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Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study

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The aim of this study was to compare the efficacy and safety of an oral enzyme–rutosid combination (ERC) containing rutosid and the enzymes bromelain and trypsin, with that of diclofenac in patients with osteoarthritis (OA) of the knee. A total of 103 patients presenting with painful episodes of OA of the knee were treated for 6 weeks in two study centers in a randomized, double-blind, parallel group trial. Altogether, 52 patients were treated in the ERC group and 51 patients were treated in the diclofenac group. Primary efficacy criteria were Lequesne’s Algofunctional Index (LFI) and a ‘complaint index’, including pain at rest, pain on motion and restricted function. The efficacy criteria were analyzed by applying the Wilcoxon–Mann–Whitney test that provides the Mann–Whitney estimator (MW) as a measure of relevance. Non-inferiority was considered to be proven if the lower bound of the 97.5% one-sided confidence interval (CI-LB) was higher than MW=0.36 (benchmark of not yet relevant inferiority). Both treatments resulted in clear improvements. Within the 6-week observation period, the mean value of the LFI decreased from 13.0 to 9.4 in the ERC group and from 12.5 to 9.4 in the diclofenac group. Non-inferiority of ERC was demonstrated by both primary criteria, LFI (MW=0.5305; CI-LB=0.4171) and complaint index (MW=0.5434; CI-LB=0.4296). Considerable improvements were also seen in secondary efficacy criteria, with a slight tendency towards superiority of ERC. The global judgment of efficacy by physician resulted in at least good ratings for 51.4% of the ERC patients, and for 37.2% of the diclofenac patients. In the majority of patients tolerability was judged in both drug groups as very good or good. The current study indicates that ERC can be considered as an effective and safe alternative to NSAIDs such as diclofenac in the treatment of painful episodes of OA of the knee. Placebo-controlled studies are now needed to confirm these results.

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Enzyme–rutosid combination


Lequesne’s Algofunctional Index


  1. Pelletier JP, Martel_Pelletier J, Abramson SB (2001) Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum 44:1237–1247

    Article  CAS  PubMed  Google Scholar 

  2. Pincus T (2001) Clinical evidence for osteoarthritis as an inflammatory disease. Curr Rheumatol Rep 3:524–534

    CAS  PubMed  Google Scholar 

  3. Brooks P (1998) Use and benefits of nonsteroidal anti-inflammatory drugs. Am J Med 104:9S–13S; discussion 21S–22S

    Article  CAS  Google Scholar 

  4. Roth SH, Bennett RE (1987) Nonsteroidal anti-inflammatory drug gastropathy. Recognition and response. Arch Intern Med147:2093–2100

    Article  Google Scholar 

  5. Langman MJ, Weil J, Wainwright P et al. (1994) Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs [see comments] [published erratum appears in Lancet 1994 May 21;343 (8908):1302]. Lancet 343:1075–1078

    Article  CAS  PubMed  Google Scholar 

  6. Wittenborg A, Bock PR, Hanisch J, Saller R, Schneider B (2000) Vergleichende epidemiologische Studie bei Erkrankungen des rheumatischen Formenkreises am Beispiel der Therapie mit nichtsteroidalen Antiphlogistika versus einem oralen Enzymkombinationspräparat [comparative epidemiological study in patients with rheumatic diseases illustrated in an example of a treatment with non-steroidal anti-inflammatory drugs versus an oral enzyme combination]. Arzneim Forsch/Drug Res 50:728–738

  7. Kelly GS (1996) Bromelain: a literature review and discussion of its therapeutic applications. Alt Med Rev 1:243–257

    Google Scholar 

  8. Klaschka F (1996) Oral enzymes—new approach to cancer treatment: immunological concepts for general and clinical practice; complementary cancer treatment. Gräfelfing: Forum-Med-Verl-Ges

  9. Food and Drug Administration (1995) Labeling guidance diclofenac sodium delayed-release tablets.

  10. US Department of Health and Human Services Food and Drug Administration (1998) Guidance for Industry: Clinical development programs for drugs, devices, and biological products intended for the treatment of osteoarthritis (OA), draft guidance, February 1998

    Google Scholar 

  11. Karbowski A, Schwitalle M, Eckardt A (1998) Oxaprozin versus diclofenac retard in treated of activated arthrosis. Zeitschri Rheumatol 57:108–113

    Article  CAS  Google Scholar 

  12. Lequesne MG, Mery C, Samson M, Gerard P (1987) Indexes of severity for osteoarthritis of the hip and knee. Validation – value in comparison with other assessment tests [published errata appear in Scand J Rheumatol Suppl 1988;73:1 and Scand J Rheumatol 1988;17 (3):following 241]. Scand J Rheumatol Suppl 65:85–89

    Google Scholar 

  13. Colditz GA, Miller JN, Mosteller F (1988) Measuring gain in the evaluation of medical technology. The probability of a better outcome. Int J Technol Assessment Health Care 4:637–642

    CAS  Google Scholar 

  14. Dougados M, Leclaire P, van der Heijde D, Bloch DA, Bellamy N, Altman RD (2000) Response criteria for clinical trials on osteoarthritis of the knee and hip: a report of the Osteoarthritis Research Society International Standing Committee for Clinical Trials response criteria initiative. Osteoarthritis and Cartilage/Oars. Osteoarthritis Res Soc 8:395–403

    Article  Google Scholar 

  15. Klein G, 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

    CAS  Google Scholar 

  16. Singer F (1997) Phlogenzym in the treatment of a monoarticular gonarthritis – efficacy and tolerance, study no. MU-695 414. Geretsried: Mucos Pharma

  17. Singer F, Singer C, Oberleitner H (2001) Phlogenzym versus diclofenac in the treatment of activated osteoarthritis of the knee. A double-blind prospective randomized study. Int J Immunother XVII :135–141

    Google Scholar 

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The authors are indebted to Dr V. W. Rahlfs, IDV, Gauting, Germany, for performing the statistical analysis. We are grateful to Dr Mehnaz Rashid, Pacific Pharmaceuticals Ltd, Lahore (Pakistan) for her advice and support in conducting this trial, and to Dr W. Schiess, Mucos Pharma, for helpful assistance in preparing this manuscript.

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Correspondence to Abid Z. Farooqi.

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Dr. Mehnaz Rashid was the Clinical Trials monitor on behalf of Pacific Pharmaceuticals (Lahore, Pakistan) and Dr. W. Schiess played the same role on behalf of Mucos Pharma (Germany)

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Akhtar, N.M., Naseer, R., Farooqi, A.Z. et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study. Clin Rheumatol 23, 410–415 (2004).

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