents, Regional Research Laboratory, Jammu-Tawi, India 24 November p33 1984. 4. Jyllands-Posten, June 20, 1987; July 5. 1987; May 4 1989. 5. Srivastava K C. Effects of aqueous extracts of onion, garlic and ginger at platelet aggregation and metabolism of arachidonic acid in the blood vascular system: in vitro study. Prostaglandins, Leukotrienes and Medicine 13: 227-23.5. 1984. 6. Srivastva K C. Aqueous extracts of onion. garlic and ginger inhibit platelet aggregation and alter arachidonic acid metabolism. Biomedica Biochimica Acta 43: S335S346. 1984. I. Srivastava K C. Isolation and effects of some ginger conpcments on platelet aggregation and eicosanoid biosynthesis. Prostaglandins, Leukotrienes and Medicine 25: 187-198, 1986. 8. Srivastava K C. Effect of onion and ginger consumption on platelet thromboxane production in humans. Prostaglandins, Leukotrienes and Essential Fatty Acids 35: 183-185. 1989. 9. Srivastava K C, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Medical Hypotheses 29: 25-28. 1989. 10. Fahey J V, Ciosek C P, Newcombe D S. Human synovial fib&lasts: the relationship between cyclic AMP, bradykinin and prostaglandins. Agents and Actions 7: 255-264, 1977. 11. Lippiello Y, Yamamoto K. Robinson D et al. Involvement of prostaglandins from rheumatoid synovium in inhibition of articular cartilage metabolism. Arthritis and Rheumatism 21: 909-917. 1978. 12. Kopicky J A, Peters S P, Lennox D W, Wigley F M. Leukotriene production by human synovial membrane. Artbritis and Rheumatism 28: abstract B30, p ~60, 1985. 13. Rae S A, Davidson E M, Smith H J H. Leukotriene B4, an inflammatory mediator in gout. Lancet ii: 1122-l 123. 1982. 14. Palmer R J. Stephney R, Higgs G A, Eakins K E. Chemokinetic activity of arachidonic acid lipoxygenase products on leukocytes from different species. Prostaglandins 20: 411418, 1980. 15. Bray M A. The pharmacology and pathophysiology of leukotriene B4. British Medical Bulletin 39: 249-254, 1983. 16. Higgs G A. Salmon J A, Spayne J A. The inflammatory effects of hydroperoxy and hydroxy acid products of arachidonate lipoxygenase in rabbit skin. British Journal of Pharmacology 74: 429-433. 1981. 17. Klickstein L B, Shapleigh C. Goetzl E J. Lipoxygenation of arachidatic acid as a source of polymorphonuclear leucocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondyloarthritis. Journal of Clinical Investigation 66: 1166-1170. 1980. 18. Borgeat P, Fruteau de Laclos B. Maclouf J. New concepts in
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the modulation of leukotriene synthesis. Biochemical Pharmacology 32: 381-387, 1983. Vanderhoek J Y, Bailey J M. Postphospholipase activation of lipoxygenase/leukotriene systems. In: Bailey J M (ed.) Prostaglandins, Leukotrienes and Lipoxins, Plenum Press, New York, ~133, 1985. Van Beek T A, Posthumus MA, Llyveld G P et al. Investigation of the essential oil of Vietnamese ginger. Phytochemistry 26: 3005-3010, 1987. Chen C, Ho C&i-Tang. Gas chmmatographic analysis of volatile components of ginger oil (Zingiber officinale Roscoe) extracted with liquid carbon dioxide. Journal of Agriculture and Food Chemistry. 36: 322-328, 1988. Kiuchi F, Shibuya M, Sankawa Il. Inhibitors of prostaglandin biosynthesis fran ginger. Chemical and Pharmaceutical Bulletin 30: 747-754, 1982. Flynn D L. Rafferty M F, Boctor A M. Inhibition of human neutrophil S-lipoxygenase activity by gingerdione, shagaol, capsaicin and related pungent compounds. Prostaglandins, Leukotrienes and Medicine 24: 195-198, 1986. Suekawa M, Yuasa K, bono M et al. Pharmacological studies on ginger. IV Effect of (6)shogaol on the arachidonic acid cascade. Folia Pharacologica Japonica 88: 263-269, 1986. Duke J A, Ayensu E S. Medicinal Plants of China, Reference Publications Inc. Michigan p657, 1985.
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Mascolo N, Jain R, Jain S C, Capasso F. Ethnopharmacologic investigation of ginger Qingiber officinale) Journal of Ethopharmacology 27: 129-140. 1989. Dorso C R, Levin R I. Eldor A, Jaffe E A, Wed&r B B. Chinese fcod and platelets. New England Journal of Medicine 303: 756-757, 1980. Grontved A. Brask T, Kambskard J. Hentzer E. Ginger root against sea-sickness: A controlled trial on the open sea. Acta Gtolatyngologica (Stockholm) 105: 4549, 1988. Blackshear J L, Napier J S, Davidman M. Stillman M T. Renal complications of non-steroidal antiinflammatory drugs: Identification and monitoring of those risks. Seminars in Arthritis and Rheumatism 14: 163-175. 1985. Roy A K, Sinha K, Chourasia H K. Allatoxin contamination of some common drug plants. Applied and Environmental Microbiology 54: 842-843. 1988. Mowery D B, Clayson D E. Motion sickness, ginger and psychophysics. Lancet i: 655-657, 1982. Mustafa T, Srivastava K C. Ginger (Zingiber ofticinale) in migraine headache. Journal of Ethnopharmacology 29: 267-273, 1990. Backon J. Ginger inhibition of thromboxane and stimulation of prostacyclin: Relevance for medicine and psychiatry. Medical Hypotheses 20: 271-278, 1986.
Medical HypoUlser OLODpUlGarpuKW19V2
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Ginger (Zingiber officinale) in Rheumatism and Musculoskeletal Disorders K. C. SRIVASTAVA’ and T. MUSTAFAt ‘Department of Environmental Medicine, Institute of Community Health, Odense University, Winsbwpatien 17, DK-5000 Odense M, Denmark Institute of Biology, Odense University, Campusvej 55, DK-5230 Odense iU, Denmark (Reprint requests to KCS)
Abstract-One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways-the cyclooxygenase (CO) and the 5-lipoxygenase (!I-LO)-leading to the production of prostaglandins and leukotrienes respectively. Amongst the CO products, PGE2 and amongst the 5LO products, LTB4 are considered important mediators of inflammation. More than 200 potential drugs ranging from non-steroidal anti-inflammatory drugs, corticosteroids, gold salts, disease modifying anti-rheumatic drugs, methotrexate, cyclosporine are being tested. None of the drugs has been found safe; all are known to produce from mild to serious side-effects. Ginger is described in Ayurvedic and Tibb systems of medicine to be useful in inflammation and rheumatism. In all 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort) used powdered ginger against their afflictions. Amongst the arthritis patients more than three-quarters experienced, to varying degrees, relief in pain and swelling. All the patients with muscular discomfort experienced relief in pain. None of the patients reported adverse effects during the period of ginger consumption which ranged from 3 months to 2.5 years. It is suggested that at least one of the mechanisms by which ginger shows its ameliorative effects could be related to inhibition of prostaglandin and leukotriene biosynthesis, i.e. it works as a dual inhibitor of eicosanoid biosynthesis.
Introduction
The average life span of people living in the industrialized world has increased. Incidence of chronic and degenerative afflictions such as cardiovascular disease, cancer and arthritis is also on the upswing in such populations. Arthritis in the USA is called ‘the nation’s primary crippler’, and with grim reason. As estimates have put it, arthritis affects more than 37 Date received 3 June 1992 Date accepted 10 July 1992
million Americans-one in every seven suffer from arthritis, and one in every three families is touched by the disease. Arthritis actually encompasses more than 100 afflictions which range from the ravaging disease like rheumatoid arthritis (RA) to osteoarthritis (which usually affects and cripples the elderly), to tendinitis affecting mostly athletes. Together, these afflictions in USA alone account for 27 million lost work-days a year which in terms of economy is estimated to be US
342
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DISORDERS
dollars 8.6 billion a year. It is known that 94% of the arthritis patients during the course of the disaease try one or the other of the dozen or so known unconventional remedies to treat their affliction (1, 2). Most of these remedies have no sound scientific basis. Ginger is not included in the list of unconventional remedies for the treatment of arthritis though the use of ginger has been known to several civilizations. Ginger is used in folk medicine, and is popular as a food spice. Its therapeutic uses are many; it is useful in flatulence, flatulent colic, and spasmodic affections of the bowels. It helps in some forms of headache and various affections of the throat. It is mentioned in British and other Pharmacopoeas as a carminative. It finds an important place both in the Ayurvedic and Tibb systems of medicine where amongst other things it is recommended against rheumatic disorders (3). Also in the Chinese folk medicine it is mentioned to ameliorate or even cure several diseases. Even today at the end of the 20th century a majority of the world’s population receives its health care from traditional systems of medicine. This has prompted the present WHO’s Director General Dr Hiroshi Nakajima to stale that ‘a medical knowledge that works-no matter how scientific its origins-is a treasure that cannot be ignored’. In this paper, we report on the effect of ginger in arthritis and muscular discomfort, and suggest a possible mechanism of action. Rationale of the study It would not be inappropriate to mention here the situation under which this study with ginger began. One of us happened to mention during an interview, by a journalist of a leading Danish newspaper, about the usefulness of ginger in some diseases including rheumatic disorders he had known in his native country in the Indian sub-continent (4). That there might be some scientific basis in such claims was obviously based on the author’s experience with ginger in his laboratory experiments. It was found that ginger contained components with strong antiplatelet and prostanoid synthesis inhibiting activity (5-8). Initially, after the interview some arthritis patients in Denmark began consuming powdered ginger in different doses on their own, and apparently those who experienced relief contacted us. A short report involving 7 rheumatic patients in which ginger was found to have helped was published 3 years ago (9). Since then the number of arthritis patients who found benefit with ginger has increased several fold. We then prepared a questionnaire and sent them out to those who were interested to fill them out and return. This report is, therefore, a questionnaire-based open-trial on the effects of ginger in arthritis and muscular discomfort
together with some other cases with related symptoms where ginger was found to ameliorate mainly pain and inflammation. Case histories
Below are given case histories, selected one from each of RA and osteoarthritis, and two from muscular discomfort. We did not have access to the clinical reports of the patients. We had to depend, therefore, on the information submitted to us on the questionnaires by patients. Rheumatoid arthritis The patient is a male of Asian origin and settled in
Canada. At the age of 50 he was afflicted with RA which was diagnosed in Canada. The patient took ginger in an amount of ca 50 gram raw/fresh daily in the first month after the diagnosis. Ginger was taken through lightly cooked vegetable and meat dishes. Relief in pain and swelling was evident after 1 month of ginger intake. The patient was completely free of pain and swelling after 3 months of ginger consumption. He is active in his job as an automechanic, and 13-14 years have passed without relapse of symptoms. Since last year nodules have appeared on some of the joints of the fingers of both hands without any deformity and loss of function or pain. Osteoarthritis
A woman of 69 years suffered from back pain since she was 17 years of age due apparently to a bad sitting posture while she worked in an office. She later developed osteoarthritis involving 4-5, 5-6 and 67 vertebrae which was diagnosed in 1974. About a decade later the upper joint in right thumb was also afflicted. In 1990 both the knees and elbows were affected. The patient was given antiarthritis drugs of various types. The drugs produced side-effects, especially stomach irritation on prolonged use. She started taking powdered ginger since mid April 199 1. A sample provided by the patient to us weighed 7.6 gram, a dose she took daily. After four months on ginger she noticed relief in symptoms. Swelling in the right knee disappeared after 2 months. However, swelling persists in the thumb and the first finger. After 6 months on ginger she stopped taking antiarthritis drugs. Nevertheless, the patient was prescribed 2 tablets a day of a drug containing codein phosphate (9.6mg), phenobarbital (SOmg) and quininsulphate (50mg). This made her drowsy. She reduced the dose to 1 tablet a day which did not help. Now she takes half tablet of
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MEDICAL
the drug without having this discomfort (drowsiness). The patient was not able to turn her head to left and look upwards due to osteoarthritic condition of the neck vertebrae, which she can do now with a little care after about 10 years. The patient has been advised to reduce the dose to about l/4 (ca &am/day). She continues to take this dose. Muscular disorder
The patient, a man of 49 years, developed muscular pain and pain in some joints about 5 years ago. The nature of his job was such that he had to cycle for several hours a day which he found hard to carry on. His condition was diagnosed to be muscular ‘arthritis’. He was prescribed analgesics which produced gastro-intestinal irritation. The patient’s condition became worse; the pain was more intense with the result he had to give up an extra job 3 years later. At times he could not leave bed and abstained from work. On advice of some of his friends he took one teaspoonful powdered ginger a day. He noticed marked reduction in pain after 14 days which disappeared completely in a month. He continued to take ginger in half dose for several months. He no longer takes it. Another patient, having myositis, is a woman now in her late forties. She developed stiffness in the neck some 25 years ago which she still suffers from. Stiffness is worst in the morning on getting out of bed. Analgesics do help, but she avoids them due to gastrointestinal irritation. She administered ginger on her own taking ca 3-4g powdered ginger a day. Within
HYPOTHESES
a few days relief was observed with the muscles of the neck relaxed. She consumes ginger in this dose whenever the stiffness becomes unbearable. Our observation on the efficacy of ginger-as reported by patients voluntarily-in arthritis and muscular discomfort involved 28 patients with RA, 18 patients with osteoarthritis and 10 with muscular discomfort. Besides, 7 other patients having one of the afflictions such as, stomach catarrh, sciatica, fibromyositis, gout (2 patients) and tendinitis also felt relief. Effect of ginger-intake on the usual symptoms-pain and swelling-in arthritis is shown in the Table. Marked reduction in pain was observed by all the patients with muscular discomfort after consumption of ginger. None of the patients, with the exception of two who were of Asian origin, were familiar with ginger and have used it in their diet as a condiment. The majority of patients included in this survey have had their afflictions for more than 3 years before taking ginger. Discussion The 19th century British physician Sir William Osler said ‘When a patient with arthritis walks in the front door, I feel like leaving out the back door’. The physicians of the present day may not feel this extreme way, but they do know that science has no cure for most forms of arthritis. However, the arsenal of medications is growing. The drugs range from non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, gold salts, disease-
Table Effect of ginger consumption in the relief of pain and swelling among rheumatoid arthritis and osteoathritis patients Relief (%) No.of patients
Marked
Moderate
Minimal
None
28 22
14 59
11 18
4
11 23
Rheumatoid arthritis*
Pain Swelling Osteoarthritis P&l
18
55
22
swelling
10
50
20
11 10
12 20
arthritis and osteoarthritis patients Pain
46
61
swelling
32
56
15 19
I 3
11 22
Total of rheumatoid
Total no. of patients (Age: Mean rLSD) Male 20 (58 f 13), Female 36 (59 f 15). Amount of ginger powder consumed was not uniform, and the degree of relief was evaluated by the patients themselves. ‘Includes 3 patients with non-specific arthritis (Bechterew’s syndrom&pondylitis)
GINGER IN RHEUMA’IXjM AND hlUSCULOSKELETAL DISORDERS
345
modifying anti-rheumatic drugs (DMARDs), antimalarial agents (hydroxychloroquine), methotrexate, cyclosporine---cmrently more than 200 potential drugs are being tested. None of the drugs has been found to be safe; all are known to produce from mild to serious side-efects. NSAIDs relieve pain and can reduce inflammation, but to achieve this the use of large doses over a long period of time is required. Gastro-intestinal irritation and intestinal blood loss are the usual side-effects. Hydroxychloroquine can cause eye damage. Methotrexate affects the liver and blood. Immune modulating drugs can affect the body’s ability to ward off infections. Corticosteroids, initially a drug of great promise, can produce devastating side-effects which include asceptic bone necrosis (brittle bones), thin skin and raised blood pressure. Thus, a race is on to design and/or find anti-inflammatory drug(s) which will suppress the manifestations without toxic effects.
Monohydroxy lipoxygenase products, 12-HETE and 5-HETE, show weak chemokinetic and chemotactic properties both in vitro and in vivo in human and rabbit polymorphonuclear leuccxzytes (PMNL) (14). The dihydroxy product, LTB4, on the contrary shows powerful effects on the PMNL. Its chemokinetic and chemotactic properties were demonstrated both in vitro and in vivo; it produced degranulation of PMNL of several species in vitro and accumulation of these cells in vivo (15, 16). That LTB4 had a similar effect in humans was tirst demonstrated by Klickstein et al (17), who showed that synovial fluids of patients with RA and spondyloarthritis contained higher levels of LTB4 and also of the pivotal product of 5lipoxygenase, 5-HETE from which leukotrienes are derived. From the above mentioned studies it is obvious that synovial tissue can produce 5-LO as well as cyclooxygenase products. Other cellular systems (polymorphonuclear and monomorphonuclear leucocytes, platelets, lymphocytes) which have important functions in controlling inflammation, produce much varied moeities of eicosanoids compared to those produced by synovial tissue. As one would expect, there are clear differences in the types and quantities of both cyclooxygenase and LO products produced by the inflammatory cells. Cellular co-operativity in the production of LO products has also been observed. For instance, 12-HPETE from blood platelets stimualte the production of 5, 12-diHETEs in lcucocytes (18), and stimulation of the 5-LO enzyme by 15-HETE (19) are examples of the co-operativity.
Eicosanoids in arthritis
Mechanical, chemical or immunological challenge stimulates phospholipase activity and living tissue responds to irritation and injury by producing inflammation. While enhanced production of arachidonic acid (AA)-oxygenated products is a characteristic feature in the inflamed tissues, it is becoming apparent that there may be qualitative as well as quantitative differences in the AA-metabolites produced in the inflamed tissues in different arthritic conditions. Of the eicosanoids, prostaglandin E2 (PGE2) is the prominent product although prostaglandin Fza (PGFz.J, prostaglandin D2 (PGDz), thromboxane B2 (TXB2) and 6-keto-PGFl, have also been detected. Prostaglandin E2 plays a crucial role in two ways: firstly, by causing resorption of bone by synoviocytes through increased number of bone osteoclasts, and secondly, by stimulating the secretion of collagenase by macrophages coupled with inhibition of the formation of proteoglycans by articular chondrocytes and synoviocytes (10, 11). Besides producing cyclooxygenase products (prostanoids), it has been found that human rheumatoid and osteoarthritic synovium can generate 5lipoxygenase (5-LO)-products: leukotrienes (LT) CJ, D4 and E4 which were identified in the synovial membranes from rheumatoid and osteoarthritic patients (12). The level of LTB4 in the thuds of RA patients is slightly in excess of that in the fluids horn osteoarthritis patients (13). Interestingly, the levels of LTB4 have been found to be increased six-fold in the synovial fluids from patients with gout compared to the LTB4 levels in corresponding fluids obtained from patients with RA and osteoarthritis (13).
Possible role of ginger in arthritis The chemical composition of dried ginger is as fol-
lows: ca 4060% starch, 10% proteins, 10% fats, 5% fibres, 6% inorganic material, 10% residual moisture and l-4% essential oil (oleoresin) (20). During the last 45 years many chemical investigations have been carried out on the constituents of the essential oil (20, 21). All together more than 200 different volatiles have been identified in essential oil wherein the pharmacological activity is confined. The essential oil contains mixture of various terpenes as well as some other non-terpenoid compounds. Due to the large battery of compounds belonging to various chemical classes, it is likely that crude ginger powder intake brings about amelioration of symptoms by interfering with the production and release of products of lipid membranes (eicosanoids, reactive oxygen), peptides and proteins (lysosomal enzymes, growth factors, lymphokines, bradykinin), amino acids (histamin, serotonin) etc. Although this is mostly speculative, the experimental data in our hands and observa-
346 tions of others suggest that ginger inhibits both the cyclooxygenase (7, 22) and lypoxygenase products (23, 24), i.e. it can be a dual inhibitor of eicosanoid synthesis. Ginger is reported to contain antihistaminic and antioxidant factors as well (25). Non-steroidal anti-inflammatory drugs have three major actions, all of which are related to inhibition of cycle-oxygenase resulting in decreased formation of prostanoids. Firstly, an anti-inflammatory action achieved by reduced production of vasodilator prostaglandins (PGE2, PGIi) which means less vasodilation and, indirectly less oedema. Secondly, an analgesic effect achieved by reduced prostaglandin production (less sensitisation of nociceptic nerve endings to the inflammatory mediators bradykinin and 5hydroxytryptamine). Thirdly, an antipyretic effect which is probably due to a decrease in the mediator PGE;! generated in response lo inflammatory pyrogens, such as interleukin-I. Since ginger inhibits prostanoid synthesis and also products of 5lipoxygenase, its ameliorative effects in arthritis and muscular discomforts could be related to reduced formation of prostanoids and leukotrienes. Because of such a possibility a decrease in the cararegeenan-induced cedema formation in the rat’s paw after 3h of ginger extract administration has been demonstrated and the potency of the extract in the acute inflammation test appears to be comparable to that exhibited by acetyl salicylic acid reported in the same study (26). Regimen and the safety ofginger Most of the spices from Allium to Zingiber are on the Food and Drug Administration’s (FDA’s) Generally Recognized as Safe (GRAS) list (Duke J A, personal communication). Accordingly, one should not have worries if ginger is consumed in amounts normally available through food for any length of time. Some of the patients with arthritic disorders who mistakenly took 34 times, or even more, the dose (OS-l.0 gram powdered ginger/day) suggested by us, reported quicker and better relief than those on the recommended dose. This might suggest that effective components in ginger are present in very small amounts, and to achieve an effective dose of the desired component(s) one would require large doses of powdered ginger. Most of the patients for reasons of convenience took one-half to a teaspoonful powdered ginger for which the corresponding weight would be ca 1 and 2 gram respectively. No adverse reactions were observed by any of the patients who had taken ginger from periods ranging from 3 months to 2.5 years. Most of the patients observed relief of symptoms
MEDICAL HY1’0’17l1iS12’
within l-3 months. Compelled by the nature of the disease most of them are coninuing with ginger. On our advice some of the patients who stopped taking their daily doses suffered a return of symptoms within weeks to 2 months. Relief was again achieved with the resumption of ginger intake. However, one incidental observation by Dr Dorso (the donor of blood) that only one-time consumption the previous evening of a large quantity of an excellent marmalade (Ginger with Grapefruit, Crabtree and Evelyn, London) whose major ingredient (15%) was ginger produced inhibition of AA-induced platelet aggregation which returned to normal after 1 week, might indicate that ginger components appear to remain in the body for several days (27). From this observation it could be inferred that like the NSAIDs, bioactive components of ginger remain effective while their blood levels are sustained, with symptoms of inflammation recurring after the withdrawal of ginger consumption which was observed in every case where ginger consumption was withheld. In acute toxicity test mice tolerated ginger extract as gavage of up to 2.5 g/kg with no mortality or side effects during a 7-day trial period. However, increase in doses to 3.0-3.5 g/kg the extract resulted in lO-30% mortality. Under similar experimental conditions, acetyl salicylic acid (600 mg/kg) produced mortality in 25% of animals, stomach ulcers in 40% of animals and discomfort and/or hypothermia in 60% of animals (26). Nevertheless, in SOS Chromotest on the toxicity and embryotoxicity test ginger was found to be non-toxic (Backon J, personal communication). There is no mention of adverse effects of ginger in the literature (28). However, as only one-time consumption of ginger resulted in producing a persistent effect on the function of blood platelets (27), the patients were advised to withhold consumption of ginger and to reduce the daily dose to half a gram powdered ginger. It would be worthwhile to mention a case of ginger consumption in a female osteoarthritis patient of 80 years of age whose one kidney was removed; she has consumed ginger for the last 3 years, in the first 6 months about 6g powdered ginger daily which was reduced later to ca 2g daily-dose. She has been able to tolerate this dose without any side-effects. As she has felt relief in symptoms, she is regularly taking it. Continued use and tolerance of ginger consumption by this patient may provide some insight towards the effect of ginger on renal function. It is known that in people with impaired renal function and advanced age NSAIDs reduce the creatinine clearance and increase serum creatinine concentrations probably by suppressing the vasodilatory function of re-
MUSCULOSKELETAL DISORDERS
341
nal prostaglandins. A number of NSAIDs cause acute nephritis though most patients recover with drug discontinuation (29). The fact that this patient of such an advanced age with one kidney has tolerated consumption of ginger for 3 years indicates that ginger unlike the NSAIDs does not impair renal perfusion or function especially in the elderly who may be predisposed with interstitial nephritis and/or decreased circulating blood volume. Like any other natural product if raw or powdered ginger is not stored properly danger of atlatoxin contamination is greater (30). Therefore, use of qualitycontrolled powdered ginger preferably from a drug store was suggested.
planned. A more specific study could also address to a possible interaction of ginger with other drugs. This information would be useful in evaluating the use of ginger-intake in juvenile and elderly arthritic patients.
GINGER IN RHJXJMATtSM
AND
Other benefits of ginger-intake Ginger has been used in Ayurvedic and Tibb systems of medicine for headache, nervous diseases, nausea and vomiting for centuries. Some of these age old observations have proven true when subjected to scientific scrutiny. Not long ago it was demonstrated that gastrointestinal symptoms of kinetosis were alleviated better by ginger than antihistamine agent in a controlled trial (31). In a double-blind randomized trial ginger was shown to reduce symptoms of nausea and vertigo (28). Rexently we have reported on the abortive and prophylactic effects of ginger in migraine headache (32). Possible use of ginger in several psychiatric problems where inhibition of thromboxane A2 is required has been suggested (33). Some of our patients have observed added benefits on taking ginger, and they include relief in cold sores and throat touchiness (‘squeamish throat’), fewer colds, amelioration of stomach irritation and constipation. Quite a few observed reduced tendency of motion-related nausea--an observation which has been confirmed in a controlled study (28). The patients slept better and suffered less pruritus and edema. Conclusion In the present study an observation describing the ameliorative effect of ginger consumption in arthritis and musculoskeletal disorders is described. It is suggested that bioactive components of ginger may act as dual inhibitors of cyclooxygenase and lipoxygenase pathways, and may act by inhibiting PGE2 and leukotriene B4 synthesis. It may be emphasized that this study presents only a hypothesis and must be verified in a double-blind placebo study. To evaluate the issue of life-long ginger consumption in prevention and/or amelioration of arthritic diseases, more detailed, larger and epidemiological studies should be
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