Chronic oedema: treatment and the impact of prescribed medicines

Chronic oedema is increasingly recognised as a common condition and can be defined as soft tissue swelling that has been present for three months or more^[1]
. Chronic oedema is more frequently seen in those aged over 65 years, in women and in obese patients, with the number affected likely to increase along with the increasing levels of obesity^[2]
. Swelling, usually of the legs, leads to distortion of the shape of the limb, skin changes, fluid leakage and longer term complications, such as cellulitis and ulceration.

In 2000, a study of healthcare professionals from dedicated lymphoedema services, specific outpatient clinics, hospital wards and community services in south-west London, identified 823 patients with chronic oedema; 83% were female with a prevalence that rose from 1.3 in 1,000 patients across all age groups, to around 1 in 200 in those aged over 65 years and 1 in 100 in those aged over 85 years^[3]
. Other study data are scarce, but results from a Derby Hospital survey study from 2012 showed that around 25% of all inpatient respondents had some degree of chronic oedema^[4]
.

Unfortunately, the presence of chronic oedema is not always taken into consideration when prescribing medicines in patients with multiple morbidities. This can lead to patients with chronic oedema inadvertently being prescribed a medicine that worsens it; for example, those with diabetes being prescribed a thiazolidinedione or dipeptidylpeptidase-4 inhibitor.

This article aims to highlight medicines that can cause or worsen chronic oedema, to describe treatment options and consider how pharmacists and healthcare professionals can contribute to the care of patients with lower-leg oedema. It is therefore important to understand the process of oedema formation and the mechanisms by which medicines can influence this.

Oedema formation

Oedema is the term used to describe the accumulation of fluid in the interstitial space. The human body is around 60% water by weight^[5]
and this can be found either within the cells (intracellular) or between the cells (extracellular)^[6]
.

The transcapillary movement of fluid between plasma and the interstitial space, controlled by both hydrostatic and oncotic pressure, was described by Starling in 1896^[7]
. Hydrostatic pressure is produced by the fluid pressure of the blood volume entering the capillaries, and oncotic pressure is generated by proteins within the plasma^[7]
. In a healthy individual, hydrostatic pressure is greater than oncotic pressure at the arterial or pre-capillary end, thus fluid moves into the interstitial space. At the venous or post-capillary end, where oncotic pressure is greater than hydrostatic pressure, the opposite was thought to be true and fluid was believed to move back into the capillaries. Excess interstitial fluid is then drained away via the lymphatic system^[8]
.

However, it has now been established that there is no sustained venous reabsorption of interstitial fluid. Thus, the fluid filtered from blood vessels is reabsorbed by lymphatic vessels (except for minor transient periods of reabsorption)^[9]
. Therefore, all chronic oedema represents lymph drainage failure, either because the lymphatic system cannot cope owing to high lymph load (increased fluid entry), or a fault in the lymphatic system (reduced outflow), or both.

Increased fluid entry into the interstitial space

This may be a result of an increase in hydrostatic pressure, or an increase in capillary permeability. Conditions such as heart failure can lead to fluid overload and an increase in hydrostatic pressure, while allergic reactions and local infection can increase capillary permeability^[6]
.

Reduced outflow of fluid from the interstitial space

As it has now been demonstrated, tissue fluid balance depends upon lymphatic function in most tissues^[10]
. A decrease in lymphatic drainage resulting in oedema may be primary (genetic), or secondary to damage to the lymphatic system. Decreases are most commonly caused by tumour, surgery, radiation therapy and infection^[11]
.

A vicious cycle

The unfortunate result of fluid accumulating in the interstitial space in the form of oedema is a reduction in circulatory volume, which activates the renin-angiotensin-aldosterone system, promoting sodium and water retention and further increasing the plasma volume^[6]
(see Figure 2).

How medicines cause oedema

Increased hydrostatic pressure

Drugs that cause vasodilation or fluid retention can increase hydrostatic pressure, causing an increase in movement of fluid into the interstitial space. This results in oedema if the capacity of the lymphatic system to drain away the fluid is overwhelmed. Calcium channel blockers (CCBs) act to increase blood flow into the capillaries as a result of dilation of the small arteries that carry blood to the capillaries^[12]
. CCBs have also been implicated in reducing lymph drainage (see ‘Decrease in lymphatic drainage’). Corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), sex hormones and related compounds (e.g. raloxifene and megestrol) result in fluid retention^[12]
.

Increased capillary permeability

Capillary leak syndrome (CLS) has been reported with filgrastim and pegfilgrastim^[13]
. Symptoms of CLS include hypotension, oedema, hypoalbuminaemia and haemoconcentration. CLS may be fatal unless promptly diagnosed and managed^[13]
.

Decrease in lymphatic drainage

It has been suggested that CCBs reduce lymph drainage by decreasing the spontaneous contraction of smooth muscle within the lymph vessels^[4]
, but a more recent study with nifedipine suggests that while this may occur in vitro, it does not occur in vivo
^[14]
.

Medicines that cause oedema

Many medicines can cause or worsen oedema; CCBs and NSAIDs are among the most commonly implicated^[6]
. Table 1 lists some of the medicines most frequently reported and the method by which they cause oedema; these are discussed further below.

Calcium channel blockers

Peripheral oedema is a recognised adverse effect of CCBs^[15]
with up to 50% of patients on CCBs developing oedema^[16]
. Female gender, increasing age, heart failure, upright postures and warm environment appear to increase the risk of developing ankle oedema while using CCBs and the frequency with which peripheral oedema occurs is both compound-specific and dose-dependent^[17]
. Table 2 indicates the frequency with which peripheral oedema occurs with some of the CCBs. The UK Medicines Information Service provides more detailed information^[18]
. Table 3, which gives the frequency of oedema seen with different doses of the CCBs amlodipine and felodipine, illustrates how oedema is dose-dependent.

Corticosteroids

Sodium and water retention^[15]
caused by corticosteroids is a recognised cause of peripheral oedema^[6]
. This effect is dependent upon both the dose and the duration of treatment. Patients receiving a short-term course (one to two weeks) for asthma tend not to develop much oedema, while patients on long-term treatment may experience significant swelling^[4]
.

NSAIDs

NSAIDs commonly cause fluid retention^[26]
, although there are differences in the frequency with which this occurs between different drugs^[12]
. There are also concerns regarding the risk of necrotising fasciitis and dermal infection with the use of NSAIDs^[27]
,[28]
, which is relevant to this group of patients (see ‘Analgesia’).

Sex hormones and related compounds

Anti-oestrogens and aromatase inhibitors, common sex hormones and related compounds may cause oedema because of fluid retention^[12]
. One difficulty is that several of these medicines are used in the management of patients with breast cancer, who may have had a partial or radical mastectomy with or without removal of lymph nodes and who are at high risk of developing lymphoedema. It may be necessary to weigh up the risk/benefit ratio in these patients, or to consider an alternative.

Other drugs that can cause oedema

Box 1 lists some other frequently prescribed medicines that are known to cause oedema, but this list is not exhaustive. If pharmacists or healthcare professionals suspect that a medicine may be causing oedema, it would be advisable to check the summary of product characteristics (SPC) and highlight any concerns to the clinician managing the patient.

Although peripheral oedema is an uncommon side effect of proton pump inhibitors, they have been included because of the high frequency with which they are prescribed. For many of these drugs the exact mechanism by which they cause oedema is unknown.

Information on adverse effects is also available from the Medicines and Healthcare products Regulatory Agency (MHRA). Table 5 lists the drugs most frequently reported as suspected to have caused peripheral oedema over the five year period from December 2011 to December 2016. However, it is important to be aware that these data cannot be used to identify the drugs that most commonly cause peripheral oedema, because many factors can influence the level of reporting and reports are submitted on suspicion of an association^[68]
.

It should be noted that there are several difficulties in identifying medicines that cause peripheral oedema. Part of the problem is the way in which information related to medicine side effects is recorded and interpreted. Within an SPC, the manufacturer often lists side effects that occurred at an incidence greater than is seen with placebo and in more than 1% of patients; however, the difference in incidence may be small. For example, the SPC for alendronate lists peripheral oedema in the tabulated list of side effects, but it also notes that the frequency in clinical trials was actually similar in the drug and placebo groups^[50]
.

Treatment options for chronic oedema

Chronic oedema occurs in a range of conditions including lymphoedema and venous insufficiency and is a common feature of patients with venous ulceration^[69]
. It is important that treatment is tailored to the individual patient’s needs and comorbidities. The primary treatment for the majority of patients with chronic oedema is a combination of compression bandaging and exercise^[26]
. However, drug therapy can have a place in treatment for some patients. The following are medicines that may be used.

Corticosteroids

This may seem counterintuitive, but there is a role for corticosteroids in the management of oedema in some patients with advanced cancer. Corticosteroid treatment is believed to reduce peritumour oedema and relieve compression of the venous and lymphatic systems, thereby reducing oedema^[26]
. Dexamethasone may be given at a dose of 4mg–6mg twice daily for a one to two week trial and then stopped if ineffective or the dose reduced until the minimum effective dose is identified^[26]
.

Diuretics

It is important to consider the cause of the chronic oedema when prescribing diuretic treatment. Diuretics are often ineffective, particularly in patients with lymphoedema,^[26]
and can cause hypokalaemia, hyponatraemia and hypotension^[15]
. Another concern is the rebound retention of sodium and water that occurs on stopping diuretic treatment^[70]
. Diuretics are therefore not generally indicated in patients with lymphoedema, oedema caused by peripheral venous stasis, or oedema caused by CCBs^[15]
. However, loop diuretics are indicated in the treatment of oedema associated with heart failure, which is commonly associated with peripheral oedema^[71]
.

Not all patients fit neatly into one diagnosis — some will have both heart failure and lymphoedema. In these patients, a trial of diuretics might be appropriate. In some patients, such as those in whom corticosteroids are essential, diuretics can be helpful in countering the side effects of sodium and water retention^[4]
.

Oxerutins

There has been interest in the use of benzopyrones, such as coumarin and oxerutins, in the treatment of chronic oedema because of lymphatic and venous disease^[12]
. Coumarin is no longer available but oxerutins are licensed in the UK for the relief of symptoms of oedema associated with chronic venous insufficiency^[72]
; however, it is considered less suitable for prescribing^[15]
. In 2004, a Cochrane review of the use of benzopyrones in patients with lymphoedema found that it was not possible to draw conclusions about the effectiveness of benzopyrones used for the management of lymphoedema from the current available trials. Therefore, benzopyrones are not currently used in the routine management of lymphoedema^[73]
.

Improving patient care

It is important that pharmacists and healthcare professionals work in line with the current guidance on polypharmacy, in particular being alert to the risk of adverse drug reactions^[74]
, or adverse drug events^[75]
. This will help identify medicines that may be causing or worsening a concurrent condition. When a patient who has developed oedema or one whose pre-existing oedema is worsening presents, the following points should be considered:

• Causal relationship — needs to be investigated;
• Possible dose reduction — may be sufficient to resolve the problem;
• Switching to an alternative — there might be a more suitable option for the patient;
• Withdrawal of the/the offending medicine — may be necessary.

Pharmacists and healthcare professionals should first consider whether this is a worsening of the patient’s condition or if it could be medicine related. If a patient has recently started a new medicine, further investigation may be required regarding the timing of this and the subsequent development or worsening of the oedema. The likelihood of that medicine causing oedema is also important and the SPC for the product may be more helpful than the British National Formulary (BNF) in establishing this.

If there is a clear relationship between the introduction of a medicine and the development or exacerbation of oedema, a dose reduction or withdrawal of the drug might need to be considered. In some instances, it may be possible to switch to another drug, either from a different class, or within the same class. For example, in a hypertensive patient who develops CCB-associated oedema, it might be ideal to change to another class of drug; however, if that is not an option, then a decrease in dose, or switching to another CCB could help resolve or reduce the problem.

Notably, one study suggests that the combination of a renin-angiotensin-aldosterone system blocking drug (ACE inhibitor, angiotensin receptor blocker or direct renin inhibitor) with a CCB might reduce the incidence of CCB-induced oedema. The authors of the study also note that ACE inhibitors may be more effective than angiotensin receptor blockers but further evidence is required to confirm this^[76]
.

Pharmacists can also give advice on other treatments that can influence patients’ quality of life. These are described in the following sections.

Analgesia

Pain — most commonly described as aching, heaviness and tenderness — has been reported in 50% of patients with chronic oedema^[3]
. Non-drug measures such as compression may be effective in relieving pain^[26]
, but it can also occur because of the increased weight of a limb and association with cellulitis or venous thrombosis, which these patients are predisposed to develop. Careful consideration should be given to the choice of analgesic, especially as these patients are likely to take it long term. An analysis of the French national pharmacovigilance database has led to concern about the use of NSAIDs because its results suggest that NSAIDs increase the risk of necrotising fasciitis and dermal infection^[27]
. However, Souyri et al. found it was not possible to say whether NSAIDs increase the risk of necrotising complications in all patients, but notes that their use may mask the symptoms and delay diagnosis^[68]
.

The British Lymphology Society and Lymphoedema support network ‘Consensus document on the management of cellulitis in lymphoedema’ states that it is advisable to avoid NSAIDs during an acute attack of cellulitis, as they may be associated with complications such as necrotising fasciitis^[77]
. Other medicines that should be used with caution include anticonvulsant drugs pregabalin and gabapentin, which are used in the management of neuropathic pain and are listed as commonly causing peripheral oedema. In one study, patients taking gabapentin showed a higher incidence of peripheral oedema in those aged over 65 years than in younger patients^[31]
. However, this is probably true for patients taking placebo too and it is hard to make an informed decision without accessing the full data.

Skin care

Patients with chronic oedema are susceptible to skin problems, therefore adequate skin care is an extremely important part of the management of chronic oedema, because this helps maintain skin integrity and reduce the risk of infection^[78]
. Deep folds of the skin that result from extensive swelling provide an ideal environment for the development of bacterial and fungal infection. Chronic inflammation of the skin tissues causes the deposition of fibrin and collagen, resulting in skin thickening^[69]
. Fibrosclerotic tissue describes an affected area of skin in which inflammatory proteins of the lymph, including fibrin, have built up and caused the tissues of the skin to harden^[69]
. Fibrosclerotic areas will remodel over time with appropriate compression therapy^[69]
.

Skin should be cared for to improve and preserve the barrier function by washing with natural and pH neutral soaps. Skin folds should be kept clean and dry and moisturised with hypoallergenic emollients, which are used to re-establish the skin’s protective lipid layer and need to be applied frequently. Skin also needs to be monitored for any trauma that might be susceptible to infection. Patients should be taught good skin hygiene because if skin changes are left untreated they can quickly escalate in severity.

Infection

Fungal infections (e.g. tinea pedis) are common in oedematous weeping legs, especially between the toes^[79]
. There is increasing evidence that tinea pedis infections may provide a portal of entry for bacteria and increase the risk of cellulitis^[80]
. Cellulitis is an infection of connective tissue between neighbouring tissues and organs, commonly resulting from bacterial infection and can be located in the toes, dorsum and plantar surfaces of the feet and lower leg. It is generally reddish and painful^[81]
.

Skin infections in patients with chronic oedema are primarily caused by Group A β-haemolytic streptococcal bacteria and, less commonly, staphylococcal bacteria^[82]
,[83]
. Patient education should be aimed at prevention through meticulous skin hygiene and management of oedema and drainage. To prevent recurring fungal infections, patients should be encouraged to identify and treat symptoms early with a topical antifungal to avoid the risk of recurrent cellulitis. Where cellulitis does occur, or is suspected, an urgent referral is necessary as prompt antibiotic treatment is essential. Complications of cellulitis include fasciitis, myositis, subcutaneous abscesses, septicaemia, post-streptococcal nephritis and death^[84]
.

Mental health

The physical changes associated with chronic oedema can have serious effects on mental wellbeing. Having to adapt clothing and footwear to disguise enlarged, disfigured and often exudating limb causes embarrassment and affects patients’ self-esteem and body image^[2]
. Acute complications due to the condition cause major disruption to life, and the chronic nature of the condition significantly impairs quality of life, affecting the ability to function physically, socially and emotionally^[3]
. Employment is often affected with (in one study) 80% of patients having to take time off, 2% having to change jobs because of their oedema, and 8% having to give up work because of it^[3]
. Loss of control, fear, depression and social isolation result and pharmacists should be sensitive to these issues and prepared to signpost patients appropriately.

Importance of early diagnosis and referral

The importance of early diagnosis of chronic lower limb oedema cannot be overemphasised, to prevent early oedema becoming chronic. Pharmacists and other healthcare professionals should be encouraged to visually look for signs of chronic oedema when assessing patients and to refer patients where possible to a specialist local service. Tissue viability teams are starting to develop specific chronic oedema referral and treatment pathways which are helping to reduce the development of costly, long term complications.

Communication between the multidisciplinary team is essential to highlight common medicines that may cause or exacerbate chronic oedema as many healthcare professionals are unaware of this and may not realise that the expertise of the pharmacist (e.g. identifying medicines that are causing or contributing to the development of lower limb oedema and training regarding drug therapy in these patients) could help to control this condition.