Drugs for systemic enzyme therapy (SET) provide one of the options of pharmacotherapy of osteoarthritis and other painful disorders of the musculoskeletal apparatus. These oral preparations containing proteolytic enzymes of plant and animal origin combine primarily anti-inflammatory, anti-oedematous and analgesic effects. Due to a good tolerability, they are a safe alternative for persons who for some reason cannot receive nonsteroidal anti-inflammatory drugs NSAIDs). Good tolerability and safety in a long-term treatment is beneficial mainly for older patients with NSAIDs contraindication due to age and potential comorbidities. Therapeutic polypragmasia, common in the elderly, is associated with risks of dangerous interactions if drugs are used concomitantly with NSAIDs [1].

The main active ingredients of SET drugs (Wobenzym® and Phlogenzym®) are proteolytic enzymes (trypsin, chymotrypsin, bromelain, papain), pancreatin (enzyme mix with proteolytic, lipolytic and amylolytic activity) and flavonoid rutin [2]. They are administered orally in the form of acid-resistant tablets. Enterosolvent coating protects enzymes against their damage in the acidic environment of the stomach. Absorption of enzymes which is a prerequisite for a systemic effect takes place in the upper part of the small intestine. Absorption of undamaged enzyme molecules with the preserved activity has been repeatedly proved both experimentally and clinically by means of selective immunoanalytical and enzymatic methods [3, 4].

The primary aim of conservative treatment of osteoarthritis is to manage pain and preserve an optimal function of the joint. SET drugs may be applied as an adjuvant therapy not only in acute inflammatory exacerbations and in chronic painful conditions within conservative treatment but also after surgical treatment of arthritis.

The advantage of these drugs consists in combination of anti-inflammatory (or better inflammation modulating) and anti-oedematous effects together with the ability to relieve pain, to improve antibiotic tissue penetration and to promote haematoma absorption [5].

Prolonged swelling with haematoma and impaired microcirculation and both venous and lymphatic drainage of tissues affected by inflammation or damaged by surgery or trauma may significantly hinder healing.

Reduction of swelling by SET preparations improves microcirculation, similarly as the positive influence on the rheological properties of blood, associated with the fibrinolytic and antiaggregation effect of proteolytic enzymes [6, 7]. Improved microcirculation promotes venous and lymphatic drainage. All this conduces to a better oxygen supply to tissues, supply of nutrients, removal of metabolic waste products and, consequently, healing. These effects contribute also to secondary analgesic effect of SET drugs. However, they obviously have also a primary analgesic effect, i.e. a direct influence on degradation of pain mediators and pain receptors. Accelerated absorption of haematoma is attributed to stimulation of the activity of phagocytic cells by proteolytic enzymes contained in these preparations [8]. If there develop infectious complications of healing (e.g. postoperatively), the vehicle effect of enzyme preparations promotes absorption and penetration of antibiotics to tissues, thus improving the therapeutic effect [9, 10].

In view of new findings about the role of free oxygen radicals in the pathogenesis of osteoarthritis, attention has focused on the SET antioxidative effect [11]. Additional explanations of the positive effect of SET in arthritis and other inflammatory disorders of the musculoskeletal apparatus are provided by studies dealing with the role of lymphatic blood vessels, lymphatic circulation and lymphatic swelling at different sites affected by inflammation [12–15], mainly because lymphatic swelling has been for a long time a generally accepted indication for SET, Wobenzym® (WE) in particular.

Safety and efficacy of SET medical preparations was proved by a number of randomised double blind trials controlled by placebo or active comparator as early as in the 1980s and 1990s of the last century.

Later the outcomes of minor clinical assessments were confirmed by two large multicentric retrolective cohort studies [16, 17]. Data obtained from these studies were processed by the method of epidemiological retrolective analysis. The first one compared the efficacy and safety of Wobenzym® (pancreatin, papain, bromelain, trypsin, chymotrypsin, amylase, lipase, rutin) or Wobenzym N (pancreatin, papain, bromelain, trypsin, chymotrypsin, rutin) (WE) and NSAIDs (most often diclofenac, ibuprofen or piroxicam). The study was conducted in 203 centres and included a total of 1426 patients (863 patients, WE, versus 563 patients, NSAIDs). Patients with rheumatic diseases (most often vertebrogenic syndrome, activated arthritis, soft tissue rheumatic syndromes, rheumatoid arthritis, Bechterev’s disease or combination of these diagnoses) were treated in 1990–1997. The primary criterion of assessment of efficacy was a change in the intensity of symptoms at the end of the treatment. Evaluation with the use of several statistic methods revealed a significantly more successful treatment with WE as compared to NSAIDs (p < 0.0001) with a markedly lower incidence of adverse effects (WE 1.6 % of patients vs. NSAIDs 15.3 % of patients).

The other study compared efficacy and safety of Phlogenzym® (PHL – bromelain, trypsin, rutin) and NSAIDs in 3326 patients (70 % PHL vs. 30 % NSAIDs) with rheumatic diseases (involving limb and spinal joints, soft tissue rheumatic syndromes) treated in 1993–1995 by 380 general practitioners.