When nonsteroidal anti-inflammatory drugs are not enough: how to enhance anti-inflammatory therapy?

Traditional monotherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of acute and chronic inflammatory processes of various genesis is often limited by the phenomenon of «therapeutic ceiling», in which dose escalation does not enhance the analgesic effect, but radically increases the risk of gastro-, cardio- and nephrotoxic complications. The key pathogenetic barrier to the effectiveness of NSAIDs is the formation of interstitial edema, fibrin accumulation and mechanical compression of lymphomicrovascular structures in the focus of alteration. These changes lead to the emergence of a local histohematological barrier, which limits the diffusion of systemically administered drugs into the affected area even when their high concentrations in the blood plasma are achieved. The aim of this review is the molecular biological and pharmacodynamic substantiation of the multimodal synergism of the combined use of serratiopeptidase (Serrata^®) and NSAIDs as a strategy for overcoming resistance to standard anti-inflammatory therapy. Analysis of current experimental data and results of randomized clinical trials shows that serratiopeptidase acts as a direct biological modulator of the inflammatory microenvironment, performing selective hydrolysis of non-viable protein substrates and polymerized fibrin. Due to targeted fibrinolysis and cleavage of mediators of the kinin system, the enzyme eliminates the edema matrix, restores the patency of the initial lymphatic capillaries and reduces extravascular hydrostatic pressure. Decompression of the vascular bed restores local perfusion and tissue oxygenation, which dramatically increases the bioavailability and penetration of NSAIDs directly into the focus of inflammation. The combination of mechanisms of action provides a pronounced «dose-sparing effect», allowing to achieve faster and more stable relief of pain and edema syndromes when using standard or minimal therapeutic doses of NSAIDs. The introduction of this combination ensures the acceleration of functional rehabilitation of patients in surgical, traumatological, neurological and ENT practice, optimizing the overall safety profile of treatment.