Papaya Enzyme [Discontinued] by Nature's Plus

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral papain for cancer, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Dental caries. It is unclear if topical papain gel is beneficial for reducing procedure time or pain in children having caries removed by a dentist. Details: A small clinical study in children 3-9 years of age with dental caries shows that application of a specific papain gel (Brix3000, Brix Medical Science) 3000 U/mg during atraumatic restorative treatment (ART) by a dentist actually increases the time required to remove caries tissue, with no effect on pain, when compared with ART alone (107434).
• Diabetic foot ulcers. Although there has been interest in using topical papain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Exercise-induced muscle soreness. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination enzyme tablet containing papain 50 mg, trypsin 75 mg, bromelain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, improves recovery of contractile muscle function and decreases muscle soreness when compared with placebo (67838). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Herpes zoster (shingles). Although there has been interest in using oral papain for shingles, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Insect bite. It is unclear if topical papain is beneficial in individuals with fire ant stings. Details: A small clinical study in individuals with fire ant stings shows that applying gauze soaked with a specific papain-containing meat tenderizer (Adolph's meat tenderizer) to the sting for 20 minutes does not reduce pain or itching when compared with placebo (67845).
• Intestinal parasite infection. Although there has been interest in using oral papain for intestinal parasite infections, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Jellyfish stings. It is unclear if topical papain is beneficial in individuals with jellyfish stings. Details: A small clinical study in individuals with jellyfish stings shows that submerging affected skin into a solution with a papain-containing meat tenderizer (Adolph's meat tenderizer), starting two minutes after a jellyfish sting and continuing for at least 20 minutes, is less effective than hot water alone in decreasing pain caused by the jellyfish sting (67835).
• Pressure ulcers. Although there has been interest in using topical papain for pressure ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Radiation dermatitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not attenuate skin deterioration when compared with placebo (67834). However, another small, open-label clinical study in patients with uterine carcinoma shows that taking three capsules of the same combination product four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces skin reactions when compared with control (67831). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Radiation-induced cystitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with uterine carcinoma receiving radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces genitourinary symptoms when compared with control (67831).
• Radiation-induced nausea and vomiting. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma), containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not reduce radiation-related nausea or vomiting when compared with placebo (67834).
• Tonsillopharyngitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small clinical studies in patients with pharyngitis and/or tonsillitis shows that use of throat lozenges containing papain 2 mg, lysozyme 5 mg, and bacitracin 200 IU daily for 4 days reduces pain and inflammation of the throat and lymph nodes when compared with placebo or disinfectant alone (964,968). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Traumatic oral ulcers. Although there has been interest in using topical papain for traumatic oral ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Venous leg ulcers. Although there has been interest in using topical papain for venous leg ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Wound healing. Topical papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with purulent wounds shows that applying papain 1% solution plus dimethylsulfoxide (DMSO) followed by phonophoresis, a process by which ultrasound is used to increase topical drug delivery, improves wound healing when compared to baseline (67843). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these findings are due to papain, DMSO, or the combination. More evidence is needed to rate papain for these uses.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Papain has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short-term. Papain has been used in combination with other proteolytic enzymes at a dose of up to 1200 mg daily for up to 9 weeks (964,965,968,67831,67834). ...when used topically as a diluted solution in appropriate doses for up to 20 minutes (67835,67843,67845).

POSSIBLY UNSAFE ...when used orally in large amounts. In excessive doses, papain can cause significant side effects including esophageal perforation (6). ...when raw papain is used topically. Raw papain or papaya latex is a severe irritant and vesicant (6).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is some concern that crude papain is teratogenic and embryotoxic (6).

LACTATION:
Insufficient reliable information available; avoid using.

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WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, papain might increase the effects and side effects of warfarin.  Details In one case report, a patient previously stable on warfarin was found to have an international normalization ratio (INR) of 7.4, which was attributed to ingestion of a supplement containing papain from papaya extract (613).

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General ...Orally and topically, papain seems to be well tolerated when used short-term at appropriate doses. Taking high oral doses may be unsafe.
Most Common Adverse Effects:
Orally: Allergic reactions in sensitive individuals.
Topically: Urticaria and pruritus in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Esophageal perforation and severe gastritis with high doses.

Dermatologic ...Topically, papain can cause itching (966). Urticarial reactions and itching have been reported in people occupationally exposed to papain, with papain confirmed as the causative agent by skin prick tests or radioallergosorbent tests (RAST) (95533,95534). In a randomized controlled trial assessing the effects of papain, trypsin, and chymotrypsin on adverse effects from radiotherapy, moderate to severe epitheliolysis was more frequent in the enzyme-treated group than the placebo group (67834). It is unclear if this adverse effect is due to papain, other enzymes, or the combination.

Gastrointestinal ...Orally, papain has been associated with diarrhea. In a randomized controlled trial assessing the effects of papain, trypsin, and chymotrypsin on adverse effects from radiotherapy, moderate to severe diarrhea was more frequent in the enzyme-treated group than the placebo group (67834). However, it is unclear if this adverse effect is due to papain, other enzymes, or the combination. Papain has also been associated with gastric ulcers and esophageal perforation in case reports of phytobezoars treated with papain (67848). In general, large amounts of papain can cause esophageal perforation (6). Ingestion of papaya latex (raw papain) can cause severe gastritis.

Genitourinary ...Orally, papain has been associated with hypernatremia in case reports of phytobezoars treated with papain (67848).

Immunologic ...Orally, papain may cause allergic reactions, including itchy watery eyes, runny nose, sneezing, abdominal cramps, sweating, and diarrhea, in individuals sensitive to papain (6,967). Occupational exposure to airborne papain dust may also cause respiratory allergic reactions (95532,95533,95534,95535,95536).

Pulmonary/Respiratory ...Occupational exposure to airborne papain dust may cause respiratory allergic reactions. Symptoms include rhinitis, sneezing, conjunctivitis, dyspnea, wheezing, cough, and asthma. In most cases, papain is confirmed as the causative agent by skin prick tests, radioallergosorbent tests (RAST), or detection of papain-specific immunoglobulin E (IgE) and IgG (95532,95533,95534,95535,95536).

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