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Over-the-Counter Enzyme Supplements: What a Clinician Needs to Know

      Abstract

      Over-the-counter (OTC) enzyme use is increasing in frequency in the United States. The numerous health benefit claims by manufacturers are leading to a surge in enzyme use for various conditions and symptoms. Clinicians need to help patients navigate this complex realm and make informed decisions about the use of OTC enzymes. This review focuses on key concepts for health care providers to understand the current evidence, risks, and benefits of OTC enzymes.

      Abbreviations and Acronyms:

      IL (interleukin), OA (osteoarthritis), OTC (over the counter), TNF (tumor necrosis factor)
      CME Activity
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      Credit Statement: Mayo Clinic College of Medicine designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.
      Learning Objectives: On completion of this article, you should be able to (1) identify common over-the-counter (OTC) enzymes being used by consumers in the United States, (2) develop a practical approach to reviewing current research on the efficacy of OTC enzymes for various conditions, and (3) communicate with patients regarding the risks and benefits of OTC enzymes.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
      Method of Participation: In order to claim credit, participants must complete the following:
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        Read the activity.
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      Date of Release: 8/4/2014
      Expiration Date: 8/31/2016 (Credit can no longer be offered after it has passed the expiration date.)
      Questions? Contact [email protected] .
      During clinical encounters, patients often inquire about the use of dietary enzyme supplements (also termed over-the-counter [OTC] enzymes) to relieve symptoms. The Dietary Supplement Health and Education Act of 1994 classified OTC enzymes as dietary supplements, which specifically exempts manufacturers from having to prove the safety or efficacy of a product as long as it does not claim to prevent, treat, or cure a specific disease.

      National Institutes of Health Office of Dietary Supplements. Dietary Supplement Health Education Act of 1994: Public Law 103-417: 103rd Congress. http://www.ods.od.nih.gov/About/DSHEA_Wording.aspx. Accessed January 22, 2014.

      Despite these restrictions, manufacturers market OTC enzymes as being effective for inflammatory disorders, multiple sclerosis, pancreatic insufficiency, allergies, burns, infections, and cancer. The popularity of these OTC enzymes is demonstrated by increased US sales in the past few years.

      SPINSscan Natural, SPINSscan Specialty Gourmet, SPINSscan Conventional 52 Weeks Ending 12/25/2012. Vol 2013. http://www.spins.com. Accessed February 12, 2014.

      Nevertheless, the quality of dietary supplements has been a cause for concern and has led to the dismissal of these supplements by physicians. The purpose of this review was to summarize the current evidence for the use of OTC enzymes in various disease states, equipping clinicians to have the conversation with the patient.

      What Are OTC Enzymes?

      Most clinicians are familiar with prescription pancreatic enzyme products that are used to treat pancreatic insufficiency, such as protease, pancrelipase, and pancreatic amylase. However, some enzymes are sold directly to consumers, including bromelain, papain, trypsin, and chymotrypsin, as well as numerous combination products (Table 1). Bromelain is a group of proteolytic enzymes derived from the stem and fruit of the pineapple (Ananas comosus).

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Taking oral bromelain combined with trypsin and rutin may improve the symptoms of osteoarthritis (OA). The papaya fruit (Carica papaya) contains several proteolytic enzymes (papain, chymopapain A, chymopapain B, and papaya peptidase A)

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      and is mainly used in wound débridement. Over-the-counter trypsin is typically produced from bacterial, fungal, or porcine sources.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Similar to papain, it is also used conventionally to aid in wound débridement (topical). As a supplement, most chymotrypsin is produced from bovine or porcine sources. Some evidence suggests that chymotrypsin might decrease tissue destruction in burn patients. Oral chymotrypsin seems to be effective for reducing the inflammation and edema associated with hand fractures.
      • Miller P.C.
      • Bailey S.P.
      • Barnes M.E.
      • Derr S.J.
      • Hall E.E.
      The effects of protease supplementation on skeletal muscle function and DOMS following downhill running.
      Enzymes derived from plant sources are touted as remaining active over a broader pH range, whereas animal-derived enzymes function in a narrower pH range. This wider pH range may protect plant-based enzymes from being degraded in the acidic environment of the stomach. Information about some of the more commonly used OTC enzymes, including dosage and adverse effects, are presented in Table 2.
      Table 1Common Claims About Over-the-Counter Enzymes by Their Manufacturers
      • “Enzymes: The Brawn Behind Better Digestion”
      • “Proteolytic Enzymes—A Potential Cure for Arthritis”
      • “Enzymes for Cancer: Low Enzymes Are Always Found in Cancer …”
      • “How Systemic Enzymes Work to Cure Diseases”
      Table 2Use, Dosage, and Potential Adverse Effects of Common Over-the-Counter Enzymes
      NameCommon indicationDosagePotential adverse effectsPotential drug interactions
      BromelainAcute postoperative and posttraumatic conditions of swelling, burn débridement, anti-inflammatory action, allergic rhinitisUp to 400 mg/d POGastrointestinal cramping, diarrhea, IgE–mediated allergic reactionsModerate interaction with amoxicillin and anticoagulant or antiplatelet drugs
      PapainPosttraumatic and postoperative inflammation, digestive aid, pharyngitis, herpes zoster symptoms, chronic diarrheaUp to 1500 mg/d POEsophageal perforation, gastritis, allergic reactionsNone known
      TrypsinDigestive enzyme supplementation, osteoarthritis, topically for promoting normal wound healingUp to 50 mg, usually combined with bromelainLocalized pain and transient burningNone known
      ChymotrypsinReducing inflammation and edema associated with abscesses, ulcers, surgery, or traumatic injuriesUp to 100,000 U USP, 4 times daily POAnaphylactic reaction (rare)None known
      PO = per os (by mouth); USP = United States Pharmacopeia.

      Mechanism of Action of OTC Enzymes

      The mechanism of action of OTC enzymes is not entirely clear as there are a number of studies demonstrating both pro-inflammatory and anti-inflammatory effects. The constituent of bromelain interferes with the growth of malignant cells and inhibits platelet aggregation. Animal studies suggest that it helps reduce inflammation and edema and has fibrinolytic activity.
      • Hale L.P.
      • Greer P.K.
      • Sempowski G.D.
      Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation.
      Some evidence suggests that papain can increase the release of reactive oxygen species by polymorphonuclear cells.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Multienzyme preperations also seem to induce tumor necrosis factor (TNF) α, interleukin (IL)-1β, and IL-6 in a time- and dose-dependent manner.
      • Desser L.
      • Rehberger A.
      • Paukovits W.
      Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro.
      The main mechanism of trypsin is its proteolytic activity, especially in wounds.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Chymotrypsin has ingredients with proteolytic, anti-inflammatory, and antioxidant activities that reduce tissue destruction.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Does Enzyme Production Decrease With Aging and Can OTC Enzymes Help?

      One of the main theories advocated by OTC enzyme proponents is that with age, natural enzyme production decreases and enzyme supplementation, therefore, becomes essential. However, enzyme production does not inherently decrease with age. For example, levels of amylin, a peptide hormone released from the endocrine pancreas, decrease in middle age but then increase in older age. Amylin has been implicated in appetite regulation because it is a potent anorectic agent when administered peripherally in rats. Increased amylin levels in older age suggests that it may contribute to anorexia of aging and delayed gastric emptying.
      • Edwards B.J.
      • Perry H.M.
      • Kaiser F.E.
      • et al.
      Age-related changes in amylin secretion.
      No evidence indicates that exocrine pancreatic secretions decrease with age. Evidence supporting OTC enzyme supplementation in older patients is lacking.

      Do OTC Supplements Help Digestion in Healthy Adults?

      Although enzyme supplementation for patients with documented pancreatic insufficiency is well established,
      • DiMagno E.P.
      Medical treatment of pancreatic insufficiency.
      a recently growing trend is the use of supplemental enzymes to aid digestion in individuals with no obvious pancreatic pathology. Proponents suggest that common symptoms, such as gas and bloating, may indicate a relative deficiency of digestive enzymes that can be overcome with oral supplementation. A commonly cited study describes healthy participants who were given enzyme supplements (containing lipase, protease, and amylase) before and after a fatty meal and reported significantly less gas, bloating, and fullness than controls.
      • Suarez F.
      • Levitt M.D.
      • Adshead J.
      • Barkin J.S.
      Pancreatic supplements reduce symptomatic response of healthy subjects to a high fat meal.
      However, the pancreatic supplement used (Creon 10; Solvay Pharmaceutical Inc) was a prescription enzyme product. Thus, the results are not necessarily applicable to the typical OTC enzyme supplements. Current evidence does not permit endorsement of the use of supplemental enzymes to treat common gastrointestinal tract symptoms, such as bloating, gas, and irritable bowel syndrome.

      Do Oral Enzyme Supplements Reach the Bloodstream?

      For enzyme supplements to have an effect on systemic symptoms, such as those in OA, rheumatoid arthritis, or muscle soreness, the intact enzyme must reach the joints or muscle tissue after absorption from the gastrointestinal tract. Enzymes (proteins), if not enterically coated or supplemented with a proton pump inhibitor or histamine blocker, would essentially be denatured in the acidic environment of the stomach. However, some evidence suggests that undegraded protein can be detected in the plasma after oral intake. In a study of 19 volunteers, the permeability of the intestinal mucosa for large protein molecules was studied using bromelain as the model enzyme; small amounts of bromelain were detected in the plasma, with part of its enzymatic activity retained.
      • Maurer H.R.
      Bromelain: biochemistry, pharmacology and medical use.
      Another double-blind multicenter trial of immunocompetent patients with herpes zoster showed the effectiveness of OTC enzymes in decreasing acute pain after oral ingestion.
      • Kleine M.W.
      • Stauder G.M.
      • Beese E.W.
      The intestinal absorption of orally administered hydrolytic enzymes and their effects in the treatment of acute herpes zoster as compared with those of oral acyclovir therapy.

      Enzyme Supplements and Inflammation

      The purported ability of OTC enzymes to suppress inflammation and edema may stem from their proteolytic properties. One study reported a reduction in edema and improved healing with bromelain.
      • Taussig S.J.
      • Batkin S.
      Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application: an update.
      In animal models, the combination of oral trypsin and bromelain was shown to be superior to the single enzymes.
      • Lotz-Winter H.
      On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects.
      • Ito C.
      • Yamaguchi K.
      • Shibutani Y.
      • et al.
      Anti-inflammatory actions of proteases, bromelain, trypsin and their mixed preparation (author’s transl).
      Some evidence suggests that its effects on blood coagulation and prostaglandin levels is vital for decreasing inflammation.
      • Maurer H.R.
      Bromelain: biochemistry, pharmacology and medical use.
      In another study, in vitro treatment of human peripheral blood mononuclear cells with bromelain, papain, and amylase resulted in the production of large amounts of TNF-α, IL-1β, and IL-6. Interferon-α and interferon-γ, which had no effect alone, synergistically increased TNF-α production when applied together with the enzymes.
      • Desser L.
      • Rehberger A.
      • Paukovits W.
      Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro.
      Further large-scale studies are required before existing treatments can be replaced. Thus, with the current evidence, it is unclear whether OTC enzymes are anti-inflammatory or proinflammatory.

      Do OTC Enzyme Supplements Improve the Symptoms of OA?

      In laboratory studies, enzyme supplements seem to have anti-inflammatory properties, making them at least a plausible candidate to help with the symptoms of OA.
      • Ito C.
      • Yamaguchi K.
      • Shibutani Y.
      • et al.
      Anti-inflammatory actions of proteases, bromelain, trypsin and their mixed preparation (author’s transl).
      Recently, a randomized prospective trial compared a commercial enzyme preparation containing bromelain, trypsin, and rutin with diclofenac in the treatment of 73 patients with OA of the knee joint. The commercial enzyme preparation significantly reduced pain indices (80% after 3 weeks’ treatment) compared with diclofenac. This effect was sustained for 4 weeks after completion of the drug phase of the study. Furthermore, the commercial enzyme had lower rates of adverse events and withdrawal and was better tolerated overall compared with diclofenac.
      • Klein G.
      • Kullich W.
      • Schnitker J.
      • Schwann H.
      Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip: a double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs.
      In a subsequent study of the same combination product, patients with symptomatic OA of the knee were randomized to receive either an oral enzyme-flavonoid preparation or a nonsteroidal anti-inflammatory drug for 6 weeks.
      • Akhtar N.M.
      • Naseer R.
      • Farooqi A.Z.
      • Aziz W.
      • Nazir M.
      Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee: a double-blind prospective randomized study.
      Both groups demonstrated reduced pain and improved joint function, but the enzyme-flavonoid product seemed to be slightly more effective. No serious adverse events were reported. The OTC enzymes may have a clinical role in improving symptoms of OA, but larger studies are needed to confirm these effects.

      Do OTC Enzyme Supplements Improve Muscle Soreness in Athletes?

      Evidence regarding the effectiveness of OTC enzymes in improving muscle soreness is contradictory. A study of 20 healthy men aged 18 to 29 years showed that protease supplements hasten the recovery of contractile capabilities and attenuate perceived increases in pain after downhill running.
      • Miller P.C.
      • Bailey S.P.
      • Barnes M.E.
      • Derr S.J.
      • Hall E.E.
      The effects of protease supplementation on skeletal muscle function and DOMS following downhill running.
      Another trial showed effectiveness in reducing the pain and swelling associated with various injuries and hastening of the healing process.
      • Deitrick R.E.
      Oral proteolytic enzymes in the treatment of athletic injuries: a double-blind study.
      However, a double-blind randomized controlled trial with 40 participants showed no difference between bromelain and placebo in treating delayed-onset muscle soreness.
      • Stone M.B.
      • Merrick M.A.
      • Ingersoll C.D.
      • Edwards J.E.
      Preliminary comparison of bromelain and ibuprofen for delayed onset muscle soreness management.
      A subsequent double-blind trial of 50 individuals with soft-tissue ankle injuries showed, on average, no significant difference in swelling, bruising, and function in the group given oral proteolytic enzymes vs enteric-coated lactose tablets.
      • Craig R.P.
      The quantitative evaluation of the use of oral proteolytic enzymes in the treatment of sprained ankles.
      Currently, evidence of OTC enzymes improving muscle soreness in athletes is insufficient.

      Enzyme Supplements and Cancer

      Many OTC enzyme studies related to cancer focus on decreasing the complications of therapy, not on the effects on the disease process itself. Several studies have claimed that OTC enzymes improve the complications associated with chemotherapy, but these studies either were not statistically analyzed or did not show significant improvement with OTC enzymes.
      • Sakalova A.
      • Bock P.R.
      • Dedik L.
      • et al.
      Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.
      • Popiela T.
      • Kulig J.
      • Hanisch J.
      • Bock P.R.
      Influence of a complementary treatment with oral enzymes on patients with colorectal cancers: an epidemiological retrolective cohort study.
      • Martin T.
      • Uhder K.
      • Kurek R.
      • et al.
      Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? results of a double-blind randomized trial.
      For example, a retrospective study reported that complementary treatment with OTC enzymes improved quality of life for patients with colorectal cancer by reducing signs and symptoms of disease and reducing adverse reactions associated with adjuvant antineoplastic therapies.
      • Popiela T.
      • Kulig J.
      • Hanisch J.
      • Bock P.R.
      Influence of a complementary treatment with oral enzymes on patients with colorectal cancers: an epidemiological retrolective cohort study.
      However, a randomized controlled trial of prophylactic treatment with proteolytic enzymes to reduce the acute toxic effects of adjuvant pelvic radiotherapy showed no reduction in acute toxic effects. Furthermore, it did not improve tolerance to adjuvant pelvic radiotherapy.
      • Martin T.
      • Uhder K.
      • Kurek R.
      • et al.
      Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? results of a double-blind randomized trial.
      An in vitro study investigated the effects of exposing polymorphonuclear cells to a combination product of bromelain and papain and reported a time-dependent and statistically significant increase in the release of reactive oxygen species.
      • Zavadova E.
      • Desser L.
      • Mohr T.
      Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation.
      In another study, long-term rectal administration of an enzyme mixture containing papain, trypsin, and chymotrypsin in a 1:1:1 ratio was evaluated for antitumor effects in mice inoculated with melanoma cells. Thirty percent of the animals in the test group were reported to be cancer free.
      • Wald M.
      • Zavadova E.
      • Pouckova P.
      • Zadinova M.
      • Boubelik M.
      Polyenzyme preparation Wobe-Mugos inhibits growth of solid tumors and development of experimental metastases in mice.
      One retrospective study reported increased survival of patients recovering from multiple myeloma who were receiving additive therapy with an oral enzyme for more than 6 months.
      • Sakalova A.
      • Bock P.R.
      • Dedik L.
      • et al.
      Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.
      To our knowledge, no published study explains the mechanism of action of OTC enzymes in patients with cancer. Although the effects of OTC enzymes on various cytokines and serine and cysteine proteinases have been proposed by many authors, none have been validated through clinical studies.

      What Are the Risks of Enzyme Supplementation?

      The risks associated with enzyme supplement use generally seem to be low. However, because these products are sold as dietary supplements, they may include various contaminants, and the actual amount per dose may vary among different brands. Their interactions with other substances or drugs also are not well understood. Fibrosing colonopathy is a rare but potentially severe complication of prescription enzyme supplementation in children with cystic fibrosis.
      • FitzSimmons S.C.
      • Burkhart G.A.
      • Borowitz D.
      • et al.
      High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.
      Oral bromelain may cause gastrointestinal tract disturbances or diarrhea. Immunoglobulin E–mediated allergic reactions to bromelain may occur and include a cross-allergenicity between bromelain and wheat flour. In excessive doses, papain can cause clinically significant adverse effects, such as esophageal perforation. Raw papain or papaya latex is a severe irritant and vesicant. Little is known about the adverse effects of trypsin, but topical application may cause localized pain and transient burning.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Rare reports of anaphylaxis have been associated with oral chymotrypsin. General gastrointestinal tract discomfort has been commonly noted with OTC enzymes, especially with increased dosage. Pregnant and lactating women are advised to consult doctors before taking these products.

      Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

      Counseling Patients Who Intend to Use Enzyme Supplementation Regardless of the Evidence

      Despite the absence of robust clinical trial data supporting the use of supplemental enzymes, many patients still want to try them, especially because product marketing seems to be increasing. Given the general safety profile of these products (when used according to manufacturer directions), the overall risk for personal trials is probably low. Health professionals should advise patients who are embarking on a trial of enzyme supplements (or who are currently using them) to be aware of potential adverse effects on the gastrointestinal tract and the need to discontinue use should they occur. For patients who insist on using OTC enzymes, physicians should counsel them on a time-limited personal trial approach. This would encourage discontinuation of the product if there is no significant improvement of their symptoms. In addition, health professionals can advise patients to not give OTC enzymes to children with cystic fibrosis.

      Conclusion

      The use of enzyme supplements in general seems to be increasing in the United States, both by patients seeking to treat conditions or symptoms and by consumers seeking to enhance general health. The historical and preclinical data on enzymes are intriguing regarding digestion, anti-inflammatory effects, and anticancer properties. Emerging clinical data seem to support many of these purported benefits. However, as with many dietary supplements, the existing research is generally challenged by methodologic weaknesses, small sample sizes, heterogeneity of product, and lack of uniform outcome measures. Thus, well-designed studies with sufficient power are critically needed to further characterize the proper role of enzyme supplements in health promotion and disease treatment.

      Supplemental Online Material

      References

      1. National Institutes of Health Office of Dietary Supplements. Dietary Supplement Health Education Act of 1994: Public Law 103-417: 103rd Congress. http://www.ods.od.nih.gov/About/DSHEA_Wording.aspx. Accessed January 22, 2014.

      2. SPINSscan Natural, SPINSscan Specialty Gourmet, SPINSscan Conventional 52 Weeks Ending 12/25/2012. Vol 2013. http://www.spins.com. Accessed February 12, 2014.

      3. Therapeutic Research Faculty. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Updated January 22, 2014. Accessed January 22, 2014.

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