Bromelain is a concentrated mixture of proteolytic enzymes derived from the pineapple plant Ananas comosus. Commercial bromelain is not a chemically homogeneous substance because if the enzyme is highly purified it loses its stability and most of its physiological activity. The main ingredient is a proteolytic enzyme (a glycoprotein), but it also contains small amounts of an acid phosphatase, a peroxidase, several protease inhibitors, and organically bound calcium (Hatano et al 1996; Taussig 1980).
Pineapple stem cysteine proteinases include bromelain, comosain, and ananain. Bromelain has a structural similarity to comosain but not ananain (Napper et al 1994).
The crude extract of bromelain is a combination product containing enzymes, proteins, carbohydrates, and seven protease inhibitors that are active against bromelain, papain, and ficin (Cooreman et al 1976).
Ananas comosus, bromelins
Actions & Pharmacology
Bromelain is a proteolytic enzyme that has anti-inflammatory, antitumor, and digestive properties.
Bromelain selectivity inhibits the biosynthesis of pro-inflammatory prostaglandins (Taussig 1980). Bromelain lowers kininogen and bradykinin in serum and tissues and may alter prostaglandin synthesis (Lotz-Winter 1990). The action of bromelain can be compared to endogenous protease plasmin because it acts on fibrinogen to stimulate the biosynthesis of anti-inflammatory prostaglandins. Bromelain inhibits prostaglandin E(2), which does not block the synthesis of all pro-inflammatory and anti-inflammatory prostaglandins as in the case of aspirin, but instead results in a partial inhibition of thromboxane synthetase. This partial and dose-dependent inhibition decreases the total amount of pro-inflammatory prostaglandins and improves the ratio of anti-inflammatory prostaglandins (Taussig 1980).
In vitro studies with bromelain indicate specific retardation of Lewis lung carcinoma, YC-8 lymphoma, and MCA-1 ascitic tumor cells, as well as a human gastric carcinoma cell line (KATO III). Fractionation of bromelain by ultra-filtration produces a high molecular weight fraction (greater than 30,000) and a low molecular weight fraction (5,000). Only the high molecular weight fraction contains proteases that retard Lewis lung tumor growth (Batkin et al 1988). Bromelain also induces cytokine production in peripheral blood mononuclear cells in vitro. A polyenzymatic preparation that included bromelain had a synergistically increased immunomodulatory effect when used in combination with interferon-gamma, with respect to tumor necrosis factor production (Desser et al 1993).
Bromelain effectively degrades third-degree burn eschar fragments at 37º to 38º Celsius when oxygen is excluded to avoid enzyme inactivation. Investigators propose that bromelain activates collagenase in the living tissue to hydrolyze the denatured collagen at the interface of the eschar and the live tissue (Felton 1980). The debridement activity of bromelain appears to be enhanced by mercaptans such as N-acetylcysteine, penicillamine, and cysteine (Levenson et al 1981).
When administered orally to piglets in vivo, bromelain inhibited the attachment of enterotoxigenic Escherichia coli to the small intestine. Therefore, bromelain therapy may be useful for the prevention of enterotoxigenic E. coli-induced diarrhea (Mynott et al 1996). When bromelain was compared to gastric and intestinal proteases in digestive functions, it had equivalent casein-splitting activity at pH 3.3 as gastric proteases and at pH 6.0 as the intestinal proteases with almost the same rate, suggesting that bromelain can take over full digestive functions in the stomach as well as in the intestine (Hennrich et al 1965).
Fibrinolytic Activity/Platelet Aggregation
Numerous clinical studies have shown that bromelain possesses fibrinolytic activity, apparently via an indirect mechanism (substituting for the inhibited plasmin), which increases both anti-inflammatory and serum fibrinolytic activity. The physiological activity of bromelain resides in its protease fraction, as measured by inhibition of adenosine diphosphate-stimulated human platelet aggregation (Taussig 1980).
In contrast, bromelain does not inhibit aggregation of washed platelets, indicating that it might act on fibrinogen to yield peptides that affect the arachidonate cascade. It has been proposed that the plasmin cleaves Hageman factor, leading to a strong release of kallikrein but a weak release of thrombin, which seems to be sufficient enough to stimulate the release of the prostaglandins that increase cyclic-adenosine monophosphate. The mechanism of action in this regard needs further investigation for a better assessment (Taussig 1980).
Clinical studies in humans have demonstrated analgesic and anti-inflammatory effects such as reduced swelling, pain, and tenderness (Kelly 1996). The reduction of edema and bruising was more rapid in bromelain-treated patients than those taking placebo. In rats, the anti-inflammatory effects of bromelain are comparable to those of prednisolone (Kelly 1996). Bromelain-treated patients showed a clear reduction in all parameters at all time points as compared with baseline in an open, uncontrolled study of 59 patients with blunt injuries to the musculoskeletal system who were treated with orally administered enteric-coated bromelain. High-dose Bromelain-POS® (exact dose not specified) was administered according to the nature and severity of the lesion between 1 and 3 weeks. On the day of injury and on 5 subsequent days, the patients were evaluated for swelling, pain at rest, pain during movement, and tenderness. The preparation was well-tolerated and patient compliance was high (Masson 1995). It should be noted that some studies were poorly designed and yielded inconclusive results. More controlled studies are necessary.
Enhanced Antibiotic Absorption
Antibiotic absorption differs widely among individuals but may be improved by the addition of bromelain. Bromelain (as part of a multiple-enzyme treatment product) was a significant adjuvant to antibiotic therapy in a randomized, double-blind, placebo-controlled study. Fifty-six patients with adnexitis were treated for 28 days with antibiotic therapy (doxycycline) plus placebo, or the same antibiotic therapy plus a multiple enzyme preparation (Wobenzyme®) containing bromelain 45 mg, pancreatin 100 mg, papain 60 mg, lipase 10 mg, amylase 10 mg, trypsin 24 mg, chymotrypsin 1 mg, and rutin 50 mg. Significant improvement in individual scores and the adnexitis score was seen in both groups but there was a significant difference between the two groups. By the end of the study, the advantage of enzymes combined with antibiotic therapy compared to placebo was highly significant (p=7.45x10-10). The effect due to just bromelain was not established. Measures used to evaluate the effect were body temperature, white blood cell count, ESR, tenderness scores, and vaginal discharge (Dittmar et al 1992).
Enzyme treatment improved symptoms of fibrocystic mastopathy in a double-blind, placebo-controlled, randomized study using the enzyme preparation Wobenzyme®. The regimen was 10 tablets a day for 6 weeks. Each tablet contained pancreatin 100 mg, papain 60 mg, bromelain 45 mg, lipase 10 mg, amylase 10 mg, trypsin 24 mg, chymotrypsin 1 mg, and rutin 50 mg. Enzyme treatment of 96 women with fibrocystic mastopathy resulted in reduced size of cysts (p=0.003), lower score of complaints (p=0.001), and less subjective disturbance by symptoms (p=0.001). The number of cysts was not altered (p=0.695). The profiles of the active-treatment and control groups were similar (Dittmar et al 1993). The effect of bromelain by itself was not evaluated.
The role of bromelain in the treatment of osteoarthritis remains inconclusive. A recently published randomized, double-blind, placebo-controlled trial studied the effectiveness of bromelain in treating osteoarthritis (OA) of the knee. Forty-seven subjects with a confirmed diagnosis of knee OA (moderate to severe in nature) were enlisted; 31 completed the trial. Of these, 14 received bromelain 800 mg/day, and the remaining 17 received placebo. After 12 weeks of treatment, no statistically significant differences between groups were noted for the primary outcome measure (the change in total WOMAC score from baseline to end of treatment) (Brien et al 2006).
An earlier review by the same primary author concluded that bromelain may have potential for the treatment of OA of the knee, but noted that further studies were warranted. Out of the 10 studies identified in the review that assessed the efficacy of bromelain in OA of the knee, several were suspected to have been underpowered, and the findings inconclusive. Additionally, in many of the studies, the treatment period did not parallel that used in clinical practice, being of much shorter duration. In one study, there was no control group; in another, no formal medical diagnosis of knee pain for those enrolled. However, two comparative studies cited in the review showed reduced symptoms of pain (Brien et al 2004).
Indications & Usage
Approved by Commission E
- Wounds and burns
Bromelain may be of therapeutic value in modulating inflammation, edema, tumor growth, blood coagulation, and debridement of third-degree burns. It could possibly enhance absorption of some drugs, including antibiotics.
Bromelain is contraindicated in patients who have severe liver or kidney impairment or who need dialysis. The supplement should also be avoided by patients who have a coagulation disorder such as hemophilia or who have demonstrated hypersensitivity to bromelain, pineapple, or the inactive ingredients of enzyme preparations.
Precautions & Adverse Reactions
Bromelain is capable of inducing IgE-mediated respiratory and gastrointestinal allergic reactions. Human subjects can exhibit a cross-reaction between the two plant proteases bromelain and papain (Baur et al 1979). Hypersensitivity reactions have been reported, including skin rashes and asthma. There is some evidence for sensitization due to bromelain inhalation that resulted in occupationally acquired asthma. This has not been reported after ingestion (Gailhofer et al 1988).
Bromelain may increase heart rate at higher doses. It should be used cautiously (doses less than 500 mg per day) in patients with heart palpitations or tachycardia (Kelly 1996).
Anticoagulants, Low-Molecular-Weight Heparins, and Thrombolytic Agents
Concurrent use of bromelain and these agents may result in an increased risk of bleeding. Clinical Management: Caution is advised if bromelain is taken with these medications. Monitor the patients for signs and symptoms of bleeding.
The LD50 intravenously was 30 to 35 mg/kg (mice) and 20 mg/kg (rats). The LD50 after intraperitoneal administration to mice was 36.7 mg/kg and in rats was 85.2 mg/kg (Cooreman et alb 1976).
Mode of Administration
Capsules, cream, suspension, tablets
Available preparations of bromelain tablets vary widely in their concentrations, and caution must be exercised in determining dosage regimens. For best results, the total daily dosage should be divided into 4 doses and taken an hour before or after food (Kelly 1996).
General use – 500 to 2,000 mg daily.
Carpal tunnel syndrome – 1,000 mg (with a potency of at least 3,000 microunits/gram) given 3 times a day, between meals (Miller et al 1997).
Inflammation – 500 to 2,000 mg per day (Kelly 1996). A European manufacturer recommends 450 to 1,500 Federation Internationale Pharmaceutique (FIP) units divided into 3 daily doses and administered over 8 to 10 days (Fachinfo: Traumanase/forte 1997).
Pediatric dosage – 150 to 300 FIP units daily, divided into 3 doses.
Store at room temperature, away from heat, moisture, and direct light. The shelf-life of bromelain is 5 years (Fachinfo: Traumanase/forte 1997).