Proteolytic enzymes as a therapeutic supplement

DEFINITION: Natural substance of the human body and of plants used as a supplement to treat specific health conditions.

PRINCIPAL PROPOSED USES: Dyspepsia, neck pain and other forms of chronic musculoskeletal pain, osteoarthritis, pancreatic insufficiency, shingles (herpes zoster), sports injuries, surgery support

OTHER PROPOSED USES: Breast engorgement, food allergies, reducing side effects of radiation therapy for cancer, rheumatoid arthritis, sports and fitness support and recovery, scar tissue reduction

Overview

Proteolytic enzymes (proteases) help the body digest the proteins in food. Although the body produces these enzymes in the pancreas, certain foods also contain proteolytic enzymes. Papaya and pineapple are two of the richest plant sources, as attested by their traditional use as natural tenderizers for meat. Papain and bromelain are proteolytic enzymes found in these fruits. The enzymes made in the human body are called trypsin and chymotrypsin.

The primary use of proteolytic enzymes is as a digestive aid for people who have trouble digesting proteins. However, proteolytic enzymes may also be absorbed internally to some extent and may reduce pain and inflammation.

Requirements and Sources

People do not need proteolytic enzymes from food because the body manufactures them (primarily trypsin and chymotrypsin). However, deficiencies in proteolytic enzymes do occur, usually resulting from diseases of the pancreas (exocrine pancreatic insufficiency). Other causes include cystic fibrosis, gastrointestinal surgeries, diabetes, a gluten allergy, inflammatory bowel disease, or Shwachman–Diamond syndrome. Symptoms of proteolytic enzyme deficiencies include abdominal discomfort, gas, bloating, indigestion, poor absorption of nutrients, fatty or oily stool, and passing undigested food in the stool.

For use as a supplement, trypsin and chymotrypsin are extracted from the pancreas of various animals, primarily pigs and cows. Bromelain extracted from pineapple stems and papain made from papayas can also be purchased. Other proteolytic enzyme food sources include ginger, kiwi, yogurt, sauerkraut, miso, and kefir.

Therapeutic Dosages

The amount of an enzyme is expressed not only in grams or milligrams but also in activity units or international units. These terms refer to the enzyme’s potency (specifically, its digestive power). Recommended dosages of proteolytic enzymes vary with the form used. Because of the wide variation, label instructions regarding dosage should be followed.

Proteolytic enzymes can be broken down by stomach acid. To prevent this from happening, supplemental enzymes are often coated with a substance that does not dissolve until it reaches the intestine. Such a preparation is called enteric-coated.

Most supplements should be taken around twenty minutes before meals for best results. Supplements include trypsin, bromelain, chymotrypsin, ficin, papain, and serrapeptase, but supplements often combine these enzymes in one dose. These supplements may be taken as gelcaps, pills, chewables, or powders produced by Wobenzym, Wobe-Mugos, and Zymactive.

Therapeutic Uses

The most obvious use of proteolytic enzymes is to assist digestion. However, a small, double-blind, placebo-controlled trial found no benefit from proteolytic enzymes as a treatment for dyspepsia (indigestion).

Proteolytic enzymes can also be absorbed into the body whole and may help reduce inflammation and pain; however, the evidence is inconsistent. Several studies found that proteolytic enzymes might be helpful for neck pain, osteoarthritis, and post-herpetic neuralgia (an aftereffect of shingles). However, these studies have significant limitations, like omitting a placebo group, and they do not provide substantially reliable information.

Studies performed in the late twentieth century suggest that proteolytic enzymes may help reduce the pain and discomfort that follow injuries (especially sports injuries). However, a later, better-designed, and far larger study failed to find any benefit. Proteolytic enzymes have also been evaluated to aid recovery from the pain and inflammation caused by surgery, but most studies are decades old, and in any case, the results were mixed.

A double-blind, placebo-controlled trial published in the 1960s found that the use of proteolytic enzymes helped reduce the discomfort of breast engorgement in lactating women. A study tested bromelain for enhancing recovery from heavy exercise by decreasing delayed-onset muscle soreness but found no benefits. Another study, which used a mixed proteolytic enzyme supplement, failed to find any benefits. Two studies failed to find proteolytic enzymes helpful for reducing the side effects of radiation therapy for cancer. Research continues to indicate that cancer is not effectively treated in humans with proteolytic enzymes despite positive test tube research.

Some alternative medicine practitioners believe that proteolytic enzymes may help reduce symptoms of food allergies, presumably by digesting the food so well that there is less to be allergic to; however, there is no scientific evidence for this proposed use.

Another theory popular in certain alternative medicine circles suggests that proteolytic enzymes can aid rheumatoid arthritis, multiple sclerosis, lupus, and other autoimmune diseases. Supposedly, these diseases are made worse when whole proteins from foods leak into the blood and cause immune reactions. Digestive enzymes are said to help foil this so-called leaky gut problem. Again, however, there is no meaningful evidence to substantiate this theory. Furthermore, one fairly large (301-participant) study failed to find proteolytic enzymes helpful for multiple sclerosis.

Scientific Evidence

Most of the studies described in this section used combination products containing various proteolytic enzymes plus other substances, such as the bioflavonoid rutin.

Chronic musculoskeletal pain. Several studies provide preliminary evidence that proteolytic enzymes might be helpful for various forms of chronic pain, including neck pain and osteoarthritis. A double-blind, placebo-controlled trial of thirty people with chronic neck pain found that the use of a proteolytic enzyme mixture modestly reduced pain symptoms compared with a placebo.

Osteoarthritis. Studies enrolling more than four hundred people compared proteolytic enzymes to the standard anti-inflammatory drug diclofenac for treating osteoarthritis-related conditions of the shoulder, back, or knee. The results generally showed that the supplement had benefits equivalent to those of the medication. However, these studies suffered from various flaws that limited their reliability; the most important flaw was the absence of a placebo group. Of all the uses proposed for proteolytic enzymes, improving inflammation and pain associated with osteoarthritis of the knee is the most scientifically endorsed with twenty-first-century research.

Shingles (herpes zoster).Shingles is an acute, painful infection caused by the varicella-zoster virus, the organism that causes chickenpox. Proteolytic enzymes have been suggested as treatment. However, there is little evidence to support their use. A double-blind study of 190 people with shingles compared proteolytic enzymes to the standard antiviral drug acyclovir. Participants were treated for fourteen days, and their pain was assessed at intervals. Although both groups had similar pain relief, the enzyme-treated group experienced fewer side effects. However, since acyclovir offers minimal benefit at most, these results do not mean very much. Similar results were seen in another double-blind study in which 90 people were given an injection of either acyclovir or enzymes, followed by a course of oral medication for seven days.

Sports injuries. Several small studies have found proteolytic enzyme combinations helpful for the treatment of sports injuries. However, the best and largest trial by far failed to find benefit. A double-blind, placebo-controlled study of 44 people with sports-related ankle injuries found that treatment with proteolytic enzymes resulted in faster healing and reduced the time away from training by about 50 percent. Based on these results, a very large (721-participant), double-blind, placebo-controlled trial of people with sprained ankles was undertaken. This study failed to find benefits with rutin, bromelain, or trypsin, separately or combined.

Three other small double-blind studies involving about eighty athletes found that treatment with proteolytic enzymes significantly speeded healing of bruises and other mild athletic injuries compared with placebo. In another double-blind trial, one hundred people were given an injection of their own blood under the skin to simulate bruising following an injury. Researchers found that treatment with a proteolytic enzyme combination significantly speeded up recovery. In addition, a double-blind, placebo-controlled trial of seventy-one people with finger fractures found that treatment with proteolytic enzymes significantly improved recovery. However, these studies were performed decades ago and are not quite up to modern standards.

Surgery. Numerous studies have evaluated various proteolytic enzymes to aid surgery recovery, but the results have been mixed. Most of the research in this area is not up to modern standards. A double-blind, placebo-controlled trial of eighty people undergoing knee surgery found that treatment with mixed proteolytic enzymes after surgery significantly improved the rate of recovery, as measured by mobility and swelling. Another double-blind, placebo-controlled trial evaluated the effects of a similar mixed proteolytic enzyme product in eighty individuals undergoing oral surgery. The results showed reduced pain, inflammation, and swelling in the treated group compared with the placebo group. Benefits were also seen in another trial of mixed proteolytic enzymes for dental surgery and in one study involving only bromelain. A 2023 double-blind, randomized, placebo-controlled study evaluated the effect of a product called Anaheal, containing the proteolytic enzyme bromelain, on recovery following periodontal surgery in twenty-eight adults. Those who took Anaheal experienced reduced bleeding, but no other evaluation indices showed statistically significant improvements.

A double-blind, placebo-controlled study of 204 women receiving episiotomies during childbirth found evidence that a mixed proteolytic enzyme product can reduce inflammation. Bromelain was also found helpful for reducing inflammation following episiotomy in one double-blind, placebo-controlled trial of 160 women, but a very similar study found no benefit.

Other double-blind, placebo-controlled studies have found that bromelain reduces inflammation and pain following nasal surgery, cataract removal, and foot surgery. However, a study of 154 individuals undergoing facial plastic surgery found no benefit.

A small double-blind, placebo-controlled trial of twenty-four people having surgical extraction of third molars found that serrapeptase given during the procedure reduced postoperative pain and swelling (significant differences on days two, three, and seven).

Safety Issues

In studies, proteolytic enzymes are believed to be quite safe, although they occasionally cause digestive upset and allergic reactions. One proteolytic enzyme, pancreatin, may interfere with the absorption of vitamin B folate, so it is advisable to take a folate supplement when taking pancreatin. In addition, the proteolytic enzyme papain might increase the blood-thinning effects of warfarin and possibly other anticoagulants. Bromelain might also cause problems if combined with drugs that thin the blood, like heparin. It should not be mixed with sedative drugs and should be avoided by individuals taking antibiotics because it may increase blood concentrations of certain antibiotics.

Important Interactions

People taking the proteolytic enzyme pancreatin may need extra folate. People taking warfarin (Coumadin, Jantoven), aspirin, or other drugs that thin the blood should not take the proteolytic enzymes papain or bromelain except under a doctor’s supervision. Those taking sedative drugs should not take bromelain except under a physician’s supervision.

Bibliography

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Al-Khateeb, T. H., and Y. Nusair. “Effect of the Proteolytic Enzyme Serrapeptase on Swelling, Pain, and Trismus after Surgical Extraction of Mandibular Third Molars.” International Journal of Oral Maxillofacial Surgery vol. 37, 2008, 264-68.

Babazade, Hossein, et al. “The Effect of Bromelain in Periodontal Surgery: A Double-Blind Randomized Placebo-Controlled Trial.” BMC Oral Health, vol. 23, no. 1, 2023, p. 286, doi.org/10.1186/s12903-023-02971-7.

Baumhackl, U., et al. “A Randomized, Double-Blind, Placebo-Controlled Study of Oral Hydrolytic Enzymes in Relapsing Multiple Sclerosis.” Multiple Sclerosis 11, 2005, 166-68.

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Klein, G., et al. “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.” Clinical and Experimental Rheumatology vol. 24, 2006, 25-30.

Varilla, Carolina, et al. "Bromelain, a Group of Pineapple Proteolytic Comples Enzymes (Ananas Comosus) and Their Possible Therapeutic and Clinical Effects. A Summary." Foods, vol. 10, no. 10, 2021, DOI: 10.3390/foods10102249.