Proteolytic Enzymes for Chronic Pain Conditions
Proteolytic Enzymes for Chronic Pain Conditions
By Steven Bratman, MD
Dietary supplements containing proteolytic enzymes as the presumed primary active ingredients have become popular in recent years. The two proprietary proteolytic enzyme mixtures most widely used in clinical trials (Wobenzyme and Phlogenzym) are widely available in the United States.
Wobenzyme contains 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). The usual dose is 5-7 tablets three or four times daily; even the lower dose involves so many capsules that compliance is reportedly low.
Phlogenzym contains bromelain (90 mg), trypsin (48 mg), and rutoside (100 mg). The usual dose is two tablets three times daily. Numerous other products that are available on the market list similar ingredients on the label. However, due to the lack of regulation of dietary supplements, as well as the fact that the constituent enzymes themselves are available in various potencies, equivalence among products cannot be assumed.
These enzyme products are advertised in the United States primarily for treating sports injuries, a potential use that has been tested in numerous studies (references available on request, contact information on page 26). In Europe during the 1960s and 1970s, proteolytic enzymes were widely used and studied for reducing post-surgical inflammation and pain (references available on request). Proteolytic enzymes also have been tested for the treatment of acute herpes zoster.1
Recently, studies have begun to evaluate the use of proteolytic enzyme combinations for the treatment of chronic musculoskeletal pain conditions.
Effects in Chronic Pain
Five double-blind trials of proteolytic enzymes for the treatment of chronic pain were identified. Only one of these was placebo-controlled; the other four compared the supplement with diclofenac. All trials used either Wobenzyme or Phlogenzym.
Cervical syndrome. A double-blind placebo-controlled trial tested Wobenzyme (five tablets tid) in 30 individuals, ages 19-80, with "verified cervical syndrome" and signs of inflammation.2 Cervical syndrome, a term more commonly used in Europe, was defined as chronic pain, of various etiologies, in the region of the neck and back of the head and often including the arm and shoulder. Chronic muscle tension is said to lead to exacerbation and maintenance of pain. The primary outcome measure was subjective pain level measured by a modified visual analog scale collected at six-hour intervals. Participant characteristics were similar between groups. Analgesics were permitted, and all participants received routine adjuvant therapy (not described). Three subjects (two from the treated group, one from placebo) dropped out.
Using an intention-to-treat analysis, the Mantel-Haenszel test found that treatment was significantly superior to placebo in the time course of subjective pain (P < 0.05) When assessed clinically, however, the benefits were slight.
Secondary outcome measures included changes in inflammation-related variables. Erythrocyte sedimentation rates increased over the course of the study in the placebo group, but not in the Wobenzyme group; the difference was significant (P < 0.05). Mean leukocyte counts and mean percentage of lymphocytes increased in the placebo group (P < 0.01), but not in the Wobenzyme group. The report does not state whether the inter-group difference was statistically significant.
Other measured variables were described briefly, without statistical analysis. Physician assessment was described as compatible with self-assessment scores. Both groups experienced decreased pain measured by "palpometer" (possibly a dolorimeter), slightly decreased gamma-GT and uric acid values, and no changes in creatinine or serum glucose. One subject in the Wobenzyme group complained of tiredness and malodorous bowel movements.
Osteoarthritis of the knee. A four-week, double-blind trial (using a double-dummy design) compared Wobenzyme (seven tablets qid, a very high dose) to diclofenac (50 mg bid) in 80 individuals (68 completed) with osteoarthritis of the knee who had not taken analgesic or anti-inflammatory therapy during the preceding two months.3 All subjects had X-ray confirmed osteoarthritis accompanied by clinical signs. Subjects were comparable at baseline with respect to age, sex, and disease severity. The primary outcome measure was a rating scale incorporating measures of knee joint mobility (measured by the neutral-zero method); edema (maximum circumference of upper edge of the patella); and subjective pain subdivided into getting up in the morning, at rest, during movement, during weight bearing, at night, and with pressure (rated on a scale of 1-5). No physical therapy modalities were used during the trial.
It is stated that both groups improved from baseline (P < 0.05) and that the treatments were equivalent (statistical test not stated).
Fourteen patients in the Wobenzyme group and 11 in the diclofenac group reported side effects, primarily gastrointestinal; six in the Wobenzyme group and three in the diclofenac group discontinued due to side effects. The rate of side effects was not significantly different between groups.
Another double-blind, three-week trial, reported only in abstract form, compared Phlogenzym to diclofenac.1 Seventy-three patients with osteoarthritis of the knee received either Phlogenzym two tablets tid or diclofenac 50 mg tid. Pain levels were measured using a visual analog scale; in addition, the Lequesne Index was measured. Mean duration of symptoms was 4.94 years in the enzyme group and 4.65 years in the diclofenac group. At three weeks, pain symptom scores improved in both groups, and were statistically equivalent according to the Wilcoxon Mann Whitney Test. Results of the Lequesne Index were not stated in the abstract. One patient in the Phlogenzym group reported moderate diarrhea; in the diclofenac group, one patient reported moderate nausea and another a duodenal ulcer.
Periarthritis of the shoulder. A three-week, double-blind study, presented only in abstract form, compared Phlogenzym (two capsules tid) to diclofenac (50 mg bid) in 40 individuals (ages 38-60) with periarthritis of the shoulder.1 A double-dummy design was used. The primary outcome measure was total pain score based on resting pain, pain during movement, pain on pressure, and night-time pain.
After three weeks of therapy, the level of pain reduction in the two groups was statistically equivalent according to the Wilcoxon Mann Whitney Test.
Back pain. Another three-week, double-blind study, presented in abstract form, compared Phlogenzym (two capsules tid) to diclofenac (50 mg bid) in a double-dummy design in 120 individuals with various painful syndromes of the spine.1 At the end of the trial, total pain scores were statistically equivalent according to the Wilcoxon Mann Whitney Test. Side effects seen in the Phlogenzym group included two cases of stomach pain and one case of mild diarrhea. In the diclofenac group, there was one instance of "slight leukopenia," one case of moderate stomach pain, and one case of severe stomach pain.
Mechanism of Action
Animal and human trials suggest that the proteolytic enzyme bromelain is absorbed systemically4,5 and produces anti-inflammatory, anti-edema, analgesic, immunomodulatory, and fibrinolytic effects.6
The mechanism of action of proteolytic enzymes is not known. Studies of the proteolytic enzyme bromelain suggest effects on eicosanoid pathways, but the evidence remains scant.7-11
In clinical trials, use of oral proteolytic enzyme combinations have been associated with relatively mild side effects, consisting primarily of gastrointestinal distress and allergic exanthema. However, when Wobenzyme is taken at its highest dose, the rate of these side effects can be high; in one study, 35% of subjects reported side effects.3
Bromelain is the best-studied proteolytic enzyme. Acute and chronic studies in rats and dogs have failed to find evidence of toxicity or carcinogenicity.8,9 Allergic reactions have been reported;12-14 cross-allergenicity with bromelain may occur with wheat flour, rye flour, kiwi fruit, perennial ryegrass, grass pollen, and birch pollen.12,15-17
Maximum safe doses in severe renal and kidney disease are not known.
There are limited data available on digestive enzymes and pregnancy. The Collaborative Perinatal Project did not find an association between digestive enzymes as a group, or pancreatin alone, and an increase in adverse pregnancy outcome.18 Papain was not separately considered. Treatment of pregnant rats with trypsin and chymotrypsin reportedly caused malformations in the offspring.19 Administration of troxerutin, a hydroxyethyl rutoside, to pregnant rats did not produce an increase in anomalies in the offspring.20
Pancreatin may interfere with folate absorption.21 Papain has been reported to potentiate anticoagulant and antiplatelet agents.22
Bromelain inhibits platelet aggregation,7-9,11 but in a human trial (40 mg qid for one week), it did not alter hemostasis parameters.23 Nonetheless, interactions with anticoagulant or antiplatelet agents are possible. Bromelain may increase absorption and tissue levels of various antibiotics, including amoxicillin, tetracycline, chloramphenicol, and penicillin.24-26 In an animal study, bromelain was found to increase pentobarbital sleeping time.8
Preliminary evidence suggests that oral use of proteolytic enzyme combinations might offer benefits equivalent to those of non-steroidal anti-inflammatory drugs (NSAIDs) in various forms of chronic pain. Presumably, they offer a better long-term side effect profile, since animal studies have not found evidence of chronic toxicity. However, the rate of short-term side-effects does not appear to be superior with proteolytic enzymes as compared to NSAIDs. v
Dr. Bratman is the former medical director of TNP.com.
1. Klein G, Kullich W. Reducing pain by oral enzyme therapy in rheumatic diseases [translated from German]. Wien Med Wochenschr 1999;149:577-580.
2. Tilscher H, et al. Results of a double-blind, randomized comparative study of Wobenzym-placebo in patients with cervical syndrome [translated from German]. Wien Med Wochenschr 1996;146:91-95.
3. Singer F, Oberleitner H. Drug therapy of activated arthrosis. On the effectiveness of an enzyme mixture versus Diclofenac [translated from German]. Wien Med Wochenschr 1996;146:55-58.
4. Castell JV, et al. Intestinal absorption of undegraded proteins in men: Presence of bromelain in plasma after oral intake. Am J Physiol 1997;273:G139-G146.
5. Smyth RD, et al. Studies establishing the absorption of bromelains (proteolytic enzymes) from the gastrointestinal tract. Exp Med Surg 1964;22:46-59.
6. Lotz-Winter H. On the pharmacology of bromelain: An update with special regard to animal studies on dose-dependent effects. Planta Med 1990;56:249-253.
7. Heinicke RM, et al. Effect of bromelain (Ananase) on human platelet aggregation. Experientia 1972;28: 844-845.
8. Moss JN, et al. Bromelains. The pharmacology of the enzymes. Arch Int Pharmacodyn Ther 1963;145: 166-188.
9. Taussig SJ, et al. Bromelain: A proteolytic enzyme and its clinical application. A review. Hiroshima J Med Sci 1975;24:185-193.
10. Vellini M, et al. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung 1986;36:110-112.
11. Metzig C, et al. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo 1999;13:7-12.
12. Baur X. Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain. Clin Allergy 1979;9:451-457.
13. Baur X, Fruhmann G. Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clin Allergy 1979;9:443-450.
14. Gailhofer G, et al. Asthma caused by bromelain: An occupational allergy. Clin Allergy 1988;18:445-450.
15. Gall H, et al. Kiwi fruit allergy: A new birch pollen-associated food allergy. J Allergy Clin Immunol 1994;94:70-76.
16. Pike RN, et al. Immunological cross-reactivity of the major allergen from perennial ryegrass (Lolium perenne), Lop p I, and the cysteine proteinase, bromelain. Int Arch Allergy Immunol 1997;112:412-414.
17. Tanabe S, et al. Cross-reactivity between bromelain and soluble fraction from wheat flour [in Japanese; English abstract]. Arerugi 1997;46:1170-1173.
18. Heinonen OP, et al. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group; 1977.
19. Lauro V, et al. Experimental findings on the effects of substances with an enzymatic action (trypsin and chymotrypsin) on the reproductive function of the rat [in Italian]. Arch Obstet Ginecol 1966;71:179-193.
20. Preuss-Ueberschar C, et al. Reproduction toxicologic studies on rats following oral administration of benzopyrene preparations [in German]. Arzneimittelforschung 1984;34:1305-1313.
21. Russell RM, et al. Impairment of folic acid absorption by oral pancreatic extracts. Dig Dis Sci 1980;25: 369-373.
22. Shaw D, et al. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Saf 1997;17:342-356.
23. Cirelli MG, Smyth RD. Effects of bromelain anti-edema therapy on coagulation, bleeding, and prothrombin times. J New Drugs 1963;3:37-39.
24. Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx, and ovary. Drugs Exp Clin Res 1978;4:45-48.
25. Mori S, et al. The clinical effect of proteolytic enzyme containing bromelain and trypsin on urinary tract infection evaluated by double blind method. Acta Obstet Gynaecol Jpn 1972;19:147-153.
26. Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drugs Exp Clin Res 1978;4:39-44.Bratman S. Proteolytic enzymes for chronic pain conditions. Altern Ther Women's Health 2002;4:28-30.
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