Why do Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) cause swelling?

From the Guidelines

NSAIDs typically don't cause swelling; they actually reduce swelling, but they can cause fluid retention in some people as a side effect, particularly in those with heart, kidney, or liver problems. This happens because NSAIDs can affect kidney function by reducing blood flow to the kidneys, leading to sodium and water retention, as noted in a study published in the American Family Physician in 2009 1. The mechanism of action of NSAIDs involves blocking enzymes called cyclooxygenases (COX-1 and COX-2) that produce prostaglandins, which are chemicals that promote inflammation, pain, and fever. By inhibiting these enzymes, NSAIDs decrease prostaglandin production, thereby reducing inflammation and swelling in the body. However, in certain individuals, especially those with pre-existing conditions such as heart failure, the use of NSAIDs can lead to increased morbidity and mortality, as highlighted in the 2013 ACCF/AHA guideline for the management of heart failure 1. Some key points to consider include:

• NSAIDs can cause sodium and water retention, leading to swelling in the hands, feet, ankles, or legs, particularly in individuals with heart, kidney, or liver problems.
• The use of NSAIDs should be avoided in persons with preexisting renal disease, congestive heart failure, or cirrhosis to prevent acute renal failure, as recommended in a study published in the Journal of Hepatology in 2010 1.
• If you experience unusual swelling while taking NSAIDs, you should consult your healthcare provider, as it could indicate an adverse reaction requiring medical attention or medication adjustment.
• The 2017 AHA/ACC clinical performance and quality measures for adults with ST-elevation and non-ST-elevation myocardial infarction also note that NSAIDs likely increase the risk of major adverse events in patients with myocardial infarction 1. Overall, while NSAIDs are effective in reducing inflammation and swelling, their use should be carefully considered in individuals with certain pre-existing conditions, and patients should be monitored for potential adverse effects, such as fluid retention and kidney problems, as discussed in various studies, including one published in the American Family Physician in 2009 1.

From the FDA Drug Label

NSAIDs can cause serious side effects, including: ... swelling of the face or throat ... swelling of the arms, legs, hands, and feet The FDA drug label states that NSAIDs can cause swelling, including swelling of the face or throat and swelling of the arms, legs, hands, and feet.

• Key side effects of NSAIDs include swelling, which can be a serious side effect. 2

From the Research

NSAIDs and Swelling

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can cause swelling due to their effects on the body's physiological processes, particularly their inhibition of prostaglandin synthesis 3.
• The use of NSAIDs has been associated with various adverse effects, including gastrointestinal ulcers, serious cardiovascular events, hypertension, acute renal failure, and worsening of preexisting heart failure, which can lead to swelling 3, 4.
• In patients with chronic kidney disease (CKD), NSAID use has been linked to acute kidney injury, progressive loss of glomerular filtration rate, electrolyte derangements, and hypervolemia, all of which can contribute to swelling 4, 5.
• The mechanism of NSAID-induced swelling is complex and involves the inhibition of cyclooxygenase (COX) enzymes, which play a role in maintaining normal physiologic functions, such as renal function and blood pressure regulation 6.
• The risk of NSAID-induced swelling can be modified by various factors, including the dose and duration of NSAID use, individual patient characteristics, and the presence of comorbid conditions 5, 7.

Factors Contributing to NSAID-Induced Swelling

• High-dose NSAID use has been shown to increase the risk of accelerated chronic kidney disease progression, which can lead to swelling 5.
• The use of NSAIDs in patients with preexisting heart failure or hypertension can exacerbate these conditions, leading to swelling 3, 4.
• The inhibition of COX-1 and COX-2 enzymes by NSAIDs can disrupt normal physiologic processes, including renal function and blood pressure regulation, contributing to swelling 6, 7.

Management of NSAID-Induced Swelling

• The cautious use of NSAIDs in patients with CKD or other risk factors for swelling is recommended, with careful consideration of individual patient characteristics and comorbid conditions 4, 5.
• The use of alternative analgesics or anti-inflammatory agents, such as acetaminophen or corticosteroids, may be considered in patients at high risk of NSAID-induced swelling 4.
• Monitoring of renal function, blood pressure, and electrolyte levels is recommended in patients taking NSAIDs, particularly in those with preexisting kidney disease or other risk factors for swelling 3, 4.