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The Bromelain Study: an open investigation into the effect of bromelain on knee pain

1. Knee Pain

Large numbers of people suffer from knee pain. Medical problems which may give rise to this condition may be classified as diseases (e.g. osteoarthritis and rheumatoid arthritis), infections, or inflammatory conditions brought about by injury. It is the latter type of problem that we are concerned with in this study. In sportsmen and women the knee is considered to be the most commonly injured joint. However, many activities can put the knees at risk, so it is not just sports people who suffer from this type of knee pain. Even people who do not participate in hazardous activities may still be at risk, as some problems may arise through under-use (Grisogono, 1988).

Injury to the knee may be caused by trauma or overuse. The knee is vulnerable to twisting and shearing forces, and twisting suddenly whilst walking or even crouching can be enough to traumatize the knee. Overuse injuries are typically associated with repetitive activities such as walking, running or cycling (Grisogono, 1988). Just a slight change in the stress of the activity, e.g. new running shoes, can lead to injury and inflammation. Another type of injury is housemaid's knee, where excessive kneeling leads to inflammation of the bursa of the knee and pain.

So it can be seen that there are many different everyday causes of knee pain. As inflammation is a pathogenic factor in these types of knee pain, non-steroidal anti-inflammatory drugs (NSAIDS) are prescribed to reduce pain and swelling. However, NSAIDS are associated with unwanted side-effects (Henry, 1988). Bromelain represents a safe alternative to these drugs.

2. Bromelain

Bromelain is the name for a group of closely related proteolytic enzymes obtained from the stem of the pineapple plant (Ananas comosus Merr.). Since the 17^th century pineapple has been documented to have medicinal properties. Explorers who visited Central and South America at this time recorded its effects; "admirably recreates and exhilarates the Spirits and comfort of the heart; it also fortifies the stomack, cureth queasiness and causeth Appetite" (Rochfort, 1605).

Such descriptions may appear outdated now, but nevertheless evidence continues to be published describing the medicinal actions of bromelain. These medicinal actions are varied (Taussig and Batkin, 1988), so this review will concentrate on the analgesic and anti-inflammatory actions of bromelain which suggest it would be useful in the treatment of knee pain.

2.1 Clinical studies of Bromelain

The following trials suggest that oral bromelain therapy is able to produce anti-inflammatory and analgesic actions in humans.

Cohen and Goldman (1964) investigated 29 subjects whom suffered from arthritis (25 subjects had rheumatoid arthritis, 2 had osteoarthritis, 1 had both and the last had gout) and had residual swelling in a joint after long-term steroid therapy. Subjects were given 1 or 2 tablets of bromelain (20 mg) 3 or 4 times daily. Although this study was uncontrolled, after starting the bromelain therapy soft tissue swelling subsided mostly, or completely, in 72.4 % of the subjects.

Bodi (1966) investigated pain response to the application of bradykinin in surgically-denuded blisters (the blisters had been induced by cantharidin). Bradykinin is a substance generated during inflammation, and is a potent pain-producing agent. The study was double-blind and placebo-controlled, and 18 healthy subjects were included. The results showed that the bromelain treated group experienced significantly less pain on application of the painful stimuli.

Lotti et al., (1993) investigated the benefit of giving the anti-inflammatory drug Nimesulide alongside antimicrobial therapy in the treatment of urogenital inflammation. In this randomized, double-blind study the efficacy of Nimesulide was compared to bromelain and to placebo. Bromelain (240 mg/day) was given to 20 subjects and acted as a positive control. From the results the authors concluded that bromelain appeared to be more effective than placebo.

Kane and Goldberg (2000) report on two case histories of patients with ulcerative colitis (a disease characterized by inflammation of the colon). Both patients achieved clinical and endoscopic remission after bromelain therapy.

Klein and Kullich (2000) conducted a randomized, double-blind trial comparing oral enzymes therapy (Phlogenzym) with diclofenac in treating gonarthritis (arthritis of the knee joint) in 73 patients. Phlogenzym is a preparation containing bromelain, trypsin and rutin. The duration of the study was three weeks. One treatment group received 50 mg diclofenac three times daily for the first week, followed by 50 mg twice daily for the second and third weeks. The other treatment group was given two enzyme tablets (bromelain 90 mg, trypsin 48 mg and rutin X H₂O 100 mg per tablet) three times a day throughout all three weeks. No other anti-inflammatory or analgesic preparations were allowed during the three weeks of treatment. The primary outcome was the reduction of acute symptoms of painful arthritis after 3 weeks. Also a follow-up assessment was carried out to investigate longer lasting effects, and this was done after 7 weeks. The results showed the two treatments to be equivalent at a statistically significant level, with the oral enzymes being better tolerated.

In addition to the above studies, Klein and Kullich (1999) referred to 2 other studies where equivalence was found between oral enzymes and a NSAID. One of these studies included subjects with periarthritis of the shoulder, and the other painful vertebral syndrome. Further details are not available as the articles were published in German.

2.2 Animal Studies

Various studies have shown bromelain to be effective in rat models of inflammation (Uhlig and Seifert, 1981; Pirotta and De Guili-Morghen, 1978; Sugio and Daly, 1983).

Emancipator et al. (1997) compared the effects of Phlogenzym with ibuprofen in a murine model of rheumatoid arthritis. In this study both treatments led to significantly reduced joint swelling compared to the control group, with no difference between the treatments. However, the Phlogenzym treated animals suffered significantly less joint degeneration than those treated with ibuprofen.

2.3 Mechanisms of action

It appears that the mechanisms responsible for the anti-inflammatory action of bromelain are multifaceted. There is experimental evidence to suggest that effects on (1) blood coagulation, (2) kinins and (3) prostaglandin synthesis may be important. In addition, bromelain may affect immune cell function which may be important in more chronic inflammation (4).

(1) Bromelain given to rats lowered plasma fibrinogen levels (Livio et al., 1978), and increased serum fibrinolytic activity (Pirotta and De Guili-Morghen, 1978). These effects would tend to reverse the coagulation that occurs in inflammation. Plasma coagulation, by impeding re-entry of fluid into the vessels, leads to stasis and the formation of oedema.

(2) Kinins are peptides generated during inflammation, which enhance the inflammatory process. Bradykinin is a kinin responsible for causing vasodilation, increased vascular permeability and pain. Kumakura et al. (1988) found that bromelain caused a dose-dependent decrease in bradykinin levels in experimentally-induced inflammation in rats.

(3) Prostaglandins are important mediators and regulators of the inflammatory reaction. Bromelain has been shown to decrease the production of prostaglandin E₂ and thromboxane B₂ during experimentally induced inflammation (Vellini et al., 1986).

(4) Bromelain may influence certain immune cells by the cleaving off cell adhesion molecules (CAM's), which are found on the cell surface of these cells (Hale and Haynes, 1992, Kleef et al., 1996). These molecules are involved in cell signaling and function, and appear to play a role in the pathogenesis of arthritis (Mojcik and Shevach, 1997). In addition to these effects on CAM's, Mynott et al. (1999) found bromelain to inhibit T-cell function via inhibition of intracellular signaling pathways.

2.4 Safety

Bromelain is freely available in health food stores, and pineapples are freely eaten as food. No serious adverse reactions have been reported with consumption of either. However, in view of the effects of bromelain on blood coagulation, volunteers taking oral anticoagulants will be excluded from the study

In the study by Klein and Kullich (2000) physician and patient assessment of the tolerability of Phlogenzym (a product containing bromelain) was very good in most patients. One patient on Phlogenzym therapy withdew from the study due to headache, that was probably not related to the drug. Furthermore, clinically relevant changes were not seen in any of the evaluated laboratory parameters: complete red and white blood count, platelets, serum urea, creatine, uric acid, triglycerides, cholesterol, LDL-cholesterol, HDL-cholesterol, AST, ALT, g -GT, alkaline phosphatase, LDH, total bilirubin, sodium, potassium, calcium, iron, ESR, C-reactive protein, rheumatoid factor, protein electrophoresis, fibrinogen, blood glucose, and urinanalysis.

In the study by Lotti et al., (1993) 3 patients on bromelain therapy (who were also receiving concurrent microbial therapy) reported side-effects. One reported slight nausea, one abnormal gastric sensation and the other gastralgia, who then withdrew from treatment. The causal relationship with bromelain therapy was possible, probable and highly likely respectively in these 3 cases. Laboratory tests aimed at assessing tolerability did not show any clinically significant changes in renal, hepatic or metabolic parameters.

Cohen and Goldman (1964) in their study stated that no side effects were observed or reported.

3. The Bromelain Study

The proposed study is an investigation into the treatment of knee pain using bromelain in otherwise healthy individuals.

3.1 Aims

1. To investigate the effects of bromelain on knee pain in an open study.

2. To compare different doses of bromelain on the response to treatment.

3.2 Recruitment

500 healthy men and women currently suffering from knee pain, will be recruited by articles in national newspapers, magazines and radio programs.

3.3 Exclusion Criteria

Subjects will be screened for exclusion criteria by their responses to the General Questionnaire (Appendix I). This questionnaire contains specific questions on current medication, as well as questions which screen for the presence of disease.

Specific exclusion criteria:

• As this is a study in essentially healthy people, subjects with any serious medical disorder that requires treatment (medical or otherwise) for the normal functioning, well-being or life expectancy of the individual will be excluded

• Volunteers on anticoagulant therapy will be specifically excluded

• Volunteers currently using anti-inflammatory/analgesic drugs for knee pain will also be excluded

3.4 Inclusion Criteria

• Healthy men and women aged 25-50 years; a ceiling of 50 years has been chosen to exclude osteoarthritic changes which are common in those above this age

• Current knee pain; onset within the last 3 months

3.5 Experimental Design

The study will include 500 subjects. Subjects will be allocated to one of two treatment groups (see section 3.6), and treatment will last one month. Assessment of knee pain will be carried out by comparing questionnaire scores (section 3.7) at baseline and at the end of the study.

3.6 Interventions

• 200 mg bromelain extract/ day (1 tablet of one-a-day Bromelin (brand name) per day)

• 400 mg bromelain extract/ day (1 tablet of one-a-day Bromelin twice per day)

3.7 Outcome Measures

The following questionnaires will be completed by volunteers at baseline and again after treatment. These questionnaires will form the outcome measures of the study (questionnaires are attached in Appendix I).

1. The Western Ontario and Mcmaster Universities (WOMAC) Osteoarthritis Index (Bellamy, 1988). Although originally designed as an index of hip/knee osteoarthritis, this questionnaire has been used in other studies of knee pain (Clark, 2000), and inquires about pain, stiffness and function.

2. The Psychological Well-Being Shedule (Dupuy, 1984).

3. Post Study Questionnaire. This questionnaire asks subjects to rate their global impression of the treatment, and inquires about any side-effects.

3.8 Statistics

Paired t-tests will be used to compare baseline and after treatment scores in the outcome measures. Statistical significance will be set at p < 0.05.

3.9 References

Bellamy N., Buchanan, W.W., Goldsmith, C.H., Campbell, J. and Stitt, L.W. (1988). Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15(12), 1833-40.

Bodi, T. (1966). The Effects of Oral Bromelains on Tissue Permeability to Antibiotics and Pain Response to Bradykinin: Double Blind Studies on Human Subjects. Clinical Medicine 61-65.

Clark, D.I., Downing, N., Mitchell, J., Coulson, L., Syzpryt, E.P. and Doherty, M. (2000). Physiotherapy for anterior knee pain: a randomised controlled trial. Ann Rheum Dis 59, 700-704.

Cohen, A. and Goldman, J. (1964). Bromelains Therapy in Rheumatoid Arthritis. The Pennsylvania Medical Journal 27-30.

Dupuy, H.J. (1984). In: Assessment of Quality of Life in Clinical Trials of Cardiovascular Therapies. New York, Le Lacq, pp 170-183.

Emancipator, S.N., Chintalacharuvu, S.R., Urankar Nagy, N., Petersilge, C. and Stauder, G. (1997). Effects of Oral Enzymes in Collagen II Induced Arthritis in Mice. Int. J. Immunotherapy XIII, 67-74.

Grisogono V. (1988). In: Knee Pain. John Murray Ltd, London.

Hale, L.P. and Haynes, B.F. (1992). Bromelain Treatment of Human T Cells Removes CD44, CD45RA, E2/MIC2, CD6, CD7, CD8 and Leu 8/LAM1 Surface Molecules and Markedly Enhances CD-2Mediated T Cell Activation. The Journal of Immunology 149, 3809-3816.

Henry, D.A. (1988). Side-effects of non-steroidal anti-inflammatory drugs. Ballieres Clin Rheumatol 2(2), 425-454.

Kane, S. and Goldberg, M.J. (2000). Use of Bromelain for Mild Ulcerative Colitis. Annals of Internal Medicine 132, 680.

Kleef, R., Delohery, T.M. and Bovbjerg (1996). Selective Modulation of Cell Adhesion Molecules on Lymphocytes by Bromelain Protease 5. Pathobiology 64, 339-346.

Klein, G. and Kullich, W. (1999). Reducing pain by oral enzyme therapy in rheumatic diseases. Wien Med Wochenschr 149, 577-580.

Klein, G. and Kullich, W. (2000). Short-Term Treatment of Painful Osteoarthritis of the Knee with Oral Enzymes; A Randomised, Double-Blind Study versus Diclofenac. Clin Drug Invest 19, 15-23.

Kumakura, S., Yamashita, M. and Tsurufuji, S. (1988). Effect of Bromelain on kaolin-induced inflammation in rats. European Journal of Pharmacology 150, 295-301.

Livio, M., Bertoni, M.P., De Gaetano,G. andDonati, M.B. (1978). Drugs Exptl. Clin. Res. 4, 49.

Lotti, T., Mirone, V., Imbimbo, C., Corrado, F., Corrado, G., Garofalo, F. and Scaricabarozzi, I. (1993). Controlled Clinical Studies of Nimesulide in the Treatment of Urogenital Inflammation. Drugs 46, 144-146.

Mojcik, C. and Shevach, E. (1997). Adhesion Molecules: A Rheumatologic Perspective. Arthritis and Rheumatism 40, 991-1004.

Mynott, T., Ladhams, A., Scarmato, P. and Engwerda, C. (1999). Bromelain, from Pineapple Stems, Proteolytically Blocks Activation of Extracellular Regulated Kinase-2 in T Cells. The Journal of Immunology 163, 2568-75

Pirotta, F. and De Giuli-Morghen, C. (1978). Drugs Exptl. Clin. Res. 4, 1.

Rochefort, C., (1605). Histoire Naturelle et morale des iles Antilles de l'America. A. Leers, Rotterdam.

Sugio, K. and Daly, J.W. (1983). Life Sciences 33,65.

Taussig, S.J. and Batkin, S. (1988). Bromelain, the enzyme complex of Pineapple (Ananas Comosus) and its clinical application. An update. Journal of Ethnopharmacology 22, 191-203.

Uhlig, G. and Seifert, J. (1981). Fortschritte der Medizin 15, 554.

Vellini, M., Desideri, D., Milanese, A., Orini, C., Daffonchio, L., Hernandez, A. and Brunelli, G. (1986). Arzneim-Forsch 36,110.