The Benzo-pyrone Drugs in the Treatment of Lymphoedema (and other High-Protein Oedemas)

Judith R. Casley-Smith
It is very important for patients to obtain the agreement of their doctor before taking any medication listed  below!
Oral benzo-pyrones have in the past been an option for treatment of lymphoedemas.
However, the oral form (Lodema) was taken off the Australian and other markets due to hepatotoxicity effects.  For a review of these issues see Farinola and Piller (2007) CYP2A6 polymorphisms: Is there a role for pharmacogenomics in preventing coumarin induced hepatotoxicity in lymphoedma patients?  Pharmacogenomics 8(2) 151-158.
There are other medications around in the broad Flavonoid group which have not had reported hepatotoxic effects and these include such preparations as  Paroven and Paroven Forte, Lymphodran etc. The reason for these still being on the market is that they are not coumarins but rutosides whose structure and metabolic paths are different.  
There is quite a wealth of older literature regarding coumarin and its benzopyrone relatives and some of those details are presented below in the interests of our history of the treatment of lymphoedema.  Coumarin in its oral form should however NOT be considered or used for the treatment of lymphoedema.   
A review of the literature in 2003  found that benzo-pyrones have been tested by over 37 authors in 8 countries, in (effectively) 51 clinical trials. (The word "effectively" is used since different Grades were counted separately if they were evaluated separately.) These are all the trials known to the authors which could be evaluated objectively. The benzo-pyrones were: coumarin, coumarin plus troxerutin, oxerutins (O-(-hydroxyethyl)-rutosides, HR) and diosmin. There were 39 trials of oral and 12 of topical preparations (11 and 6, respectively, were combined with other therapies). In all of them, oral or topical benzo-pyrones significantly reduced lymphoedema (usually to a clinically important extent). In almost all the symptoms were similarly reduced - including infections (Secondary Acute Inflammation, SAI). Combining all 25 trials of oral benzo-pyrones alone, in which the reduction of oedema could be estimated, gave a mean reduction of oedema of 36% (S.E. 6%) per year (1,225 patients in all). (About 1 to 10% should be added to this if comparing it with untreated patients since these worsen by amounts varying with the duration of their lymphoedema.) There were no significant differences between arms and legs. Elephantiasis was reduced less (15% per year) than Grades 1 and 2 (57%) but this was of course much greater initially. As the dose of benzo-pyrones increased, so did their efficacy. Nor are these drugs merely useful by themselves. Both oral and topical forms, and these combined, very materially increased reductions of lymphoedema obtained by a variety of physical and surgical techniques. In these, they often also greatly reduced the incidence, and the severity, of attacks of SAI.
The year 1993 saw the publication of three trials of oral coumarin for lymphoedema: in Australia and (for the W.H.O.) in India and China. They appeared in: the New England J. Medicine 329 (1993), 1158-1163, Annals. Tropical Medicine Parasitology (1993) 87, 247-258, and the British Medical J., 307 (1993) 1037-1040, respectively. The average reduction for Grade 2 arms was 2.2 % of the initial volume per month (or 40 % of the oedema in 6 months); that for Grade 2 legs was 1.5 % of the initial volume per month (or 33 % of the oedema in 6 months).
The large oedemas of elephantiasis reduced more rapidly, but were often still great at the end of the trials because they were so much larger initially. Reductions are slow, but the drugs convert a disease which otherwise slowly (or sometimes rapidly) gets worse into one which slowly improves. The drug also improved many symptoms of lymphoedema (pain, lack of mobility, etc). Importantly, they lessen the number and severity of attacks of acute inflammation (sometimes called: cellulitis, erysepilas).
An analysis has been made of the first 628 Australian limbs treated with C.P.T., with and without the benzo-pyrones (Lymphology, 20 (1996) 76-82, and see Section on Results ). Both oral and topical benzo-pyrones increase the already large reductions which Complex Physical (Lymphedema) Therapy (C.P.T.) produces in lymphoedema and elephantiasis. A typical one-month course of C.P.T. gave average reductions of 13 % of the initial volume of a Grade 2 arm and 11 % of a Grade 2 leg; these were improved by a further 5 % if oral benzo-pyrones were taken for 3 months before the Course started, and by yet a further 2 to 3 % if topical Coumarin was used as well. During the next 12 months, some limbs increased in volume, others reduced still further. Oral benzo-pyrones improved these reductions by 10 % of the volume at the end of the first Course of C.P.T. The next Course of C.P.T. by itself gave a 16 % reduction relative to the limb volume at the start of the Course. Again coumarin ointment gave a further 11 % and powder a further 16 % improvement. Patients at risk, after operations which cause lymphoedema, are less likely to get it if they take benzo-pyrones prophylactively. It also considerably reduces the oedema of accidental trauma to the limb (cuts, bruises, fractures, burns, stings, etc.). These are also often greatly helped by topical coumarin (cream or powder).
Similar reductions to those obtained with coumarin have also been observed with the (bio)flavonoid Paroven - also called: Venoruton, Relvène (British J. Plastic Surgery, 41 (1988), 20-27). However note that the doses of this need to be much larger (3,000 mg/day rather than 400, as with coumarin). Another benzo-pyrone - diosmin (Daflon 500®)- has also been shown to be effective in lymphoedema (Int. Angiol. (Suppl) 14 (1995) 39-43). Again the doses of this need to be much larger (2,000 mg/day rather than 400, as with coumarin).
Some similar drugs, which are not strictly-speaking benzo-pyrones, are also effective. These include Unguentum lymphaticum® (however this can only be applied to the skin) and Doxium®. A double-blind trial of an extract of Ruscus aculeatus (mainly ruscogenin and neoruscogenin plus hesperidin methyl chalcone) over 3 months, reduced oedema by 13%, compared with a 9% increase in the controls, symptoms were improved significantly (Lymphology, 29 (1996) 29-35).
There has been some interest in Pycnogenol® and similar products, with anecdotal reports of their effectiveness. However in spite of the claims by those who promote these products, clinical trial data is regrettably lacking. We can only find one: a double-blind trial, matched-group, placebo-controlled, trial was performed on post-mastectomy lymphoedema using procyanidolic oligomeres Endotélon™(33 active, 30 placebo) for 6 months (Cluzan RV, Pecking AP, Lokiec FM [eds.] Progress in Lymphology - XIII. Amsterdam, Elsevier, Int Cong Ser 994 (1992) 655-658). Symptoms were considerably improved, but there was no significant difference in the oedema (which only decreased by 1%). However the dose was only 300 mg/day. From their molecular weight, at least 800 mg/day would be needed to equal 400 mg/day of coumarin. So this substance may help, but lack of good clinical trials with adequate doses makes it impossible to be sure of this. By contrast, many of the other benzo-pyrones (including the flavonoids) have had such successful trials.

How the Benzo-Pyrones Act

All oedemas cause swelling, pain (if they increase rapidly), loss of function (at both gross and cellular levels), poor oxygenation and poor wound healing. Chronic, high-protein oedemas cause chronic inflammation with excess fibrosis. Benzo-pyrones have been shown to improve all of these. {For a general review for this section, see: Casley-Smith JR & Casley-Smith, Judith R.. High-Protein Oedemas and the Benzo-Pyrones. Lippincott, Syd. & Balt., 1986 )
The benzo-pyrones reduce all forms of high-protein oedema. Almost any oedema is a high-protein oedema, except those from uncomplicated varicose veins, late congestive cardiac failure and some kinds of renal disease. The dividing line is a protein concentration in tissue fluid of 1 g/dl. Above this, the colloidal osmotic pressure of the protein contributes greatly to the accumulation of fluid, and the benzo-pyrones can reduce the oedema by removing the cause of this.
Benzo-pyrones reduce all high-protein oedemas by causing macrophages (scavanger cells in the tissues) to increase both their numbers and their normal lysis of the excess protein. Thus the increased colloidal osmotic pressure is reduced via this alternative pathway for the removal of protein. This can be detected about 4 hours after administration and is maximal by 24 hours.
However some of the actions in lymphoedema are much slower than this since it takes many months to remove the accumulated excess fibrous tissues. The removal of protein and the excess fluid this causes (and its other deleterious effects) starts within days, but he effects of this are usually not obvious for some six months because of all the fibrous tissue.
Many benzo-pyrones also improve pumping by the collecting lymphatics, again aiding in the removal of the oedema. Some consider that this is how they act, but at least in animal studies it is evident that proteolysis is much more important (although increased pumping by any remaining lymphatics must also help).
Benzo-pyrones seldom affect the underlying condition but, by reducing the excess protein, reduces the oedema and its sequelae. They enhance another pathway for the removal of protein and water from the tissues when the lymphatics can no longer handle these.
If the oedema is within 1 - 2 cm of the surface of the skin, topical applications (the powder or the ointment) are suitable; if deeper, the oral form is also necessary.
Coumarin has a secondary action on injured blood vessels if applied topically to burns and acute injuries. It impairs the degradation of adrenalin, hence arterioles are more contracted. Immediate topical application reduces oedema (and hence the pain) via the reduction of leaking from the injured blood capillaries.
It also improves oxygenation of ischaemic regions by a separate mechanism: opening arterio-venous communications. This reduces most exchanges with the tissues but, since gases are mainly exchanged via arterioles, it increases these. This is also useful with ischaemic skin grafts and flaps.
Please note that while the correct chemical name for 5,6 benzo-alpha-pyrone, or 1,2-benzopyrone is coumarin, it is NOT an anticoagulant. Coumarin anticoagulants are its complex derivatives. Unfortunately, all this causes some confusion!. Another benzo-pyrone derivative 'Coumadin' is NOT 'coumarin' and their effects are quite different. Note that benzo-pyrones have no relationship whatever to benzo-pyrenes.

Side-Effects of the Benzo-Pyrones

Coumarin

Coumarin was used in clinical trials for over 30 years, in many countries, and in over 100,000 patients, however the reported hepatoxic effects resulted in the cessation  of its use in most countries.  With further research it may make a reappearance as a treatment choice.