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Enzymes for inflammation

Enzymes for inflammation

Proteolytic enzymes—naturally occurring substances derived from animal or plant sources—are under investigation as alternatives to conventional pharmaceutical treatments for pain and swelling associated with a number of common conditions.

Heat, swelling and pain: These familiar symptoms of inflammation accompany acute problems like cuts, bruises, sprains, fractures, toothaches and surgical procedures. Inflammation is also a culprit in such chronic conditions as osteoarthritis, rheumatoid arthritis and asthma, and researchers have recently begun to suspect it even plays a role in colon cancer, atherosclerosis, diabetes and Alzheimer's disease. As researchers work to sort out the complexities of different inflammatory cascades and their relationships to many conditions, the findings are changing not only scientific understanding of the inflammatory process, but also clinical approaches to treatment.

In the meantime, proteolytic enzymes—naturally occurring substances derived from animal or plant sources—are under investigation as alternatives to conventional pharmaceutical treatments for pain and swelling associated with a number of common conditions. While their precise mechanism of action remains unclear, studies suggest that proteolytic enzymes may have important contributions to make in the treatment of inflammation.

An intricate system of cellular defense

As a natural and essential response to cellular injury, the inflammatory response may arise in instances of trauma, oxygen or nutrient deprivation, temperature extremes, exposure to chemical agents or radiation, invasion by microorganisms, or the presence of dead cells. As such, almost every injury or illness will have an inflammatory component. By drafting the help of many key players to release myriad chemical mediators, inflammation acts with the intent to heal: protecting nearby cells from further injury, disposing of pathogenic or cellular debris and promoting timely repair of injured tissues. If an acute inflammatory event is not resolved, as in the case of a degenerative process like osteoarthritis, a chronic inflammatory response may ensue.

Proinflammatory agents such as the hormone-like eicosanoids (prostaglandins, thromboxanes, leukotrienes and lipoxins) play an important role in the inflammatory response. One metabolic pathway is particularly important to symptoms such as swelling and pain: the metabolism of arachidonic acid, a fatty acid compound found in the cell's membrane. Three promoting enzymes (COX-1, COX-2, and 5-LOX) follow that metabolic cascade on separate pathways, to eventually influence the production of eicosanoids (see diagram, above). The pathway mediated by COX (cyclooxygenase) has been extensively researched; indeed, intervention in this cascade with nonsteroidal anti-inflammatory drugs or corticosteroids is the common approach to mediating inflammatory pain. Recent analyses of the COX cascades, however, are revealing complex functional overlaps and greater roles for the 5-LOX (lipooxygenase) and other pathways in inflammatory promotion or inhibition. Today, both COX and LOX pathways are being explored as potential sites for therapeutic intervention. As researchers further unravel these complex interrelationships, more effective interventions for inflammatory symptoms should soon follow.

Taming the flames with proteolytic enzymes

We've seen how some naturally occurring enzymes promote symptoms of inflammation in the body, but what about the growing use of enzyme products to treat swelling and pain? Proteolytic or protein-splitting enzymes (also known as proteases) have been shown to play roles in various physiological functions, including digestion and the inflammatory cascade.1 Research lends credibility to a long history of use of orally ingested enzymes for digestive support, and these enzymes are currently being used to treat various inflammatory conditions, including sports injuries, post-surgical swelling and osteoarthritis.2,3,4

Pancreatic enzymes, such as pancreatin, typically derived from pork pancreas, are often used for systemic treatment of inflammation. Trypsin and chymotrypsin (commonly extracted from ox bile) are other important proteases found in many natural anti-inflammatory products. Some manufacturers employ methodologies to derive these enzymes from plants and bacteria. Other widely used proteolytic enzymes include bromelain, derived from pineapples, and papain, from papayas.

The precise mechanism of action of proteolytic enzymes against inflammation remains unclear—a fact complicated by the paucity of current well-controlled, peer-reviewed studies originally published in English. Though compelling, much of the information available about systemic enzyme therapies is based upon empirical evidence, foreign studies or old research. Given that caveat, we'll explore some of the research relating to supplementation with proteolytic enzymes—the most natural of anti-inflammatory interventions.

Proteolytic enzymes for the treatment of inflammation are usually marketed as formulas that combine two or more of the following: pancreatin or its primary proteases, trypsin and chymotrypsin; plant-derived bromelain or papain; amylase; lipase; other enzymes; and possibly, a plant-derived flavonoid. These are typically supplied as enterically coated tablets. Some products also include other botanical agents known to inhibit symptoms of inflammation.

The original idea behind such combination preparations may be an old study conducted in 1977, which compared the activity of seven NSAID substances to a combination of proteolytic enzymes, flavonoids and ascorbic acid in four separate tests of inflammation. When assessing swelling, the authors reported a "more complete spectrum of action" from the combined ingredients compared with NSAID substances; these conclusions have not been repeated in the ensuing years.5 Two Czech studies conclusively debunked the myth that enzymes would be destroyed by digestive acid by demonstrating that approximately 25 percent of a systemic enzyme therapies combination did, indeed, pass intact into the bloodstream3,6

Bromelain, a plant-derived proteolytic enzyme, is able to enhance tissue permeability and has demonstrated a potentiating (strengthening) effect with antibiotics, glucosamine and possibly flavonoids.4 Further research is required to substantiate the theory that the addition of bromelain to a SET protocol might stimulate the activity of some components of the immune system, thereby enhancing the body's own natural healing resources.4 A German report on several experimental studies claimed a commercially available proteolytic enzyme-flavonoid combination was capable of influencing the inflammatory pathway at several stages of healing: inhibiting and breaking down fibrin, inhibiting aggregation of platelets, breaking up fresh clots and accelerating blood flow.7 Proteolytic enzymes have been credited in German studies with accelerating healing from bruises, abrasions and hematomas, improving post-surgical movement and shortening postoperative recuperation.7,8

In the quest to find optimal treatments to shorten healing time after cosmetic surgery, one Czech study of 20 cosmetic surgery patients tested the effects of a commercially available proteolytic enzyme preparation containing pancreatin, trypsin, chymotrypsin, papain, bromelain and rutin (a flavonoid) on hematoma, swelling and pain following eyelid surgery. Researchers claimed "excellent results" in reduction of edema (swelling) for the group treated with the enzymatic preparation, compared with controls treated with systemic prescription medications. Noting the absence of undesirable side effects, they opined that SET might be prescribed without limitation for patients with concurrent cardiovascular, hepatic or renal disease.9 In 2004, another small, randomized, placebo-controlled study assessed the effects of a combination enzyme preparation on soft-tissue wound healing in 26 volunteers. Of the 22 subjects completing the study, 17 demonstrated a statistically significant, 17 percent acceleration of wound-healing time, in addition to less redness.10

Osteoarthritis is another area in which enzymes have been put to the test. One study compared a formula containing trypsin, bromelain and rutoside with the prescription NSAID diclofenac in 103 subjects with painful osteoarthritis of the knee. In the randomized, double-blind, parallel group trial, researchers concluded the SET to be an "effective and safe alternative to NSAIDs" and called for placebo-controlled studies to confirm their results.11 A study involving 50 subjects with osteoarthrosis of the knee compared a commercially available enzyme compound with diclofenac and demonstrated a statistically significant reduction in joint tenderness (p12 A number of other German studies comparing this particular enzyme combination with diclofenac reached similar conclusions, although better-controlled research is needed before definitive conclusions can be drawn.13,14,15

In addition to their use in combined product preparations, bromelain and papain have also long been used individually. Their particular mechanism of action remains unclear; indeed, researchers believe that bromelain's biochemical activity may be only partially attributable to its proteolytic attributes.16 Their physiologic activity is, however, prone to variability due to the effects of different growing environments, processing and storage, and bromelain has demonstrated variable activity after exposure to heat. Various studies have demonstrated that bromelain offers therapeutic benefits in treatment of arthritis, sports injuries and musculoskeletal injuries.4 An old but often-cited study demonstrated bromelain's superiority to placebo in quickly reducing swelling and pain of acute inflammation for 74 boxers with facial bruises and hematomas on lips, eyes, ears, chests and arms. After treatment with bromelain four times a day for four days, 58 of the boxers had complete clearing of all bruising and the remaining 16 required an additional eight to 10 days for healing. In contrast, only 10 of the controls receiving placebo had complete clearance on day four, and the remaining 62 required seven to 14 days for healing.4

A literature review published in 2005 concluded that bromelain does, indeed, have potential use in the treatment of osteoarthritis and called for controlled studies to determine optimal dosages.17 One recent study is particularly notable with respect to the effects of bromelain in osteoarthritis. The controlled study, conducted in 2002, measured the effects of high- and low-dose bromelain on mild acute knee pain and the psychological well-being of otherwise healthy subjects. Compared to baseline data, improvements in total symptom scores, stiffness and physical function were significantly better for high-dose (400 mg per day) subjects than for low-dose (200 mg per day) subjects.18 In other studies, bromelain has demonstrated anti-inflammatory effectiveness in the treatment of bacterial infections, bronchitis, cellulitis, inflammation and edema, sinusitis, surgical trauma, thrombophlebitis and inflammatory bowel disease.4,16,19

Another promising proteolytic enzyme, widely used in Asia and Europe since its discovery in 1978, is serratia peptidase. Originally isolated as serrapeptase from the intestinal bacteria of a silkworm, it was made commercially available by isolation from nonpathogenic bacteria and introduced to the United States in 1997 as serratia peptidase. In a multi-center, double-blind, randomized study involving 193 participants, serratia peptidase acted rapidly to reduce local inflammation and ease symptoms in people suffering from ear, nose and throat disorders. People who took three serratia peptidase tablets twice daily experienced "significant symptom regression" in only three to four days, compared with the same level of improvement in seven to eight days for those who took placebo. Although the exact mechanism of action remains unclear, researchers noted that the enzyme demonstrated anti-inflammatory, edema-suppressing and fibrinolytic (blood clot-dissolving) properties while mediating symptoms of localized inflammation.20

Serratia peptidase may also block the release of pain-inducing compounds from inflamed tissues.20 A prospective German study involving three randomized groups of post-operative patients who had undergone knee surgery found a commercial preparation of serratia peptidase produced a 50 percent reduction in swelling and pain by the third day compared with two control groups (using leg elevation and bed rest, with or without ice application) who experienced no such reductions. Additionally, the enzyme-treated group became pain-free more rapidly than controls; by day 10, pain was completely resolved. In this study, pain reduction was postulated to correlate with swelling reduction.21 Apparently free of side effects, serratia peptidase appears to be another valuable aid in taming the pain and swelling of inflammation.


Proteolytic enzymes appear to simply support the body's own natural ability to manage its inflammatory response appropriately and efficiently. Appearing at least equal in efficacy to NSAIDs and with fewer undesirable side effects, they seem a worthy alternative for treating the pain and swelling of inflammation.

Kathryn Montgomery is a Denver-based freelance writer.

Dos and Don'ts ... Cautions and Recommendations

  • Do take proteolytic enzymes between meals for inflammatory conditions.
  • Do take extra folate with long-term pancreatin supplementation, which impairs folate absorption over time.22
  • Do consider adding bromelain to a supplement regimen containing glucosamine—bromelain appears to potentiate (strengthen) the effect of glucosamine.4
  • Do store bromelain with care—it has demonstrated variable activity after exposure to heat.4
  • Don't take proteolytic enzymes with other products that thin the blood.23
  • Don't take bromelain if you have a history of pineapple allergy or heart palpitations.4
  • Don't eat potato protein or soybean products with bromelain—these foods may inhibit the enzyme's effectiveness.24

1. Black JM, et al. Medical-surgical nursing clinical management for positive outcomes (6th ed). Philadelphia: WB Saunders Co., 2001, pp 319,635-6.
2. King J. Nutritional enzymes update. Nutraceuticals World.
3. Nouza K. Outlooks of systemic enzyme therapy in rheumatoid arthritis and other immunopathological diseases. Acta Univ Carol 1994;40(1-4):101-4.
4. Kelly GS. Bromelain: a literature review and discussion of its therapeutic applications. Alt Med Review 1996;1(4):243-57.
5. Tarayre JP and Lauressergues H. Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with nonsteroid anti-inflammatory agents. Arneimittelforschung 1977;27(6):1144-9.
6. Nouza K and Wald M. Systemic enzyme therapy: problems of resorption of enzyme macromolecules. Cas Lek Cesk 1995;134(19):615-9.
7. Kleine MW. Introduction to systemic enzyme therapy and results of experimental trials. In: Hermans GPH and Mosterd WL, eds. Sports, Medicine and Health. Excerpta Medica. Amsterdam:1990, p1131.
8. Rahn HD. Efficacy of hydrolytic enzymes in surgery. In: Hermans, GPH and Mosterd WL, eds. Sports, Medicine and Health. Excerpta Medica. Amsterdam: 1990.
9. Duskova M and Wald M. Orally administered proteases in aesthetic surgery. Aesthetic Plas Surg 1999;23(1):41-4.
10. Brown SA, et al. Oral nutritional supplementation accelerates skin wound healing: a randomized, placebo-controlled, double-arm, crossover study. Plas Recon Surg 2004;114(1):237-44.
11. Akhtar NM, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee. Clin Rheum 2004;23(5):410-5.
12. Tilwe GH, et al. Efficacy and tolerability of oral enzyme therapy as compared to diclofenac in active osteoarthrosis of the knee joint: an open randomized controlled clinical trial. J Assoc Physicians India 2001;49:617-21.
13. Singer F, et al. Phlogenzyme versus diclofenac in the treatment of activated osteoarthritis of the knee. A double-blind prospective randomized study. International Journal of Immunotherapy 2001;17(2-4):135-41.
14. Klein G. Short-term treatment of painful osteoarthritis of the knee with oral enzymes. Clin Drug Invest 2000;19(1):15-23.
15. Heyll U, et al. Proteolytic enzymes as an alternative in comparison with nonsteroidal anti-inflammatory drugs (NSAID) in the treatment of degenerative and inflammatory rheumatic disease: systematic review. Med Klin 2003; 98(11):609-15.
16. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58(9):1234-45.
17. Brien S, et al. Bromelain as a treatment for osteoarthritis: a review of clinical studies. ECAM 2004;1(3):251-7.
18. Walker AF, et al. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine 2002;9(8):681-6.
19. Hale LP, et al. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immun 2005;116:135-42.
20. Mazzone A, et al. Evaluation of serratia peptidase in acute or chronic inflammation of otorhinoloaryngology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res 1990;18(5):379-88.
21. Esch PM, et al. Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase—a prospective study. Fortschr Med 1989;107(4):67-8, 71-2.
22. Russell RM, et al. Impairment of folic acid absorption by oral pancreatic extracts. Dig Dis Sci 1980;25(5):369-73.
23. Proteolytic enzymes. Swedish Medical Center. EBESCO Publishing.
24. Jellin JM, et al. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database (5th ed.) Therapeutic Research Faculty, Stockton, Calif.: 2003. p 224.

Natural Foods Merchandiser volume XXVI/number 11/p. 36, 38-39

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