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Previous Volume 329:1158-1163 October 14, 1993 Number 16 Next

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ABSTRACT

Background Benzopyrones can reduce the volume of high-protein edema fluid by stimulating proteolysis. These compounds provide a method for removing excess protein and its consequent edema and reduce its clinical sequelae, such as chronic inflammation and secondary infections.

Methods We conducted a randomized, double-blind, placebo-controlled, crossover trial of 5,6-benzo-[alpha]-pyrone in 31 patients with postmastectomy lymphedema of the arm and 21 patients with lymphedema of the leg of various causes. This agent is also known as 56 BaP, 1,2-benzopyrone, and coumarin, although it has no anticoagulant activity. The patients received 400 mg of the active drug or placebo, each for six months.

Results During the placebo period, lymphedema often worsened, especially in the arms. Measurements of limb volume showed that the active drug reduced the mean amount of edema fluid in the arms from 46 percent above normal to 26 percent above normal (P<0.001) and the amount in the legs from 25 percent to 17 percent above normal (P<0.001). The circumference of the arms was reduced from 17 percent to 13 percent above normal, and the circumference of the legs from 11 percent to 7 percent above normal (P<0.001). The softness of the limb tissue was increased (P<0.001), and elevated skin temperatures were reduced (P<0.001). There were fewer attacks of secondary acute inflammation (P = 0.01). Bursting pains and feelings of hardness were decreased, as were feelings of tightness, tension, swelling, and heaviness; limb mobility also improved. The active drug was preferred to the placebo by 93 percent of the patients (P<0.001). Side effects -- mild nausea or diarrhea -- occurred in seven patients taking the active drug. None withdrew from the trial, and the side effects disappeared after the first month of therapy.

Conclusions 5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.

Benzopyrones reduce lymphedema in both humans and animals^{1,8,9,10,11,12,13,14,15,16}. These drugs have very low toxicity and are effective when given orally, and some are inexpensive¹. They reduce lymphedema by increasing proteolysis by tissue macrophages¹. Thus, they serve as an alternative pathway for the removal of the excess protein. Once excess protein is eliminated, the edema fluid that it causes is no longer retained. Removal of the excess protein also reduces the medium in which secondary bacterial and fungal infections may incubate^{1,9,10,12,14,16}.

Chronic high-protein edema, such as lymphedema, also gives rise to a chronic inflammatory state and consequent fibrosis^1,8. If the excess protein is removed by benzopyrones, the chronic inflammatory condition disappears and the fibrosis diminishes^1,8.

The benzopyrone 5,6-benzo-[alpha]-pyrone (also known as 56 BaP, coumarin, or 1,2-benzopyrone; it is not yet available for general use in North America) was effective in the treatment of postmastectomy lymphedema in a large open, controlled trial,⁹ a small double-blind, crossover trial,¹⁰ and other trials^11,12. It even reduced lymphedema due to filariasis and elephantiasis^13,14. Other benzopyrones have also been shown to reduce lymphedema^1,15,16. It is important to note that although "coumarin" is the correct common chemical name of 5,6-benzo-[alpha]-pyrone, this agent is not an anticoagulant like its derivatives the bis-4-hydroxycoumarins¹. In the present double-blind, crossover trial, we tested the efficacy of 5,6-benzo-[alpha]-pyrone in several forms of chronic lymphedemas.

Methods

We studied 31 patients with unilateral postmastectomy lymphedema (lymphedema affecting the arms) and 21 patients with unilateral leg lymphedema of various causes. The lymphedema was a primary condition in 15 patients and developed after surgery or in a setting of extensive inflammation in the other 37; it was diagnosed by history and physical examination, with computed tomography and venography performed if there was any doubt about the diagnosis. Patients were excluded if there was any suspicion of metastases as a result of clinical examination, chest radiography, or radionuclide bone scanning. All had moderately severe to severe grade 2 lymphedema, without elephantiasis (according to the classification of the International Society for Lymphology³) -- i.e., the edema was not spontaneously reversible by elevation or compression of the limb, moderate-to-severe fibrosis was present, and elephantiasis was absent.

Informed consent was obtained from all patients, and the trial was approved by the ethics committees of all institutions. In addition to the 52 patients described in this report, 11 patients were enrolled who were later excluded: 5 with postmastectomy lymphedema and 5 with leg lymphedema withdrew for reasons unconnected with the trial (i.e., they moved away from the study center or had difficulty getting to it), and 1 patient with leg edema was excluded because she seldom returned for follow-up. The age, sex, and duration of lymphedema in the patients are shown in Table 1.

View this table: [in this window] [in a new window]   Table 1. Prestudy Characteristics of 52 Patients with Lymphedema.

 
"Conservative" measures for lymphedema had usually been tried -- e.g., physiotherapy or compression by a pump or elastic sleeves or stockings. Except for short courses of antibiotics given for attacks of secondary acute inflammation, all other therapy was stopped one month before the trial and during its course. The patients agreed to forgo further conservative treatment during the trial. We strongly believe in correct conservative treatment, but did not use it during the study period in order to test the effect of 5,6-benzo-[alpha]-pyrone alone.

The trial was a randomized, double-blind, placebo-controlled study with a crossover design. There were two six-month treatment periods, with no washout period. Blinding was performed by the pharmacist, who used a random-number table to assign patients to treatment groups. The code was broken only after the end of the trial. Two tablets, each containing 200 mg of medication (5,6-benzo-[alpha]-pyrone or placebo) were given orally once a day.

Follow-up examinations were performed once a month. Compliance was checked by counting tablets, and the patients were asked about any side effects and the particular symptoms that they reported. A symptom was recorded as being better, the same, or worse. Usually, symptoms were present at the start of a period, but some developed during a period. If a symptom disappeared during the first period and did not reappear during the second, it was included only in the first.

Limb volumes were measured twice at each examination by means of a water-displacement tank and standardized procedures¹⁷. Limb circumferences were measured at up to eight points on the legs and six points on the arms, at 10-cm intervals. Tissue tonometry was performed three times at two sites: 10 cm proximal and distal to the elbow on the anterior surface of the arm, or 20 cm above and below the knee on the posterior surface of the leg. The plunger of the tonometer depresses the skin under a constant weight¹⁸; the softer the tissue, the deeper it is pushed, producing a higher positive reading. Skin temperatures were measured 10 cm proximal to the elbow or 20 cm distal to the knee (CIG Medishield medical digital skin thermometer, CIG, Melbourne, Australia), with a second remote electrode on the normal limb, in a temperature-controlled room.

Statistical Analysis

Both the edematous and the normal limbs were measured at each examination, because the size of the normal limb is important in relation to the actual amount of edema. In addition, because of the effect of ambient temperature and exercise on edema, using a normal limb as a control greatly reduces the standard error by excluding the considerable variations in all measurements. In each patient at each examination, the value for the edematous limb was expressed as the ratio of its measurement to the measurement of the normal limb. Linear regression lines were fitted to the ratios for each patient. These lines were only combined to give the grand means (overall means) and grand slopes (average slopes) of the regression lines as the final step, thus reducing between-patient variation.

The differences between the grand means and grand slopes were evaluated for significance by two-tailed t-tests (Microsoft Excel, version 4 [Microsoft, New York], was used for all the tests), as were the differences between the means of the volumes and the means of the average circumferences at the start and end of each treatment period. F-tests showed that the variances were not significantly different. Changes in symptoms were evaluated with chi-square tests (using Yates' correction if five or fewer patients were being evaluated). The placebo period was compared for symptoms with the active-drug period, in terms of the numbers of patients reporting that they felt better, the same, or worse during these periods. Patients' preferences for treatment periods were assessed by binomial distribution.

Since there were no significant differences between the values for the patients given the placebo first and those for the patients given the active drug first, these values were combined for greater accuracy. For this reason also, all the measurements of circumferences were combined, as were those of proximal and distal sites by tonometry. In addition, the measurements of arms and legs were combined to evaluate changes in symptoms. All P values are two-tailed.

Results

Changes in symptoms during the placebo and the active-drug periods are shown in Table 2. The symptoms experienced by the majority of patients were significantly reduced by the active drug but not by the placebo. The improvement was not rapid, usually becoming evident only by the fourth or fifth month. When treatment was switched from the active drug to the placebo, worsening of symptoms only became noticeable after one to three months. The active drug was preferred to the placebo by 93 percent of patients.

View this table: [in this window] [in a new window]   Table 2. Changes in Symptoms after Each Treatment Period.

 
The results of measurement of the arms and legs are shown in Table 3 and Table 4 and Figure 1 and Figure 2. During the placebo period, the slopes of the regression lines for the arms all showed significant worsening (P = 0.01 to 0.001), except the slope for skin temperature. None of the regression lines for the legs showed significant worsening (P = 0.4 to 0.1).

View this table: [in this window] [in a new window]   Table 3. Differences between Measurements of Edematous and Normal Limbs in 31 Patients with Lymphedema of the Arms.

 

View this table: [in this window] [in a new window]   Table 4. Differences between Measurements of Edematous and Normal Limbs in 21 Patients with Lymphedema of the Legs.

 

View larger version (28K): [in this window] [in a new window]   Figure 1. Measurements of Edematous Arms during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines). The regression lines are shown for the four measurements; each percentage denotes the percentage of increase above normal. Because there were no significant differences between the groups given placebo first and those given active drug first, the groups were combined.

 

View larger version (34K): [in this window] [in a new window]   Figure 2. Measurements of Edematous Legs during the Placebo Period (Dashed Lines) and the Active-Drug Period (Solid Lines). The regression lines are shown as percentages of increases above normal. Because there were no significant differences between the groups given placebo first and those given active drug first, the groups were combined.

 
The differences between the limb volumes and the average limb circumferences at the end of the placebo period and those at the end of the active-drug period were significant, as were the percentages for measurements in which a normal limb was used as a control. The differences between the means of the regression lines for the placebo and active-drug periods were significant for all measurements of both the arms and legs (Table 3 and Table 4). The slopes of the lines for measurements other than temperature measurement also reflected significant improvement during the active-drug period as compared with the placebo period. Volume measurements showed that in six months the active drug reduced the edema of the arms from an amount 46 percent above normal to 26 percent above normal; the amount of edema of the legs was reduced from 25 percent to 17 percent above normal. The 95 percent confidence intervals for the reduction in the arms were 44 to 48 percent at the start of the active-drug period and 25 to 28 percent at the end; the confidence intervals for the reduction in the legs were 24 to 27 percent and 16 to 18 percent. Thus, nearly half of the edema fluid was removed from the arms and nearly one third from the legs. During the six months of the placebo period, the amount of edema of the legs was unchanged from 24 percent above normal, and that of the arms increased from 38 to 45 percent above normal -- i.e., nearly one fifth.

For the active-drug periods there were inverse correlations between the slopes of the individual regression lines and the initial differences between the values for the edematous and normal limbs. The following correlation coefficients were found for the arms and legs, respectively: volumes, -0.603 (P<0.001) and -0.596 (P<0.001); circumferences, -0.303 (P = 0.1) and -0.688 (P<0.001); tonometry, -0.243 (P = 0.2) and -0.408 (P = 0.06); and skin temperature, -0.099 (P = 0.6) and -0.492 (P = 0.02). The more edematous the limb, the more rapidly it tended to improve. The corresponding coefficients for the placebo period were not significant (P = 0.8 to 0.3).

The compliance rate was 99 percent. Of the 17,472 tablets to be taken during each period, only 245 were not taken during the placebo period and 227 during the active-drug period. No serious side effects were reported, but seven patients taking the active drug had slight gastrointestinal disturbances (mild nausea or diarrhea). These were not severe enough to cause any patient to leave the trial and disappeared after the first month.

Discussion

Our data show that 5,6-benzo-[alpha]-pyrone effectively reduces the volume of lymphedema. The improvement was both statistically significant and clinically meaningful. These results confirm previous studies of this and other benzopyrones in the treatment of lymphedema with diverse causes^{1,9,10,11,12,13,14,15,16}. Reduction of the increased skin temperature has also been observed before^1,10,16. It is encouraging that the more lymphedematous the limb, the more rapid its improvement, as has been shown in other studies^13,14.

Improvement in the symptoms related to lymphedema has also been observed in other double-blind studies,^{10,11,12,13,14,16} including studies of lymphedema resulting from filariasis and elephantiasis^13,14. Efforts to increase patients' comfort are greatly needed; contrary to what is sometimes asserted, lymphedema can be very painful, especially if it develops rapidly. Such pain, together with loss of mobility and of the use of the limb, is often of great concern to patients^1,19.

As in the other trials,¹ side effects were infrequent and mild. The mild gastrointestinal problems reported here were not sufficient to cause any patient to leave the trial, and all side effects disappeared after the first month. We have since found that coating the tablets with a lacquer prevents these side effects almost completely¹³. Many patients reported a feeling of increased general well-being, quite apart from a lessening of the symptoms related to lymphedema. This has been noted in other trials, particularly among the elderly, whose diets often have only low levels of benzopyrones^1,16.

Many benzopyrones have been shown to reduce the amount of high-protein edema fluid due to various factors in humans and animals¹. These agents may have many effects on the body, almost all of which may help reduce edema fluid¹; they may increase the pumping action of collecting lymphatics, reduce abnormal permeability of blood vessels, stabilize plasma and lysosomal membranes, and reduce the effects of many mediators of inflammation such as scavenging free radicals.

However, all the benzopyrones that have been tested have one effect in common: they reduce the volume of high-protein edema fluid by increasing proteolysis by macrophages^1,8. These cells normally lyse some protein in the tissues. All the benzopyrones increased both the rate of proteolysis per macrophage and the numbers of macrophages at the site of edema¹. The drugs' ability to reduce high-protein edema fluid largely disappears if the macrophages are selectively poisoned with silica¹. 5,6-Benzo-[alpha]-pyrone has also been shown to increase macrophage proteolysis in vitro¹. In chronic lymphedema, many macrophages are present but their activity is greatly reduced; this state can also be reversed by the benzopyrones¹. These drugs still reduce experimentally induced lymphedema even when all lymphatics are completely occluded¹. All these observations indicate that benzopyrones reduce lymphedema by increasing proteolysis by macrophages.

Any form of edema can cause symptoms such as pain, disfigurement, and disability^1,19. Edema fluid also reduces the oxygenation of the tissues, impairing cellular function and slowing healing,¹ reducing mobility, and increasing vulnerability to injury. However, edema fluid with high levels of protein injures tissues more than fluid with low levels. After 64 days, a simple excess of an animal's own protein produced all the signs of chronic inflammation, including considerable fibrosis; 5,6-benzo-[alpha]-pyrone virtually eliminated the changes due to chronic inflammation, including the excess fibrosis, along with the excess interstitial protein, and the excess numbers of new blood and lymph vessels⁸.

Any excess protein also acts as a good growth medium for bacteria, which worsen preexisting lymphedema^1,3. The elimination of such protein by 5,6-benzo-[alpha]-pyrone accounts for the reduction in the episodes of secondary acute inflammation (so-called erysipelas³), as shown in the present trial and others^{1,9,10,13,14,16}. This finding does not mean that antibiotics are unnecessary when such episodes occur, but that they are needed far less frequently.

Although benzopyrones quite rapidly reduce acute edema involving high-protein fluid (e.g., edema due to accidental or surgical trauma¹), they do not rapidly reduce chronic forms of edema (e.g., lymphedema). Even complex physical therapy, the most rapid and effective treatment, removes only about 50 percent of the fluid per year^4,5,6. This proportion is removed in about four weeks, but another year is required before tissue remodeling will allow much more to be removed. Also, such removal requires four weeks of intensive treatment by specially trained therapists (for one to two hours a day per limb). This is expensive and time-consuming, as is surgery, which is often ineffective^1,4,7.

The benzopyrones offer slow but safe and effective treatment. They convert an inexorable increase in edema and discomfort into a slow reduction of the volume of edema fluid and a more rapid reduction of discomfort. 5,6-Benzo-[alpha]-pyrone combined with complex physical therapy will reduce volume and discomfort more than either treatment alone²⁰. Thus, 5,6-benzo-[alpha]-pyrone is best used as a complement to adequate conservative therapy, but can be used alone if the patient cannot wear compression garments. Indeed, the slow reduction of edema by the benzopyrones is an advantage when compression garments cannot be worn^13,14. If the reduction were rapid, the elimination of the excess fluid might leave huge cavities. In the absence of limb compression, these would rapidly refill with protein and edema fluid, providing good sites for bacterial growth in a limb prone to injury.

5,6-Benzo-[alpha]-pyrone is not yet available for use in North America. Flavonoids (benzo-[gamma]-pyrones) are available, and may also be beneficial in the treatment of lymphedema,¹⁶ although gastric irritation may be a problem.

Supported by the Lymphoedema Association of Australia.

We are indebted to Mrs. G.A. Piller, Miss J. Newman, and Miss R. McLauchlan for performing the measurements, to the Flinders Medical Centre for the use of its facilities, and to Hamilton Laboratories (Adelaide, Australia) for providing the tablets of the drug and its placebo.

Source Information

From the Henry Thomas Laboratory (Microcirculation Research), University of Adelaide, Adelaide (J.R.C.-S.); the Department of Surgery, Flinders Medical Centre, Bedford Park (R.G.M.); and the Faculty of Health Sciences, Flinders University, Bedford Park (N.B.P.) -- all in Australia.

Address reprint requests to Dr. Casley-Smith at the Henry Thomas Laboratory, University of Adelaide, Box 498 G.P.O., Adelaide, S.A. 5001, Australia.

References

1. Casley-Smith JR, Casley-Smith JR. High-protein oedemas and the benzo-pyrones. Sydney, Australia: J.B. Lippincott, 1986. 
2. Lymphatic filariasis: report of a WHO expert committee. WHO Tech Rep Ser 1984;702:1-112.
3. Casley-Smith JR, Foldi M, Ryan TJ, et al. Lymphedema: summary of the 10th International Congress of Lymphology Working Group discussions and recommendations, Adelaide, Australia, August 10-17, 1985. Lymphology 1985;18:175-180. 
4. Foldi E, Foldi M, Clodius L. The lymphedema chaos: a lancet. Ann Plast Surg 1989;22:505-515. [Medline]
5. Foldi M, Kubik S. Lehrbuch der Lymphologie fur Mediziner und Physiotherapeuten. Stuttgart, Germany: Gustav Fischer, 1991.
6. Casley-Smith JR, Casley-Smith JR. Modern treatment of lymphoedema. I. Complex physical therapy: the first 200 Australian limbs. Australas J Dermatol 1992;33:61-68. [Medline]
7. Clodius L, Gibson T. Surgical therapy for lymphedema. In: Foldi M, Casley-Smith JR, eds. Lymphangiology. Stuttgart, Germany: F.K. Schattauer, 1983:683-721.
8. Casley-Smith JR, Gaffney RM. Excess plasma proteins as a cause of chronic inflammation and lymphoedema: quantitative electron microscopy. J Pathol 1981;133:243-272. [Medline]
9. Clodius L, Piller NB. The conservative treatment of post mastectomy lymphoedema patients with coumarin results in a marked continuous reduction in arm swelling. In: Bartos V, Davidson JW, eds. Advances in lymphology. Prague: Avicenum, 1982:471-4.
10. Casley-Smith JR, Piller NB, Morgan RG. Behandlung chronischer Lymphodeme der Arme und Beine mit 5,6-Benzo--pyron: placebokontrollierte Doppelblind-cross-over-Studie uber die Dauer von einem Jahr. Therapiewoche 1986;36:1068-1076. 
11. Cluzan R, Pecking A. Benzopyrone (Lysedem) double blind crossing over study in patients with secondary upper limb edemas. In: Nishi M, Uchino S, Yabuki S, eds. Progress in lymphology -- XII: proceedings of the XIIth International Congress of Lymphology, Tokyo, Kyoto, Japan, 27 August-2 September 1989. Amsterdam: Excerpta Medica, 1990:453-4.
12. Desprez-Curely JP, Cluzan R, Pecking A. Benzopyrones and post-mastectomy lymphedemas: double-blind trial placebo versus sustained release coumarin with trioxyethylrutin (TER). In: Casley-Smith JR, Piller NB, eds. Progress in lymphology, X: proceedings of the Xth International Congress of Lymphology, Adelaide, 1985. Adelaide, Australia: University of Adelaide Press, 1985:203-5.
13. Casley-Smith JR, Jamal S, Casley-Smith JR. Reduction of filaritic lymphoedema and elephantiasis by 5,6 benzo-a-pyrone (coumarin), and the effects of diethylcarbamazine (DEC). Ann Trop Med Parasitol 1993;87:247-258. [Medline]
14. Casley-Smith JR, Wang CT, Casley-Smith JR, Cui Z. Reduction of filaritic lymphoedema and elephantiasis using 5,6 benzo-[alpha]-pyrone (coumarin). BMJ (in press).
15. Braun HD, Becker T, Meyer U. Behandlung von Stauungserscheinungen nach Ablatio mammae und Bestrahlung: Erfahrungen mit physikalischer Therapie und Venoruton. Munch Med Wochenschr 1971;113:1630-1633. [Medline]
16. Piller NB, Morgan RG, Casley-Smith JR. A double-blind cross-over trial of O-(beta-hydroxyethyl)-rutosides (benzo-pyrones) in the treatment of lymphoedema of the arms and legs. Br J Plast Surg 1988;41:20-27. [CrossRef][Medline]
17. Swedborg I. Voluminometric estimation of the degree of lymphoedema and its therapy by pneumatic compression. Scand J Rehabil Med 1977;9:131-135. [Medline]
18. Piller NB, Clodius L. The use of a tissue tonometer as a diagnostic aid in extremity lymphoedema: a determination of its conservative treatment with benzo-pyrones. Lymphology 1976;9:127-132. [Medline]
19. Swedborg I, Borg G, Sarnelid M. Somatic sensation and discomfort in the arm of post-mastectomy patients. Scand J Rehabil Med 1981;13:23-29. [Medline]
20. Casley-Smith JR, Casley-Smith JR. Effects of various combinations of complex physical therapy, benzo-pyrones and Mercury compression on lymphoedema; which combination works best? In: Cluzan RV, Pecking AP, Lokiec FM, eds. Progress in lymphology -- XIII: proceedings of the XIIIth International Congress of Lymphology, Paris, 29 September-5 October 1991. Amsterdam: Excerpta Medica, 1992:537-8.

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