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Vol. 24, No. 4 October - December 2012 Article Reprints
Drugs and Lymphoedema: Those Which May Cause Oedema or
Make Lymphoedema Worse
By: Vaughan Keeley, MD, PhD, FRCP
Derby Hospitals NHS Trust, Derby, UK whose unwanted effects include oedema In the clinic setting, drugs which are Many people with lymphoedema and a few years ago (Keeley, 2008) revealed a commonly used and which commonly other chronic oedemas take medication large number of examples (930 in the cause oedema are likely to be the most to treat other conditions. For example, Summary of Product Characteristics in frequently encounter, e.g. calcium channel women who have breast cancer treat- the Electronic Medicines Compendium blockers, however, for individual patients ment related lymphoedema may receive and 333 in Micromedex). However, in a rare side effect in a rarely used drug is chemotherapy or hormone medication, these listings different types of oedema equally important. e.g. Tamoxifen or Anastrozole. People are not always distinguished. For exam- How may drugs cause oedema? with chronic leg oedema due to reduced ple, the term "oedema" may refer to aller- To understand the possible mechanisms mobility, e.g. as a result of rheumatoid gic oedemas or oedema in the lungs and by which drugs cause swelling, the pro- arthritis, may be taking a number of not necessarily relate to peripheral cesses which lead to fluid formation in drugs to treat the arthritis, e.g. non-ste- oedema, e.g. in the arms and legs. Fur- tissues need to be considered. Figure 1 roidal anti-inflammatories. Furthermore, thermore, it is not always easy to deter- shows a simplified diagram of circulation people with lymphoedema may be mine how significant or frequent these of blood and lymph. Blood is carried from treated for other conditions which are not side effects may be. The incidence of the heart through arteries to the small directly related to their oedema, for unwanted effects is more readily available blood vessels (capillaries) in the tissues. example, high blood pressure. for recently introduced medication where clinical trials results are available. How- The capillaries naturally "leak" fluid into With the growing recognition that ever, for drugs which have been used for the tissues to take water, food, etc., to chronic oedema is much more common many years, e.g. corticosteroids, aspirin, the cells. Once the fluid has entered the than has been previously appreciated, etc., accurate figures of incidence are not tissues its main exit route is through the there is an increasing need to understand lymph vessels which carry the fluid back the impact of medications on existing into the blood circulation via the large oedema and also their role in causing Although not routinely used in all veins near the heart. The balance of the oedema in the first instance.
sources, table 1 gives an indication of the amount of fluid leaked from the capillaries definitions of "common, uncommon, rare, In a recent survey in our hospital in (capillary filtration), and the amount Derby in the UK, around 25% of inpa- drained from the tissues by the lymph tients had some degree of chronic system (lymphatic drainage) is therefore oedema. An understanding of which key to the understanding of oedema Frequency of Side Effects of Drugs drugs may contribute to oedema forma- formation. If capillary filtration exceeds tion is therefore important in the assess- ment and management of people with Blood and Lymph Circulation chronic oedema.
Do many drugs cause oedema? Information on which drugs may con- tribute to oedema is not easy to find. A search of drug databases for drugs (Adapted from Keeley, 2008) Figure 1. Diagram of blood and lymph circulation NATIONAL LYMPHEDEMA NETWORK, INC. • 116 NEW MONTGOMERY ST., SUITE 235 • SAN FRANCISCO, CA 94105 INFOLINE: 1-800-541.3259 • TEL: 415-908-3681 • FAX: 415-908-3813 • EMAIL: [email protected] • WEBSITE: WWW.LYMPHNET.ORG PAGE 1 OF 3
lymphatic drainage, fluid will accumulate in clinic with oedema seemingly related to this. Dose (per day) Frequency (%) the tissues and oedema forms. It is likely that this drug, like the related drug, Drugs may have an impact on either Sirolimus, causes oedema by affecting the or both of these processes but perhaps way that lymph vessels repair themselves.
most commonly cause an increase in capil- It is therefore, recommended that clini- lary filtration. For example, drugs which cians take note of new medications which make the body retain fluid cause an increase patients are taking as part of their full in blood volume which leads to an increase in pressure of the capillaries and an increase Interpretation of data on the frequency of in capillary filtration. This will cause swelling Table 2. Frequency of oedema compared with dose of calcium channel blocker (adapted from if the lymph system cannot keep up with the Keeley, 2008) extra fluid. Drugs which may do this include Much modern data on (the frequency of) corticosteroids, non-steroidal anti-inflamma- side effects are derived from placebo con- Sometimes there is a clear relationship tory drugs, e.g. ibuprofen, and hormones, trolled clinical trials (in which a new drug is between the introduction of one of these e.g. oestrogens. compared with an inactive one) or trials of drugs and the exacerbation of chronic leg one drug compared with another. The inter- Other drugs may cause increased capil- swelling. If this is the case, then dose reduc- pretation of the results of the former may be lary filtration by increasing the amount of tion and/or withdrawal of the drug should complicated by the fact that the illness for blood which flows into the capillaries as a be considered.
which the drug is used may cause oedema result of dilation of the small arteries which (seen in the placebo group). In the latter, In some instances it is not always clear carry blood to the capillaries, e.g. calcium both drugs may cause oedema as an whether the calcium channel blocker is channel blockers such as amlodipine. unwanted effect. The effects of the drug in contributing to the oedema or not. In these Calcium channel blockers such as amlo- question on oedema is therefore not always circumstances continuation of the drug, dipine also reduce lymph drainage by immediately clear. For example, in a study of particularly if it is an effective agent for man- reducing the regular spontaneous contrac- Raloxifene in older post-menopausal women aging another condition, e.g. high blood tions of muscle in the lymph vessels which compared with placebo, the frequency of pressure, is recommended.
propel lymph back towards the heart. peripheral oedema in the patients taking 2. Corticosteroids (Toland et al, 2000).
Raloxifene was 14.4% and in patients tak- Corticosteroids e.g. Prednisolone and For a number of drugs however, it is not ing placebo was 12.1% (Barrett-Connor et Dexamethasone are well recognised causes clear how the oedema is caused. al, 2006). As this is a placebo study, it is of peripheral oedema. They cause sodium implied that this group of patients had a The introduction of new treatments can also and water retention. The effect is dependent natural frequency of peripheral oedema of alter the clinical picture seen in lymphoe- upon the duration of treatment and the around 12% which was increased to 14% dema clinics. For example, the chemother- dose. People receiving short courses of with Raloxifene. apy agent Docetaxel is now frequently corticosteroid steroids over 1-2 weeks for incorporated into the routine chemotherapy To further complicate interpretation, it is asthma do not tend to develop much regimen for the adjuvant treatment of breast clear that the combination of drugs may oedema, whereas those on long-term affect the incidence of oedema. The drug corticosteroids can experience significant Rosiglitazone caused oedema in 4.8% of swelling. Figure 2 shows the legs of a man Docetaxel may cause severe fluid retention people in whom it was used alone to treat who has been taking Prednisolone for a with oedema of the legs or more generalised diabetes, but in combination with Insulin the rheumatological condition for one year. swelling (including abdominal swelling). This frequency increased to 14.7% (Micromedex, Prior to starting this, he had no leg swelling. usually occurs after 4-5 courses of Docetaxel 2007).
Clinically the Prednisolone seems to be the and may take on average 29 weeks to cause. The clinical features of the swelling resolve following discontinuation. The use may not be specific to Prednisolone but of corticosteroids with the Docetaxel may 1. Calcium channel blockers. people on long-term corticosteroids may reduce the problem. It can also be treated These are probably the most frequently exhibit other side effects, e.g. "moon-face", with diuretics.
seen cause of oedema or worsening of thinning of the skin and bruising. Withdrawal In addition a recent meta-analysis has oedema in our clinical practice. They are shown that women who have Docetaxel as frequently used in the treatment of hyper- part of their treatment for breast cancer may tension and angina. They cause oedema in be 6 times more likely to develop arm a dose dependent fashion. (see table 2) lymphoedema than those who do not (Qin In our clinical experience, we occasionally et al, 2011).
see patients whose leg oedema is solely The drug Everolimus has recently been caused by calcium antagonists. Withdrawal employed as part of a number of cancer and discontinuation of the medication may treatments, and we are seeing patients in lead to complete resolution of the oedema in these cases.
Fig 2. Leg oedema due to Prednisolone PAGE 2 OF 3
of the steroids, if possible clinically, leads to when the drug concerned is considered improvement in the swelling but there may to be an important part of managing the be a significant delay between the cessation Anticonvulsants (for epi- persons other illnesses. of corticosteroids and this improvement.
lepsy) e.g. Pregabalin In some circumstances, e.g. as described In some instances where the corticoste- above with corticosteroids, diuretics may roids are essential, the use of diuretics to Antidepressants e.g. play a part in managing the side effects. If counteract the fluid retaining effect may be diuretics are used long term, it should be Antidiabetics e.g. remembered that sudden withdrawal of 3. Sex, hormones and related compounds. these drugs can make oedema worse and therefore gradual reduction and withdrawal These also seem to cause oedema by Antipsychotics e.g. over a period of weeks is recommended.
inducing fluid retention. The frequency for different hormones is given in Table 3.
Bisphosphonates (e.g. breast cancer treatment) The cause of chronic oedema in many Oestrogens (HRT) e.g. Zoledronic Acid patients is often multi-factorial. Drugs can play a significant part in the aetiology and Cytotoxic chemotherapy therefore it is recommended that they are considered in the initial assessment of patients presenting with chronic oedema, Table 3. Frequency of oedema caused by e.g. Baclofen (for muscle but also when existing oedema worsens. In hormones (adapted from Keeley, 2008) some situations, withdrawal of the drugs is As can be seen from this table, some of appropriate, whereas in others it may not be Sirolimus (in transplants) these drugs are essential in the manage- possible. Any proposed changes to medi- ment of breast cancer and depending upon Table 4. The frequency of oedema caused by cations should always be discussed with other drugs. (Adapted from Keeley, 2008) the benefit of the drugs, a clinical decision the prescribing physician and patients about whether to continue with them or 3. Are there signs of more widespread should be cautioned not to discontinue change to an alternative may need to be medication on their own.
For example, if somebody is being treated References 4. Other drugs.
for arm lymphoedema, have the legs Keeley V. Drugs that may exacerbate and those Table 4 gives examples of other drugs become swollen? If somebody is being used to treat lymphoedema. Journal of where oedema can be quite a common side treated for unilateral leg lymphoedema, has Lymphoedema (2008) Vol 3, No 1: 57-65 the other leg become swollen? Evidence of Toland HM, McCloskey K.D, Thornbury K.D, et more widespread oedema may help in Clinical assessment of the importance of al Calcium activated chloride current in sheep determining whether a drug effect is drugs in individual patients lymphatic smooth muscle. American Journal Physiology Cell Physiology (2000) In assessing the importance of drugs, which If a drug effect is suspected how should may be playing a part in the clinical picture this be managed? of oedema the following should be Qin Y. Y, Guo X.J, Ye X.F et al. Adjuvant Che- In some situations e.g. new onset motherapy with or without Taxanes, in Early oedema caused by a drug such as a cal- or Operable Breast Cancer : A Meta-Analysis 1. Is there a clear time relationship between cium channel blocker, withdrawal or discon- of 19 Randomized Trials with 30698 patients. the use of the drug and the effect on the tinuation of the drug is the best way for- PLoS ONE (2011) 11,e26946 ward. For many people with hypertension Barrett-Connor E, Mosca L, Collins P, et al It should be noted that the oedema does alternative drugs are available which do not Effects of Raloxifene on Cardiovascular not always appear immediately and may have the same side effect.
Events and Breast Cancer in Postmeno- take a few weeks, e.g. in the case of corti- In some cases where conditions such as pausal Women. The New England Journal of costeroids, to become evident.
hypertension have been difficult to manage, Medincine (2006) 355(2): 125–37 2. Is oedema a well recognised side effect of a dose reduction in the drug may bring Micromedex R Healthcare Series (2007) Avail- the drug concerned? about an improvement in oedema without able online at: compromising the control of high blood It is suggested that databases of unwanted drug effects are consulted but it should be borne in mind that for an indi- On occasion, if the oedema is not too vidual patient a rare effect is just as impor- severe, it may be possible to manage it by tant as a common effect. other means e.g. compression garments, PAGE 3 OF 3


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