Pineapple Enzyme (Bromelain)

Indications

Pain and inflammation. All types of arthritis, trauma, and surgical recovery; phlebitis and vascular trauma; autoimmune and allergic inflammation; eczema, hives, and allergic airway diseases; inflammatory bowel diseases.

Mechanism of Action

Bromelain is an enzyme found in the stems of pineapple. A very small amount is found in the fresh juice. Bromelain has numerous immune-modulating and anti-inflammatory mechanisms including effects on cytokines, platelet aggregation, and fibrin formation. Some of the anti-inflammatory effects of bromelain are attributed to proteolytic, fibrinolytic, gelatinase, and collagenase activities, all of which contribute to bromelain’s wound healing abilities.¹ Bromelain accelerates the recoveries of blood perfusion and oxygen partial pressure in wound tissue; controls the expression of tumor necrosis factor-α; and raises the expression of transforming growth factor-β,^2,3 all mechanisms that also improve allergic and systemic inflammation and help reduce pain.

Animal models of allergic airway disease have shown bromelain to significantly reduce bronchial leukocytes and eosinophils and decrease activation of CD4 and CD 8 T cells in the bronchi, but not the hilar lymph nodes or spleen, compared to control in animal models.^4,5 Bromelain also decreased proinflammatory interleukin (IL)-4, -12, and -17 as well as interferon-γ. These cytokines contribute to the broad anodyne and anti-inflammatory effects of bromelain.

Tissue culture studies obtained from biopsied tissue of ulcerative colitis patients have shown bromelain to reduce inflammatory cytokines released from colonic mucosal cells including decreases in granulocyte colony-stimulating factor, interferon-γ, and tumor necrosis factor.⁶ Oral bromelain may also decrease the production of proinflammatory prostaglandin 2 series and pain-inducing substance P, furthering anti-inflammatory and pain-relieving mechanisms.⁷

Although moderate exercise has a positive effect on the immune system and reduces upper respiratory tract infections (URIs) associated with low levels of inflammatory markers, marathon running induces an increase in inflammation and is associated with an increased occurrence of URIs. Marathon running may also traumatize muscle and promote a prothrombotic state. Studies on human marathon runners suggest that bromelain (with trypsin and rutoside) exerts anti-inflammatory and fibrinolytic effects that normalize some of inflammatory changes seen with heavy exercise, by normalizing interleukins and immunoglobulin A via anti-inflammatory effects.⁸ Human lab investigation shows bromelain to attenuate exercise-induced skeletal muscle damage owing to unaccustomed exercise.⁹ Bromelain use was associated with lower levels of cyclooxygenase 2, IL-6, and IL-12 compared with placebo when taken after intense exertion. Bromelain has also been shown to reduce fatigue and show a trend toward maintaining serum testosterone concentration acutely in endurance athletes.¹⁰

Another area of bromelain research focus has been on fibroblast activation. All soft tissue healing involves promotion of fibroblasts, recruited initially to help cells adhere to one another, and then eventually be replaced with functional cells, with the type of cell dependent on the injured tissue type. Cells that can fully recover do so, and cells that are too damaged to survive undergo apoptosis and replacement. Fibroblasts migrate to the injured area as well forming out of precursor cell types. However, excessive or inappropriate recruitment of fibroblasts leads to fibrosis in organs, loss of elasticity in blood vessels, or when in the skin, excessive scars or keloids. This also occurs with inappropriately directed autoimmune reactivity contributing to fibrosis, loss of function, and pain in arthritis and connective tissue disease. Bromelain may help control excessive fibrosis by promoting a resting state in cells encouraging cell recovery, lowering elevated IL-6 levels, and reducing apoptosis.¹¹

Bromelain is also shown to interfere with neutrophil binding sites for P-selectin (an endogenous lectin), thereby limiting the tethering of neutrophils to substrates,¹² reducing inflammation, and reducing glycation of cells in diabetic and other inflammatory states.¹³ Bromelain may affect the surface of various leukocytes, thereby affecting their activation and migration, neutrophilic chemotaxis, and adhesion of leukocytes to blood vessels,¹⁴ all of which are mechanisms that contribute to antiedema, anti-inflammatory, and antifibrotic effects. Cell surface components shown to be affected by bromelain include l-selectin.

Evidence-Based Research

Bromelain is shown to have pain-relieving effects and the ability to reduce inflammation in a variety of allergic, traumatic, postsurgical, and chronic musculoskeletal conditions including osteoarthritis,¹⁵ tendonitis,^16,17,18,19, allergic airway disease,²⁰ and ulcerative colitis.⁶ One animal model of inflammatory bowel disease showed bromelain to significantly improve clinical symptoms and histological signs using 1000 mg/kg/day for 18 weeks.²¹

Several human clinical trials have shown bromelain to improve knee pain.^22,23,24 Several randomized controlled trials (RCTs) have shown bromelain combination products to have positive outcomes on osteoarthritis pain,^25,26 although these particular studies are limited by lack of investigating a single product at a time. Other human trials on bromelain alone have shown it to be as effective as the nonsteroidal anti-inflammatory (NSAID) diclofenac in patients with osteoarthritis of the hip experiencing a high level of pain.²⁷

One RCT investigated the effects of bromelain compared with standard anti-inflammatories on postoperative swelling in patients requiring surgical intervention for setting long bone fractures. Bromelain was found to significantly speed postoperative recovery, reduce swelling, and reduce the need for additional analgesia.²⁸ Bromelain may also prevent the formation of adhesions, pathological fibrous connections between peritoneal or other tissue surfaces, resulting from incomplete repair after surgery, trauma, or acute inflammation.²⁹

Bromelain seems effective on allergic as well as traumatic inflammation. Animal studies show bromelain to reduce symptoms in models of allergic airway disease by reducing eosinophil and lymphocyte activation.³⁰ One human cohort study showed bromelain to improve symptoms and speed recovery in chronic sinusitis compared with control groups using bromelain in addition to standard therapies (antihistamines and antibiotics), or a standard-only control group.³¹ A small pilot study investigated the effects of bromelain on chronic rhinosinusitis on patients who had previously undergone sinus surgeries and found bromelain to improve before and after symptom scores after 3 months of daily use, with greater efficacy being seen for those without nasal polyps than those with polyps.³²

Bromelain may also reduce inflammation and support healing postoperatively in patients undergoing oral surgery of the molars.³³ One RCT treated patients undergoing maxillofacial surgery with either bromelain or placebo, along with an analgesic if requested. Patients were evaluated for pain, edema, and erythema 3 hours, 48 hours, and 7 days after surgery, and the bromelain group displayed lower scores in all areas as well as less analgesic use compared with the control. There were no apparent side effects, and the only adverse event occurred in the control group.³⁴ A similar study dosed patients undergoing oral surgery for impacted molars with either 250 mg of bromelain, 25 mg of diclofenac sodium, or placebo and evaluated for effects on pain, with all groups taking four doses a day. Patients were evaluated for pain, swelling, and trismus at days 1, 2, and 7 postoperatively, and the researchers reported both the bromelain and the diclofenac to reduce pain compared with placebo,³⁵ with diclofenac showing a significant reduction and bromelain an insignificant reduction in pain compared with placebo. A similar study showed bromelain to reduce edema compared with control.³⁶ Both treatment groups showed an insignificant reduction in trismus compared with placebo. Another similar study dosed bromelain at 150 mg/day for 3 days and 100 mg/day for three additional days, and compared it with placebo on reducing pain after oral surgery. They reported a trend toward better pain relief with bromelain compared with placebo.³⁷ It should be noted that many clinicians use five or more times this dose for postsurgical pain.

Safety in Pregnancy and Breastfeeding

Regarding pregnancy, there have been no reports of adverse effects on the mother or developing fetus, or studies showing that bromelain can be harmful. Among the traditional uses of pineapple leaf extracts are reported emmenagogue and abortifacient effects,¹ although this is not reported for the juice of pineapple itself.

Bromelain is considered safe during lactation and, in fact, may improve the symptoms of breast engorgement in nursing women.³⁸

General Safety

Clinical trials have shown bromelain to have an excellent safety profile.^{15,27,28,31,34}

There is one anecdotal report of a 10-year-old male patient, with a known pineapple allergy, experiencing a self-limiting mild allergic reaction,³¹ but no other adverse events have been reported.³⁹

Pineapple leaf extracts have not induced any toxicity in rats after oral administration of acute and subacute doses.¹

Because of the effects on coagulability, it is logical to use bromelain with caution in patients on warfarin or other anticoagulants.⁴⁰ However, although bromelain is increasingly being reported to reduce excessive or inappropriate clotting and platelet activation, the use of bromelain does not seem to interfere with appropriate clotting and is reportedly safe for surgical patients to use in the perioperative period. One human investigation reported bromelain to be well tolerated by patients undergoing knee surgery and did not increase the risk of hemorrhage even when used concomitantly with heparin.⁴¹

Bromelain may enhance the absorption of some drugs, particularly of antibiotics,^39,42 and has been shown to be a valuable adjuvant to antibiotics in childhood sepsis.⁴³

Dosage

This enzyme is generally considered safe at dosages of 1000–2000 mg/day.

Because different pineapples grown in different conditions may have different enzyme strengths and profiles, and because some manufacturers are developing technology to obtain bromelain from pineapple rind and waste material, bromelain is often quantified by its strength, rather than purely by milligram weights. In Europe, the Fédération Internationale Pharmaceutique (FIP) is a quantification method used. The German Commission E has recommended 80–320 mg (200–800 FIP units) be taken two to three times per day. In the United States, milk-clotting units (MCUs) or gelatin-dissolving units (GDUs) are sometimes used, indicating quantification based on proteolytic effects on milk proteins. Most commercial preparations contain 500 mg each and may also include a MCU or GDU figure. For example, a common product may provide bromelain standardized to 2000 GDU/MCU in 500-mg tablets. A Rorer unit is another measure of activity rather than weight. Some of the early research on bromelain used tablets quantified to 2500 Rorer units per milligram and dose 120–240 mg at a time. Other companies use papain units (PUs). One GDU is equivalent to 15,000 Food Chemical Codex (FCC) PU.

When the intended use of bromelain is as a digestive enzyme, 500–1000 g is taken with each meal. To treat pain and inflammation, bromelain is taken between meals or 30 min before meals and before bed to ensure that the proteolytic enzymes are absorbed into the bloodstream for the best systemic effect, rather than be used in the stomach and intestines for digestive effects.

For chronic pain and inflammation, 500–1000 mg is taken two to three times per day between meals and before bed.

For acute postsurgical pain, or to help dissolve a thrombus, 2500 mg may be taken every few hours for several days, reducing the dose as symptoms abate.

The minimum concentration of bromelain that results in modified coagulation⁴⁴ or exerts a thrombolytic effect is 0.4 U/mL.

Traditional Uses

Bromelain is a mixture of cysteine, sulfur-containing proteolytic enzymes that is extracted from the stems, rinds, core, and fruit of the pineapple (Ananas comosus) plant. Pineapple juice and fruit are long-standing folkloric remedies for treating poor digestion and digestive upset, supporting weight loss, and treating diabetes, inflammation, and pain. Eating fresh pineapple or regular consumption of fresh pineapple juice is also a traditional remedy for treating intestinal parasites and worms, particularly pinworms. Unripe pineapple and papayas have been traditionally used topically on skin wounds and for cosmetic facials to soften the skin and loosen old, devitalized cells. Bromelain may also have mucolytic effects and has been included in many traditional formulas for cough, bronchitis, allergic rhinitis, and lung congestion. The list of painful and inflammatory conditions that pineapple extracts have been used to treat is extensive and includes strains; sprains; phlebitis; angina; menstrual cramps; connective tissue disease; digestive pain and cramping; infectious diarrhea; neuralgia; hemorrhoids; and many other common inflammatory, vascular, infectious, and autoimmune disorders. Bromelain was traditionally combined with turmeric in the ancient healing traditions of India. Clinical trials that combine bromelain with turmeric, which will not be detailed here, show the combination to be an effective and safe anti-inflammatory alternative to NSAIDs in patients suffering from degenerative joint diseases.⁴⁵

The traditional use of bromelain for pain has evolved into bromelain being approved to treat traumatic and surgical injuries of the sinus and nasal passages in Germany, to treat traumatic musculoskeletal pain, to reduce bruising and thrombi risk post-surgically, and to improve digestion when taken with food as a digestive enzyme. Current research is also investigating bromelain to whiten the teeth as a result of its proteolytic enzyme effects⁴⁶ and as an alternative to pesticides in some crops.⁴⁷ Bromelain is also being investigated for its anticancer effects on breast cancer⁴⁸ and gastrointestinal cancer cell lines⁴⁹ and for its ability to alleviate many digestive symptoms of chemotherapy side effects.⁵⁰ Many naturopathic physicians use bromelain in topical treatments for cervical dysplasia and cancer.⁵¹