Enzyme therapy for inflamation and pain management

Category: Integrative Nutrition


Inflammation is a natural defence mechanism that our body triggers when it detects any tissue damage, whether caused by trauma, fractures or cuts, or by exposure to pathogens such as viruses, bacteria and allergens. It is manifested by redness of the affected area, increased volume, pain, loss of function and a sensation of warmth. The inflammatory response, however unpleasant it may be, is essential and is intended to localise and eliminate the tissue damage and thus allow the body to recover. It is very important to be able to resolve acute inflammation before it becomes chronic and there are different treatments for this. The most common is the use of non-steroidal anti-inflammatory drugs (NSAIDs) which, although they are effective in blocking COX-2 (the enzyme responsible for triggering the inflammatory process), have numerous adverse effects. A natural, safe and effective alternative for the prevention and treatment of joint inflammation is systemic enzyme therapy.

When our immune system detects a signal of tissue damage, certain helper cells begin to secrete a series of messenger proteins (cytokines) responsible for cell communication. The fundamental action of cytokines is to regulate the mechanism of inflammation. There are cytokines that promote inflammation in the acute phase (IL-1, TNF-α, IL-8, interferons, etc.) and other cytokines that inhibit it (e.g., IL-10). It is the imbalance between pro-inflammatory and anti-inflammatory cytokines that causes inflammation not to resolve properly. Proteolytic enzymes can act to restore this balance and help to quickly and efficiently resolve the acute inflammatory process before it becomes chronic.

Systemic enzyme therapy (SET) involves the oral administration of a combination of various proteolytic enzymes to regulate the body’s metabolic processes to help relieve pain associated with inflammatory processes. Once the proteolytic enzymes are absorbed and enter the bloodstream, they bind to a plasma protein called alpha-2-macroglobulin (alpha 2M), which acts as a protease inhibitor. (1) This binding forms a complex that causes a change in the conformation of alpha 2M, allowing small peptides (cytokines) to bind to the free binding site and be transported for further degradation. (2) This restores the appropriate levels of cytokines that allow the inflammatory process to be terminated.

There are a number of clinical studies that demonstrate the efficacy of oral enzyme combinations in various disciplines: traumatology, rheumatology, sports medicine, gynaecology, surgical support, etc. Specifically, the bibliography contains a meta-analysis of various randomised, double-blind clinical trials of patients with osteoarthritis of the knee who were administered a combination of proteolytic enzymes and bioflavonoids and an anti-inflammatory NSAID for at least 3 weeks, with the aim of comparing the efficacy, safety and tolerability of both treatments. The results indicated that SET provided comparable pain relief and improvement in joint function to the anti-inflammatory, but with better tolerability and fewer adverse effects. (3)

This therapy may also be useful for people with a weakened immune system as the immune response to different pathogens (viruses and bacteria) is a complex process that is also regulated by numerous enzymes.

If, in addition to proteolytic enzymes, we incorporate in our diet or through supplementation certain nutrients with antioxidant properties (vitamins and bioflavonoids) that protect cells against oxidative damage and boost our immune system, we will contribute to maintaining a general state of joint wellbeing.

In short, if we are looking for a natural alternative to non-steroidal anti-inflammatory drugs for the treatment of inflammatory processes that is effective and has fewer adverse effects, SET may be a highly recommendable option.

An important aspect to consider in the case of enzyme supplementation is that the tablets or capsules should be enteric-coated to preserve the enzymes from the acid pH of the stomach so that they can be directly absorbed in the small intestine.

Below is a list of proteolytic enzymes, as well as other nutrients that when taken together can help reduce inflammation, relieve pain, maintain normal immune system function and combat oxidative damage caused by free radicals.


  • Bromelain Bromelain is a proteolytic enzyme extracted from the fruit or stem of the pineapple (Ananas comosus). Due to its broad spectrum of biological activities and lack of side effects, it has been used for many years as a phytotherapeutic agent. Its properties include anti-inflammatory, anti-oedematous, anti-thrombotic and fibrinolytic effects, anti-cancer activity and immunomodulatory effects.(4) Bromelain decreases most inflammatory mediators and has been shown to play an important role as an anti-inflammatory agent in a variety of conditions. For example, it has been shown to be effective in inflammatory bowel disease by reducing the expression of INF-γ and TNF-α.(5) Another study showed that bromelain reduces cell damage caused by advanced glycation end products (AGEs) through proteolytic degradation of the receptor, thereby controlling inflammation.(6) In patients with osteoarthritis of the knee, bromelain significantly reduced pain and stiffness, while in patients with rheumatoid arthritis it reduced inflammation and tissue destruction by modulating TGF-β expression. (7)
  • Papain is a complex of several enzymes with proteolytic, amylolytic and lipolytic activity. It is extracted from the fruit of the papaya (Carica papaya) and like bromelain also exhibits anti-inflammatory and immunomodulatory properties and is commonly used for the relief of bruising, swelling and oedema caused by traumatic or inflammatory injuries. Papain contains certain substances that protect the body against tissue damage. It supports the immune system by regulating and balancing the expression of Th1 and Th2 cytokines. It has been shown to be helpful in reducing joint inflammation and some trials have suggested it may help relieve back pain. (8)
  • Serratiopeptidase It is a proteolytic enzyme extracted from cultured bacteria of the genus Serratia. It was first isolated from an enterobacterium that is present in the gut of the silkworm and allows the emerging moth to dissolve the cocoon. Due to its anti-inflammatory, analgesic, fibrinolytic and anti-oedematous properties, this enzyme has been used to reduce pain and inflammation in different medical specialties such as surgery (post-operative inflammation), gynaecology (breast engorgement), dentistry (treatment of periodontitis), etc. It is also frequently used in the field of sports for the treatment of injuries, as well as in cases of rheumatoid arthritis and pulmonary diseases.(9) It acts by reducing the amount of fluids in the tissues and facilitates drainage by reducing inflammation in the injured area. It may also act by modifying cell surface adhesion molecules and inhibiting leukocyte recruitment to sites of local inflammation. (10)
  • Pancreatin One of the most significant functions of the pancreas is to produce enzymes that help the body digest food. If there are not enough pancreatic enzymes produced, it is difficult to achieve optimal nutritional status. Pancreatin is a complex of pancreatic enzymes of porcine origin. In particular, it contains lipases (lipid hydrolysis), proteases (necessary for protein breakdown) and amylases (digest sugars). It is frequently used in the treatment of pancreatic insufficiency, cystic fibrosis or in case of pancreatitis (inflammation of the pancreas). (11) These situations can lead to weight loss, fat in the stool, colic, indigestion and bloating, which is often accompanied by bloating and abdominal pain.(12) The addition of pancreatin to SET may contribute to the degradation of plasma proteins that invade the interstitial space in acute inflammation and appears to be involved in the clearance of inflammatory mediators.
  • Trypsin and chymotrypsin The combination of the proteases trypsin:chymotrypsin has been used to accelerate tissue repair in trauma, surgery and orthopaedics. It is highly bioavailable as an anti-inflammatory, anti-oedematous, fibrinolytic, antioxidant, and anti-infective agent. (13) These properties make it an excellent alternative as a modulator of inflammation and facilitates the repair process. Its anti-inflammatory activity is due to several mechanisms. Like other proteolytic enzymes, its anti-inflammatory action is partly due to the formation of a complex with alpha-2M, which favours the elimination of excess pro-inflammatory cytokines and restores balance. It is also a powerful antioxidant which reduces oxidative stress and inflammation. It also acts by increasing the phagocytic activity of macrophages, preventing infection and facilitating tissue repair. (14)


  • Quercetin Quercetin is the most abundant and popular flavonoid in the human diet. It is generally found as a glycoside in many fruits and vegetables. Its many beneficial effects include its high antioxidant and anti-inflammatory properties, which means that its consumption can be beneficial in the prevention and treatment of joint inflammation and mild inflammatory processes. Its antioxidant action is due to its high capacity to neutralise reactive oxygen species (ROS) by activating antioxidant enzymes and chelating metals that accelerate oxidative stress. Its anti-inflammatory activity is exerted by inhibiting pro-inflammatory mediators such as cytokines, prostaglandins and leukotrienes, as well as the release of histamine. There is scientific evidence of its applicability in joint inflammation due to its inhibitory effect on the enzyme xanthine oxidase, reducing uric acid formation, making it potentially useful in the prevention and treatment of gout. (15)
  • Vitamin C Ascorbic acid (vitamin C) is an essential nutrient involved as a cofactor in numerous metabolic processes. Its benefits include its immune-regulating action and its antioxidant activity, which protects cells from oxidative damage. It also helps regenerate the reduced form of vitamin E and improves iron absorption. Vitamin C also acts as an essential cofactor for the normal formation of collagen, the main component of our body’s connective tissues and is present in blood vessels, bones, cartilage, skin and teeth. Two of the main components of collagen are 4-hydroxyproline and 5-hydroxylysine. Their function is to stabilise and consolidate the collagen triple helix through hydrogen bonds. In this respect, vitamin C acts as a cofactor for the enzymes lysine hydroxylase and proline hydroxylase, which are necessary for the hydroxylation of proline and lysine. These enzymes require iron to catalyse hydroxylation. The function of vitamin C is to maintain iron in its ferrous state (Fe+2) present at the catalytic site of the hydroxylases enzymes. (16) In addition, vitamin C increases the mRNA levels of collagen, aggrecan and α-prolyl 4-hydroxylase, which increases proteoglycan and protein synthesis in articular chondrocytes. For all these reasons, vitamin C can be very useful in maintaining good joint health. (17)
  • Vitamin E Vitamin E belongs to the group of fat-soluble vitamins, like vitamins A, D and K. Its active form is α-tocopherol and is key to the normal metabolism of all cells. Its deficiency can affect several vital functions. It is found abundantly in cell membranes and in all lipid tissues. Its main and most studied property is that of an antioxidant agent, helping to protect cells against free radical damage. Changes in the redox balance induced by endogenously and exogenously generated reactive oxygen species (ROS) (smoking, environmental pollution, ultraviolet rays, etc.) are involved in various diseases (cardiovascular diseases, eye disorders, cancer and neurodegenerative diseases), but are also a phenomenon considered essential for survival. (18) As we age, oxidative stress increases and antioxidant capacity decreases, as does the efficiency of repair systems. Optimal vitamin E levels are therefore essential. In addition, the body also needs a supply of this vitamin to stimulate the immune system so that it can fight invading bacteria and viruses.
  • Coenzyme Q10 Coenzyme Q10 (ubiquinone) is an antioxidant produced naturally by the body. It is part of mitochondrial enzyme complexes and is involved in cellular respiration, generating energy in the form of ATP. Organs with very high metabolic demands such as the heart, liver and kidney have the highest concentrations of this coenzyme. It is closely related to vitamin E, as it helps regenerate its active form. It is involved in cytosolic glycolysis and has oxidoreductase activity in the plasma membrane, Golgi apparatus and lysosomes. It improves membrane fluidity and prevents peroxidation of membrane lipids. Health benefits are attributed to it, such as boosting the immune system, improving heart failure and slowing down cellular ageing. For this reason, supplementation with Q10 could be an important adjuvant in the treatment of various diseases, especially chronic diseases affecting the elderly, as our capacity to generate this coenzyme decreases considerably as we age. Coenzyme Q10 promotes tissue oxygenation, endurance and cardiac function. Oxidative damage caused by a high concentration of ROS is the cause of many diseases. Q10 supplementation has been shown to have beneficial effects on cardiovascular disease, mitochondrial deficiency, inflammation and in the protection of healthy ageing. (19)
  • NADH NADH (reduced form of nicotine adenine dinucleotide) is a coenzyme whose primary function is to provide energy to all cells through an exchange of electrons and protons. NAD+, NADH and the NAD+/NADH ratio are known to control the activity of several oxidoreductase enzymes. Recent research has revealed that NAD+ is involved in the regulation of sirtuins, enzymes involved in delaying ageing and cell death. NADH-dependent sirtuins are thought to have cardiometabolic benefits, reduce inflammation and increase resistance to stress. (20) 20 Age, obesity and an excessively sedentary lifestyle have a negative impact on NADH production, so extra NADH through supplementation will not only give us strength and vitality, but will also help us counteract many age-related diseases, including neurodegenerative, cardiovascular and metabolic diseases. (21)


Bibliographical references:
  1. LaMarre J. et al. Cytokine binding and clearance properties of proteinase-activated alpha 2-macroglobulins. Lab Invest. 1991 Jul; 65(1):3-14.
  2. French K. et al. Protease activation of alpha2-macroglobulin modulates a chaperone-like action with broad specificity. Biochemistry. 2008 Jan 29; 47(4):1176-85.
  3. Ueberall MA. Et al. Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials. J Pain Res. >2016 Nov 4; 9:941-961.
  4. Rathnavelu V. et al. Potential role of bromelain in clinical and therapeutic applications. Biomed Rep. 2016; 5(3):283-288.
  5. Hale L.P et al. Treatment with oral bromelain decreases colonic inflammation in the IL-10 deficient murine model of inflammatory bowel disease. Clin Immunol. 2005; 116: 135-142.
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  11. de la Iglesia-García D, et al. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut 2017; 66:1474–1486.
  12. Björn Lindkvist. Diagnosis and treatment of pancreatic exocrine insufficiency. World J Gastroenterol. 2013; 19(42): 7258-7266.
  13. Chandanwale A et al. A randomized, clinical trial to evaluate efficacy and tolerability of trypsin:chymotrypsin as compared to serratiopeptidase and trypsin:bromelain:rutoside in wound management. Adv Ther. 2017; 34:180–98.
  14. Dilip Shah et al. The Role of Trypsin:Chymotrypsin in Tissue Repair. Adv Ther. 2018; 35:31–42.
  15. Ahmad NS et al. Pharmacological basis for use of Pistacia integerrima leaves in hyperuricemia and gout. J Ethnopharmacol. 2008;117(3):478-82.
  16. Kelly L. G. and Ronald T. R. Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol. 2010; 45(2): 106–124.
  17. Ameye L.G. y Chee W.S. Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence. Arthritis Research and Therapy; 2006; 8(4): R127.
  18. Miyazawa T. et al. Vitamin E: Regulatory Redox Interactions. IUBMB Life. 2019 ;71(4):430-441.
  19. Hargreaves IP et al. Coenzyme Q10 Supplementation in Fibrosis and Aging. Adv Exp Med Biol. 2019; 1178:103-112.
  20. Kane AE et al. Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases. Circ Res. 2018;123(7):868-885.
  21. Imai S. et al. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8):464-71.

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