CHAPTER 30 Pharmacologic Treatment of Lymphedema
When clinicians identify a patient’s nonadherence to long-term conservative therapies, such as the wearing of compression garments and manual lymphatic drainage, pharmacotherapy is an option that is often overlooked.
Although benzopyrones are not routinely used as treatment for lymphedema, many clinical studies have found that they offer therapeutic benefits.
There is a growing trend toward the use of complementary and alternative medicine as a supplement to allopathic treatments for lymphedema. This includes the use of herbal therapies as well as vitamins, with variable efficacy in symptom reduction.
Filariasis is the most common cause of secondary lymphedema; it affects 120 million people worldwide, and if left untreated, will develop into disfiguring elephantiasis. Treatment involves elimination of the infective organisms and should be initiated promptly.
Repeated bouts of lymphedema-related cellulitis may require long-term prophylactic antibiotic therapy.
In patients whose impaired lymphatic system is overwhelmed by the task of absorbing the body’s basal interstitial fluid load, the administration of certain drugs that further increase capillary filtration will worsen fluid pooling. Resultant edema can cause further damage to lymphatic structures through the dilation of these vessels. Where possible, individuals should avoid these medications.
More methodologically robust clinical trials are necessary to verify the efficacy of the various pharmacotherapies for chronic lymphedema.
The lymphatic system is a network of lymph nodes and vessels that operate in parallel with the vascular system to provide immune and transport functions; lymphedema is a chronic condition caused by an acquired or congenital defect of the lymphatic system. Normal and healthy lymphatic vessels are responsible for absorbing and then transporting excess interstitial fluid to the blood. Compromised lymphatic integrity diminishes this transport capacity, and high-protein fluids remain trapped in the interstitial spaces (principally the subcutaneous fatty tissues), which results in edema. Fluid that pools in the lymphatic vessels also causes their dilation, thereby producing incompetent lymphatic valves in the collecting ducts as well as compounded fluid stasis. This promotes a cascade of cellular events that favor chronic inflammation and pain. In addition, ongoing edema compresses the surrounding healthy lymphatic vessels, which impedes fluid flow and exacerbates regional swelling. If there are sufficient lymphatic structures to compensate for local defects, the problem remains subclinical. More commonly, however, a clinical picture of lymphedema is observed. Patients present with severely edematous limbs, poor wound healing, and acute episodes of cellulitis. 1
Current best practices recommend conservative combination treatment for lymphedema, 2 which is generally biphasic. 3 The first “intensive” phase involves the timely provision of manual lymphatic drainage (MLD) massage by a trained service provider, instructions for therapeutic exercises, and medical-grade short-stretch compression bandages to be worn daily. This phase may last a few months, depending on the frequency of treatment sessions; its aim is to stabilize the lymphedema by preventing further damage to the lymphatic system from regional fluid overload. The subsequent “maintenance” phase lasts indefinitely. Lymphedema is a chronic and progressive condition, but it is subject to an individual’s willingness to continue with the tasks of maintenance. These tasks include wearing a well-fitted gradient pressure garment during the day and compression bandages at night, performing appropriate skin care, continuing therapeutic exercises, and self-administering MLD. 4 For some patients, these tasks represent an overwhelming ongoing burden, and they discontinue their daily efforts. 5 This is understood as nonadherence.
Nonadherence is a significant challenge to the management of lymphedema for both patients and clinicians. This is especially true when it comes to patients wearing compression garments (which is pivotal for controlling lymphedema progression 6 ) and continuing with MLD treatment. There are often understandable reasons for nonadherence. Many patients with lymphedema report trouble with accessing correctly fitted garments in a timely manner. For elderly individuals and those with mobility impairment, donning such garments is a daily struggle. Individuals who live in hot, humid climates find it difficult to wear compression garments, because these will be uncomfortable in this weather, even when correctly fitted. The cost of purchasing compression garments is another barrier to continued use, especially because these garments need to be replaced frequently to remain therapeutic. Many patients also struggle to access and afford MLD, which is an ongoing cost that can make long-term treatment prohibitive. 7
For cases in which there are legitimate reasons for nonadherence to conservative therapies, alternatives must be considered. Surgery is one such option, particularly if conservative treatments are adhered to but are still ineffective. Pharmacotherapy is another option, but it remains fairly overlooked in clinical practice. This chapter will provide an overview of the drugs that have been trialed for the treatment of different types of lymphedema and for the complications associated with lymphedema.
Benzopyrones are considered to have antiedematous properties and have been used successfully for the treatment of certain venous diseases. There are two major groups of benzopyrones: coumarins and flavonoids. 8
Coumarins, which are alpha-benzopyrones, belong to the coumarol family; they act on vascular permeability, macrophages, and inflammatory mediators. 9 Many authors advocate their use for the treatment of lymphedema because of their potential to reduce high-protein edema through multimodal mechanisms. Coumarin and its metabolites adhere to the endothelium of small blood vessels, reducing vascular permeability and decreasing protein leakage into the interstitial tissues. 8 Coumarins also promote the influx of macrophages into edematous tissues, which stimulates proteolysis to reduce the accumulation of the proteins that favor the development of edema. This in turn reduces the interstitial oncotic pressure and helps with the vascular uptake of fluid to ease the lymphatic fluid overload.
In patients with chronic lymphedema, macrophages can become structurally altered (they have fewer pseudopodia and are more lipid rich) and less functionally active. 10 There is research to suggest that this inactivated state can be reversed by benzopyrones and that it is accompanied by a correlated elevation in proteases (typically secreted by activated macrophages). 11
Coumarins also inhibit the synthesis of inflammatory mediators such as prostaglandins and leukotrienes to lessen the chronic inflammatory processes that cause irreversible tissue fibrosis. 8 Finally, animal models have shown that coumarins increase lymph flow. 10 This is presumably facilitated by increased lymphatic contractility and pumping, which improve lymphatic clearance through healthy neighboring lymphatic structures to reduce edema.
Flavonoids are gamma-benzopyrones that include flavones; diosmin; flavan and its derivative hesperidin; quercetin and its derivatives rutin, oxerutin, and the rutosides; and proanthocyanidins. Like the coumarins, flavonoids are thought to reduce the symptomatic swelling seen in patients with lymphedema, because they reduce vascular leakage and the capillary filtration rate. Flavonoids are also antioxidant compounds with inhibitive actions that affect the enzymatic promoters of inflammation. 8 However, it has been observed that larger quantities of flavonoids (compared with coumarins) need to be consumed to produce similar effects. 10
Benzopyrones are not routinely used as treatment for lymphedema, but many clinical studies have found that they offer therapeutic benefits. A meta-analysis of 27 clinical trials (of varying quality) that studied the effects of oral benzopyrones on peripheral lymphedema was carried out by prominent lymphedema researchers. 10 The lymphedemas studied included congenital (primary), iatrogenic (after surgery and radiotherapy), and filarial. Most trials spanned 6 months, but some lasted 1 year or more. The benzopyrones investigated included the coumarins, the oxerutins/rutosides, the troxerutins, diosmin, and hesperidin. Coumarin dosages were typically 400 mg/day (although some were as low as 100 mg/day) and produced significant improvements in edema, limb circumference, skin softness and thickness, pain, limb heaviness and mobility, frequency of acute inflammatory episodes and ulcers, and general wellbeing. Oxerutin trials involved the administration of 3000 mg/day and had variable results. Some studies found no significant symptomatic changes, whereas others found improvements in skin temperature, edema, limb circumference, limb mobility, pain, heaviness, and wellbeing. Troxerutin was only studied in combination with coumarin, and dosages varied from 60 to 270 mg/day. Several studies reported reduced limb circumference and secondary inflammation (cellulitis, lymphagitis, and lymphadenitis) as well as improved lymph flow and symptoms. A few studies observed improved lymph flow but no changes in symptoms. Finally, one study found reductions in edema and other symptoms in addition to improved lymph flow when patients were given a mixture of micronized diosmin (90%) and hesperidin (10%) at 1000 mg/day. The meta-analysis of the combined results of these clinical studies demonstrated that benzopyrone is effective for the reduction of limb edema and symptoms, but it also found that these effects can take at least 6 months to become clinically evident. It was also noted that higher doses were correlated with higher reductions and that the coumarins and oxerutins were superior to other benzopyrones. The results from 13 of the 16 double-blind trials showed significant symptomatic improvement, and a reduced rate of secondary inflammation was found in all 16 trials. In light of these promising results, the authors of the meta-analysis recommended the use of benzopyrones for the treatment of lymphedema.
By contrast, a more recent Cochrane review found insufficient evidence to support this treatment recommendation. 12 The authors believed that there were too many methodologic problems in the 15 trials that were identified to conduct a rigorous meta-analysis. Thus they were unable to conclusively comment on the efficacy of benzopyrones or to recommend their use.
For clinicians who are interested in using benzopyrones to treat lymphedema, it should be noted that oral coumarins are associated with potentially fatal hepatotoxicity in up to 6% of patients 13 and that they have been withdrawn from the market in both the United Kingdom and Australia. 8 Topical coumarin is an alternative to the oral version, and it was demonstrated in four trials to improve swelling when used in combination with compression garments. 14 It can sting if it is applied directly to the mucous membranes, but very few application-site rashes have been reported. 10
Around the world, there is a growing trend toward the use of complementary and alternative medicine (CAM) as a supplement to allopathic therapy. This includes the use of herbal therapies as well as vitamins. In Australia, nearly half of the population use CAM and annually spend approximately $2.3 billion on these products. 15 MacLennan et al 16 found that many CAM consumers are self-prescribers; this is particularly alarming for herbal medicines, which can have as many toxic side effects as conventional synthetic drugs. Many herbal therapies are misrepresented as safe by virtue of their being “natural,” and considerable ambiguity exists in the scientific and gray literature with regard to their efficacy. The herbs discussed in the following sections have been clinically studied. Each description details the herb’s active ingredients, its posited mechanism of action, the evidence of its efficacy (or lack thereof), and its documented contraindications and possible adverse reactions.
HORSE CHESTNUT SEED (AESCULUS HIPPOCASTANUM)
The active component of horse chestnut seed extract (HCSE) is escin, a triterpenic saponin that can inhibit the activity of elastase and hyaluronidase. 17 These enzymes normally degrade proteoglycan in capillary endothelium and promote vascular leakage, which can overload the lymphatic system. HCSE also increases the acid protease activity levels associated with an increased rate of edema resolution and reduced swelling. Therefore, it has potential for the treatment of lymphedema. Hutson et al 18 clinically tested HCSE use by 25 breast cancer survivors with stable arm lymphedema. For 3 months the participants were given either the HSCE equivalent of 50 mg of escin twice daily, or placebo. Unfortunately, no significant changes in lymphedema were observed, either in terms of objective arm fluid and size measurements or the participants’ subjective ratings of improvement. Despite the lack of evidence supporting HCSE’s therapeutic benefit, some patients may still choose to try it. These patients must be warned about its side effects. Although no teratogenicity, embryo toxicity, or chronic toxic effects have been reported with HCSE use, it can cause a number of other side effects, including muscle twitching, weakness, impaired coordination, dilated pupils, dizziness, headaches, pruritus, vomiting, and diarrhea. Dosages should not exceed 600 mg/day because of the risk of nephrotoxicity. Furthermore, HCSE should not be ingested by pregnant or breast-feeding women, people with bleeding disorders or with renal or hepatic impairments, or people who are taking anticoagulants.
BUTCHER’S BROOM (RUSCUS ACULEATUS)
The active components of butcher’s broom include the saponin glycosides of ruscogenin and neoruscogenin, which have antiinflammatory, 19 antiexudative, and edema-reducing properties. To date, no trial has studied butcher’s broom extract without other additives. The most widely available form is Cyclo 3 Fort (C3F), which is a combination of butcher’s broom extract (150 mg), hesperidin methyl chalcone (150 mg), and ascorbic acid (100 mg). Cluzan et al 20 administered three C3F tablets daily to 27 patients with lymphedema and found that those taking the C3F had a significantly greater total decrease in whole arm volume compared with the placebo group. This observation was true on days 30, 60, and 90 of the clinical trial. In addition, 75% of the C3F group also reported improvements in arm quality, softness, and mobility, whereas only 32% of the placebo group reported these effects; this was a statistically significant difference. However, there were problems with the study’s methodology, including reporting, attrition, and selection biases. Therefore, despite the encouraging results, the study’s validity is questionable. The researchers also noted nausea and abdominal pain in two participants, which suggests that not all individuals are able to tolerate C3F.
GINKGO (GINKGO BILOBA)
The main active ingredients in ginkgo are ginkgolides and flavonoids, which are thought to protect cellular lysosomes from free radicals and to improve the integrity of collagen fibers. Cluzan et al 21 studied the effect of Ginkor Fort, a ginkgo extract, on breast-cancer–related arm lymphedema. Forty-eight patients were studied, and a statistically significant improvement in limb heaviness (based on self-reported measures) was observed. However, no definitive conclusions could be drawn with regard to this herb’s effect on lymphatic migration speed, and the researchers recommended further investigation to establish efficacy.
SWEET CLOVER (MELILOTUS OFFICINALIS) AND TONKA BEANS (DIPTERYX ODORATA)
The primary active ingredient in both sweet clover and tonka beans is coumarin. For 6 months Pastura et al 22 administered 400 mg/day of sweet clover, which contained 8 mg of coumarin, to 21 survivors of breast cancer with secondary lymphedema. The researchers concluded that sweet clover effectively reduced lymphedema in 79% of the participants treated. Unfortunately, these results need to be viewed with caution, because only 14 participants were treated, according to the study protocol. Although the reduction was statistically significant, it was small (about 5%). Three participants also experienced transitory gastrointestinal side effects.
In another study, Vettorello et al 23 studied the effect of sweet clover, tonka beans, and ginkgo combined. Seventy-six patients with lower limb lymphedema were treated in an open-label study for 6 to 8 months, and significant improvements in limb circumference, edema, episodes of infection, and limb pain and heaviness were demonstrated. However, there were methodologic problems with this study.
Health care providers should be aware that coumarin can cause hepatotoxicity in people with inactive or nonfunctional cytochrome P450 2A6. 24 Patients who insist on trying plant-based coumarin should undergo an assay of their cytochrome P450 2A6 function before they begin taking the drug.